ROCKVILLE, Md., May 30 — When Dr. Andrew C. von Eschenbach took over the Food and Drug Administration in 2005, the agency had a crisis over drug approvals that had missed or ignored dangerous side effects in Vioxx, antidepressants and other prominent medications.
Dr. von Eschenbach promised improvements, and agency officials said they would no longer be caught flatfooted on drug safety.
But this month, The New England Journal of Medicine published a study suggesting that a major diabetes pill, Avandia, might increase the risk of heart attacks.
Concerns over that drug and others have led Republicans and Democrats in the House and the Senate to call for investigations. A House hearing is planned for June 6.
Dr. von Eschenbach said in a briefing on Wednesday that his agency needed to collaborate more closely with drug companies.
“The point is that we need to look at the role of the F.D.A. in being a bridge to the future, not a barrier to the future,” he said at his office here.
Responding to a suggestion that promoting collaborations with drug makers, including an effort to modernize human testing and find genetic markers to predict suffering from side effects, may not be politic, Dr. von Eschenbach said the agency was not working solely with pharmaceutical companies.
“It’s with everyone,” including government agencies and independent scientists, he said.
He defended the agency in the Avandia case, saying, “I believe we did it right with regard to Avandia.”
Hints of the heart risks from Avandia were, however, present from the beginning. The original trials, overseen by GlaxoSmithKline, the drug’s maker, showed that patients taking the drug had more than twice the rate of ischemic heart disease as recipients of placebos.
The medical reviewer for the F.D.A. expressed concerns, but in a further analysis decided that it was less of a problem.
The hearing next week may highlight the growing internal dissension between officials who approve drugs and those who track the safety of drugs after they have been approval. Tension between the groups has long been common, but in recent months it has erupted into sniping.
Congressional investigators said the safety group recommended months ago that the drug agency put its severest warning on Avandia. The review group, which holds sway, has not done so.
The sniping became public in an exchange at an advisory committee hearing last month on whether to approve a new arthritis drug.
On one side was Dr. David Graham, author of an internal report that found that Avandia substantially increased the risks of heart attack, findings similar to the medical journal’s report.
On the other, Dr. Robert J. Meyer, an office director in the drug review division, and his boss, Dr. John Jenkins, were in a group deciding against warning about the potential risks.
There was little chance that the advisory committee or the drug agency would approve the arthritis drug, Arcoxia, at the hearing.
Behind the scenes, agency officials were battling over Avandia. Dr. Graham told the committee that top agency officials had demanded an unreasonable level of certainty about a drug’s risks before agreeing to warn the public.
“They assume it’s safe,” Dr. Graham said of the top officials’ analyses of safety data. “Which is just looking at things all the way wrong.”
Dr. Jenkins said Dr. Graham’s “characterization of how we look at safety data is simply false.”
“We make our best informed judgment about what the regulatory action should be,” Dr. Jenkins added.
Senator Charles E. Grassley, Republican of Iowa, and others on Capitol Hill, say the rift between the approval office and the safety office means that the two must separate and that the safety group must have more power. Mr. Grassley proposed such a split in an amendment this month; it failed by one vote.
Top House staff members said the Avandia case had breathed new life into Mr. Grassley’s proposal, because the House will soon debate changing the drug agency.
Curt Furberg, a professor of public health sciences at Wake Forest and a co-author of the New England Journal of Medicine’s editorial on Avandia, said the agency remained broken.
“Safety is just not a high priority for them,” said Dr. Furberg, who serves on the F.D.A. Drug Safety and Risk Management Advisory Committee.
Thursday, May 31, 2007
Drug-Maker Defends Rosiglitazone in Letter to The Lancet
KING OF PRUSSIA, Pa., May 30 -- Despite reports linking rosiglitazone (Avandia) to increased risk of cardiac events, the data safety monitoring boards assessing that risk in three studies of the drug agreed that the trials should continue.
Ronald L. Krall, M.D., chief medical officer of GlaxoSmithKline, maker of rosiglitazone, disclosed the decisions of the safety panels in a letter released online today by The Lancet.
The disclosure that all three trials -- RECORD, BARI 2D, and ACCORD -- will continue as planned could be construed as the most reassuring news about rosiglitazone since May 21 when the New England Journal of Medicine published online a meta-analysis that found a 43% increase in relative risk of myocardial infarction for patients using rosiglitazone.
Or, it may simply indicate the studies have reached their pre-specified safety stopping points.
Dr. Krall said the relative safety of rosiglitazone could also be gleaned from a balanced cohort observational study of 33,363 patients in a managed care database who began treatment with oral antidiabetic drugs from 2000 to 2004. That study, commissioned by GSK, assessed the risk of MI, coronary revascularization or both among patients taking rosiglitazone, metformin, or sulfonylurea monotherapy, or combinations of those drugs.
"The incidence of composite cardiovascular endpoint was 1.75 events per 100 patient-years for rosiglitazone-containing regimen and 1.76 events per 100 patient-years for the non-rosiglitazone-containing regiment (hazard ratio 0.93, 95% CI 0.80-1.10), he wrote.
Dr. Krall concluded that the company believed "these studies provide clear evidence of the cardiovascular safety of rosiglitazone and that the estimates of cardiovascular morbidity from the meta-analyses are not robust."
The system for drug approval and safety monitoring of drugs, he said, "is working," said Dr. Krall.
The meta-analysis in the NEJM was conducted by Steven Nissen, M.D., of the Cleveland Clinic, and colleagues.
In the week since the NEJM published his study, Dr. Nissen has been both lionized and lambasted. Tonight ABC News reported that Douglas Arbesfeld, a senior communications consultant at the FDA, sent emails to several reporters suggesting that Dr. Nissen targeted pharmaceutical companies that didn't fund Cleveland Clinic research.
Dr. Nissen, meanwhile, has not retreated from his findings. He said the furor that followed publication has been the ugliest in his personal experience and that he was especially offended by slurs directed at the clinic.
The FDA said the Arbesfeld email did not reflect the FDA's position but was merely private correspondence from a consultant.
That GSK statement will be closely scrutinized on June 6 when Rep. Henry Waxman (D-Calif.) opens a congressional hearing into FDA oversight of rosiglitazone from its initial approval in 1999 through post-marketing surveillance. Dr. Nissen will testify.
The FDA has already confirmed that its own ongoing meta-analysis of rosiglitazone studies will also show an increased cardiac event rate for patients using rosiglitazone. But the agency has also maintained that its review of preliminary data from RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes), provided evidence that contradicted the meta-analyses.
A week ago, The Lancet published an unsigned editorial -- also released online -- urging calm until results of prospective trials, such as RECORD are available.
Dr. Krall, who said he was responding to The Lancet editorial, conceded that the company's own meta-analyses conducted in 2005 and 2006 found hazard ratios "in the same direction" as Dr. Nissen's meta-analysis.
But he pointed out that there was "a very low frequency of events (0.6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0.1%."
Dr. Krall said data from ADOPT (A Diabetes Outcomes Progression Trial) and DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) offer more reliable evidence of rosiglitazone safety than findings from meta-analyses.
In support of that assertion, he presented data from a GSK post hoc analysis of the ADOPT database. "Our analysis, which adjusted for medication exposure, found that such events were rare in this population and that all treatments were comparable," he wrote.
ADOPT compared rosiglitazone to metformin or glyburide. The hazard ratios "varied from 0.58 to 1.52 and 95% CIs for all comparisons included unity," Dr. Krall wrote.
Initial published findings from the DREAM trial, which used a 2 x2 design that randomized patients to rosiglitazone plus placebo, rosiglitazone plus ramipril, ramipril plus placebo or placebo-placebo found no significant difference in cardiovascular endpoints. But a post hoc cell-level intention-to-treat analysis found an increase in cardiovascular events among patients in the rosiglitazone-ramipril arm, a finding that Dr. Krall said "is currently unexplained."
Ronald L. Krall, M.D., chief medical officer of GlaxoSmithKline, maker of rosiglitazone, disclosed the decisions of the safety panels in a letter released online today by The Lancet.
The disclosure that all three trials -- RECORD, BARI 2D, and ACCORD -- will continue as planned could be construed as the most reassuring news about rosiglitazone since May 21 when the New England Journal of Medicine published online a meta-analysis that found a 43% increase in relative risk of myocardial infarction for patients using rosiglitazone.
Or, it may simply indicate the studies have reached their pre-specified safety stopping points.
Dr. Krall said the relative safety of rosiglitazone could also be gleaned from a balanced cohort observational study of 33,363 patients in a managed care database who began treatment with oral antidiabetic drugs from 2000 to 2004. That study, commissioned by GSK, assessed the risk of MI, coronary revascularization or both among patients taking rosiglitazone, metformin, or sulfonylurea monotherapy, or combinations of those drugs.
"The incidence of composite cardiovascular endpoint was 1.75 events per 100 patient-years for rosiglitazone-containing regimen and 1.76 events per 100 patient-years for the non-rosiglitazone-containing regiment (hazard ratio 0.93, 95% CI 0.80-1.10), he wrote.
Dr. Krall concluded that the company believed "these studies provide clear evidence of the cardiovascular safety of rosiglitazone and that the estimates of cardiovascular morbidity from the meta-analyses are not robust."
The system for drug approval and safety monitoring of drugs, he said, "is working," said Dr. Krall.
The meta-analysis in the NEJM was conducted by Steven Nissen, M.D., of the Cleveland Clinic, and colleagues.
In the week since the NEJM published his study, Dr. Nissen has been both lionized and lambasted. Tonight ABC News reported that Douglas Arbesfeld, a senior communications consultant at the FDA, sent emails to several reporters suggesting that Dr. Nissen targeted pharmaceutical companies that didn't fund Cleveland Clinic research.
Dr. Nissen, meanwhile, has not retreated from his findings. He said the furor that followed publication has been the ugliest in his personal experience and that he was especially offended by slurs directed at the clinic.
The FDA said the Arbesfeld email did not reflect the FDA's position but was merely private correspondence from a consultant.
That GSK statement will be closely scrutinized on June 6 when Rep. Henry Waxman (D-Calif.) opens a congressional hearing into FDA oversight of rosiglitazone from its initial approval in 1999 through post-marketing surveillance. Dr. Nissen will testify.
The FDA has already confirmed that its own ongoing meta-analysis of rosiglitazone studies will also show an increased cardiac event rate for patients using rosiglitazone. But the agency has also maintained that its review of preliminary data from RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes), provided evidence that contradicted the meta-analyses.
A week ago, The Lancet published an unsigned editorial -- also released online -- urging calm until results of prospective trials, such as RECORD are available.
Dr. Krall, who said he was responding to The Lancet editorial, conceded that the company's own meta-analyses conducted in 2005 and 2006 found hazard ratios "in the same direction" as Dr. Nissen's meta-analysis.
But he pointed out that there was "a very low frequency of events (0.6%), and the absolute difference in rates of myocardial infarctions between rosiglitazone and controls is less than 0.1%."
Dr. Krall said data from ADOPT (A Diabetes Outcomes Progression Trial) and DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) offer more reliable evidence of rosiglitazone safety than findings from meta-analyses.
In support of that assertion, he presented data from a GSK post hoc analysis of the ADOPT database. "Our analysis, which adjusted for medication exposure, found that such events were rare in this population and that all treatments were comparable," he wrote.
ADOPT compared rosiglitazone to metformin or glyburide. The hazard ratios "varied from 0.58 to 1.52 and 95% CIs for all comparisons included unity," Dr. Krall wrote.
Initial published findings from the DREAM trial, which used a 2 x2 design that randomized patients to rosiglitazone plus placebo, rosiglitazone plus ramipril, ramipril plus placebo or placebo-placebo found no significant difference in cardiovascular endpoints. But a post hoc cell-level intention-to-treat analysis found an increase in cardiovascular events among patients in the rosiglitazone-ramipril arm, a finding that Dr. Krall said "is currently unexplained."
Rosiglitazone Meta-Analysis Continues to Drive Controversy in Second Week
May 30, 2007 (New York, NY) - The fallout continues from the publication in the New England Journal of Medicine (NEJM) last week of a meta-analysis of rosiglitazone (Avandia, GlaxoSmithKline [GSK]), which suggested it increases the risk of MI and cardiovascular death [1].
As reported by heartwire, many experts have said the data were far from perfect and have expressed concern about the manner in which they were released. But new reports go one step further--suggesting that FDA whistleblowers coordinated with politicians critical of the agency and the study authors to get damaging data into the public arena before the FDA could issue a safety statement on rosiglitazone.
And damage has certainly been done in the form of a battering of the stock of GlaxoSmithKline, as Avandia was until now a $3-billion-a-year drug. Shares of the company were today at their lowest level in two years, following the sixth drop in seven trading days. Prescriptions for Avandia have also plummeted, with its slice of new oral diabetes prescriptions dropping from 10% to almost zero in the two days following the NEJM report.
As part of the company's response to the controversy, chief medical officer of GSK, Dr Ronald L Krall, has written a letter, published online in the Lancet today [2]. In support of the cardiovascular safety of rosiglitazone, he cites, among other things, the decision by the independent data safety monitoring board to continue the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, which is specifically designed to look at cardiovascular outcomes with rosiglitazone.
However Krall told the New York Times last week that the RECORD study could be under threat because some of the patients have dropped out of the trial due to safety concerns following last week’s events [3].
Conspiracy theories
An in-depth feature in a biotechnology weekly newsletter relates the tale of who knew what and when with regard to the rosiglitazone saga. US politicians have “portrayed Avandia as the quintessential. . . . Washington scandal, complete with maverick outsider who exposes wrongdoers and alerts congressional guardians of the public health,” writes Steve Usdin in BioCentury [4].
But according to an editorial by former FDA deputy commissioner Scott Gottlieb, published May 29, 2007 in the Wall Street Journal, the truth is that the study authors, the NEJM, and politicians with their own motives tried to upstage the FDA in an attempt to influence public debate [5].
According to Gottlieb, lead author Dr Steve Nissen (Cleveland Clinic, OH) submitted his manuscript to the NEJM on May 1 and did not inform either the FDA or GSK. The journal expedited the review of the paper and commissioned a commentary from two well-known critics of FDA’s drug safety record, Drs Curt Furberg (University of Washington, Seattle) and Bruce Psaty (Wake Forest University, Winston-Salem, NC) [6]. The paper and commentary were published online by the NEJM on May 21, a move Gottlieb says was “timed to get ahead of the FDA’s more careful evaluation of the same issues.”
The FDA had planned to issue a safety statement about Avandia around May 23, according to an unnamed drug safety official cited in the article by Usdin. Following publication of the NEJM paper, the FDA issued a statement on May 21 saying that its analyses were ongoing and that it would convene an advisory committee on the issues as soon as possible.
Gottlieb says the NEJM claims to have made the decision to publish quickly because of the medical importance of the research but, if that were the case, he wonders why it did not inform the FDA about its publication or the findings.
“When it comes to the issue du jour, drug safety, no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval. Yet NEJM and other journals have tried on other occasions to upstage FDA investigations through well-timed but much less complete publications,” he asserts.
He adds that there was no mention in the NEJM paper or editorial of rosiglitazone’s benefits or of how doctors should advise patients.
Steven Galson (director of the FDA’s Center for Drug Evaluation and Research) told Usdin: “Medical journals have to take their job seriously. They have a responsibility to patients and physicians to publish information in a responsible and balanced manner. I’m not sure that responsibility was adequately executed in this instance.”
But NEJM editor Dr Gregory Curfman told BioCentury that his journal is not responsible for the media reactions to the rosiglitazone paper and commentary: “We are a scholarly journal, not a news outlet. What happens in the media is beyond our control.”
RECORD study may have to be halted
Despite an interim review of RECORD finding no safety flags with the drug, GSK medical director Dr Ronald L Krall told the New York Times that the independent research committee overseeing the trial is examining what steps can be taken to prevent people from leaving the study.
RECORD is an open-label six-year cardiovascular outcomes trial with prospectively defined cardiovascular end points in 4458 patients. It began in 2000 and is scheduled to run until next year.
He said he did not yet know how many patients had withdrawn from the study as a result of last week’s events.
The Times points out that neither GSK nor the FDA has released any details of this interim assessment of RECORD, which was apparently conducted within the past few weeks. But in his letter to the Lancet today, Krall says the manuscript regarding this interim assessment is “in preparation.”
He adds that other cardiovascular-outcomes trials--such as the 2368-patient Bypass Angioplasty Revascularization Investigation Type 2 Diabetes trial (BARI 2D) and the 10 251-patient Action to Control Cardiovascular Risk in Diabetes (ACCORD) study--“will further inform the cardiovascular safety profile of rosiglitazone.”
The data safety monitoring boards of both of these studies have also confirmed that they should continue, he notes, concluding: “We should stay the course and allow ongoing trials to provide their definitive answers.”
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; DOI:10.1056/NEJMoa072761. Available at: http://www.nejm.org.
Krall RL. Cardiovascular safety of rosiglitazone. Lancet 2007; DOI: 10.1016/S0140-6736 (07) 60824-1. Available at: http://www.thelancet.com.
Saul S. Test of drug for diabetes in jeopardy. New York Times, May 26, 2007. Available at: http://www.nytimes.com.
Usdin S. Political defibrillator. BioCentury, May 28, 2007. Available at: http://www.biocentury.com.
Gottlieb S. Journalistic malpractice. Wall Street Journal, May 29, 2007. Available at: http://www.wsj.com.
Psaty B and Furberg C. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; DOI:10.1056/NEJMe078099. Available at: http://www.nejm.org.
As reported by heartwire, many experts have said the data were far from perfect and have expressed concern about the manner in which they were released. But new reports go one step further--suggesting that FDA whistleblowers coordinated with politicians critical of the agency and the study authors to get damaging data into the public arena before the FDA could issue a safety statement on rosiglitazone.
And damage has certainly been done in the form of a battering of the stock of GlaxoSmithKline, as Avandia was until now a $3-billion-a-year drug. Shares of the company were today at their lowest level in two years, following the sixth drop in seven trading days. Prescriptions for Avandia have also plummeted, with its slice of new oral diabetes prescriptions dropping from 10% to almost zero in the two days following the NEJM report.
As part of the company's response to the controversy, chief medical officer of GSK, Dr Ronald L Krall, has written a letter, published online in the Lancet today [2]. In support of the cardiovascular safety of rosiglitazone, he cites, among other things, the decision by the independent data safety monitoring board to continue the ongoing Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, which is specifically designed to look at cardiovascular outcomes with rosiglitazone.
However Krall told the New York Times last week that the RECORD study could be under threat because some of the patients have dropped out of the trial due to safety concerns following last week’s events [3].
Conspiracy theories
An in-depth feature in a biotechnology weekly newsletter relates the tale of who knew what and when with regard to the rosiglitazone saga. US politicians have “portrayed Avandia as the quintessential. . . . Washington scandal, complete with maverick outsider who exposes wrongdoers and alerts congressional guardians of the public health,” writes Steve Usdin in BioCentury [4].
But according to an editorial by former FDA deputy commissioner Scott Gottlieb, published May 29, 2007 in the Wall Street Journal, the truth is that the study authors, the NEJM, and politicians with their own motives tried to upstage the FDA in an attempt to influence public debate [5].
According to Gottlieb, lead author Dr Steve Nissen (Cleveland Clinic, OH) submitted his manuscript to the NEJM on May 1 and did not inform either the FDA or GSK. The journal expedited the review of the paper and commissioned a commentary from two well-known critics of FDA’s drug safety record, Drs Curt Furberg (University of Washington, Seattle) and Bruce Psaty (Wake Forest University, Winston-Salem, NC) [6]. The paper and commentary were published online by the NEJM on May 21, a move Gottlieb says was “timed to get ahead of the FDA’s more careful evaluation of the same issues.”
The FDA had planned to issue a safety statement about Avandia around May 23, according to an unnamed drug safety official cited in the article by Usdin. Following publication of the NEJM paper, the FDA issued a statement on May 21 saying that its analyses were ongoing and that it would convene an advisory committee on the issues as soon as possible.
Gottlieb says the NEJM claims to have made the decision to publish quickly because of the medical importance of the research but, if that were the case, he wonders why it did not inform the FDA about its publication or the findings.
“When it comes to the issue du jour, drug safety, no description of medical research in a medical journal comes close to the detail level or scrutiny imposed by the FDA on study results before approval. Yet NEJM and other journals have tried on other occasions to upstage FDA investigations through well-timed but much less complete publications,” he asserts.
He adds that there was no mention in the NEJM paper or editorial of rosiglitazone’s benefits or of how doctors should advise patients.
Steven Galson (director of the FDA’s Center for Drug Evaluation and Research) told Usdin: “Medical journals have to take their job seriously. They have a responsibility to patients and physicians to publish information in a responsible and balanced manner. I’m not sure that responsibility was adequately executed in this instance.”
But NEJM editor Dr Gregory Curfman told BioCentury that his journal is not responsible for the media reactions to the rosiglitazone paper and commentary: “We are a scholarly journal, not a news outlet. What happens in the media is beyond our control.”
RECORD study may have to be halted
Despite an interim review of RECORD finding no safety flags with the drug, GSK medical director Dr Ronald L Krall told the New York Times that the independent research committee overseeing the trial is examining what steps can be taken to prevent people from leaving the study.
RECORD is an open-label six-year cardiovascular outcomes trial with prospectively defined cardiovascular end points in 4458 patients. It began in 2000 and is scheduled to run until next year.
He said he did not yet know how many patients had withdrawn from the study as a result of last week’s events.
The Times points out that neither GSK nor the FDA has released any details of this interim assessment of RECORD, which was apparently conducted within the past few weeks. But in his letter to the Lancet today, Krall says the manuscript regarding this interim assessment is “in preparation.”
He adds that other cardiovascular-outcomes trials--such as the 2368-patient Bypass Angioplasty Revascularization Investigation Type 2 Diabetes trial (BARI 2D) and the 10 251-patient Action to Control Cardiovascular Risk in Diabetes (ACCORD) study--“will further inform the cardiovascular safety profile of rosiglitazone.”
The data safety monitoring boards of both of these studies have also confirmed that they should continue, he notes, concluding: “We should stay the course and allow ongoing trials to provide their definitive answers.”
Nissen SE and Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; DOI:10.1056/NEJMoa072761. Available at: http://www.nejm.org.
Krall RL. Cardiovascular safety of rosiglitazone. Lancet 2007; DOI: 10.1016/S0140-6736 (07) 60824-1. Available at: http://www.thelancet.com.
Saul S. Test of drug for diabetes in jeopardy. New York Times, May 26, 2007. Available at: http://www.nytimes.com.
Usdin S. Political defibrillator. BioCentury, May 28, 2007. Available at: http://www.biocentury.com.
Gottlieb S. Journalistic malpractice. Wall Street Journal, May 29, 2007. Available at: http://www.wsj.com.
Psaty B and Furberg C. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; DOI:10.1056/NEJMe078099. Available at: http://www.nejm.org.
Calcium and Vitamin D May Cut Premenopausal Breast Cancer
ReviewBOSTON, May 30 -- Calcium and vitamin D intake from food and supplements may confer a moderately lower risk of breast cancer before menopause but not afterward, researchers reported.
Among the premenopausal women, the breast cancer risks for calcium and vitamin D in the highest intake quintile, compared with the lowest, were more than a third lower, reported Jennifer Lin, Ph.D., of Harvard, and colleagues, in the May 28 issue of the Archives of Internal Medicine. The trend for the relationship with vitamin D, however, did not reach statistical significance.
The inverse association for both nutrients, emerging after a mean 10-year follow-up, appeared more pronounced in more aggressive tumors, they added.
Using a food-frequency questionnaire, the investigators evaluated total calcium and vitamin D intake in relation to breast cancer rates in a prospective cohort of 10,578 premenopausal and 20,909 postmenopausal women in the Women's Health Study.
The women, enrolled from 1993 to 1995, were 45 years or older and free of cancer and cardiovascular disease at baseline.
The mean intakes of total calcium and vitamin D in the total cohort were 1,021 mg/d and 353 IU/d, respectively, the researchers reported.
The younger and older women had statistically similar total intakes of both nutrients, with a mean total calcium intake of 965 mg/d versus 1,049 mg/d, and a mean total vitamin D intake of 332 IU/d versus 364 IU/d.
Dairy products accounted for 53% and 39% of the calcium and vitamin D intake, respectively. For vitamin D, 30% came from multivitamin supplements.
During an average 10-year follow-up, 276 premenopausal women (2.6%) and 743 postmenopausal women (3.6 %) had a confirmed diagnosis of incident invasive breast cancer.
Among the premenopausal women, the hazard ratios in the group with the highest relative to the lowest quintile of intake were 0.61 (95% confidence interval, 0.40-0.92) for calcium (P=0.04 for trend) and 0.65 (CI, 0.42-1.00) for vitamin D (P=0.07 for trend), the researchers reported.
The inverse association with both nutrients was also present for large or poorly differentiated breast tumors among premenopausal women, they said.
By contrast, neither calcium nor vitamin D cut the breast cancer risk among postmenopausal women, and the associations were unchanged by tumor characteristics.
A possible explanation for the differences by menopause status may be related to the joint relationship among calcium, vitamin D, and insulin-like growth factors (IGFs), the researchers suggested.
In-vitro studies have suggested that calcium and vitamin D exert anticarcinogenic effects on breast cancer cells expressing the highest levels of IGF-1 and IGF binding protein 3. Calcium, vitamin D, and IGF binding protein 3 have been shown to interact with one another in promoting growth inhibition in breast cancer cells, the researchers said.
Because circulating levels of these compounds decline with increasing age, the interactions are likely to be stronger in younger women, leading to a greater risk for older women.
However, it is possible that the protective effects of both calcium and vitamin D against postmenopausal breast cancer occur only when intakes of both nutrients are substantially high, they said.
The recent Women's Health Initiative randomized trial also found no reduction in breast cancer among postmenopausal women taking 1,000 mg/d of calcium and 400 IU/d of vitamin D, the researchers said.
"Data from our study suggest that postmenopausal women consuming higher levels of calcium may reduce their breast cancer risk when the level of vitamin D is also high," Dr. Lin said.
It has been suggested, the investigators added, that for older women a minimum of 1,000 IU/d of vitamin D may be necessary to achieve adequate vitamin D concentrations, especially when sunlight exposure is minimal.
Accordingly, the mean 400 IU/d of vitamin D from the subjects in the Women's Health Initiative trial may have been insufficient to reach the hypothesized risk reduction, they said.
The present study, they researchers wrote, had several limitations. Nutrient intake was assessed only at baseline and was subject to measurement error due to random within-person variation.
Furthermore, they noted that they lacked information about Vitamin D intake from sunlight, the major source of vitamin D for most people. "Our lack of information on sun exposure may have attenuated the true association with vitamin D intake," they wrote.
Finally, they said, chance may have played a role because so many subgroup analyses were done.
Further investigation, they concluded, is warranted to study the potential value of calcium and vitamin D intake in reducing the risk of breast cancer.
Among the premenopausal women, the breast cancer risks for calcium and vitamin D in the highest intake quintile, compared with the lowest, were more than a third lower, reported Jennifer Lin, Ph.D., of Harvard, and colleagues, in the May 28 issue of the Archives of Internal Medicine. The trend for the relationship with vitamin D, however, did not reach statistical significance.
The inverse association for both nutrients, emerging after a mean 10-year follow-up, appeared more pronounced in more aggressive tumors, they added.
Using a food-frequency questionnaire, the investigators evaluated total calcium and vitamin D intake in relation to breast cancer rates in a prospective cohort of 10,578 premenopausal and 20,909 postmenopausal women in the Women's Health Study.
The women, enrolled from 1993 to 1995, were 45 years or older and free of cancer and cardiovascular disease at baseline.
The mean intakes of total calcium and vitamin D in the total cohort were 1,021 mg/d and 353 IU/d, respectively, the researchers reported.
The younger and older women had statistically similar total intakes of both nutrients, with a mean total calcium intake of 965 mg/d versus 1,049 mg/d, and a mean total vitamin D intake of 332 IU/d versus 364 IU/d.
Dairy products accounted for 53% and 39% of the calcium and vitamin D intake, respectively. For vitamin D, 30% came from multivitamin supplements.
During an average 10-year follow-up, 276 premenopausal women (2.6%) and 743 postmenopausal women (3.6 %) had a confirmed diagnosis of incident invasive breast cancer.
Among the premenopausal women, the hazard ratios in the group with the highest relative to the lowest quintile of intake were 0.61 (95% confidence interval, 0.40-0.92) for calcium (P=0.04 for trend) and 0.65 (CI, 0.42-1.00) for vitamin D (P=0.07 for trend), the researchers reported.
The inverse association with both nutrients was also present for large or poorly differentiated breast tumors among premenopausal women, they said.
By contrast, neither calcium nor vitamin D cut the breast cancer risk among postmenopausal women, and the associations were unchanged by tumor characteristics.
A possible explanation for the differences by menopause status may be related to the joint relationship among calcium, vitamin D, and insulin-like growth factors (IGFs), the researchers suggested.
In-vitro studies have suggested that calcium and vitamin D exert anticarcinogenic effects on breast cancer cells expressing the highest levels of IGF-1 and IGF binding protein 3. Calcium, vitamin D, and IGF binding protein 3 have been shown to interact with one another in promoting growth inhibition in breast cancer cells, the researchers said.
Because circulating levels of these compounds decline with increasing age, the interactions are likely to be stronger in younger women, leading to a greater risk for older women.
However, it is possible that the protective effects of both calcium and vitamin D against postmenopausal breast cancer occur only when intakes of both nutrients are substantially high, they said.
The recent Women's Health Initiative randomized trial also found no reduction in breast cancer among postmenopausal women taking 1,000 mg/d of calcium and 400 IU/d of vitamin D, the researchers said.
"Data from our study suggest that postmenopausal women consuming higher levels of calcium may reduce their breast cancer risk when the level of vitamin D is also high," Dr. Lin said.
It has been suggested, the investigators added, that for older women a minimum of 1,000 IU/d of vitamin D may be necessary to achieve adequate vitamin D concentrations, especially when sunlight exposure is minimal.
Accordingly, the mean 400 IU/d of vitamin D from the subjects in the Women's Health Initiative trial may have been insufficient to reach the hypothesized risk reduction, they said.
The present study, they researchers wrote, had several limitations. Nutrient intake was assessed only at baseline and was subject to measurement error due to random within-person variation.
Furthermore, they noted that they lacked information about Vitamin D intake from sunlight, the major source of vitamin D for most people. "Our lack of information on sun exposure may have attenuated the true association with vitamin D intake," they wrote.
Finally, they said, chance may have played a role because so many subgroup analyses were done.
Further investigation, they concluded, is warranted to study the potential value of calcium and vitamin D intake in reducing the risk of breast cancer.
Temsirolimus Wins FDA Okay to Prolong Survival in Advanced Kidney Cancer
PHILADELPHIA, May 30 -- The drug temsirolimus (Torisel) prolongs survival in patients with metastatic renal cell carcinoma, researchers here reported today.
And in a rare confluence of research results and regulatory action, on the same day that the pivotal randomized trial was published in the New England Journal of Medicine the drug was approved by the FDA for the indication.
For patients getting the drug, median survival was 3.6 months longer than for those getting standard treatment with interferon alfa, Gary Hudes, M.D., of the Fox Chase Cancer Center, and colleagues in the Global ARCC Trial, reported in the May 31 issue of the NEJM.
A third arm of the industry-sponsored study, combining temsirolimus and interferon alfa, did not show any survival benefit over interferon alfa alone, Dr. Hudes and colleagues found.
"This is the first study to show that a new drug can improve overall survival for patients with metastatic renal cell cancer," Dr. Hudes said.
Early last year, sutinib (Sutent) was approved to treat metastatic renal cell carcinoma, but the studies involving that drug showed improvement in progression-free survival, rather than overall survival.
Similarly, sorafenib (Nexavar) was approved in December 2005 on the basis of a delay in disease progression in renal cell carcinoma.
While the survival improvement with temsirolimus therapy is "modest," Dr. Hudes said, patients in the study had very advanced tumors.
"It would be reasonable to hypothesize that temsirolimus could provide greater benefit to patients with less extensive metastatic disease," Dr. Hudes said.
The current study was stopped at the second interim analysis, the researchers said, when 446 of the 626 patients had died and there was significant evidence (at P<0.0135) that the drug was providing a benefit.
In the study, patients were randomized to 25 mg of temsirolimus intravenously once a week; to interferon alfa, at a dose escalating from three million to 18 million units, subcutaneously three times a week; or to a combination of 15 mg of temsirolimus weekly and six million units of interferon alfa three times a week.
The study found:
Median survival for patients getting temsirolimus was 10.9 months, compared with 7.3 months for interferon alfa and 8.4 months for the combination.
For temsirolimus patients, the hazard ratio for death, compared to interferon alfa, was 0.73 (with a 95% confidence interval from 0.58 to 0.92), which was significant at P=0.008.
Overall survival for patients in the combination group did not differ significantly from those getting interferon alfa.
Dr. Hudes and colleagues said the lack of efficacy in the combination group may have been a result of the lower dose of temsirolimus.
The study also showed a significantly longer period of progression-free survival (P<0.001) for patients getting temsirolimus, compared with those on interferon alfa, the researchers said.
Temsirolimus was better tolerated than interferon-alfa, with 67% of patients in the temsirolimus group having Grade 3 or 4 adverse events, compared with 78% of interferon patients and 87% of patients in the combination group. Both differences were significant at P=0.02.
And in a rare confluence of research results and regulatory action, on the same day that the pivotal randomized trial was published in the New England Journal of Medicine the drug was approved by the FDA for the indication.
For patients getting the drug, median survival was 3.6 months longer than for those getting standard treatment with interferon alfa, Gary Hudes, M.D., of the Fox Chase Cancer Center, and colleagues in the Global ARCC Trial, reported in the May 31 issue of the NEJM.
A third arm of the industry-sponsored study, combining temsirolimus and interferon alfa, did not show any survival benefit over interferon alfa alone, Dr. Hudes and colleagues found.
"This is the first study to show that a new drug can improve overall survival for patients with metastatic renal cell cancer," Dr. Hudes said.
Early last year, sutinib (Sutent) was approved to treat metastatic renal cell carcinoma, but the studies involving that drug showed improvement in progression-free survival, rather than overall survival.
Similarly, sorafenib (Nexavar) was approved in December 2005 on the basis of a delay in disease progression in renal cell carcinoma.
While the survival improvement with temsirolimus therapy is "modest," Dr. Hudes said, patients in the study had very advanced tumors.
"It would be reasonable to hypothesize that temsirolimus could provide greater benefit to patients with less extensive metastatic disease," Dr. Hudes said.
The current study was stopped at the second interim analysis, the researchers said, when 446 of the 626 patients had died and there was significant evidence (at P<0.0135) that the drug was providing a benefit.
In the study, patients were randomized to 25 mg of temsirolimus intravenously once a week; to interferon alfa, at a dose escalating from three million to 18 million units, subcutaneously three times a week; or to a combination of 15 mg of temsirolimus weekly and six million units of interferon alfa three times a week.
The study found:
Median survival for patients getting temsirolimus was 10.9 months, compared with 7.3 months for interferon alfa and 8.4 months for the combination.
For temsirolimus patients, the hazard ratio for death, compared to interferon alfa, was 0.73 (with a 95% confidence interval from 0.58 to 0.92), which was significant at P=0.008.
Overall survival for patients in the combination group did not differ significantly from those getting interferon alfa.
Dr. Hudes and colleagues said the lack of efficacy in the combination group may have been a result of the lower dose of temsirolimus.
The study also showed a significantly longer period of progression-free survival (P<0.001) for patients getting temsirolimus, compared with those on interferon alfa, the researchers said.
Temsirolimus was better tolerated than interferon-alfa, with 67% of patients in the temsirolimus group having Grade 3 or 4 adverse events, compared with 78% of interferon patients and 87% of patients in the combination group. Both differences were significant at P=0.02.
Wednesday, May 30, 2007
Decision Aid Improves Statin Compliance Among Diabetics
ROCHESTER, Minn., May 29 -- A dose of blunt reality, without sugarcoating, helped patients with diabetes appreciate their cardiovascular risks and gave them incentives to be compliant with statins.
Patients with diabetes who received a straightforward guide outlining their heart risks and explaining the benefits and risks of statins were better informed and were more likely to adhere to their drug regimens than controls, reported Audrey J. Weymiller, C.N.P. of the Mayo Clinic here, and colleagues.
"Compared with usual care in our setting, use of this decision aid improved the accuracy of patients' estimate of cardiovascular risk without statin therapy, improved their knowledge about statins and the potential relative merits of statin therapy, and improved the accuracy of their estimate of absolute cardiovascular risk reduction with statin therapy," the authors wrote in the May 28 issue of the Archives of Internal Medicine.
The investigators tested a decision aid, called Statin Choice, for its ability to help patients make timely informed decisions about their care. The guide can be customized to individual patient.
"Using information about your health we've estimated that you have a ___ chance of having a heart attack sometime in the next 10 years," the one page, single-sided decision aid reads.
In the example shown in the article, the hypothetical patient's cardiovascular risk is estimated to be at 15% to 30% over the next decade, based on gender, age, duration of diabetes, presence of proteinuria, latest HbA1c, blood pressure, total cholesterol/HDL, and smoking status.
The guide also contains a graphic showing 80 green "smiley" faces and 20 frowning red faces to represent a 20% risk, and a similar graphic with six of the 20 red faces turned to smiling yellow faces to represent the number of heart attacks that might be avoided through statin use.
The guide then explains the drawbacks of taking statins, including chronic use and costs; common side effects such as nausea, diarrhea, constipation; muscle aching/stiffness; elevated liver enzymes, and muscle/kidney damage, which the guide notes occurs in "1 in 20,000 patients, (requires patients to stop statins)."
Finally, the guide presents patients with a checklist asking which action they now wish to follow, based on the information provided: "take (or continue to take) statins, not take (or stop taking) statins, discuss with your clinician today discuss with your clinician in the future (when?) discuss with others (who?)"
To determine whether the guide could have an effect on the decision-making process, the authors randomly assigned 98 patients with diabetes to the guide or a standard Mayo Clinic cholesterol management pamphlet as a control. The allocation of the educational materials was concealed, patients were blinded to the study goals, and the analysis was by intention to treat.
The guide or the control pamphlets were given to patients by one of 21 endocrinologists working in specialty outpatient metabolic consultations. The investigators examined the acceptability of the guide, patient knowledge about options and cardiovascular risk, and decisional conflict immediately after the visit. They also looked at drug adherence three months after the intervention.
They found that patients favored using the decision aid (odds ratio vs. controls, 2.8; 95% confidence interval, 1.2-6.9). In addition, the 52 patients who received the decision aid knew more about cardiovascular risk than controls, (a difference of 2.4 of 9 points; 95% CI, 1.5-3.3), and were far better than their counterparts at estimating cardiovascular risk (odds ratio, 22.4; 95% CI, 5.9-85.6).
In addition, patients who received the decision aid had a nearly seven-fold better understanding of the potential absolute risk reduction with statins (odds ratio 6.7; 95% CI, 2.2-19.7), and had less decisional conflict than controls, as measured by a difference of −10.6 (95% CI, −15.4 to −5.9) on a 100-point scale.
The decision aid also appeared to improve drug adherence. Among 33 patients in the intervention group taking statin drugs at three months, two reported one or more doses in the last week, compared with six of 29 patients in the control group. The odds ratio for taking statin drugs in the decision-aid group was 3.4 (95% CI, 1.5-7.5).
The study was limited by enrollment of patients who were already taking statins (slightly more than half of the patients in each group), patient self-report of adherence without verification, and the fact that the study was conducted with well-educated patients in a single clinic, the authors acknowledged.
Patients with diabetes who received a straightforward guide outlining their heart risks and explaining the benefits and risks of statins were better informed and were more likely to adhere to their drug regimens than controls, reported Audrey J. Weymiller, C.N.P. of the Mayo Clinic here, and colleagues.
"Compared with usual care in our setting, use of this decision aid improved the accuracy of patients' estimate of cardiovascular risk without statin therapy, improved their knowledge about statins and the potential relative merits of statin therapy, and improved the accuracy of their estimate of absolute cardiovascular risk reduction with statin therapy," the authors wrote in the May 28 issue of the Archives of Internal Medicine.
The investigators tested a decision aid, called Statin Choice, for its ability to help patients make timely informed decisions about their care. The guide can be customized to individual patient.
"Using information about your health we've estimated that you have a ___ chance of having a heart attack sometime in the next 10 years," the one page, single-sided decision aid reads.
In the example shown in the article, the hypothetical patient's cardiovascular risk is estimated to be at 15% to 30% over the next decade, based on gender, age, duration of diabetes, presence of proteinuria, latest HbA1c, blood pressure, total cholesterol/HDL, and smoking status.
The guide also contains a graphic showing 80 green "smiley" faces and 20 frowning red faces to represent a 20% risk, and a similar graphic with six of the 20 red faces turned to smiling yellow faces to represent the number of heart attacks that might be avoided through statin use.
The guide then explains the drawbacks of taking statins, including chronic use and costs; common side effects such as nausea, diarrhea, constipation; muscle aching/stiffness; elevated liver enzymes, and muscle/kidney damage, which the guide notes occurs in "1 in 20,000 patients, (requires patients to stop statins)."
Finally, the guide presents patients with a checklist asking which action they now wish to follow, based on the information provided: "take (or continue to take) statins, not take (or stop taking) statins, discuss with your clinician today discuss with your clinician in the future (when?) discuss with others (who?)"
To determine whether the guide could have an effect on the decision-making process, the authors randomly assigned 98 patients with diabetes to the guide or a standard Mayo Clinic cholesterol management pamphlet as a control. The allocation of the educational materials was concealed, patients were blinded to the study goals, and the analysis was by intention to treat.
The guide or the control pamphlets were given to patients by one of 21 endocrinologists working in specialty outpatient metabolic consultations. The investigators examined the acceptability of the guide, patient knowledge about options and cardiovascular risk, and decisional conflict immediately after the visit. They also looked at drug adherence three months after the intervention.
They found that patients favored using the decision aid (odds ratio vs. controls, 2.8; 95% confidence interval, 1.2-6.9). In addition, the 52 patients who received the decision aid knew more about cardiovascular risk than controls, (a difference of 2.4 of 9 points; 95% CI, 1.5-3.3), and were far better than their counterparts at estimating cardiovascular risk (odds ratio, 22.4; 95% CI, 5.9-85.6).
In addition, patients who received the decision aid had a nearly seven-fold better understanding of the potential absolute risk reduction with statins (odds ratio 6.7; 95% CI, 2.2-19.7), and had less decisional conflict than controls, as measured by a difference of −10.6 (95% CI, −15.4 to −5.9) on a 100-point scale.
The decision aid also appeared to improve drug adherence. Among 33 patients in the intervention group taking statin drugs at three months, two reported one or more doses in the last week, compared with six of 29 patients in the control group. The odds ratio for taking statin drugs in the decision-aid group was 3.4 (95% CI, 1.5-7.5).
The study was limited by enrollment of patients who were already taking statins (slightly more than half of the patients in each group), patient self-report of adherence without verification, and the fact that the study was conducted with well-educated patients in a single clinic, the authors acknowledged.
Soy: The Way to a Woman's Heart Is Through the Stomach
BOSTON, May 29 -- Substituting soy into an otherwise healthy diet may be cardioprotective for postmenopausal women, researchers found.
In a prospective trial, replacing 25 grams of protein with half a cup of soy nuts (dry-roasted soybeans) lowered systolic blood pressure 9.9% and diastolic 6.8% in hypertensive women, said Francine K. Welty, M.D., Ph.D., of Beth Israel Deaconess Medical Center here, and colleagues.
It also dropped low-density lipoprotein cholesterol by 11% and apolipoprotein B by 8%, they reported in the May 28 issue of Archives of Internal Medicine.
While the dietary intervention lasted only eight weeks, long-term intake would likely have substantial benefits, they wrote.
"A 12-mm of mercury decrease in systolic blood pressure for 10 years has been estimated to prevent one death for every 11 patients with stage one hypertension treated," they said.
"Therefore, the average reduction of 15-mm Hg in systolic blood pressure in hypertensive women in the present study could have significant implications for reducing cardiovascular risk and death on a population basis," they continued.
In the randomized crossover study, 60 healthy postmenopausal women -- 12 of whom were hypertensive -- were put on the Therapeutic Lifestyle Changes diet recommended by the Adult Treatment Panel of the National Cholesterol Education Program for lowering heart disease risk.
The diet consists of 30% of energy from total fat (7% or less from saturated fat), 15% from protein, and 55% from carbohydrate with less than 200 mg of cholesterol per day, 1200 mg of calcium, and two meals of fatty fish per week.
During one of two eight-week periods, participants substituted one-half cup of soy nuts a day for 25 g of protein from other sources. The soy nut serving contained 25 g of soy protein and 101 mg of aglycone isoflavones.
Participants could not use lipid-lowering drugs, hormone therapy, osteoporosis medications, or soy products during or in the two months prior to the study.
Among the findings for soy nut supplementation compared with the diet alone, the researchers reported:
9.9% lower systolic blood pressure among hypertensive women (137 versus 152 mm Hg, P=0.003).
5.2% lower systolic blood pressure among normotensive women (110 versus 116 mm Hg, P<0.001).
6.8% lower diastolic blood pressure among hypertensive women (82 versus 88 mm Hg, P=0.001).
2.9% lower diastolic blood pressure among normotensive women (67 versus 69 mm Hg, P=0.02)
11% lower LDL cholesterol among hypertensive women (146 versus 164 mg/dL, P=0.04) but no effect for normotensive subjects.
8% lower apolipoprotein B among hypertensive women (116 versus 126 mg/dL, P=0.04) but no effect for normotensive subjects.
Together, the results "are comparable with those seen with antihypertensive drugs" and suggest important health benefits, Dr. Welty said.
Even the modest diastolic blood pressure reductions are likely to reduce cardiovascular risk, they noted.
In one previous study, a 2-mm Hg reduction similar to that found in Dr. Welty's study yielded a 6% reduction in coronary heart disease and a 15% reduction in stroke.
Exercise and weight loss did not appear to account for the effects since neither differed between diet periods, Dr. Welty said. However, total and saturated fat of the soy diet were significantly lower than in the control diet.
The difference was likely caused by the increased isoflavone content of the soy diet, the researchers noted. But since previous studies have shown that isoflavone supplements by themselves have no effect on blood pressure, whole soy may be the key, they added.
The researchers said the findings are likely to be generalizable to postmenopausal women in clinical practice because the study had women follow the diet at home with instruction from a dietician only initially.
"Therefore, dietary soy may be a practical, safe, and inexpensive modality to reduce blood pressure," they concluded. "If the findings are repeated in a larger group they may have important implications for reducing cardiovascular risk in postmenopausal women on a population basis."
In a prospective trial, replacing 25 grams of protein with half a cup of soy nuts (dry-roasted soybeans) lowered systolic blood pressure 9.9% and diastolic 6.8% in hypertensive women, said Francine K. Welty, M.D., Ph.D., of Beth Israel Deaconess Medical Center here, and colleagues.
It also dropped low-density lipoprotein cholesterol by 11% and apolipoprotein B by 8%, they reported in the May 28 issue of Archives of Internal Medicine.
While the dietary intervention lasted only eight weeks, long-term intake would likely have substantial benefits, they wrote.
"A 12-mm of mercury decrease in systolic blood pressure for 10 years has been estimated to prevent one death for every 11 patients with stage one hypertension treated," they said.
"Therefore, the average reduction of 15-mm Hg in systolic blood pressure in hypertensive women in the present study could have significant implications for reducing cardiovascular risk and death on a population basis," they continued.
In the randomized crossover study, 60 healthy postmenopausal women -- 12 of whom were hypertensive -- were put on the Therapeutic Lifestyle Changes diet recommended by the Adult Treatment Panel of the National Cholesterol Education Program for lowering heart disease risk.
The diet consists of 30% of energy from total fat (7% or less from saturated fat), 15% from protein, and 55% from carbohydrate with less than 200 mg of cholesterol per day, 1200 mg of calcium, and two meals of fatty fish per week.
During one of two eight-week periods, participants substituted one-half cup of soy nuts a day for 25 g of protein from other sources. The soy nut serving contained 25 g of soy protein and 101 mg of aglycone isoflavones.
Participants could not use lipid-lowering drugs, hormone therapy, osteoporosis medications, or soy products during or in the two months prior to the study.
Among the findings for soy nut supplementation compared with the diet alone, the researchers reported:
9.9% lower systolic blood pressure among hypertensive women (137 versus 152 mm Hg, P=0.003).
5.2% lower systolic blood pressure among normotensive women (110 versus 116 mm Hg, P<0.001).
6.8% lower diastolic blood pressure among hypertensive women (82 versus 88 mm Hg, P=0.001).
2.9% lower diastolic blood pressure among normotensive women (67 versus 69 mm Hg, P=0.02)
11% lower LDL cholesterol among hypertensive women (146 versus 164 mg/dL, P=0.04) but no effect for normotensive subjects.
8% lower apolipoprotein B among hypertensive women (116 versus 126 mg/dL, P=0.04) but no effect for normotensive subjects.
Together, the results "are comparable with those seen with antihypertensive drugs" and suggest important health benefits, Dr. Welty said.
Even the modest diastolic blood pressure reductions are likely to reduce cardiovascular risk, they noted.
In one previous study, a 2-mm Hg reduction similar to that found in Dr. Welty's study yielded a 6% reduction in coronary heart disease and a 15% reduction in stroke.
Exercise and weight loss did not appear to account for the effects since neither differed between diet periods, Dr. Welty said. However, total and saturated fat of the soy diet were significantly lower than in the control diet.
The difference was likely caused by the increased isoflavone content of the soy diet, the researchers noted. But since previous studies have shown that isoflavone supplements by themselves have no effect on blood pressure, whole soy may be the key, they added.
The researchers said the findings are likely to be generalizable to postmenopausal women in clinical practice because the study had women follow the diet at home with instruction from a dietician only initially.
"Therefore, dietary soy may be a practical, safe, and inexpensive modality to reduce blood pressure," they concluded. "If the findings are repeated in a larger group they may have important implications for reducing cardiovascular risk in postmenopausal women on a population basis."
AAPA: Obstructive Sleep Apnea Wearies the Heart
PHILADELPHIA, May 29 -- The most obvious clinical feature of obstructive sleep apnea may be weariness of mind, but this breathing disorder also slowly and silently wears down the heart, according to researchers.
Recent evidence suggests that 60% of people hospitalized for myocardial infarction also have obstructive sleep apnea. Yet occurrence among the general population is only about 9%, said Jose R. Marquina, M.D., of the Collier County Medical Society in Naples, Fla., at the American Academy of Physician Assistants meeting here.
In addition, recent research also suggests that as many as 70% of patients hospitalized for stroke have obstructive sleep apnea as a comorbid condition, Dr. Marquina said.
During the night, severe sleep apnea sufferers stop breathing anywhere from 30 to 120 times per hour, and the resulting lack of oxygen in the body strains and stupefies the cardiovascular system, Dr. Marquina said.
Over the years, hypoxemia in patients with obstructive sleep apnea can damage the sinus node, the group of specialized heart cells that govern cardiac rhythm, he said. This hypoxic damage causes a variety of cardiac arrhythmias including bradycardia, atrial fibrillation, and sinus arrest.
In addition, he said, the stress of hypoxemia causes the body to release catecholines, a group of hormones linked to hypertension.
Oxygen levels in the blood are also involved in controlling pulmonary artery pressure, Dr. Marquina said, and chronic hypoxemia can, therefore, also lead to pulmonary hypertension. In fact, recent evidence suggests that 12% to 17% of patients with obstructive sleep apnea also have pulmonary hypertension, he said.
These cardiovascular effects of obstructive sleep apnea occur in addition to the more well known neurological effects, which include cerebral anoxia, cerebrovascular disease, and impaired memory and concentration, Dr. Marquina said.
Obstructive sleep apnea can also severely reduce a person's overall quality of life. The condition has been associated with poor performance at work or school, depression, and marital problems, he said.
Men are affected twice as often as women: occurrence is 4% among men versus 2% among women, Dr. Marquina said. The risk for obstructive sleep apnea also increases among those who are overweight. Among overweight men the occurrence rises to 24%, and it reaches 9% for overweight women, he said.
As many as 90% of cases of obstructive sleep apnea go undiagnosed, Dr. Marquina said. Clinicians should be more aware of the symptoms, which include excessive daytime sleepiness or tiredness upon waking. "The typical patient will say they slept for eight hours but woke up still feeling tired," he said.
Another symptom is loud snoring, although snoring also occurs normally in about 70% of individuals age 35 and older, Dr. Marquina said. Patients will often deny snoring, so it may be more useful to ask a bed partner about this condition, he added.
Up to five episodes of apnea per hour while sleeping is also normal for healthy individuals, Dr. Marquina said. But five to 15 episodes identified by polysomnography indicate mild obstructive sleep apnea, 15 to 30 are defined as a moderate condition, and 30 or more are defined as severe obstructive sleep apnea, he said.
In addition, obstructive sleep apnea tends to be associated with a neck circumference of 18 inches or more, he said.
"Obstructive sleep apnea must be treated not only to improve the symptoms of fatigue and overall quality of life but to prevent the development of cardiovascular problems," Dr. Marquina concluded.
Recent evidence suggests that 60% of people hospitalized for myocardial infarction also have obstructive sleep apnea. Yet occurrence among the general population is only about 9%, said Jose R. Marquina, M.D., of the Collier County Medical Society in Naples, Fla., at the American Academy of Physician Assistants meeting here.
In addition, recent research also suggests that as many as 70% of patients hospitalized for stroke have obstructive sleep apnea as a comorbid condition, Dr. Marquina said.
During the night, severe sleep apnea sufferers stop breathing anywhere from 30 to 120 times per hour, and the resulting lack of oxygen in the body strains and stupefies the cardiovascular system, Dr. Marquina said.
Over the years, hypoxemia in patients with obstructive sleep apnea can damage the sinus node, the group of specialized heart cells that govern cardiac rhythm, he said. This hypoxic damage causes a variety of cardiac arrhythmias including bradycardia, atrial fibrillation, and sinus arrest.
In addition, he said, the stress of hypoxemia causes the body to release catecholines, a group of hormones linked to hypertension.
Oxygen levels in the blood are also involved in controlling pulmonary artery pressure, Dr. Marquina said, and chronic hypoxemia can, therefore, also lead to pulmonary hypertension. In fact, recent evidence suggests that 12% to 17% of patients with obstructive sleep apnea also have pulmonary hypertension, he said.
These cardiovascular effects of obstructive sleep apnea occur in addition to the more well known neurological effects, which include cerebral anoxia, cerebrovascular disease, and impaired memory and concentration, Dr. Marquina said.
Obstructive sleep apnea can also severely reduce a person's overall quality of life. The condition has been associated with poor performance at work or school, depression, and marital problems, he said.
Men are affected twice as often as women: occurrence is 4% among men versus 2% among women, Dr. Marquina said. The risk for obstructive sleep apnea also increases among those who are overweight. Among overweight men the occurrence rises to 24%, and it reaches 9% for overweight women, he said.
As many as 90% of cases of obstructive sleep apnea go undiagnosed, Dr. Marquina said. Clinicians should be more aware of the symptoms, which include excessive daytime sleepiness or tiredness upon waking. "The typical patient will say they slept for eight hours but woke up still feeling tired," he said.
Another symptom is loud snoring, although snoring also occurs normally in about 70% of individuals age 35 and older, Dr. Marquina said. Patients will often deny snoring, so it may be more useful to ask a bed partner about this condition, he added.
Up to five episodes of apnea per hour while sleeping is also normal for healthy individuals, Dr. Marquina said. But five to 15 episodes identified by polysomnography indicate mild obstructive sleep apnea, 15 to 30 are defined as a moderate condition, and 30 or more are defined as severe obstructive sleep apnea, he said.
In addition, obstructive sleep apnea tends to be associated with a neck circumference of 18 inches or more, he said.
"Obstructive sleep apnea must be treated not only to improve the symptoms of fatigue and overall quality of life but to prevent the development of cardiovascular problems," Dr. Marquina concluded.
AAPA: Obstructive Sleep Apnea May Lurk Behind A-Fib
PHILADELPHIA, May 29 -- More than half of patients with atrial fibrillation are also likely to have obstructive sleep apnea, investigators suggested here.
A small study of patients treated for atrial fibrillation at the investigator's practice found that 19% had been diagnosed with obstructive sleep apnea and 66% were at high risk for the condition, said Jonathan Gietzen, M.S., P.A.-C., of Heart Rhythm Consultants in Portland, Ore., and colleagues.
Previous studies have suggested that the hypoxic effects of obstructive sleep apnea might lead to atrial fibrillation, which is the most common sustained cardiac arrhythmia and affects an estimated two million Americans, Gietzen said at the American Academy of Physician Assistants meeting.
"If such a relationship exists, by screening patients with known atrial fibrillation for obstructive sleep apnea, you have detected a treatable condition that may help decrease the recurrence of atrial fibrillation," the investigators said.
"Similarly, by screening patients with known obstructive sleep apnea for atrial fibrillation, you can rule out other such complications of both disorders, such as heart failure and stroke," they said.
The study used the Berlin Questionnaire and the Epworth Sleepiness Scale to assess the risk for obstructive sleep apnea in patients treated for atrial fibrillation at a specialty cardiology office from 2004 through May 2006. The instruments were mailed to the patients, who filled them out and mailed them back.
A total of 66 patients were categorized as high-risk for obstructive sleep apnea according to their answers on the 10-question Berlin assessment. Of these, 19 reported a previous diagnosis of obstructive sleep apnea. None of the patients identified as low-risk reported a previous diagnosis of sleep apnea.
Patients in the high-risk group tended to have a higher body mass index than those in the low-risk group (mean BMI=31.3 versus 27.8; P=0.0076).
And significantly more patients in the high-risk group had a history of hypertension (49 patients versus 7 in the low-risk group; P<0.0001).
Gender did not appear to be a factor, the investigators said, with males comprising 75% of the high-risk group and 65% of the low-risk group (P=0.15).
In addition, the Epworth Sleepiness Scale revealed that 57% of patients reported being excessively sleepy, a possible indicator of obstructive sleep apnea, the authors said.
"As the number of patients with atrial fibrillation continues to grow nationwide, it is of utmost importance to find the predisposing factors. With obesity and hypertension being risk factors for both atrial fibrillation and obstructive sleep apnea, it is of clinical importance to look at the possible connection between the two disorders," the authors said.
"With the evidence that such a high prevalence of patients with atrial fibrillation also exhibit signs of obstructive sleep apnea, they concluded, the presence of obstructive sleep apnea should be considered in all patients with atrial fibrillation," especially those who are obese and have hypertension.
"However, the association between obstructive sleep apnea and atrial fibrillation is controversial because of the multiple confounding variables that occur frequently in both," the investigators acknowledged.
A small study of patients treated for atrial fibrillation at the investigator's practice found that 19% had been diagnosed with obstructive sleep apnea and 66% were at high risk for the condition, said Jonathan Gietzen, M.S., P.A.-C., of Heart Rhythm Consultants in Portland, Ore., and colleagues.
Previous studies have suggested that the hypoxic effects of obstructive sleep apnea might lead to atrial fibrillation, which is the most common sustained cardiac arrhythmia and affects an estimated two million Americans, Gietzen said at the American Academy of Physician Assistants meeting.
"If such a relationship exists, by screening patients with known atrial fibrillation for obstructive sleep apnea, you have detected a treatable condition that may help decrease the recurrence of atrial fibrillation," the investigators said.
"Similarly, by screening patients with known obstructive sleep apnea for atrial fibrillation, you can rule out other such complications of both disorders, such as heart failure and stroke," they said.
The study used the Berlin Questionnaire and the Epworth Sleepiness Scale to assess the risk for obstructive sleep apnea in patients treated for atrial fibrillation at a specialty cardiology office from 2004 through May 2006. The instruments were mailed to the patients, who filled them out and mailed them back.
A total of 66 patients were categorized as high-risk for obstructive sleep apnea according to their answers on the 10-question Berlin assessment. Of these, 19 reported a previous diagnosis of obstructive sleep apnea. None of the patients identified as low-risk reported a previous diagnosis of sleep apnea.
Patients in the high-risk group tended to have a higher body mass index than those in the low-risk group (mean BMI=31.3 versus 27.8; P=0.0076).
And significantly more patients in the high-risk group had a history of hypertension (49 patients versus 7 in the low-risk group; P<0.0001).
Gender did not appear to be a factor, the investigators said, with males comprising 75% of the high-risk group and 65% of the low-risk group (P=0.15).
In addition, the Epworth Sleepiness Scale revealed that 57% of patients reported being excessively sleepy, a possible indicator of obstructive sleep apnea, the authors said.
"As the number of patients with atrial fibrillation continues to grow nationwide, it is of utmost importance to find the predisposing factors. With obesity and hypertension being risk factors for both atrial fibrillation and obstructive sleep apnea, it is of clinical importance to look at the possible connection between the two disorders," the authors said.
"With the evidence that such a high prevalence of patients with atrial fibrillation also exhibit signs of obstructive sleep apnea, they concluded, the presence of obstructive sleep apnea should be considered in all patients with atrial fibrillation," especially those who are obese and have hypertension.
"However, the association between obstructive sleep apnea and atrial fibrillation is controversial because of the multiple confounding variables that occur frequently in both," the investigators acknowledged.
Aggressive Care Might Delay Recovery From Whiplash
Increased intensity of care by a general practitioner or chiropractor is associated with slower recovery for patients with soft tissue injuries such as whiplash, according to the results of a study published in the May 25 Early View issue and June print issue of Arthritis & Rheumatism.
"Although there are few effective treatments for whiplash, a growing body of evidence suggests that the delivery of intensive health care shortly after the injury may lead to iatrogenic disability," write Pierre Côté, DC, PhD, from the University of Toronto and the Toronto Western Research Institute and Rehabilitations Solutions in Ontario, Canada, and colleagues. "The objective of our analysis was to test whether the association between early patterns of care and time to recovery reported by Côté et al in a cohort of patients compensated under no-fault insurance is reproducible in an independent cohort of patients with whiplash compensated under tort insurance."
The study cohort consisted of 1693 adults in Saskatchewan who sustained whiplash injuries between July 1, 1994, and December 31, 1994. The investigators studied 8 initial patterns of care that integrated type of provider (general practitioners, chiropractors, and specialists) and number of visits (low vs high utilization), using Cox models to estimate the association between patterns of care and time to recovery while controlling for injury severity and other confounders.
Even after controlling for important prognostic factors, patients in the low-utilization general practitioner group and those in the general medical group had the fastest recovery. Compared with the low-utilization general practitioner group, the high-utilization chiropractic group had a 1-year rate of recovery that was 25% slower (adjusted hazard rate ratio [HRR], 0.75; 95% confidence interval [CI], 0.54 - 1.04), the low-utilization general practitioner plus chiropractic group had a rate that was 26% slower (HRR, 0.74; 95% CI, 0.60 - 0.93), and the high-utilization general practitioner plus chiropractic combined group had a rate that was 36% slower (HRR, 0.64; 95% CI, 0.50 - 0.83).
"The observation that intensive health care utilization early after a whiplash injury is associated with slower recovery was reproduced in an independent cohort of patients," the authors write. "The results add to the body of evidence suggesting that early aggressive treatment of whiplash injuries does not promote faster recovery. In particular, the combination of chiropractic and general practitioner care significantly reduces the rate of recovery."
Study limitations include possible residual confounding by indication.
"Our research complements the findings of randomized clinical trials suggesting that early minimal care that promotes activation improves prognosis," the authors conclude. "Future research should include the design of pragmatic randomized trials to test the effectiveness of various patterns of care in the community. These trials are essential to understand the influence of health care provision in preventing or facilitating disability."
Health Canada, through the National Health Research and Development Program, and the Canadian Institutes for Health Research supported this study. Dr. Côté's work was supported by a Doctoral Fellowship Training award from the National Health Research and Development Program, a New Investigator award from the Canadian Institutes of Health Research, and the Workplace Safety and Insurance Board of Ontario through the Institute for Work & Health. Another author's work was supported by a Health Scholar award from the Alberta Heritage Foundation for Medical Research. Some of the authors have disclosed various financial relationships with the Insurance Bureau of Canada.
Arthritis Rheum. 2007;57:861-868.
"Although there are few effective treatments for whiplash, a growing body of evidence suggests that the delivery of intensive health care shortly after the injury may lead to iatrogenic disability," write Pierre Côté, DC, PhD, from the University of Toronto and the Toronto Western Research Institute and Rehabilitations Solutions in Ontario, Canada, and colleagues. "The objective of our analysis was to test whether the association between early patterns of care and time to recovery reported by Côté et al in a cohort of patients compensated under no-fault insurance is reproducible in an independent cohort of patients with whiplash compensated under tort insurance."
The study cohort consisted of 1693 adults in Saskatchewan who sustained whiplash injuries between July 1, 1994, and December 31, 1994. The investigators studied 8 initial patterns of care that integrated type of provider (general practitioners, chiropractors, and specialists) and number of visits (low vs high utilization), using Cox models to estimate the association between patterns of care and time to recovery while controlling for injury severity and other confounders.
Even after controlling for important prognostic factors, patients in the low-utilization general practitioner group and those in the general medical group had the fastest recovery. Compared with the low-utilization general practitioner group, the high-utilization chiropractic group had a 1-year rate of recovery that was 25% slower (adjusted hazard rate ratio [HRR], 0.75; 95% confidence interval [CI], 0.54 - 1.04), the low-utilization general practitioner plus chiropractic group had a rate that was 26% slower (HRR, 0.74; 95% CI, 0.60 - 0.93), and the high-utilization general practitioner plus chiropractic combined group had a rate that was 36% slower (HRR, 0.64; 95% CI, 0.50 - 0.83).
"The observation that intensive health care utilization early after a whiplash injury is associated with slower recovery was reproduced in an independent cohort of patients," the authors write. "The results add to the body of evidence suggesting that early aggressive treatment of whiplash injuries does not promote faster recovery. In particular, the combination of chiropractic and general practitioner care significantly reduces the rate of recovery."
Study limitations include possible residual confounding by indication.
"Our research complements the findings of randomized clinical trials suggesting that early minimal care that promotes activation improves prognosis," the authors conclude. "Future research should include the design of pragmatic randomized trials to test the effectiveness of various patterns of care in the community. These trials are essential to understand the influence of health care provision in preventing or facilitating disability."
Health Canada, through the National Health Research and Development Program, and the Canadian Institutes for Health Research supported this study. Dr. Côté's work was supported by a Doctoral Fellowship Training award from the National Health Research and Development Program, a New Investigator award from the Canadian Institutes of Health Research, and the Workplace Safety and Insurance Board of Ontario through the Institute for Work & Health. Another author's work was supported by a Health Scholar award from the Alberta Heritage Foundation for Medical Research. Some of the authors have disclosed various financial relationships with the Insurance Bureau of Canada.
Arthritis Rheum. 2007;57:861-868.
Vitamin A (Retinol) Effaces Wrinkles in Naturally Aged Skin
Topical vitamin A (retinol) effaces fine wrinkles associated with natural aging, according to the results of a small randomized trial in elderly patients published in the May issue of the Archives of Dermatology.
"Because accelerated skin aging due to excessive sun exposure has marked collagen deficiency and effective treatments for photoaging promote procollagen synthesis, we hypothesized that similar therapies might also improve the collagen deficiency found in intrinsic aging," write Reza Kafi, MD, from the University of Michigan Medical School in Ann Arbor, and colleagues. "Compared with retinoic acid, the ability of retinol to induce skin irritation is notably less, at least according to a 4-day patch test (an occlusive treatment). Thus, retinol has the potential to deliver retinoic acid–like effects to human skin with improved tolerability."
In this double-blind, vehicle-controlled, left-and-right-arm comparison study at an academic referral center, 36 elderly participants received topical 0.4% retinol lotion or its vehicle applied at each visit by study personnel to either the right or the left arm, as often as 3 times weekly for 24 weeks. Mean age was 87 years, and all patients lived in 1 of 2 senior citizen facilities.
Primary endpoints were clinical assessment using a semiquantitative scale (0, none; 9, most severe) and biochemical measurements from skin biopsy specimens obtained from treated areas. Analysis was by intent-to-treat, using the last-observation-carried-forward method.
After 24 weeks, changes in fine wrinkling scores were different between retinol-treated and vehicle-treated skin (-1.64 [95% confidence interval [CI], -2.06 to -1.22] vs -0.08 [95% CI, -0.17 to 0.01]; P < .001). In a subgroup, retinol treatment was associated with increased glycosaminoglycan expression (P = .02 [n = 6]) and procollagen I immunostaining (P = .049 [n = 4]) compared with vehicle.
The retinol preparation was relatively well tolerated.
"Topical retinol improves fine wrinkles associated with natural aging," the authors write. "Significant induction of glycosaminoglycan, which is known to retain substantial water, and increased collagen production are most likely responsible for wrinkle effacement. With greater skin matrix synthesis, retinol-treated aged skin is more likely to withstand skin injury and ulcer formation along with improved appearance."
The Babcock Endowment for Dermatologic Research, the Merck-American Federation for Aging Research, Alpha Omega Alpha Student Research Fellowship, and the National Institutes of Health supported this study. Four of the authors have disclosed being named inventors on an issued patent application concerning methods of treating skin aging, and they will receive royalties under the University of Michigan's Intellectual Property Policy in the event that a commercial license is signed and a product is sold.
Arch Dermatol. 2007;143:606-612.
"Because accelerated skin aging due to excessive sun exposure has marked collagen deficiency and effective treatments for photoaging promote procollagen synthesis, we hypothesized that similar therapies might also improve the collagen deficiency found in intrinsic aging," write Reza Kafi, MD, from the University of Michigan Medical School in Ann Arbor, and colleagues. "Compared with retinoic acid, the ability of retinol to induce skin irritation is notably less, at least according to a 4-day patch test (an occlusive treatment). Thus, retinol has the potential to deliver retinoic acid–like effects to human skin with improved tolerability."
In this double-blind, vehicle-controlled, left-and-right-arm comparison study at an academic referral center, 36 elderly participants received topical 0.4% retinol lotion or its vehicle applied at each visit by study personnel to either the right or the left arm, as often as 3 times weekly for 24 weeks. Mean age was 87 years, and all patients lived in 1 of 2 senior citizen facilities.
Primary endpoints were clinical assessment using a semiquantitative scale (0, none; 9, most severe) and biochemical measurements from skin biopsy specimens obtained from treated areas. Analysis was by intent-to-treat, using the last-observation-carried-forward method.
After 24 weeks, changes in fine wrinkling scores were different between retinol-treated and vehicle-treated skin (-1.64 [95% confidence interval [CI], -2.06 to -1.22] vs -0.08 [95% CI, -0.17 to 0.01]; P < .001). In a subgroup, retinol treatment was associated with increased glycosaminoglycan expression (P = .02 [n = 6]) and procollagen I immunostaining (P = .049 [n = 4]) compared with vehicle.
The retinol preparation was relatively well tolerated.
"Topical retinol improves fine wrinkles associated with natural aging," the authors write. "Significant induction of glycosaminoglycan, which is known to retain substantial water, and increased collagen production are most likely responsible for wrinkle effacement. With greater skin matrix synthesis, retinol-treated aged skin is more likely to withstand skin injury and ulcer formation along with improved appearance."
The Babcock Endowment for Dermatologic Research, the Merck-American Federation for Aging Research, Alpha Omega Alpha Student Research Fellowship, and the National Institutes of Health supported this study. Four of the authors have disclosed being named inventors on an issued patent application concerning methods of treating skin aging, and they will receive royalties under the University of Michigan's Intellectual Property Policy in the event that a commercial license is signed and a product is sold.
Arch Dermatol. 2007;143:606-612.
Study Finds Soy Nuts Lower Blood Pressure
Soy nuts may reduce blood pressure in postmenopausal women, a small study published in the Archives of Internal Medicine concludes.
The randomized crossover study included 60 women. It investigated the effects of including unsalted soy nuts containing 25 g of soy protein in the National Cholesterol Education Program's Therapeutic Lifestyle Changes diet.
Compared with a diet without the nuts, adding soy nuts lowered systolic BP 9.9% and diastolic BP 6.8% in hypertensive women. The decline was a more modest 5.2% systolic and 2.9% diastolic in normotensive women.
The diet with nuts also lowered LDL 11% and apolipoprotein B 8% in hypertensive women but had no effect on these measures in normotensive women.
The authors said dietary soy "may be a practical, safe and inexpensive modality to reduce BP." They characterize the results as being "comparable with those seen with antihypertensive drugs."
The randomized crossover study included 60 women. It investigated the effects of including unsalted soy nuts containing 25 g of soy protein in the National Cholesterol Education Program's Therapeutic Lifestyle Changes diet.
Compared with a diet without the nuts, adding soy nuts lowered systolic BP 9.9% and diastolic BP 6.8% in hypertensive women. The decline was a more modest 5.2% systolic and 2.9% diastolic in normotensive women.
The diet with nuts also lowered LDL 11% and apolipoprotein B 8% in hypertensive women but had no effect on these measures in normotensive women.
The authors said dietary soy "may be a practical, safe and inexpensive modality to reduce BP." They characterize the results as being "comparable with those seen with antihypertensive drugs."
Resistant TB leaves few options
The highly dangerous form of tuberculosis that has infected a man now in quarantine resists almost all drugs used to treat TB, leaving only less effective options.
It's called "extensively drug-resistant tuberculosis," or XDR TB. It can't be cured by the two best first-line drugs, isoniazid and rifampin, or the best second-line medications.
That leaves options that are much less effective, according to the federal Centers for Disease Control and Prevention. Some programs have achieved cure rates for an estimated 30 percent of affected people, CDC says.
Success depends heavily on how resistant the germ is, how severe the disease is, and whether the patient's immune system is weakened, CDC says.
This form of TB is rare. Only 49 cases were reported in the United States between 1993 and 2006; 17 have been diagnosed since 2000. By contrast, the nation reported 13,767 ordinary TB cases last year alone, an all-time low.
The extremely resistant form can be caught from other people or develop from an ordinary case of TB. It generally appears in people who don't take their medicines regularly or don't take all of them; or those who develop active TB after having taken tuberculosis drugs in the past; or who are exposed to the germ from other people.
This dangerous form spreads the same way as ordinary TB. — when someone breathes in the germs from the air. TB germs can enter the air when an infected person coughs, sneezes, or even speaks. The germs can float for hours. TB is not spread by a handshake, sharing a glass or by kissing, the CDC says.
It's called "extensively drug-resistant tuberculosis," or XDR TB. It can't be cured by the two best first-line drugs, isoniazid and rifampin, or the best second-line medications.
That leaves options that are much less effective, according to the federal Centers for Disease Control and Prevention. Some programs have achieved cure rates for an estimated 30 percent of affected people, CDC says.
Success depends heavily on how resistant the germ is, how severe the disease is, and whether the patient's immune system is weakened, CDC says.
This form of TB is rare. Only 49 cases were reported in the United States between 1993 and 2006; 17 have been diagnosed since 2000. By contrast, the nation reported 13,767 ordinary TB cases last year alone, an all-time low.
The extremely resistant form can be caught from other people or develop from an ordinary case of TB. It generally appears in people who don't take their medicines regularly or don't take all of them; or those who develop active TB after having taken tuberculosis drugs in the past; or who are exposed to the germ from other people.
This dangerous form spreads the same way as ordinary TB. — when someone breathes in the germs from the air. TB germs can enter the air when an infected person coughs, sneezes, or even speaks. The germs can float for hours. TB is not spread by a handshake, sharing a glass or by kissing, the CDC says.
Nerve damage may occur after weight-loss surgery
Patients can develop potentially disabling neurological complications after gastric bypass surgery performed to treat morbid obesity, most likely due to deficiencies in certain nutrients, a new study shows.
While correcting these deficiencies can help patients, some are left with permanent damage, Dr. Katalin Juhasz-Pocsine and colleagues from the University of Arkansas for Medical Science in Little Rock report. Symptoms can strike many years after the surgery, they note, possibly because stores of certain nutrients may take this long to become depleted.
Some patients begin hallucinating and lose the ability to walk a couple of months after the surgery, Juhasz-Pocsine explained in an interview with Reuters Health. "After resolution of the acute symptoms they are quite weak, and it takes around a year to recover.
Some are permanently disabled," she said. Among patients who develop symptoms years down the road, the spinal cord typically is affected, resulting in falling, extreme coordination and gait problems, and severe spasticity, and some individuals need to use wheelchairs.
Juhasz-Pocsine and her team describe 26 cases of neurological problems that occurred in gastric bypass patients in the medical journal Neurology. Symptoms typically involved more than one portion of the neurological system.
While restoring nutritional deficiencies, which included lack of vitamin B12, thiamine, or copper, helped patients, many continued to have symptoms for months, while symptoms remained permanent in some patients, Juhasz-Pocsine and her team report. The patient who fared best was a woman who underwent surgery to reverse her gastric bypass after developing rapidly progressing symptoms that didn't respond to other treatment.
Gastric bypass patients and their doctors should be aware of the early signs and symptoms of neurological problems, and should know that these symptoms can strike many years after a person has had the surgery, Juhasz-Pocsine advises. Further research is needed, she added, on the risk of neurological problems in gastric bypass patients whose nutritional needs change dramatically, for example during pregnancy or breastfeeding or among individuals undergoing cancer treatment.
The researchers suggest that steps should be taken to help prevent gastric bypass patients from developing these problems in the first place by advising them to take vitamin and mineral supplements and to avoid "severe and rapid weight loss."
"Many of our patients were not instructed to take vitamin supplements, and postoperative follow-up visits with medical nutritionists were not emphasized," they note.
SOURCE: Neurology, May 22, 2007 online.
While correcting these deficiencies can help patients, some are left with permanent damage, Dr. Katalin Juhasz-Pocsine and colleagues from the University of Arkansas for Medical Science in Little Rock report. Symptoms can strike many years after the surgery, they note, possibly because stores of certain nutrients may take this long to become depleted.
Some patients begin hallucinating and lose the ability to walk a couple of months after the surgery, Juhasz-Pocsine explained in an interview with Reuters Health. "After resolution of the acute symptoms they are quite weak, and it takes around a year to recover.
Some are permanently disabled," she said. Among patients who develop symptoms years down the road, the spinal cord typically is affected, resulting in falling, extreme coordination and gait problems, and severe spasticity, and some individuals need to use wheelchairs.
Juhasz-Pocsine and her team describe 26 cases of neurological problems that occurred in gastric bypass patients in the medical journal Neurology. Symptoms typically involved more than one portion of the neurological system.
While restoring nutritional deficiencies, which included lack of vitamin B12, thiamine, or copper, helped patients, many continued to have symptoms for months, while symptoms remained permanent in some patients, Juhasz-Pocsine and her team report. The patient who fared best was a woman who underwent surgery to reverse her gastric bypass after developing rapidly progressing symptoms that didn't respond to other treatment.
Gastric bypass patients and their doctors should be aware of the early signs and symptoms of neurological problems, and should know that these symptoms can strike many years after a person has had the surgery, Juhasz-Pocsine advises. Further research is needed, she added, on the risk of neurological problems in gastric bypass patients whose nutritional needs change dramatically, for example during pregnancy or breastfeeding or among individuals undergoing cancer treatment.
The researchers suggest that steps should be taken to help prevent gastric bypass patients from developing these problems in the first place by advising them to take vitamin and mineral supplements and to avoid "severe and rapid weight loss."
"Many of our patients were not instructed to take vitamin supplements, and postoperative follow-up visits with medical nutritionists were not emphasized," they note.
SOURCE: Neurology, May 22, 2007 online.
WHO warns against water-pipe smoking
Water-pipe smoking may pose the same health risks as cigarettes, the World Health Organization said Tuesday, adding that more scientific research was needed into the link between hookah use and a number of fatal illnesses.
"Using a water pipe to smoke tobacco is not a safe alternative to cigarette smoking," the U.N. health agency said in a seven-page document on the practice. "Contrary to ancient lore and popular belief, the smoke that emerges from a water pipe contains numerous toxicants known to cause lung cancer, heart disease and other diseases."
The WHO "advisory note" warned that using water pipes to consume the tobacco, which is commonly a mixed with molasses and fruit flavors, usually exposes a person to more smoke over a longer period of time than do cigarettes. Preliminary research indicates that hookah smoking poses many of the same dangers as cigarettes and may involve "some unique health risks," the agency said.
A hookah is a bowl connected to a vase of water with a long tube and mouthpiece. The tobacco sits inside the bowl with a layer of foil and a hot coal on top. The tobacco is never lit, instead heated by the charcoal, which smokers say produces a vapor different from smoke.
The hookah, used for centuries in North Africa, the Middle East and Central and South Asia, has become increasingly popular in the United States, Europe and Brazil, particularly among college students and young adults.
WHO says the trend is partly due to "unfounded assumptions" of its safety, and misleading commercial marketing.
The agency said a person can inhale more than 100 times more smoke in a hookah session than in a single cigarette. By delivering nicotine, the water pipe can cause addiction.
"None of the accessories have been demonstrated to reduce smokers' exposure to toxins or risk of tobacco-related disease and death," WHO said.
While further research is required, the health body said those exposed to secondhand hookah smoke appeared to be at risk of the same diseases as those exposed to cigarettes. WHO warned that hookah smoke could also increase the risk of adverse effects during pregnancy.
"Using a water pipe to smoke tobacco is not a safe alternative to cigarette smoking," the U.N. health agency said in a seven-page document on the practice. "Contrary to ancient lore and popular belief, the smoke that emerges from a water pipe contains numerous toxicants known to cause lung cancer, heart disease and other diseases."
The WHO "advisory note" warned that using water pipes to consume the tobacco, which is commonly a mixed with molasses and fruit flavors, usually exposes a person to more smoke over a longer period of time than do cigarettes. Preliminary research indicates that hookah smoking poses many of the same dangers as cigarettes and may involve "some unique health risks," the agency said.
A hookah is a bowl connected to a vase of water with a long tube and mouthpiece. The tobacco sits inside the bowl with a layer of foil and a hot coal on top. The tobacco is never lit, instead heated by the charcoal, which smokers say produces a vapor different from smoke.
The hookah, used for centuries in North Africa, the Middle East and Central and South Asia, has become increasingly popular in the United States, Europe and Brazil, particularly among college students and young adults.
WHO says the trend is partly due to "unfounded assumptions" of its safety, and misleading commercial marketing.
The agency said a person can inhale more than 100 times more smoke in a hookah session than in a single cigarette. By delivering nicotine, the water pipe can cause addiction.
"None of the accessories have been demonstrated to reduce smokers' exposure to toxins or risk of tobacco-related disease and death," WHO said.
While further research is required, the health body said those exposed to secondhand hookah smoke appeared to be at risk of the same diseases as those exposed to cigarettes. WHO warned that hookah smoke could also increase the risk of adverse effects during pregnancy.
UN offers new HIV testing guidance
Health professionals should routinely offer to test people for HIV instead of waiting for patients to request it, according to new advice from the United Nations Wednesday.
In making the recommendations, the World Health Organization and UNAIDS are underlining the need to identify the millions worldwide who need treatment. WHO estimates that approximately 80 percent of HIV-positive people in developing countries are currently unaware of their status.
"If we are serious about ensuring universal access to drugs, there has to be a fundamental change in the approach to HIV testing," said Dr. Kevin De Cock, director of WHO's AIDS department.
The UN now advises health workers to test patients for HIV as part of standard medical care, but only with the patient's informed consent.
Yet there are questions about how the cash-strapped countries in Africa might adopt these guidelines. Of the estimated 40 million people living worldwide with HIV/AIDS, nearly 65 percent are in Africa.
Because current estimates of the number of HIV/AIDS patients include people who don't know their status, experts do not expect the numbers to rise dramatically if more people are tested.
Though universal testing will certainly identify more HIV-positive people needing lifesaving anti-retrovirals, there is already a long waiting list: Nearly 5 million people in sub-Saharan Africa are still without treatment.
Identifying more AIDS patients whom countries cannot afford to treat threatens to create an even bigger backlog of people who know they are sick, but have no access to care.
Most AIDS experts believe that increased HIV testing will help, even if the conditions are not perfect.
"No one wants a situation where people find out they're HIV-positive and can't get anti-retroviral treatment," said Jennifer Kates, vice president and director of HIV policy for the Kaiser Family Foundation. "But if we waited until everything was perfectly aligned, we would never respond."
Another benefit of testing: Past studies also have shown that once people are aware that they are HIV-positive, they tend to practice safer sex — which could give prevention efforts a boost.
Africa's weak health infrastructure, though, is a huge stumbling block. The continent urgently needs at least another 4 million health workers to fill the gap, according to WHO. Without doctors and nurses to administer the HIV tests or to provide the necessary treatment when patients are identified, such guidance will create even more stress for Africa's already fragile health systems.
Still, the new testing procedures should mean that HIV patients are found earlier.
"The biggest problem we have now is that our health care systems are overburdened with very sick people who come in too late," said Zackie Achmat, chairman of South Africa's Treatment Action Campaign.
"These new guidelines are long overdue," said Achmat. "We cannot deal with the burden on the health care service if we don't prevent people from becoming so sick that they become a supreme burden on it," he said.
Increased HIV testing and the treatment and infrastructure it ultimately entails will require more money, yet no new funds have been announced to help countries implement these policies.
The UN estimates that the fight against AIDS in 2007-2008 requires $22 billion, and there is still a considerable shortfall. Last year, the deficit for global AIDS programs was about $6 billion.
While health authorities would like to see the new UN recommendations adopted as soon as possible, much will depend on whether countries decide to follow their advice.
"I hope that countries start implementing this immediately," said WHO's De Cock. "But we know you can't just flip the switch and change everything in one day."
In making the recommendations, the World Health Organization and UNAIDS are underlining the need to identify the millions worldwide who need treatment. WHO estimates that approximately 80 percent of HIV-positive people in developing countries are currently unaware of their status.
"If we are serious about ensuring universal access to drugs, there has to be a fundamental change in the approach to HIV testing," said Dr. Kevin De Cock, director of WHO's AIDS department.
The UN now advises health workers to test patients for HIV as part of standard medical care, but only with the patient's informed consent.
Yet there are questions about how the cash-strapped countries in Africa might adopt these guidelines. Of the estimated 40 million people living worldwide with HIV/AIDS, nearly 65 percent are in Africa.
Because current estimates of the number of HIV/AIDS patients include people who don't know their status, experts do not expect the numbers to rise dramatically if more people are tested.
Though universal testing will certainly identify more HIV-positive people needing lifesaving anti-retrovirals, there is already a long waiting list: Nearly 5 million people in sub-Saharan Africa are still without treatment.
Identifying more AIDS patients whom countries cannot afford to treat threatens to create an even bigger backlog of people who know they are sick, but have no access to care.
Most AIDS experts believe that increased HIV testing will help, even if the conditions are not perfect.
"No one wants a situation where people find out they're HIV-positive and can't get anti-retroviral treatment," said Jennifer Kates, vice president and director of HIV policy for the Kaiser Family Foundation. "But if we waited until everything was perfectly aligned, we would never respond."
Another benefit of testing: Past studies also have shown that once people are aware that they are HIV-positive, they tend to practice safer sex — which could give prevention efforts a boost.
Africa's weak health infrastructure, though, is a huge stumbling block. The continent urgently needs at least another 4 million health workers to fill the gap, according to WHO. Without doctors and nurses to administer the HIV tests or to provide the necessary treatment when patients are identified, such guidance will create even more stress for Africa's already fragile health systems.
Still, the new testing procedures should mean that HIV patients are found earlier.
"The biggest problem we have now is that our health care systems are overburdened with very sick people who come in too late," said Zackie Achmat, chairman of South Africa's Treatment Action Campaign.
"These new guidelines are long overdue," said Achmat. "We cannot deal with the burden on the health care service if we don't prevent people from becoming so sick that they become a supreme burden on it," he said.
Increased HIV testing and the treatment and infrastructure it ultimately entails will require more money, yet no new funds have been announced to help countries implement these policies.
The UN estimates that the fight against AIDS in 2007-2008 requires $22 billion, and there is still a considerable shortfall. Last year, the deficit for global AIDS programs was about $6 billion.
While health authorities would like to see the new UN recommendations adopted as soon as possible, much will depend on whether countries decide to follow their advice.
"I hope that countries start implementing this immediately," said WHO's De Cock. "But we know you can't just flip the switch and change everything in one day."
Tuesday, May 29, 2007
AAPA: Most Doctors Don't Ask About Sleep Problems
PHILADELPHIA, May 29 -- Millions of Americans suffer from undiagnosed obstructive sleep apnea, narcolepsy, and other sleep problems, in part because most physicians simply don't ask patients about them.
In fact, 70% of primary care physicians said they did not ask patients about the quality of their sleep, according to a National Sleep Foundation poll published in 2005, said Eric Kirsch, PA-C, of United Sleep Medicine, a provider of sleep and neurology services based in Charlotte, N.C.
The reason doctors don't ask about sleep may be that they have little training in sleep disorders, Mr. Kirsch said at an industry-sponsored symposium held in conjunction with the American Academy of Physician Assistants conference here.
A 1990 study of 126 accredited U.S. medical schools found that students received an average of only 1.6 hours of instruction about sleep disorders, he said. At 37 of these schools, students received less than one hour of sleep disorder education during their first two years, he said.
The result is that sleep disorders are significantly underdiagnosed, said Paul P. Doghramji, M.D., FAAFP, a private practitioner and associate of Pottstown Medical Specialists, Inc., of Pottstown, Pa.
About 30% of men and 21% of women suffer from excessive daytime sleepiness, according to recent research, Dr. Doghramji said. But only 10% to 20% of people with obstructive sleep apnea syndrome and only 15% to 20% of individuals with narcolepsy are ever diagnosed and treated, he said.
Lack of quality sleep can have serious consequences, he noted. For example, from 1% to 4% of U.S. highway automobile crashes are caused by sleepiness, and 4% of fatal crashes are caused by driver drowsiness, according to estimates from the National Highway Traffic Safety Administration, he said.
A person trying to function on only four hours of sleep is as impaired as a person with a blood alcohol level of 0.095, which is above the legal definition of intoxication in many states, said Dr. Doghramji, quoting a study of healthy volunteers that appeared recently in the journal Sleep.
Excessive sleepiness or fatigue have also been linked to endocrine disorders, immunologic disorders, neurological disorders such as Parkinson's disease and multiple sclerosis, and rheumatological disorders including fibromyalgia, Dr. Doghramji said.
Furthermore, nearly half (46.5%) of patients with excessive sleepiness also have a psychiatric disorder, such as anxiety, depression, or bipolar disorder, he said.
Psychiatric disorders such as these may sometimes be the cause of, not the result of, poor sleep quality and excessive sleepiness, Dr. Doghramji noted. Other causes include obstructive sleep apnea, narcolepsy, insomnia, circadian sleep rhythm disorders, and sleep-related movement disorders such as restless legs syndrome and periodic limb movement disorder, he said.
A variety of effective pharmacologic options for treating excessive sleepiness and some of its underlying causes are available to clinicians, said Jonathan R.L. Schwartz, M.D., of the University of Oklahoma Health Sciences Center in Oklahoma City.
Those include central nervous system stimulants such as dextroamphetamine and methylfenidate, which are FDA-indicated for treating narcolepsy, Dr. Schwartz said. These agents promote dopamine, serotonin, and norepinephrine neurotransmission, he said. Side effects may include anxiety, restlessness, insomnia, headache, tachycardia, hypertension, and psychosis, he noted. They are classed as schedule II controlled substances.
The wake-promoting agent modafinil is FDA-approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work disorder, said Dr. Schwartz. Shift work disorder is a condition that affects about 32% of workers on the night shift and about 26% of rotating shift workers, he said.
Modafinil is thought to work by increasing activity in the hypothalamus. Side effects include headache, nausea, rhinitis, back pain, diarrhea, dyspepsia, anxiety, dizziness, and insomnia, he said. The drug is classed as a schedule IV2 controlled substance, he said.
If insomnia is the cause of excessive sleepiness, a variety of hypnotic medications can be used to promote sleep, including zolipidem, zaleplon, eszopiclone, and ramelteon, Dr. Schwartz said. If restless legs syndrome is the culprit, on the other hand, pharmacologic options include ropinirole and pramipexole. However, Dr. Schwartz did not discuss the mechanisms of action or potential side effects of the above-mentioned drugs. Iron replacement therapy may also be useful in patients with restless legs who have iron deficiency, he said.
In fact, 70% of primary care physicians said they did not ask patients about the quality of their sleep, according to a National Sleep Foundation poll published in 2005, said Eric Kirsch, PA-C, of United Sleep Medicine, a provider of sleep and neurology services based in Charlotte, N.C.
The reason doctors don't ask about sleep may be that they have little training in sleep disorders, Mr. Kirsch said at an industry-sponsored symposium held in conjunction with the American Academy of Physician Assistants conference here.
A 1990 study of 126 accredited U.S. medical schools found that students received an average of only 1.6 hours of instruction about sleep disorders, he said. At 37 of these schools, students received less than one hour of sleep disorder education during their first two years, he said.
The result is that sleep disorders are significantly underdiagnosed, said Paul P. Doghramji, M.D., FAAFP, a private practitioner and associate of Pottstown Medical Specialists, Inc., of Pottstown, Pa.
About 30% of men and 21% of women suffer from excessive daytime sleepiness, according to recent research, Dr. Doghramji said. But only 10% to 20% of people with obstructive sleep apnea syndrome and only 15% to 20% of individuals with narcolepsy are ever diagnosed and treated, he said.
Lack of quality sleep can have serious consequences, he noted. For example, from 1% to 4% of U.S. highway automobile crashes are caused by sleepiness, and 4% of fatal crashes are caused by driver drowsiness, according to estimates from the National Highway Traffic Safety Administration, he said.
A person trying to function on only four hours of sleep is as impaired as a person with a blood alcohol level of 0.095, which is above the legal definition of intoxication in many states, said Dr. Doghramji, quoting a study of healthy volunteers that appeared recently in the journal Sleep.
Excessive sleepiness or fatigue have also been linked to endocrine disorders, immunologic disorders, neurological disorders such as Parkinson's disease and multiple sclerosis, and rheumatological disorders including fibromyalgia, Dr. Doghramji said.
Furthermore, nearly half (46.5%) of patients with excessive sleepiness also have a psychiatric disorder, such as anxiety, depression, or bipolar disorder, he said.
Psychiatric disorders such as these may sometimes be the cause of, not the result of, poor sleep quality and excessive sleepiness, Dr. Doghramji noted. Other causes include obstructive sleep apnea, narcolepsy, insomnia, circadian sleep rhythm disorders, and sleep-related movement disorders such as restless legs syndrome and periodic limb movement disorder, he said.
A variety of effective pharmacologic options for treating excessive sleepiness and some of its underlying causes are available to clinicians, said Jonathan R.L. Schwartz, M.D., of the University of Oklahoma Health Sciences Center in Oklahoma City.
Those include central nervous system stimulants such as dextroamphetamine and methylfenidate, which are FDA-indicated for treating narcolepsy, Dr. Schwartz said. These agents promote dopamine, serotonin, and norepinephrine neurotransmission, he said. Side effects may include anxiety, restlessness, insomnia, headache, tachycardia, hypertension, and psychosis, he noted. They are classed as schedule II controlled substances.
The wake-promoting agent modafinil is FDA-approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea, and shift work disorder, said Dr. Schwartz. Shift work disorder is a condition that affects about 32% of workers on the night shift and about 26% of rotating shift workers, he said.
Modafinil is thought to work by increasing activity in the hypothalamus. Side effects include headache, nausea, rhinitis, back pain, diarrhea, dyspepsia, anxiety, dizziness, and insomnia, he said. The drug is classed as a schedule IV2 controlled substance, he said.
If insomnia is the cause of excessive sleepiness, a variety of hypnotic medications can be used to promote sleep, including zolipidem, zaleplon, eszopiclone, and ramelteon, Dr. Schwartz said. If restless legs syndrome is the culprit, on the other hand, pharmacologic options include ropinirole and pramipexole. However, Dr. Schwartz did not discuss the mechanisms of action or potential side effects of the above-mentioned drugs. Iron replacement therapy may also be useful in patients with restless legs who have iron deficiency, he said.
AUA: Quinolone Resistance May Threaten Prostate Biopsy Prophylaxis
ANAHEIM, Calif., May 29 -- Quinolone antibiotics for prostate-biopsy prophylaxis are showing signs of increased resistance.
A retrospective record review of 1,230 patients who received quinolone prophylaxis before a prostate biopsy during 2004 through 2006 showed that 2.7% (33) had symptoms of infection after biopsy, investigators said at the American Urological Association meeting here.
Twenty-two of the 33 had positive urine or blood cultures, and quinolone-resistant organisms were found in 16 of the 22 (73%), said Joseph Feliciano, M.D., of the State University of New York Downstate Medical School in Brooklyn.
Though the overall rate of quinolone resistance remains low, the rate more than doubled from 1.1% in 2004 to 2.6% in 2006, a non-significant rise (P=0.095), yet providing concern about the possibility of emerging resistance, he said. Additionally, quinolone-resistant organisms often were resistant to multiple antibiotics, but they were highly susceptible to cephalosporins.
"At this time, quinolones are still safe," said Dr. Feliciano. "But when patients come in with infections after prostate biopsy, quinolone resistance should be suspected, and the patient should be treated with cephalosporins."
The study involved patients who had transrectal ultrasound-guided prostate biopsy from January 2004 through October 2006. All patients were given a three-day course of levofloxacin or gatifloxacin one day prior to biopsy. Patients who returned for visits within 30 days after biopsy were questioned regarding infective symptoms, including fever, chills/rigors, elevated white count, and persistent dysuria requiring medical attention and intervention. Additionally, patient cultures were evaluated for patterns of resistance.
The overall rate of infective complications was 2.7%, roughly half of which (1.3%) involved quinolone resistance. Escherichia coli grew in 80% of the cultures, and 90% of those cultures demonstrated quinolone resistance, Dr. Feliciano reported. Quinolone-resistant E. coli also demonstrated resistance to gentamicin (17%), trimethorprim/sulfamethoxazole (47%), piperacillin (70%), and ampicillin (95%). However, the quinolone-resistant organisms exhibited 100% sensitivity to amikacin, ceftazidime, and ceftriaxone.
Overall, the quinilone resistance data do not offer a reason for immediate concern, said Dr. Feliciano.
A retrospective record review of 1,230 patients who received quinolone prophylaxis before a prostate biopsy during 2004 through 2006 showed that 2.7% (33) had symptoms of infection after biopsy, investigators said at the American Urological Association meeting here.
Twenty-two of the 33 had positive urine or blood cultures, and quinolone-resistant organisms were found in 16 of the 22 (73%), said Joseph Feliciano, M.D., of the State University of New York Downstate Medical School in Brooklyn.
Though the overall rate of quinolone resistance remains low, the rate more than doubled from 1.1% in 2004 to 2.6% in 2006, a non-significant rise (P=0.095), yet providing concern about the possibility of emerging resistance, he said. Additionally, quinolone-resistant organisms often were resistant to multiple antibiotics, but they were highly susceptible to cephalosporins.
"At this time, quinolones are still safe," said Dr. Feliciano. "But when patients come in with infections after prostate biopsy, quinolone resistance should be suspected, and the patient should be treated with cephalosporins."
The study involved patients who had transrectal ultrasound-guided prostate biopsy from January 2004 through October 2006. All patients were given a three-day course of levofloxacin or gatifloxacin one day prior to biopsy. Patients who returned for visits within 30 days after biopsy were questioned regarding infective symptoms, including fever, chills/rigors, elevated white count, and persistent dysuria requiring medical attention and intervention. Additionally, patient cultures were evaluated for patterns of resistance.
The overall rate of infective complications was 2.7%, roughly half of which (1.3%) involved quinolone resistance. Escherichia coli grew in 80% of the cultures, and 90% of those cultures demonstrated quinolone resistance, Dr. Feliciano reported. Quinolone-resistant E. coli also demonstrated resistance to gentamicin (17%), trimethorprim/sulfamethoxazole (47%), piperacillin (70%), and ampicillin (95%). However, the quinolone-resistant organisms exhibited 100% sensitivity to amikacin, ceftazidime, and ceftriaxone.
Overall, the quinilone resistance data do not offer a reason for immediate concern, said Dr. Feliciano.
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ATS: XDR-TB Gains Ground Round the World
SAN FRANCISCO, May 29 -- Extensively drug resistant tuberculosis (XDR-TB) continues to be unearthed around the globe, with implications for U.S. clinicians, researchers said here.
Just two days after a report at the American Thoracic Society meeting of a rampant XDR-TB problem in India, other investigators said at the same forum that Indian immigrants had already boosted the XDR-TB burden in New York.
"With time we will find it in every country," said Charles L. Daley, M.D., of National Jewish Medical and Research Center in Denver, who presented an overview of the issue to pulmonologists. "We just have to look for it."
As of May 1, the WHO indicated 37 nations with XDR-TB, which it defines as resistance to at least rifampicin and isoniazid from among the first line anti-TB drugs (the definition of MDR TB) in addition to resistance to any fluoroquinolone, and to at least one of three injectable second-line anti-TB drugs used in TB treatment (capreomycin, kanamycin, and amikacin).
India has joined the list, according to Sushil Jain, M.B.B.S., D.N.B., of the Hinduja National Hospital in Mumbai, and colleagues, who revealed a high XDR-TB rate emerging there.
They reviewed all 3,904 TB culture samples received at their tertiary care hospital laboratory in 2005.
Among the 32.25% of TB-positive cultures classified as multidrug resistant, 9.3% (38 samples) were extensively drug resistant.
All cases were in patients with pulmonary TB, and therefore transmissible.
Of the 32 patients who could be followed at one year, 39.47% had died.
India's rate is relatively high, according to a survey of international TB laboratories for 2000 to 2004. The rate Dr. Jain reported was lower than only Eastern Europe and Russia (14%) and South Korea (15%).
The survey, published this year in the journal Emerging Infectious Diseases, found a 6% XDR-TB rate among multidrug resistant cases for industrialized nations and Latin America.
However, in industrialized countries like the U.S., most XDR-TB cases come from foreign-born patients, Dr. Daley noted.
A study in Morbidity and Mortality Weekly Report earlier this year reported that foreign-born persons accounted for 76% of XDR-TB cases in the United States from 2000 to 2006, up from 38% from 1993 to 1999.
Dr. Daley cited data showing that most of the cases in the United States have occurred in New York and California.
In the first characterization of New York's XDR-TB burden, researchers reported here that 60% of cases were among immigrants.
These patients were born in India, China, the Ukraine, El Salvador, South Korea, and Malawi, said Shama D. Ahuja, M.P.H., of the New York City Bureau of Tuberculosis Control, and colleagues.
It is likely that all acquired the infections in their country of origin, because only 57 days had elapsed on average from arrival to diagnosis, they said.
Notably, there were no cases of transmission from these patients.
However, as XDR-TB has been recognized as an entity and given a name only in the past year or two, part of the reason for low rates and relatively few countries with cases is because no one has been looking for it, Dr. Daley said.
According to the 2007 MMWR report, there was sufficient data to rule in XDR-TB for only 50% to 65% of TB cases in the United States, he said.
But, it should have come as little surprise that XDR sprang up now, Dr. Daley said.
With the length of TB transmission and resistance acquisition cycles and the lack of any new TB drugs in the past 40 years, "this is the time that XDR should be hitting us," he said.
Now, "it will be a global effort required to control XDR-TB," Dr. Daley concluded.
Just two days after a report at the American Thoracic Society meeting of a rampant XDR-TB problem in India, other investigators said at the same forum that Indian immigrants had already boosted the XDR-TB burden in New York.
"With time we will find it in every country," said Charles L. Daley, M.D., of National Jewish Medical and Research Center in Denver, who presented an overview of the issue to pulmonologists. "We just have to look for it."
As of May 1, the WHO indicated 37 nations with XDR-TB, which it defines as resistance to at least rifampicin and isoniazid from among the first line anti-TB drugs (the definition of MDR TB) in addition to resistance to any fluoroquinolone, and to at least one of three injectable second-line anti-TB drugs used in TB treatment (capreomycin, kanamycin, and amikacin).
India has joined the list, according to Sushil Jain, M.B.B.S., D.N.B., of the Hinduja National Hospital in Mumbai, and colleagues, who revealed a high XDR-TB rate emerging there.
They reviewed all 3,904 TB culture samples received at their tertiary care hospital laboratory in 2005.
Among the 32.25% of TB-positive cultures classified as multidrug resistant, 9.3% (38 samples) were extensively drug resistant.
All cases were in patients with pulmonary TB, and therefore transmissible.
Of the 32 patients who could be followed at one year, 39.47% had died.
India's rate is relatively high, according to a survey of international TB laboratories for 2000 to 2004. The rate Dr. Jain reported was lower than only Eastern Europe and Russia (14%) and South Korea (15%).
The survey, published this year in the journal Emerging Infectious Diseases, found a 6% XDR-TB rate among multidrug resistant cases for industrialized nations and Latin America.
However, in industrialized countries like the U.S., most XDR-TB cases come from foreign-born patients, Dr. Daley noted.
A study in Morbidity and Mortality Weekly Report earlier this year reported that foreign-born persons accounted for 76% of XDR-TB cases in the United States from 2000 to 2006, up from 38% from 1993 to 1999.
Dr. Daley cited data showing that most of the cases in the United States have occurred in New York and California.
In the first characterization of New York's XDR-TB burden, researchers reported here that 60% of cases were among immigrants.
These patients were born in India, China, the Ukraine, El Salvador, South Korea, and Malawi, said Shama D. Ahuja, M.P.H., of the New York City Bureau of Tuberculosis Control, and colleagues.
It is likely that all acquired the infections in their country of origin, because only 57 days had elapsed on average from arrival to diagnosis, they said.
Notably, there were no cases of transmission from these patients.
However, as XDR-TB has been recognized as an entity and given a name only in the past year or two, part of the reason for low rates and relatively few countries with cases is because no one has been looking for it, Dr. Daley said.
According to the 2007 MMWR report, there was sufficient data to rule in XDR-TB for only 50% to 65% of TB cases in the United States, he said.
But, it should have come as little surprise that XDR sprang up now, Dr. Daley said.
With the length of TB transmission and resistance acquisition cycles and the lack of any new TB drugs in the past 40 years, "this is the time that XDR should be hitting us," he said.
Now, "it will be a global effort required to control XDR-TB," Dr. Daley concluded.
Vitamin D, Calcium Might Lower Breast Cancer Risk
TUESDAY, May 29 (HealthDay News) -- Premenopausal women who get a lot of vitamin D and calcium may cut their risk of breast cancer by almost a third, Harvard Medical School researchers report.
"Adequate intakes of calcium and vitamin D are necessary for women in keeping up their health, and additionally, these two nutrients may help prevent breast cancer development, especially among premenopausal women," said lead author Jennifer Lin, an assistant professor of medicine.
Her team's report appears in the May 28 issue of the Archives of Internal Medicine.
In the study, Lin's team collected data on more than 10,500 premenopausal and almost 21,000 postmenopausal women age 45 and older who were part of the Women's Health Study. The data included information on what they ate and the dietary supplements they took.
Over an average of 10 years, 276 premenopausal women and 743 postmenopausal women went on to develop breast cancer.
The researchers found that premenopausal women whose intake of vitamin D and calcium was high had about a 30 percent lower risk of developing breast cancer. However, they didn't find this association for postmenopausal women.
Animal studies have also found an association between calcium and vitamin D intake and breast cancer prevention, Lin's group noted.
"Calcium and vitamin D may confer protection against breast tumorigenesis," Lin said. "However, more studies are necessary to investigate the potential utility of these two nutrients in breast cancer development," she added.
One expert stressed that the evidence for a protective effect of vitamin D and calcium is still not clear.
"I really don't think that one can say from this study that the effect is only in premenopausal women, because there are a number of factors in the study that may have limited the ability to see the effect," said Victoria Stevens, an epidemiologist at the American Cancer Society. "This is particularly true for vitamin D, because most vitamin D comes from exposure to sunlight, which they did not take into account."
At this point in time, a recommendation that women take vitamin D or calcium to decrease their breast cancer risk is not warranted, she said.
"I don't think we should go that far," Stevens said. "The society doesn't recommend the use of any vitamin supplements" to prevent breast cancer.
"I don't think this study says that we should change that," Stevens said. "At this point, the evidence doesn't support anything more than getting a good diet and maintaining good levels of physical activity," she said.
"Adequate intakes of calcium and vitamin D are necessary for women in keeping up their health, and additionally, these two nutrients may help prevent breast cancer development, especially among premenopausal women," said lead author Jennifer Lin, an assistant professor of medicine.
Her team's report appears in the May 28 issue of the Archives of Internal Medicine.
In the study, Lin's team collected data on more than 10,500 premenopausal and almost 21,000 postmenopausal women age 45 and older who were part of the Women's Health Study. The data included information on what they ate and the dietary supplements they took.
Over an average of 10 years, 276 premenopausal women and 743 postmenopausal women went on to develop breast cancer.
The researchers found that premenopausal women whose intake of vitamin D and calcium was high had about a 30 percent lower risk of developing breast cancer. However, they didn't find this association for postmenopausal women.
Animal studies have also found an association between calcium and vitamin D intake and breast cancer prevention, Lin's group noted.
"Calcium and vitamin D may confer protection against breast tumorigenesis," Lin said. "However, more studies are necessary to investigate the potential utility of these two nutrients in breast cancer development," she added.
One expert stressed that the evidence for a protective effect of vitamin D and calcium is still not clear.
"I really don't think that one can say from this study that the effect is only in premenopausal women, because there are a number of factors in the study that may have limited the ability to see the effect," said Victoria Stevens, an epidemiologist at the American Cancer Society. "This is particularly true for vitamin D, because most vitamin D comes from exposure to sunlight, which they did not take into account."
At this point in time, a recommendation that women take vitamin D or calcium to decrease their breast cancer risk is not warranted, she said.
"I don't think we should go that far," Stevens said. "The society doesn't recommend the use of any vitamin supplements" to prevent breast cancer.
"I don't think this study says that we should change that," Stevens said. "At this point, the evidence doesn't support anything more than getting a good diet and maintaining good levels of physical activity," she said.
Simple Guide Helps Diabetics Manage Their Meds
TUESDAY, May 29 (HealthDay News) -- An easy-to-follow guide can boost the number of diabetes patients who take their cholesterol-lowering statin medications as prescribed, according to a new Mayo Clinic-led study.
Statins can reduce the risk of heart disease, a common complicating factor with diabetes.
The guide, designed to act as a decision aid to promote patient-doctor discussions about medication, included four questions directed at patients: What is your risk of having a heart attack in 10 years?; what are the benefits of taking statins as compared to not taking statins?; what side effects can you expect from statins?; what do you want to do now?
The guide also provides patients with individually-tailored answers to the first three questions.
"Conversations with patients about prescription medications tend to be brief and incomplete, but we found that when a decision aid was introduced, it was the start of a conversation in which the patient -- now better equipped with information -- felt empowered to participate in deciding whether a statin would be appropriate for them," Dr. Victor Montori, the study's lead investigator and a Mayo Clinic endocrinologist, said in a prepared statement.
He and his colleagues found that only about 50 percent of patients were satisfied with the way they normally received information about statins, compared with a satisfaction rate of 84 percent when they used the decision aid.
Among patients who used the decision aid, there was a threefold increase in the percentage of those still taking a statin after three months. The study also found that the decision aid had more of an impact among patients at high risk for heart attack than those with at low risk.
The study appears in the May 28 issue of the journal Archives of Internal Medicine
Statins can reduce the risk of heart disease, a common complicating factor with diabetes.
The guide, designed to act as a decision aid to promote patient-doctor discussions about medication, included four questions directed at patients: What is your risk of having a heart attack in 10 years?; what are the benefits of taking statins as compared to not taking statins?; what side effects can you expect from statins?; what do you want to do now?
The guide also provides patients with individually-tailored answers to the first three questions.
"Conversations with patients about prescription medications tend to be brief and incomplete, but we found that when a decision aid was introduced, it was the start of a conversation in which the patient -- now better equipped with information -- felt empowered to participate in deciding whether a statin would be appropriate for them," Dr. Victor Montori, the study's lead investigator and a Mayo Clinic endocrinologist, said in a prepared statement.
He and his colleagues found that only about 50 percent of patients were satisfied with the way they normally received information about statins, compared with a satisfaction rate of 84 percent when they used the decision aid.
Among patients who used the decision aid, there was a threefold increase in the percentage of those still taking a statin after three months. The study also found that the decision aid had more of an impact among patients at high risk for heart attack than those with at low risk.
The study appears in the May 28 issue of the journal Archives of Internal Medicine
Effective, Yes, but Is It Safe? A Drug’s Risks
People with diabetes have too much sugar in their blood, so a drug that lowers blood sugar ought to be a good treatment, right?
Maybe not. Consider the diabetes drug Avandia, or rosiglitazone, which was approved in 1999. It lowers blood sugar, and about a million people in the United States have been taking it for Type 2 diabetes, the most common form of the disease. But last week, doctors reported that Avandia might increase the risk of heart attacks.
Heart disease is a major complication of diabetes, so a drug that could make the risk even worse is bad news indeed.
The jury is still out on Avandia. Meanwhile, patient advocates and some politicians and researchers are already denouncing it, and the Food and Drug Administration has issued a tepid “safety alert” telling patients to ask their doctors what to do while the agency “is carefully weighing several complex sources of data.” Avandia’s manufacturer, GlaxoSmithKline, insists it is safe. Personal injury lawyers are advertising on the Internet for clients who think they were injured by the drug.
What happened here reflects a larger question — the tricky problem of how to judge whether a drug is safe and effective. Avandia was approved because it lowered blood sugar, and seemed safe in clinical trials.
But the real test of whether a drug is any good is, How are the patients? Not their blood tests or X-rays or EKGs, but the people themselves, and not after just six months, but after years, especially if they have a chronic disease and will be taking medicine for the rest of their lives. Are those taking the drug more or less likely than people not taking it to have heart attacks, die or develop heart disease or other illnesses?
The problem is, it can take a long time and a lot of patients — and, therefore, a lot of money — to get a real picture of health and survival. That is especially true for something like heart disease, which develops slowly and is so common that it may be hard to detect a small increase in risk. Studies might have to go on for years instead of months, and include far more than the few thousand patients in whom drugs are typically tested before they get approved.
So instead of waiting to see if people die or have heart attacks, drug companies have looked for other traits that seem to correlate with health and survival and that could stand in as a yardstick — objective measures like blood pressure, cholesterol levels, blood sugar or tests of heart function. Researchers call these measurements “surrogate endpoints,” and the F.D.A. has encouraged companies to find surrogates that could reliably predict how patients would fare. These kinds of tests are seen as a way to streamline the drug approval process.
But reliable surrogates are hard to find. There are plenty of endpoints that in theory should do the job, but do not. Tumor size, for instance: there are drugs that can shrink tumors without prolonging a patient’s life. Bone density is another example. Fluoride can increase it in people whose skeletons have thinned from osteoporosis, so fluoride should prevent fractures. But it doesn’t. In fact, it makes fractures more likely, because it turns bones brittle.
Heart rhythm can also be deceptive. Certain medicines can stabilize dangerous, abnormal heartbeats in people who have had heart attacks — and yet have been found to increase their odds of dying. Cholesterol levels do not always tell the whole story, either. Hormone treatment in women after menopause can raise HDL, the so-called good cholesterol, and so was expected to prevent heart disease — but does not. Similarly, researchers had high hopes for an experimental drug that raises HDL, but instead of preventing heart attacks the drug wound up increasing the risk.
Part of the problem is that surrogate endpoints do not always reflect what’s happening to the whole patient. The disease being treated may be too complicated to gauge with just one tool, and the drug in question may have many more effects than the one being measured.
Avandia, for instance, does a good job of lowering blood sugar. But it also activates a whole array of genes, and can cause weight gain, fluid retention, heart failure, anemia and unfavorable changes in lipid levels in the blood, according to an editorial last week in The New England Journal of Medicine. It’s not clear whether the drug’s benefits will trump its risks in the long run.
Is there any way to protect the public from unsafe or ineffective drugs without creating an approval process that drags on forever?
For years, researchers and government officials have been saying that the solution lies at least in part in continuing to study drugs after they are marketed — a process called postmarketing surveillance, or Phase 4 studies. But as the editorial writers pointed out, only a small proportion of the promised studies ever seem to get done.
As long as that remains the case, the consequences will be drugs like Avandia — on the market for eight years to treat one of the leading causes of death in this country, with patients now left wondering whether it will make their health better or worse.
Maybe not. Consider the diabetes drug Avandia, or rosiglitazone, which was approved in 1999. It lowers blood sugar, and about a million people in the United States have been taking it for Type 2 diabetes, the most common form of the disease. But last week, doctors reported that Avandia might increase the risk of heart attacks.
Heart disease is a major complication of diabetes, so a drug that could make the risk even worse is bad news indeed.
The jury is still out on Avandia. Meanwhile, patient advocates and some politicians and researchers are already denouncing it, and the Food and Drug Administration has issued a tepid “safety alert” telling patients to ask their doctors what to do while the agency “is carefully weighing several complex sources of data.” Avandia’s manufacturer, GlaxoSmithKline, insists it is safe. Personal injury lawyers are advertising on the Internet for clients who think they were injured by the drug.
What happened here reflects a larger question — the tricky problem of how to judge whether a drug is safe and effective. Avandia was approved because it lowered blood sugar, and seemed safe in clinical trials.
But the real test of whether a drug is any good is, How are the patients? Not their blood tests or X-rays or EKGs, but the people themselves, and not after just six months, but after years, especially if they have a chronic disease and will be taking medicine for the rest of their lives. Are those taking the drug more or less likely than people not taking it to have heart attacks, die or develop heart disease or other illnesses?
The problem is, it can take a long time and a lot of patients — and, therefore, a lot of money — to get a real picture of health and survival. That is especially true for something like heart disease, which develops slowly and is so common that it may be hard to detect a small increase in risk. Studies might have to go on for years instead of months, and include far more than the few thousand patients in whom drugs are typically tested before they get approved.
So instead of waiting to see if people die or have heart attacks, drug companies have looked for other traits that seem to correlate with health and survival and that could stand in as a yardstick — objective measures like blood pressure, cholesterol levels, blood sugar or tests of heart function. Researchers call these measurements “surrogate endpoints,” and the F.D.A. has encouraged companies to find surrogates that could reliably predict how patients would fare. These kinds of tests are seen as a way to streamline the drug approval process.
But reliable surrogates are hard to find. There are plenty of endpoints that in theory should do the job, but do not. Tumor size, for instance: there are drugs that can shrink tumors without prolonging a patient’s life. Bone density is another example. Fluoride can increase it in people whose skeletons have thinned from osteoporosis, so fluoride should prevent fractures. But it doesn’t. In fact, it makes fractures more likely, because it turns bones brittle.
Heart rhythm can also be deceptive. Certain medicines can stabilize dangerous, abnormal heartbeats in people who have had heart attacks — and yet have been found to increase their odds of dying. Cholesterol levels do not always tell the whole story, either. Hormone treatment in women after menopause can raise HDL, the so-called good cholesterol, and so was expected to prevent heart disease — but does not. Similarly, researchers had high hopes for an experimental drug that raises HDL, but instead of preventing heart attacks the drug wound up increasing the risk.
Part of the problem is that surrogate endpoints do not always reflect what’s happening to the whole patient. The disease being treated may be too complicated to gauge with just one tool, and the drug in question may have many more effects than the one being measured.
Avandia, for instance, does a good job of lowering blood sugar. But it also activates a whole array of genes, and can cause weight gain, fluid retention, heart failure, anemia and unfavorable changes in lipid levels in the blood, according to an editorial last week in The New England Journal of Medicine. It’s not clear whether the drug’s benefits will trump its risks in the long run.
Is there any way to protect the public from unsafe or ineffective drugs without creating an approval process that drags on forever?
For years, researchers and government officials have been saying that the solution lies at least in part in continuing to study drugs after they are marketed — a process called postmarketing surveillance, or Phase 4 studies. But as the editorial writers pointed out, only a small proportion of the promised studies ever seem to get done.
As long as that remains the case, the consequences will be drugs like Avandia — on the market for eight years to treat one of the leading causes of death in this country, with patients now left wondering whether it will make their health better or worse.
Simple Model May Predict Diabetes Development in Middle Age
The information needed to predict which middle-aged patients will develop type 2 diabetes is readily available, a study in Archives of Internal Medicine finds.
Using data from 3140 middle-aged participants in the Framingham Offspring Study, 99% of whom where white, researchers developed a simple algorithm that assigns points based on a parental history of diabetes and measurements of fasting glucose, BMI, HDL, triglycerides, and blood pressure. Point totals correspond to a range of 8-year risks for type 2 diabetes; the lowest score translates to a risk of 3% or less, the highest score to a risk of more than 35%.
The authors write that the algorithm needs to be validated in other populations.
Using data from 3140 middle-aged participants in the Framingham Offspring Study, 99% of whom where white, researchers developed a simple algorithm that assigns points based on a parental history of diabetes and measurements of fasting glucose, BMI, HDL, triglycerides, and blood pressure. Point totals correspond to a range of 8-year risks for type 2 diabetes; the lowest score translates to a risk of 3% or less, the highest score to a risk of more than 35%.
The authors write that the algorithm needs to be validated in other populations.
Break a Confidence? Never. Well, Hardly Ever
Anyone who has ever worked in a hospital can attest that doctors are purveyors of information: dry facts, clinical data, medical wisdom. When I was an intern, my hospital had a separate computer system for laboratory results, another for vital signs and nursing notes, and another for medical records. Clinical medicine, it seemed then, wasn’t about patient care as much as about data management.
Much of what doctors learn about patients is private and personal, which vastly complicates our enterprise. Doctors have to know how to keep secrets — from insurers, employers, family members, and even, occasionally, the police. I once took care of a business executive who had hired call girls during a weekend drug binge. When he saw a cop in the hallway, he quietly handed me an envelope containing a large amount of white powder. I wasn’t sure what to do with it — was I now an accomplice? — so I threw it away. For the next several hours he eyed me suspiciously, probably wondering whether I had ratted on him. But it never occurred to me to do so.
The duty to keep patient information private is written into the codes of ethics of several medical organizations, and is even in the Hippocratic Oath: “What I may see or hear in the course of the treatment or even outside the treatment in regard to the life of men,” it says, “I will keep to myself.” Such an obligation is necessary to foster openness and honesty, essential for a healthy doctor-patient relationship.
Still, even a cursory walk through the warrens of a hospital would reveal that doctors do sometimes betray confidentiality. We discuss patient information in the elevator. We hash over intimate details in double-occupancy rooms within earshot of neighbors. In 1996, Congress passed privacy legislation that makes it harder, and in some cases illegal, for doctors to reveal patients’ information without explicit permission. Yet such disclosure continues.
Today, confidentiality is almost a mantra in medicine, but it is not absolute. Doctors must disclose private information when it is clearly in the patient’s interest — documenting a drug allergy in the medical record, for example — or when it comes to complying with a court order or a law (as in cases of child abuse). Doctors must also betray confidentiality when it is in the “public interest” (reporting infectious diseases, for example, or to warn potential victims of violence).
But when does public interest trump individual autonomy? It is rarely clear-cut. I once performed a coronary angiogram on a hospital electrician who told me he abused cocaine daily (which no doubt contributed to his severe angina). When I asked a colleague whether I should document this habit in the patient’s chart, or even alert the patient’s — our — employer, he said: “We don’t have to do anything. Remember, first do no harm.”
I never did tell anyone, though I exhorted the patient in the strongest terms to quit using drugs. But I wonder if I did the right thing. What about the risk to the hospital, to other patients, of the man’s addiction?
The World Medical Association states that confidentiality should be breached only when the expected harm of maintaining privacy is believed to be imminent, serious and unavoidable except by unauthorized disclosure. The philosophy behind this point of view is called utilitarianism: achieving the greatest good for the greatest number.
But once in a while the issue gets turned on its head. I once had the unenviable task of informing a 22-year-old man that he was suffering from severe heart failure and would probably need a transplant. His father warned me that his son would be devastated to hear the diagnosis. “It would mean a lot to me if you could tell him he’s going to be all right,” the father told me in the cardiac care unit. “He thinks he’s going to die. Please, he has lost all hope. Please tell him that if he does the things you say, he’s going to be O.K.”
I wasn’t sure what to do, but it was obvious that this young man wasn’t prepared to hear the news I had to present. I went into his room and told him exactly what his father had requested. Over several days, I eased him into the knowledge of his true condition. Doctors have to know how to keep secrets — even, rarely, from patients themselves.
Much of what doctors learn about patients is private and personal, which vastly complicates our enterprise. Doctors have to know how to keep secrets — from insurers, employers, family members, and even, occasionally, the police. I once took care of a business executive who had hired call girls during a weekend drug binge. When he saw a cop in the hallway, he quietly handed me an envelope containing a large amount of white powder. I wasn’t sure what to do with it — was I now an accomplice? — so I threw it away. For the next several hours he eyed me suspiciously, probably wondering whether I had ratted on him. But it never occurred to me to do so.
The duty to keep patient information private is written into the codes of ethics of several medical organizations, and is even in the Hippocratic Oath: “What I may see or hear in the course of the treatment or even outside the treatment in regard to the life of men,” it says, “I will keep to myself.” Such an obligation is necessary to foster openness and honesty, essential for a healthy doctor-patient relationship.
Still, even a cursory walk through the warrens of a hospital would reveal that doctors do sometimes betray confidentiality. We discuss patient information in the elevator. We hash over intimate details in double-occupancy rooms within earshot of neighbors. In 1996, Congress passed privacy legislation that makes it harder, and in some cases illegal, for doctors to reveal patients’ information without explicit permission. Yet such disclosure continues.
Today, confidentiality is almost a mantra in medicine, but it is not absolute. Doctors must disclose private information when it is clearly in the patient’s interest — documenting a drug allergy in the medical record, for example — or when it comes to complying with a court order or a law (as in cases of child abuse). Doctors must also betray confidentiality when it is in the “public interest” (reporting infectious diseases, for example, or to warn potential victims of violence).
But when does public interest trump individual autonomy? It is rarely clear-cut. I once performed a coronary angiogram on a hospital electrician who told me he abused cocaine daily (which no doubt contributed to his severe angina). When I asked a colleague whether I should document this habit in the patient’s chart, or even alert the patient’s — our — employer, he said: “We don’t have to do anything. Remember, first do no harm.”
I never did tell anyone, though I exhorted the patient in the strongest terms to quit using drugs. But I wonder if I did the right thing. What about the risk to the hospital, to other patients, of the man’s addiction?
The World Medical Association states that confidentiality should be breached only when the expected harm of maintaining privacy is believed to be imminent, serious and unavoidable except by unauthorized disclosure. The philosophy behind this point of view is called utilitarianism: achieving the greatest good for the greatest number.
But once in a while the issue gets turned on its head. I once had the unenviable task of informing a 22-year-old man that he was suffering from severe heart failure and would probably need a transplant. His father warned me that his son would be devastated to hear the diagnosis. “It would mean a lot to me if you could tell him he’s going to be all right,” the father told me in the cardiac care unit. “He thinks he’s going to die. Please, he has lost all hope. Please tell him that if he does the things you say, he’s going to be O.K.”
I wasn’t sure what to do, but it was obvious that this young man wasn’t prepared to hear the news I had to present. I went into his room and told him exactly what his father had requested. Over several days, I eased him into the knowledge of his true condition. Doctors have to know how to keep secrets — even, rarely, from patients themselves.
Finding Some Calm After Living With ‘the Shakes’
As Sandy Kamen Wisniewski remembers, her hands always shook. She hid them in long sleeves and pockets and wrote only in block letters in school because at least that was readable. The tremor became much worse as she entered her teenage years, and if she was upset or under stress, it grew so bad she cringed with embarrassment and decided that it must all be psychological.
Ms. Wisniewski, now 40, was 14 when she learned that she had not an emotional disorder, but a neurological condition called essential tremor — “essential” not because she needed it, but because no underlying factor caused it. It was not a prelude to Parkinson’s disease, nor was it caused by a hormonal problem, a drug reaction or nervousness.
(Many people thought that Katharine Hepburn had Parkinson’s disease, when in fact she shook because she had essential tremor, as does Terry Link, a state senator in Illinois, and Gov. Jim Gibbons of Nevada.)
This disorder, which in most cases is inherited, is so misunderstood and so often misdiagnosed that Ms. Wisniewski, who lives in Libertyville, Ill., decided to write a book about it. Called “I Can’t Stop Shaking,” the book was self-published last year through Dog Ear Publishing in Indianapolis. Her intent is to help the estimated 10 million people who suffer with essential tremor, often for decades without knowing what is wrong.
John, for example, whose head shook uncontrollably, spent 27 years “being tested for nearly everything,” as he relates in the book. He even had an M.R.I. and was told by the doctor that there was nothing wrong with him.
Modern technology helped him learn the truth when he typed “head tremors” into a computer search engine and found the Web site for the International Essential Tremor Foundation. His shouts of joy upon recognizing his disorder woke his wife. He then recalled that his grandmother and all his cousins had what they called “the shakes,” also without knowing why.
Only a small minority of patients with essential tremor seek treatment, Ms. Wisniewski’s book says, although there are several medications that help and, for intractable cases, a surgical procedure that can greatly reduce, if not eliminate, the tremors.
For Shari Finsilver, who never even told her parents about the hand tremors that began at age 11, the surgery she underwent in her 50s, called deep brain stimulation, was “a life-altering experience, like someone awakened from a lifetime coma.”
As she wrote in Ms. Wisniewski’s book, “I immediately began doing all the things I had not been able to do for 40 years: write by hand, use a camera, cut with scissors, make change at the cash register, sign checks and credit card receipts, enroll in a public speaking course, dance with men other than my husband and son — all the things most people take for granted.
“But best of all, I was able to walk down the aisle at my children’s weddings, and cradle my grandchildren in my arms with steady hands.”
A Tremulous Mutation
One thorough study has indicated that in 96 percent of cases, essential tremor is familial, a result of an autosomal dominant genetic mutation. That means that every child of a person with the condition has a 50 percent chance of inheriting it. And most people, after learning the nature of their problem, are able to trace it from a parent and other family members. But the so-called penetrance of the mutated gene can vary widely, resulting in different degrees of disability.
The damaged gene interferes with voluntary muscles and can affect any body part, hands most often, but also the neck, larynx (resulting in a tremulous voice) and, less often, the legs. The tremor disappears at rest and during sleep, but becomes apparent when a person tries to do something with the affected part and is made worse by stress, fatigue, caffeine and anxiety.
In people with hand tremors, the shaking starts when they try to write or hold a cup of coffee or eat with a utensil. Many people with essential tremor devise ways to avoid such activities, like eating just sandwiches or never eating in public, typing instead of writing or paying by credit card to avoid writing a check.
One woman in Ms. Wisniewski’s book was able to return to college when she learned that disability laws entitled her to a note taker for all her classes. But many employment opportunities are out of reach. Jean Moore worked in a payroll office until she could no longer read her own numbers. Another woman was fired from her job as a waitress when she could no longer carry cups of liquid and plates of food without spilling them.
Head tremor is more difficult to disguise. Some people sit with their elbows planted on a firm surface, holding their head in their hands.
While the disorder can show itself at any age, essential tremor usually does not become apparent until midlife and then worsens with age.
Treatment Options
In diagnosing essential tremor, a doctor must first rule out other causes like medications, drug or alcohol withdrawal, excessive caffeine intake, overactive thyroid, heavy metal poisoning, fever and anxiety. A doctor also must check for other neurological conditions like Parkinson’s disease, multiple sclerosis or dystonia.
A number of drugs have been found, mostly by accident, to relieve tremors. They include beta blockers like propranolol, marketed as Inderal, used mainly to control high blood pressure; primidone, found in Mysoline; and topiramate, or Topamax, used mainly to treat epilepsy.
Several other drugs have helped some patients, and sometimes a combination of medications proves helpful. Dosages are limited by the patient’s ability to tolerate side effects. Injections of botulinum toxin A, in Botox, help many people with head tremors.
If drug treatment is not helpful, implanting a stimulatory in the thalamus of the brain can block the nerve signals that cause tremors in the upper extremities. The procedure has its hazards and is usually a last resort.
Most people with essential tremor have discovered on their own that alcohol provides temporary relief. But over time, more and more alcohol is needed to be helpful, so excessive intake and alcoholism are real dangers. This remedy is best used sporadically.
Members of the essential tremor foundation have provided a host of “survival” tips that Ms. Wisniewski lists in her book. They include these ideas:
¶Using half-full mugs and holding them with all five fingers on the top.
¶Using a travel mug with a lid and straw.
¶Asking the server to deliver your plate with the food already cut in bite-size pieces.
¶Using a bib or fastening the napkin under your chin with a dentist’s chain.
¶Writing with a fat pen that has a rubber grip.
¶At the computer, wearing wrist weights and keeping palms anchored to the front of the keyboard.
¶Using an electric toothbrush and razor.
¶Using Velcro instead of buttons.
¶Carrying preprinted labels with your name, address and telephone number.
For further information, including support groups for people with essential tremor and their families, the foundation has a Web site at www.essentialtremor.org, and a toll-free telephone number, (888) 387-3667.
Ms. Wisniewski, now 40, was 14 when she learned that she had not an emotional disorder, but a neurological condition called essential tremor — “essential” not because she needed it, but because no underlying factor caused it. It was not a prelude to Parkinson’s disease, nor was it caused by a hormonal problem, a drug reaction or nervousness.
(Many people thought that Katharine Hepburn had Parkinson’s disease, when in fact she shook because she had essential tremor, as does Terry Link, a state senator in Illinois, and Gov. Jim Gibbons of Nevada.)
This disorder, which in most cases is inherited, is so misunderstood and so often misdiagnosed that Ms. Wisniewski, who lives in Libertyville, Ill., decided to write a book about it. Called “I Can’t Stop Shaking,” the book was self-published last year through Dog Ear Publishing in Indianapolis. Her intent is to help the estimated 10 million people who suffer with essential tremor, often for decades without knowing what is wrong.
John, for example, whose head shook uncontrollably, spent 27 years “being tested for nearly everything,” as he relates in the book. He even had an M.R.I. and was told by the doctor that there was nothing wrong with him.
Modern technology helped him learn the truth when he typed “head tremors” into a computer search engine and found the Web site for the International Essential Tremor Foundation. His shouts of joy upon recognizing his disorder woke his wife. He then recalled that his grandmother and all his cousins had what they called “the shakes,” also without knowing why.
Only a small minority of patients with essential tremor seek treatment, Ms. Wisniewski’s book says, although there are several medications that help and, for intractable cases, a surgical procedure that can greatly reduce, if not eliminate, the tremors.
For Shari Finsilver, who never even told her parents about the hand tremors that began at age 11, the surgery she underwent in her 50s, called deep brain stimulation, was “a life-altering experience, like someone awakened from a lifetime coma.”
As she wrote in Ms. Wisniewski’s book, “I immediately began doing all the things I had not been able to do for 40 years: write by hand, use a camera, cut with scissors, make change at the cash register, sign checks and credit card receipts, enroll in a public speaking course, dance with men other than my husband and son — all the things most people take for granted.
“But best of all, I was able to walk down the aisle at my children’s weddings, and cradle my grandchildren in my arms with steady hands.”
A Tremulous Mutation
One thorough study has indicated that in 96 percent of cases, essential tremor is familial, a result of an autosomal dominant genetic mutation. That means that every child of a person with the condition has a 50 percent chance of inheriting it. And most people, after learning the nature of their problem, are able to trace it from a parent and other family members. But the so-called penetrance of the mutated gene can vary widely, resulting in different degrees of disability.
The damaged gene interferes with voluntary muscles and can affect any body part, hands most often, but also the neck, larynx (resulting in a tremulous voice) and, less often, the legs. The tremor disappears at rest and during sleep, but becomes apparent when a person tries to do something with the affected part and is made worse by stress, fatigue, caffeine and anxiety.
In people with hand tremors, the shaking starts when they try to write or hold a cup of coffee or eat with a utensil. Many people with essential tremor devise ways to avoid such activities, like eating just sandwiches or never eating in public, typing instead of writing or paying by credit card to avoid writing a check.
One woman in Ms. Wisniewski’s book was able to return to college when she learned that disability laws entitled her to a note taker for all her classes. But many employment opportunities are out of reach. Jean Moore worked in a payroll office until she could no longer read her own numbers. Another woman was fired from her job as a waitress when she could no longer carry cups of liquid and plates of food without spilling them.
Head tremor is more difficult to disguise. Some people sit with their elbows planted on a firm surface, holding their head in their hands.
While the disorder can show itself at any age, essential tremor usually does not become apparent until midlife and then worsens with age.
Treatment Options
In diagnosing essential tremor, a doctor must first rule out other causes like medications, drug or alcohol withdrawal, excessive caffeine intake, overactive thyroid, heavy metal poisoning, fever and anxiety. A doctor also must check for other neurological conditions like Parkinson’s disease, multiple sclerosis or dystonia.
A number of drugs have been found, mostly by accident, to relieve tremors. They include beta blockers like propranolol, marketed as Inderal, used mainly to control high blood pressure; primidone, found in Mysoline; and topiramate, or Topamax, used mainly to treat epilepsy.
Several other drugs have helped some patients, and sometimes a combination of medications proves helpful. Dosages are limited by the patient’s ability to tolerate side effects. Injections of botulinum toxin A, in Botox, help many people with head tremors.
If drug treatment is not helpful, implanting a stimulatory in the thalamus of the brain can block the nerve signals that cause tremors in the upper extremities. The procedure has its hazards and is usually a last resort.
Most people with essential tremor have discovered on their own that alcohol provides temporary relief. But over time, more and more alcohol is needed to be helpful, so excessive intake and alcoholism are real dangers. This remedy is best used sporadically.
Members of the essential tremor foundation have provided a host of “survival” tips that Ms. Wisniewski lists in her book. They include these ideas:
¶Using half-full mugs and holding them with all five fingers on the top.
¶Using a travel mug with a lid and straw.
¶Asking the server to deliver your plate with the food already cut in bite-size pieces.
¶Using a bib or fastening the napkin under your chin with a dentist’s chain.
¶Writing with a fat pen that has a rubber grip.
¶At the computer, wearing wrist weights and keeping palms anchored to the front of the keyboard.
¶Using an electric toothbrush and razor.
¶Using Velcro instead of buttons.
¶Carrying preprinted labels with your name, address and telephone number.
For further information, including support groups for people with essential tremor and their families, the foundation has a Web site at www.essentialtremor.org, and a toll-free telephone number, (888) 387-3667.
The Claim: C.L.A. Supplements Can Help You Lose Weight
THE FACTS
It has been called a miracle pill, able to help you shed fat, lose weight and build muscle. It can be found in health food stores all over, but is C.L.A. — also known as conjugated linoleic acid — all it’s cracked up to be?
Discovered more than two decades ago, the substance is popular among dieters and body builders, and reportedly reduces body fat gain and enhances lean body mass. Over the years, a number of studies have found that C.L.A., unlike many other supplements, may actually help users trim fat. But it also carries side effects.
The most recent study was published this month in The American Journal of Clinical Nutrition. The report, a meta-analysis that pooled the results of more than a dozen randomized studies, found that people who took 3.2 grams of C.L.A. a day showed a drop in fat mass of about 0.2 pounds a week — or nearly a pound a month — compared with those given a placebo. The researchers, at the University of Wisconsin School of Medicine, concluded that the supplement “produces a modest loss in body fat in humans.”
But other studies have hinted at serious adverse health effects. Researchers have found that it can increase blood levels of C-reactive protein, lipoprotein and leptin — all of which can heighten the risk of heart disease. There is also some evidence that taking C.L.A. daily increases insulin resistance, a sign of impending Type 2 diabetes.
THE BOTTOM LINE
Studies have found that C.L.A. supplements can produce slight reductions in body fat, but that it may carry health risks.
It has been called a miracle pill, able to help you shed fat, lose weight and build muscle. It can be found in health food stores all over, but is C.L.A. — also known as conjugated linoleic acid — all it’s cracked up to be?
Discovered more than two decades ago, the substance is popular among dieters and body builders, and reportedly reduces body fat gain and enhances lean body mass. Over the years, a number of studies have found that C.L.A., unlike many other supplements, may actually help users trim fat. But it also carries side effects.
The most recent study was published this month in The American Journal of Clinical Nutrition. The report, a meta-analysis that pooled the results of more than a dozen randomized studies, found that people who took 3.2 grams of C.L.A. a day showed a drop in fat mass of about 0.2 pounds a week — or nearly a pound a month — compared with those given a placebo. The researchers, at the University of Wisconsin School of Medicine, concluded that the supplement “produces a modest loss in body fat in humans.”
But other studies have hinted at serious adverse health effects. Researchers have found that it can increase blood levels of C-reactive protein, lipoprotein and leptin — all of which can heighten the risk of heart disease. There is also some evidence that taking C.L.A. daily increases insulin resistance, a sign of impending Type 2 diabetes.
THE BOTTOM LINE
Studies have found that C.L.A. supplements can produce slight reductions in body fat, but that it may carry health risks.
Monday, May 28, 2007
Scientists Explore Genetic Risk of Breast Cancer
In a long-delayed harvest from the human genome project, researchers say they have found six new sites of variation in the genome that increase the risk of breast cancer.
Together with already-known genes, the discovery means that a sizable fraction of the overall genetic risk of breast cancer may now have been accounted for, researchers say, and much of the rest could be captured in a few years.
The findings do not point to any new treatment and are too little understood to serve as the basis of a diagnostic test. But they are a critical step toward understanding the biology of breast cancer, scientists say, from which new treatments should emerge.
Understanding the genetic basis of common disease was the promised payoff of the $3 billion human genome project, which was completed in 2003 but has taken some time to show many tangible results. The logjam seems to be breaking. Last month, seven new DNA variations associated with diabetes were discovered, and advances with other diseases are expected to be announced soon.
The new findings have been made possible by new instruments, known as chips, which enable up to 500,000 points of variation on the human genome to be tested simultaneously for possible association with disease. But to attain statistical strength, large numbers of patients must be recruited, which has prompted otherwise competitive groups to work together.
Using the new chips, scientists can compare breast cancer patients with healthy individuals, looking for variant sites on the DNA of the human genome which seem associated with the disease. Because the chips sample each patient’s entire genome, the new approach is known as a whole genome association study.
With this approach, a large consortium of breast cancer scientists, led by Douglas F. Easton of the Cancer Research-UK Genetic Epidemiology Unit in Cambridge, England, says it has found five new sites on the genome where a common variation confers a risk of breast cancer. Their findings were reported Sunday in the journal Nature.
Two of the same sites of variation have been found by a second team, led by David Hunter of the Harvard School of Public Health. Decode Genetics, a gene-finding company based in Iceland, has also identified two new sites of variation, one of which is the same as one found in Dr. Easton’s study. The reports from Dr. Hunter and Decode Genetics were published online in the journal Nature Genetics.
Scientists involved in the three studies expressed confidence that most of the genetic risk of breast cancer will be detected through the whole genome association approach. “Once the dust has settled, yes, it’s possible we may have captured most of the genetic variation,” Dr. Easton said.
Genes already known to be associated with breast cancer, such as BRCA1 and BRCA2, carry a high risk but are rare in the general population. The new DNA variations are quite common but confer a lesser risk.
A team lead by Simon N. Stacey of Decode Genetics reports that 25 percent of women of European descent carry one copy of a DNA variant on the second of the 23 human chromosomes, conferring a 44 percent greater risk of breast cancer than for women without it, and that 7 percent of women have inherited two copies, with a 64 percent greater risk.
The sites of variation discovered by Decode and the other two groups do not lie in genes and for the most part have no known biological function, though some are conjectured to control the activity of nearby genes. It is purely on the basis of statistics that the sites of variation on the DNA are believed to be associated with disease.
Their discoverers say that the sites will, when understood, reveal new biology that underlies the progression toward breast cancer. But not everyone is convinced.
Mary-Claire King, a biologist at the University of Washington in Seattle who pioneered the search for the BRCA1 cancer gene, criticized the statistical basis of the studies and suggested they should not have been published until the biological significance of the suspect sites had been established.
“I believe the motivation to publish based on so little biological or genetic evidence,” she said, “is that an enormous amount of money has been put into these efforts and hence the need to see positive results is huge.” Her principal criticism of the three studies’ statistics is that when 500,000 sites of variation are tested all at once for association with disease, many may come out positive just by chance, not because of any real link.
Dr. Easton, Dr. Hunter and Kari Stefansson, Decode’s chief executive, all said the criticism was correct in principle but could be sidestepped, as they had each done, by taking the few most promising sites in one whole genome association scan and testing them in a second population.
Dr. Stefansson rejected the suggestion that the three groups should not have published their statistical findings until the biology of the sites was worked out, saying that science proceeds in small steps and that “we never have the entire story on day one.” With publication, the sites are available for other scientists to investigate.
All three scientists expressed confidence that their whole genome association studies have avoided the many pitfalls of the past and are pointing to sites of variation that either cause disease or lie close to those that do so.
“This is the apotheosis of the genome project and the HapMap, to be able to look diagnostically at the whole genome,” Dr. Hunter said, referring to a map of variation in the human genome. “Suddenly all at once we have half a dozen robust associations.”
Dr. Stefansson said firmly, “The statistics are not leading us astray.”
Together with already-known genes, the discovery means that a sizable fraction of the overall genetic risk of breast cancer may now have been accounted for, researchers say, and much of the rest could be captured in a few years.
The findings do not point to any new treatment and are too little understood to serve as the basis of a diagnostic test. But they are a critical step toward understanding the biology of breast cancer, scientists say, from which new treatments should emerge.
Understanding the genetic basis of common disease was the promised payoff of the $3 billion human genome project, which was completed in 2003 but has taken some time to show many tangible results. The logjam seems to be breaking. Last month, seven new DNA variations associated with diabetes were discovered, and advances with other diseases are expected to be announced soon.
The new findings have been made possible by new instruments, known as chips, which enable up to 500,000 points of variation on the human genome to be tested simultaneously for possible association with disease. But to attain statistical strength, large numbers of patients must be recruited, which has prompted otherwise competitive groups to work together.
Using the new chips, scientists can compare breast cancer patients with healthy individuals, looking for variant sites on the DNA of the human genome which seem associated with the disease. Because the chips sample each patient’s entire genome, the new approach is known as a whole genome association study.
With this approach, a large consortium of breast cancer scientists, led by Douglas F. Easton of the Cancer Research-UK Genetic Epidemiology Unit in Cambridge, England, says it has found five new sites on the genome where a common variation confers a risk of breast cancer. Their findings were reported Sunday in the journal Nature.
Two of the same sites of variation have been found by a second team, led by David Hunter of the Harvard School of Public Health. Decode Genetics, a gene-finding company based in Iceland, has also identified two new sites of variation, one of which is the same as one found in Dr. Easton’s study. The reports from Dr. Hunter and Decode Genetics were published online in the journal Nature Genetics.
Scientists involved in the three studies expressed confidence that most of the genetic risk of breast cancer will be detected through the whole genome association approach. “Once the dust has settled, yes, it’s possible we may have captured most of the genetic variation,” Dr. Easton said.
Genes already known to be associated with breast cancer, such as BRCA1 and BRCA2, carry a high risk but are rare in the general population. The new DNA variations are quite common but confer a lesser risk.
A team lead by Simon N. Stacey of Decode Genetics reports that 25 percent of women of European descent carry one copy of a DNA variant on the second of the 23 human chromosomes, conferring a 44 percent greater risk of breast cancer than for women without it, and that 7 percent of women have inherited two copies, with a 64 percent greater risk.
The sites of variation discovered by Decode and the other two groups do not lie in genes and for the most part have no known biological function, though some are conjectured to control the activity of nearby genes. It is purely on the basis of statistics that the sites of variation on the DNA are believed to be associated with disease.
Their discoverers say that the sites will, when understood, reveal new biology that underlies the progression toward breast cancer. But not everyone is convinced.
Mary-Claire King, a biologist at the University of Washington in Seattle who pioneered the search for the BRCA1 cancer gene, criticized the statistical basis of the studies and suggested they should not have been published until the biological significance of the suspect sites had been established.
“I believe the motivation to publish based on so little biological or genetic evidence,” she said, “is that an enormous amount of money has been put into these efforts and hence the need to see positive results is huge.” Her principal criticism of the three studies’ statistics is that when 500,000 sites of variation are tested all at once for association with disease, many may come out positive just by chance, not because of any real link.
Dr. Easton, Dr. Hunter and Kari Stefansson, Decode’s chief executive, all said the criticism was correct in principle but could be sidestepped, as they had each done, by taking the few most promising sites in one whole genome association scan and testing them in a second population.
Dr. Stefansson rejected the suggestion that the three groups should not have published their statistical findings until the biology of the sites was worked out, saying that science proceeds in small steps and that “we never have the entire story on day one.” With publication, the sites are available for other scientists to investigate.
All three scientists expressed confidence that their whole genome association studies have avoided the many pitfalls of the past and are pointing to sites of variation that either cause disease or lie close to those that do so.
“This is the apotheosis of the genome project and the HapMap, to be able to look diagnostically at the whole genome,” Dr. Hunter said, referring to a map of variation in the human genome. “Suddenly all at once we have half a dozen robust associations.”
Dr. Stefansson said firmly, “The statistics are not leading us astray.”
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