FDA Approves Bevacizumab for Metastatic Breast Cancer

NEW YORK -- Bevacizumab (Avastin) is now approved as a first-line option for patients with metastatic, HER2-negative breast cancer. The approval is based on a phase 3 study (E2100) that found bevacizumab in combination with paclitaxel reduced the risk of disease progression or death by 52 percent compared with those treated with paclitaxel alone. Adding bevacizumab to paclitaxel also doubled progression-free survival (PFS) [hazard ratio (HR) = 0.48; P < .0001].Bevacizumab was approved in advanced breast cancer under the US Food and Drug Administration's accelerated approval program, which allows the FDA to approve products for cancer or other life-threatening diseases based on initial positive clinical data. Genentech, Inc. the maker of bevacizumab has shared with the FDA a summary of the results from a second positive phase 3 trial (AVADO), and is expecting results from a third phase 3 trial (RIBBON I) in first-line metastatic breast cancer in late 2008. A full review of both the AVADO and RIBBON I data by the FDA will be required for the accelerated approval to be converted into a full approval."There is no cure for metastatic breast cancer, so it is important to control the disease as early and for as long as possible," said Kathy Miller, MD, Associate Professor of Medical Oncology, Indiana University School of Medicine, Indianapolis, and lead investigator on the E2100 trial. "Now with [bevacizumab] plus paclitaxel, we can increase the time a woman's cancer is kept under control, and offer a biologic option to women who previously were limited to chemotherapies alone."E2100 was a multicenter, randomized, controlled clinical trial (N = 722) of patients with previously untreated, locally recurrent or metastatic breast cancer. Patients received weekly treatment with paclitaxel every 3 out of 4 weeks, with or without bevacizumab. Based on an independent, blinded review of patient scans, median PFS was longer in patients treated with bevacizumab plus paclitaxel compared with paclitaxel alone (11.3 mo vs 5.8 mo). The independent review showed a similar magnitude of benefit relative to the initial results presented by the Eastern Cooperative Oncology Group (ECOG) at the American Society of Clinical Oncology annual meeting in 2005. Overall survival, a secondary endpoint, was 1.7 months longer (P = .14) in the bevacizumab-containing arm (HR = 0.87), supporting the primary endpoint of PFS.These safety findings were generally consistent with previous trials of bevacizumab plus chemotherapy, and no new safety signals related to bevacizumab were observed. Grade 3/4 adverse events that occurred more often in the bevacizumab arm included neuropathy (due to longer time on paclitaxel treatment), hypertension, arterial thromboembolic events, and proteinuria.Source: Genentech, Inc.

Diabetes Diagnostic Criteria May Be Off Target for Retinopathy

By Crystal Phend
MELBOURNE, Australia, Feb. 28 -- Retinopathy occurs at substantial rates even when glucose levels are below those that would trigger a diagnosis of diabetes, according to a meta-analysis.
More than 60% of retinopathy cases were among patients with fasting plasma glucose levels below 7.0 mmol/L (126 mg/dL), reported Tien Y. Wong, M.D., Ph.D., of the University of Melbourne here, and colleagues in the March 1 issue of The Lancet.
WHO and American Diabetes Association criteria for diabetes diagnosis were based on increasing rates of retinopathy beyond the glycemic threshold at 7.0 mmol/L (126 mg/dL) found in three earlier studies.
However, these studies assessed retinopathy from direct clinical ophthalmoscopic examination or a single retinal photograph rather than the gold standard in clinical trials--multiple field retinal photographs.
The meta-analysis of trials using the more reliable method "point to the need to revisit current diagnostic criteria for diabetes," the researchers wrote.
There's no point in throwing out the current criteria, though, commented Quresh Mohamed, M.D., and Alison Evans, MBBCh, both of Cheltenham General Hospital in Cheltenham, England, in an accompanying editorial.
The meta-analysis offered no alternative threshold that would do the job, they noted, and there is limited evidence that further lowering the criteria would be beneficial.
"We perhaps should focus less on a single universal cut-off and instead target resources on the basis of standardized, evidence-based, individual risk scores in which measures of glycemia are combined with other risk factors," they suggested.
"But what would we tell our patients when they asked if they had diabetes?" they asked. "We are probably best sticking with what we know until a better alternative diagnostic tool becomes available."
Dr. Wong and colleagues analyzed cross-sectional data from three population-based cohorts that followed the same protocol for retinopathy grading using multiple field retinal photographs.
This included 3,162 participants from the Blue Mountains Eye Study with prospective five-year follow-up for 1,903 of these patients; 2,182 participants in the Australian Diabetes, Obesity, and Lifestyle Study; and 6,079 patients in the Multi-Ethnic Study of Atherosclerosis.
The overall prevalence of retinopathy in these studies was 11.5%,
9.6%, and 15.8%, respectively.
There was no consistent fasting plasma glucose threshold at which the prevalence of retinopathy increased.
In the Blue Mountains Eye Study, retinopathy prevalence was around 10% even at fasting plasma glucose concentrations below 5.6 mmol/L (100 mg/dL) -- the current definition of normal -- and increased further at concentrations beyond about 6.3 mmol/L (115 mg/dL), the researchers noted.
In the Australian Diabetes study, retinopathy likewise occurred at a similar rate among patients with low fasting plasma glucose concentrations as in the overall cohort. Prevalence increased above 7.1 to 7.8 mmol/L (128 to 140 mg/dL) but for moderate retinopathy there was no suggestion of a threshold.
The Multi-Ethnic Study of Atherosclerosis showed the same pattern of prevalence at low fasting plasma glucose levels but there was no threshold for retinopathy overall or for moderate cases.
Putting the three studies together, 7.4% to 13.4% of participants had retinopathy at glucose levels below 5.6 mmol/L (100 mg/dL).
Earlier studies had suggested that retinopathy was uncommon, at only 2% to 4% prevalence, among patients whose fasting plasma glucose was below 5.6 (100 mg/dL).
In the combined studies, prevalence of retinopathy was 17.8% to 34.7% above the 7.0 mmol/L (126 mg/dL) cutoff for a diagnosis of diabetes.
This two- to five-fold underestimation of prevalence at low glucose levels likely inflated the sensitivity of the cutoffs derived from them, the investigators said.
Whereas the earlier studies suggested a sensitivity of more than 80% for the diagnostic threshold of 7.0 mmol/L (126 mg/dL), Dr. Wong's group found a low sensitivity of only 14.8% to 39.1% for the same cutoff.
Although the specificity was high at 80.8 to 95.8% for detecting retinopathy, the positive predictive value was low at 17.8% to 34.7%.
Limiting the analyses to cases of moderate retinopathy, performance of the 7.0 mmol/L (126 mg/dL) cutoff "remained generally poor."
When the researchers tested a higher 7.8 mmol/L (140 mg/dL) diagnostic threshold, it had lower sensitivity but higher specificity and positive predictive values.
Lowering the cutoff to 5.6 mmol/L (100 mg/dL) increased sensitivity at the expense of specificity and positive predictive values.
Overall, the analysis showed a more gradual increase of retinopathy prevalence with fasting plasma glucose than seen in prior studies, which strongly suggests a continuous rise without a threshold, the researchers said.
"These results of fasting plasma glucose and retinopathy are therefore consistent with observations that the relation between glucose and macrovascular complications such as cardiovascular disease is continuous with no threshold," Dr. Wong and colleagues concluded, "and is analogous to that of end-organ damage found with other cardiovascular risk factors such as blood pressure and serum cholesterol levels."

Primary source: The LancetSource reference:Wong TY, et al "Relation between fasting glucose and retinopathy for diagnosis of diabetes: three population-based cross-sectional studies" Lancet 2008; 371: 736-743. Additional source: The LancetSource reference: Mohamed Q, Evans A "Retinopathy, plasma glucose, and the diagnosis of diabetes" Lancet 2008; 371: b700-702.

Tendon Problems Seen as Rare Adverse Effect of Statins

By Charles Bankhead
ROUEN, France, Feb. 28 -- Statin-related adverse effects are rare, and rarer still are tendinous complications, according to a large French post-marketing surveillance program.
Nevertheless, the French pharmacovigilance program confirmed anecdotal reports that every once in a while statins seem to trigger tendinitis or even an Achilles rupture, Isabelle Marie, M.D., Ph.D., of Rouen University Hospital, and colleagues reported in the March 15 issue of Arthritis & Rheumatism.
Tendinous complications accounted for about 2% of all statin adverse events reported to the French pharmacovigilance network from 1990 to 2005. For the individual years reviewed, the proportion of statin-related adverse effects that involved tendons ranged from 0% to 3.6%.
"Our series suggests that statin-attributed tendinous complications are rare, considering the huge number of statin prescriptions," the authors concluded. "We suggest that prescribers should be aware of tendinous complications related to statins, particularly in risk situations, including physical exertion and association with medications known to increase the toxicity of statins."
Statin-associated tendon impairment had not been reported in previous pre- and postmarketing studies, although sporadic anecdotal reports suggested a possible link. To explore the issue more closely, Dr. Marie and associates retrospectively reviewed data from 31 French pharmacovigilance centers.
For the 16-year period reviewed, 4,597 statin-related adverse events were reported to the pharmacovigilance network. Of those, 96 events (2.01%) involved tendon impairment, consisting of 63 reports of tendinitis and 33 reports of tendon rupture. The Achilles tendon was the affected area in 50 (52.1%) of the cases, and 26 patients (27%) had bilateral tendon manifestations.
The median time to onset of tendon symptoms was 243 days, but occurred as early as 24 hours after starting therapy and as late as 15 years. Tendon symptoms occurred within the first year in 59% of patients.
Statin-attributed tendon complications were considered serious in 36 cases, and 17 patients required hospitalization. Moreover, 19 of the 33 patients who had tendon rupture had significant functional sequelae that included difficulty walking, decreased range of motion, and pain. Of seven patients who stopped and then reinitiated statin therapy, all seven had a recurrence of tendon symptoms.
Tendon complications were reported in patients treated with atorvastatin (Lipitor), simvastatin, pravastatin, fluvastatin (Lescol), and rosuvastatin (Crestor). The authors reported that the complications occurred at recommended dose ranges for all of the drugs.
Predisposing factors beyond statin therapy that might have led to tendon complications were not explored.
Though generally considered safe and associated with minor side effects, statins occasionally cause serious complications, especially musculoskeletal effects that include myositis, rare cases of rhabdomyolysis, and inflammatory myopathies. In clinical trials of statins, myositis occurred in 0.09% to 0.63% of patients and rhabdomyolysis in 1 case per 100,000 patient-years, the authors noted.
Despite their findings, the authors left the door open to the possibility that statins have a closer association with tendon problems than currently recognized. They noted that a literature review uncovered 43 cases of statin-related tendon complications.
"Tendinous manifestations may be an as-yet unreported side effect of statin therapy," they said. "In essence, no cases were reported during the large therapeutic trials, including more than 30,000 patients. However, the fact that statin-related tendon complications have not been described in these large clinical trials may be explained in part by control of factors predisposing to tendinopathy and regular follow-up of trial patients."
They concluded that this literature review suggests that tendon manifestations may be included within the spectrum of adverse effects of statins but future case-control studies are required to confirm this relationship.
"Our study suggests that regular tendinous clinical examination may be required in statin-treated patients, particularly during the first year following statin therapy initiation," they added.
The authors had no disclosures.
Primary source: Arthritis & RheumatismSource reference:Marie I, et al "Tendinous disorders attributed to statins: A study on ninety-six spontaneous reports in the period 1990-2005 and review of the literature" Arthritis Rheum 2008; 59: 367-372.

Vitamin pills don't cut lung cancer risk: Study

By Will Dunham
People who take vitamin supplements are just as likely as those who don't to develop lung cancer, and vitamin E supplements may actually slightly raise the risk, researchers said on Friday.
Their study involved 77,721 people in Washington state ages 50 to 76, tracking their use over the prior decade of supplemental multivitamins, vitamin C, vitamin E and folate to see if this would offer protection from lung cancer.
None of the vitamins looked at in the study was tied to a reduced risk of lung cancer. In fact, people who took high doses of vitamin E, especially smokers, had a small but statistically significant elevated risk, the researchers said.
"If you could find some sort of magic pill -- a pill you could take once a day to decrease your risk -- that would be ideal. But we obviously, unfortunately, didn't find that in our study," lead researcher Dr. Christopher Slatore of the University of Washington in Seattle said in a telephone interview.
The people in the study were followed for four years and 521 developed lung cancer, the vast majority of them smokers or former smokers, Slatore's team reported in the American Journal of Respiratory and Critical Care Medicine.
"Some estimates are that around 50 percent of the American public takes supplemental vitamins of some sort. There's been a lot of thought about: 'do these supplements actually prevent chronic diseases like lung cancer, other cancers, heart disease?"' Slatore said.
VALIDATING OTHER STUDIES
The research did not look at beta-carotene, but previous work showed that people taking beta-carotene supplements, particularly smokers, had a higher risk of developing lung cancer than those who did not.
In those in the new study who developed lung cancer, the researchers saw a small increased risk associated with vitamin E supplements in addition to the expected links to smoking, family history and age.
This amounted to a 28 percent increased risk of developing lung cancer for those taking vitamin E supplements at a dose of 400 mg daily for 10 years, the researchers said.
Vitamin E is an antioxidant, thought to protect body tissue from damage caused by so-called free radicals, which are unstable substances that can harm cells, tissues and organs. It also is important in the formation of red blood cells.
"For folks -- especially smokers -- I would definitely recommend that they not take vitamin E (as a supplement) unless they have a very strong reason to take it," Slatore said.
The notion that vitamin supplements are healthful, or at least not harmful, arises from the desire of many people to match the benefits of a healthful diet with a convenient pill, Dr. Tim Byers of the University of Colorado School of Medicine wrote in an editorial accompanying the study.
"Over the past two decades, we have been repeatedly disappointed in the ability of vitamin supplements to reduce risk for cancers at several sites, including the stomach, colorectum, breast and lung," Byers wrote.
"Foods that are rich in vitamins seem to be associated with reduced risk of cancer, but vitamins packaged as pills clearly do not have the same effect," Byers added.

Complex Interventions Can Help Older Adults Maintain Independent Living

Multifactorial interventions can help older adults maintain their independence, according to a Lancet meta-analysis.
Researchers in the U.K. pooled data from 89 randomized trials comprising nearly 98,000 adults aged 65 or older. In all trials, minimal care was compared with multifactorial interventions that involved personalized geriatric assessment plus any of the following:
community-based care after hospital discharge,
fall prevention measures, and
group education and counseling.
All trials had at least 6 months of follow-up. Overall, multifactorial interventions lowered the risk for nursing-home and hospital admissions, improved physical function, and reduced the likelihood of falls.
Editorialists acknowledge the challenges of providing multifactorial interventions (e.g., the shortage of healthcare workers), but they conclude that if done "right," such care has "the potential to improve the quality of life for elderly people and their [caregivers], and possibly even to reduce the costs of health and social care."

Cardiac surgery in select nonagenarians: should we or shouldn't we?

Ullery BW, Peterson JC, Milla F, Wells MT, Briggs W, Girardi LN, Ko W, Tortolani AJ, Isom OW, Krieger KH.
Department of Cardiothoracic Surgery, Center for Complementary and Integrative Medicine, Weill Cornell Medical College, New York, New York 10021, USA.

BACKGROUND: Patients aged 90 years and older represent a rapidly growing subset of the population, many of whom are functionally limited by cardiovascular disease. Clinical decision making about cardiac surgical intervention in nonagenarians is hindered by a paucity of data examining survival outcomes in this population.

METHODS: A consecutive series of nonagenarians who underwent cardiac operations between 1995 and 2004 were retrospectively reviewed. Data collection included baseline preoperative clinical status, intraoperative characteristics, and perioperative course. Area under the Kaplan-Meier survival estimate method was used to calculate mean survival. RESULTS: Cardiac surgical procedures were done in 49 patients (51% male); their mean age was 91.9 years (range, 90 to 97 years). Operative mortality was 8% (n = 4). Multivariate Cox proportional hazards models found preoperative chronic renal insufficiency (hazard ratio [HR], 4.88; 95% confidence interval [CI], 1.53 to 15.55; p = 0.007) and ejection fraction (HR, 0.96; 95% CI, 0.93 to 1.00; p = 0.033) were independently associated with death. Overall mean survival was 5.1 +/- 0.5 years (median, 5.2 years). Quality of life outcomes were similar to that of two related norm-based populations based on age and disease process.

CONCLUSIONS: Cardiac surgical procedures can be performed safely and with therapeutic benefit in carefully selected nonagenarians. We consider physiologic indicators, social factors, and patient preferences to be the main determinants in the patient selection process. Our results support the need for more proactive intervention in symptomatic nonagenarian patients as it relates to earlier consideration of elective, rather than emergency cardiac operations.

Herbal Supplement May Protect Memory After Age 85

By Judith Groch
CORVALLIS, Ore., Feb. 27 -- The popular plant supplement ginkgo biloba may help preserve memory in older octogenarians, but it may increase the risk of stroke, researchers found.
Among 118 people 85 or older, those who took the supplement reliably had a 70% lower risk of developing mild memory problems than those who took a placebo, Hiroko Dodge, Ph.D., of Oregon State University here, and colleagues reported online in Neurology.
However there were six strokes and one TIA among those taking ginko and none in the placebo group.
The findings came from a randomized, placebo-controlled, double-blind, 42-month pilot study with cognitively intact individuals (about 60% women) randomized to standardized ginkgo extract or placebo. Sixty individuals took a ginkgo extract three times a day and 58 took placebo.
Gingko biloba was chosen as a possible preventive agent because it is already widely used even among the oldest old, is readily available, relatively inexpensive, and it has been shown in preclinical studies to have a plausible biologic efficacy as an antioxidant and on other brain aging mechanisms, the researchers wrote.
Participants were recruited by mass mailings from August 2000 through September 2001 to age-eligible individuals in the greater Portland area.
All participants had annual in-person interviews with six-month follow-up to assess changes in health status, including Mini-Mental State Examination (MMSE) scores. These individuals had common stable medical conditions such as heart disease and hypertension.
Kaplan-Meier estimation, Cox proportional hazard, and random-effects models were used to compare the risk of progression
from Clinical Dementia Rating (CDR)=0 to CDR=0.5 and also the decline in episodic memory function between the two groups.
Overall, 21 people developed mild memory problems or questionable dementia, including 14 in the placebo group and seven who took the gingko extract, the researchers found.
In the unadjusted intention-to-treat analysis, ginkgo showed no protective effect on memory. The investigators found no reduced risk of progression to a clinical dementia rating of 0.5 (log-rank test, P=0.06) in the ginkgo group. There was also no decrease in the decline in memory function (P=0.05).
However, the researchers recognized that not all the people took the medications reliably, so they did a secondary analysis accounting for compliance.
Controlling for medication adherence, the ginkgo group had a lower risk of progression in the CDR=0 to CDR=0.5 (HR 0.33, 95% CI 0.12 to 0.89, P=0.02), and a smaller decline in memory scores (P=0.04).
The almost 70% protective effect did not change after controlling for other covariates at baseline, the researchers said. Only depressive symptoms predicted progression.
There was no overall difference in adverse events in the two groups during the study period (P=0.44 for difference in proportions).
However there were six ischemic strokes and one TIA (11.7%) in the ginkgo group compared with none in the placebo group (P=0.01).
Gingko has been reported to cause bleeding-related complications, the researchers said, but the strokes in this case were caused by blood clots, not excessive bleeding. More studies are needed to confirm this finding, they said.
There were no deaths from stroke, and there was no difference in rates of other events such as gastrointestinal ulcer, epitasis, or ecchymoses. Five individuals in each group died.
Dr. Dodge noted that this is the first randomized, controlled trial of dementia prevention in people 85 or older.
These data, he said, suggest that other larger studies should be able to establish a brain protective effect for ginkgo, assuming that such variables as dosing and the nature of the population samples enrolled (not a younger elderly group) are not major determinants.
To control medication management, the researchers suggested that once-a-day dosing might be preferable, although the optimum dosing regimen for ginkgo is not known.
The suggestion of a protective effect in this study needs to be confirmed in larger prevention trials taking into account medication compliance as well as the stroke findings, the researchers said.
These results suggest that this oldest population should not be excluded because of notions of frailty, poor adherence, or confounding medical problems. In fact, the investigators said, the participants were pleased to contribute to science and to "feel useful" at their advanced age.
The study was supported by grants from the National Institute on Aging and the National Center for Complementary and Alternative Medicine. The ginkgo biloba extract was provided by Thorne Research, Inc.
The authors reported no conflicts of interest.
Primary source: NeurologySource reference:Dodge HH, et al "A randomized placebo-controlled trial of ginkgo biloba for the prevention of cognitive decline" Neurology 2008; 70: doi:10.1212/01.wwnl.0000303814.13509.db.

Vasopressin Offers No Survival Benefit for Septic Shock

By Crystal Phend
VANCOUVER, British Columbia, Feb. 27 -- Low-dose vasopressin does not reduce septic shock mortality when used as an adjunct to conventional catecholamine vasopressors, according to a randomized controlled trial.Mortality was similar whether patients received vasopressin or norepinephrine with open-label vasopressor therapy (P=0.26 at 28 days and P=0.11 at 90 days), reported James A. Russell, M.D., of St. Paul's Hospital here, and colleagues in the Feb. 28 issue of the New England Journal of Medicine.However, the lack of benefit may have been related to timing, commented Joseph E. Parrillo, M.D., of the University of Medicine and Dentistry of New Jersey and Cooper University Hospital, both in Camden, N.J., in an accompanying editorial.
Time from meeting the diagnostic criteria to infusion of the study drug averaged about 12 hours, whereas earlier studies have suggested treatment in the first six hours is most critical for survival.
"Treatment initiated at an average of 12 hours after the onset of septic shock may be too late for any vasopressor agent to show a significant effect on mortality," Dr. Parrillo wrote.
The timing of vasopressor therapy may be more important than the specific agent used, he said.
Although vasopressin is given widely in clinical practice, its use has been based on only two small, randomized trials that were underpowered to determine mortality, organ dysfunction, or safety outcomes, the researchers said.
So, they undertook an international trial of 778 critically ill patients with septic shock who were receiving at least 5 μg of norepinephrine per minute at baseline.
All patients received open-label vasopressors and were randomized to double-blind treatment with either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 μg per minute).
These infusions were titrated and tapered per-protocol to maintain a target blood pressure.
At 28 days, there were no differences between the vasopressin and norepinephrine groups in the primary outcome of death from any cause (35.4% versus 39.3%, P=0.26).
Likewise, 90-day all cause mortality was similar for vasopressin and norepinephrine (43.9% and 49.6%, P=0.11), as were rates of organ dysfunction (P=NS for all organ systems).
Multivariate analysis did not change the lack of benefit for 28-day mortality (OR 0.88, 95% CI 0.62 to 1.26) or 90-day mortality (OR 0.81, 95% CI 0.57 to 1.16).
Adverse event rates were similar in the vasopressin and norepinephrine groups overall (10.3% versus 10.5%, P=1.00). Individual adverse event rates were similar as well.
Notably, though, cardiac arrest tended to be more common in the norepinephrine group than in the vasopressin group (2.1% versus 0.8%, P=0.14). Previous studies had suggested vasopressin could increase the incidence of cardiac arrest.
The lack of adverse cardiovascular events might have been because of the low vasopressin dose used an exclusion of patients with acute coronary syndrome or severe heart failure, the researchers said.
"If vasopressin becomes routine therapy and is given at higher doses or to patients with septic shock who have coexisting heart disease," they wrote, "the adverse reactions to vasopressin could be increased."
Another surprise, the researchers said, was that patients who had less severe septic shock tended to benefit from vasopressin more than patients who had more severe shock.
Survival trends and some post-hoc interaction analyses favored vasopressin in patients with less severe shock whereas there were no differences among more severely ill patients.
In the prospectively defined group of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinepherine group at 28 days (26.5% versus 35.7%, P=0.05).
In the more severe septic shock group there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively, P=0.76).
The researchers noted that the study may have been limited by treating without using vasopressin levels to guide the dose or duration of the infusion. In addition, many high-risk patients were excluded, a selection bias that might produce different results in a more "real-world" population.
Also, they said, since the mean arterial pressure at baseline was 72 to 73 mm Hg, the study was essentially of low-dose vasopressin as a "catecholamine-sparing drug" rather than for catecholamine-unresponsive refractory shock.
Dr. Parrillo concluded that there is no compelling reason for use of vasopressin, although it is apparently safe. He emphasized early treatment as a better way to improve survival.
"In both clinical practice and clinical trials," he concluded, "once hypotension occurs in septic shock, we need to initiate immediate antimicrobial therapy, cardiovascular support, and other effective therapies recommended by current guidelines."
The study was supported by a grant from the Canadian Institutes of Health Research.
Dr. Russell and two colleagues reported serving as officers and holding stock in Sirius Genomics, which has submitted a patent, owned by the University of British Columbia and licensed to Sirius Genomics, that is related to the genetics of vasopressin. The University of British Columbia has also submitted a patent related to the use of vasopressin in septic shock, on which Dr. Russell and two co-authors reported being inventors. Dr. Russell and a co-author reported receiving consulting fees from Ferring, which manufactures vasopressin. Dr. Russell reported receiving grant support from Sirius Genomics, Novartis, and Eli Lilly while another author reported support from Sirius Genomics.
Dr. Parrillo reported no conflicts of interest.
Primary source: New England Journal of MedicineSource reference:Parrillo JE "Septic shock -- vasopressin, norepinephrine, and urgency" N Engl J Med 2008; 358: 954-56. Additional source: New England Journal of MedicineSource reference: Russell JA, et al "Vasopressin versus norepinephrine infusion in patients with septic shock" N Engl J Med 2008; 358: 877-87.

Broccoli Sprouts May Protect Against Bladder Cancer

By Crystal Phend
BUFFALO, N.Y., Feb. 28 -- Even before broccoli matures, the much-maligned vegetable shows promise in prevention of bladder cancer. Rats given high doses of freeze-dried broccoli sprout extract were less than half as likely to develop bladder cancer when exposed to a potent carcinogen as rats not fed the extract, reported Yuesheng Zhang, M.D., Ph.D., of the Roswell Park Cancer Institute here, and colleagues in the March 1 issue of the journal Cancer Research. Broccoli sprouts are a particularly good source of a class of phytochemicals called isothiocyanates, which have been linked to reduced risk of bladder cancer in observational studies.
The sprouts contain about 30 times more isothiocyanates than mature broccoli. The broccoli sprout extract fed to the rats contained about 600 times more.
The daily intake of total isothiocyanate in humans through consumption of cruciferous vegetables is estimated to be 0.14 to 1.43 µmol/kg. Although it's probably not possible to eat enough broccoli sprouts to replicate the doses used in the study (40 to 160 µmol/kg), Dr. Zhang acknowledged, he said it likely wouldn't be necessary.
"The carcinogen exposure we as humans have is going to be much lower than those animals had," he said. "I think if we just simply extrapolate these data to humans, the dose of broccoli sprout extract required to have a similar impact on carcinogenesis is going to be much, much lower."
Dr. Zhang's group previously showed that broccoli sprout extract induced production of enzymes in the bladder that protect against carcinogens and oxidants.
To see whether this would result in lower rates of bladder cancer, the researchers randomly assigned 24 rats to each of five groups.
The control group got regular chow and water. Another group got regular chow but received N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their water as a bladder-specific carcinogen representative of nitrosamines, an important class of human carcinogens.
Another two groups got the carcinogen in their water starting two weeks after initiation of the broccoli sprout extract in their diet at a dose of either 40 or 160 µmol isothiocyanate per kg body weight per day.
The final group received broccoli sprout extract without the carcinogen.
After 12 weeks of treatment, all rats were switched to regular diets and water and were sacrificed 24 weeks later.
None of the rats in the control group or the group that received only the extract developed bladder cancer.
All the rats in the group that received only the carcinogen developed dysplasia (4.2%) or carcinoma (95.8%) of the bladder with an average of 1.96 tumors each.
Broccoli sprouts reduced the likelihood of bladder cancer in a dose-dependent manner.
In the lower dose group, 73.9% of the rats developed cancer (a 22.9% reduction) with an average of 1.39 tumors each a 29.1%).
In the higher dose group, only 37.5% developed cancer (60.9% inhibition) with an average of 0.46 tumors per animal (76.5% inhibition).
Tumor size and progression were similarly lower in extract-treated rats.
Another group of rats sacrificed at various times after being given the broccoli sprout extract showed that isothiocyanate equivalents were rapidly absorbed with a peak at one hour after dosing and excreted in the urine over the next 12 hours.
The researchers said the most remarkable finding was that urinary concentrations were two to three orders of magnitude higher in the urine than in the plasma.
Likewise, levels in the bladder were 2.7 to 3.6 times higher in the bladder than in the liver in the first 12 hours after the extract was given and 19.7 times higher at 24 hours.
Isothiocyanate levels in the bladder epithelium, which is directly exposed to urine, were likely substantially higher than those measured in the bladder tissue overall, Dr. Zhang and colleagues noted, suggesting the isothiocyanate selectively reached the target tissue.
"Given that nearly all bladder cancers occur in the epithelium," the researchers concluded, "isothiocyanate-enriched broccoli sprout extract and other cruciferous vegetables rich in isothiocyanates may be particularly useful for prevention of bladder cancer."
The study was supported by Vital Vegetables Research Program of Australia and New Zealand, which is funded by Horticulture Australia and the New Zealand Foundation for Research Science and Technology; by grants from the National Cancer Institute; and the Roswell Park Alliance Foundation.
One of the authors was a founder of Brassica Protection Products, a company that sells broccoli sprouts, and reported being an unpaid consultant for and owning stock in the company. Neither the broccoli sprout extract used in the present study nor the study itself involved the company.
Primary source: Cancer ResearchSource reference:Munday R, et al "Inhibition of Urinary Bladder Carcinogenesis by Broccoli Sprouts" Cancer Res 2008; 68: 1593-1600.

Scientists Find Cancer Culprits in Cigarette Smoke

THURSDAY, Feb. 28 (HealthDay News) -- It's long been known that smoking causes lung cancer, but a new study is the first to show that the hydrogen peroxide in cigarette smoke is what actually causes healthy lung cells to turn cancerous.
Researchers from the University of California, Davis, said their findings may help lead to new treatments for lung cancer and may help the tobacco industry develop "safer" cigarettes by eliminating such substances in the smoke.
"With the five-year survival rate for people with lung cancer at a dismally low 15.5 percent, we hope this study will provide better insight into the identification of new therapeutic targets," senior author Tzipora Goldkorn said in a prepared statement.
In this laboratory study, the researchers exposed different sets of human lung cells to cigarette smoke or hydrogen peroxide and then incubated the cells for one to two days. The cells were then compared to unexposed airway cells. The cells exposed to cigarette smoke and those exposed to hydrogen peroxide showed the same molecular signatures of cancer development. The unexposed cells showed no such changes.
The findings are published in the March issue of The FASEB Journal, published by the Federation of American Societies for Experimental Biology.
Guns kill, bombs kill and cigarettes kill," Dr. Gerald Weissmann, editor-in-chief of The FASEB Journal, said in a prepared statement. "While biologists can't do much about the first two, studies like this will help in the fight against tobacco-related death and disease. These experiments not only pinpoint new molecular targets for cancer treatment, but also identify culprits in cigarette smoke that eventually will do the smoker in."
Cigarette smoking, which causes more than 400,000 deaths a year in the United States (about one in five of all deaths) is the leading preventable cause of premature death in the country, according to the U.S. Centers for Disease Control and Prevention. Smoking causes 90 percent of all lung cancer deaths in men and about 80 percent of lung cancer deaths in women.
Tobacco smoke contains more than 4,000 chemical compounds, including 43 that are know to cause cancer, according to a U.S. Surgeon General report released in 2000.

AAPM: Pain Can Make Patients Want to Kill Physicians

By Ed Susman
KISSIMMEE, Fla., Feb. 18 -- Patients in pain are particularly prone to want to take it out on their physicians in one way or another, even to the point of having thoughts of homicide, according to research reported here. "We haven't performed a prospective validity test on our findings -- that is, do their patients carry out their wish," said psychiatrist David Fishbain, M.D., of the University of Miami. "While we don't know if these patients will take you to court or kill you, we do know that healthcare workers are at a significant risk for patient perpetrated violence."
Dr. Fishbain noted that in one study conducted from 1983 through 1990, pharmacists were at greatest risk for work-related homicides -- 16 per 100,000 -- but physicians were a close second at 15 per 100,000.
In scrutinizing study questionnaires used to develop the Battery for Health Improvement test, Dr. Fishbain found questions pertaining to a patient's hostile wish to sue his physician and the hostile wish to kill the doctor. More than 2,200 patients and healthy participants took part in the process of developing the test.
Dr. Fishbain said a logistic regression analysis confirmed that the characterization of the acute and chronic patients was statistically significant (P<0.001).
"Acute pain patients and chronic pain patients were at greater risk than patients without pain for affirming the hostile wish statements," Dr. Fishbain reported at the American Academy of Pain Medicine meeting.
The study found that the chronic pain patient most likely to harbor the hostile wish is involved in litigation -- and most frequently that is a worker's compensation legal tussle. These patients are forced to see physicians against their will -- often because of dictates of the litigation, and patients don't trust the doctors.
For the acute pain patients, the portrait of the person with the hostile wish are those depressed by the state of their health and the tasks they cannot accomplish. Because of this, they are angry with people in general, including the doctor.
In the healthy community, Dr. Fishbain found that about 1.58% of the people expressed the hostile wish to kill their doctor while 1.5% harbored an urge to sue. The relative risk of having the hostile wish to kill increased by 2.8 times in patients who are not healthy and this group's wish to sue is increased by 3.36 times or about 5.5% of the population.
Acute pain patients in rehabilitation under workmen's comp claims are five times more likely to have a wish to kill the doctor than a healthy person and are three times more likely to sue. A chronic pain patient is a little less than five times more likely to hold a hostile wish, and they are more than four times more likely to think about suing.
Remarkably, 22% of the 18 patients identified in the surveys as having acute pain and are in rehabilitation under workmen's compensation rules and are in litigation have thoughts of killing their doctor -- 14 times that of a person in good health. However, they are seven times more likely than a healthy person to think about suing the doctor.
A person with chronic pain, in rehabilitation programs and involved in litigation is 10 times more likely than a healthy person to harbor a wish about killing the doctor, are 8 times more likely to think about suing.
"I think that doctors should try to diffuse the issues when they are involved in a workmen's compensation case," Dr. Fishbain said. "Tell the patients you are there to render an independent evaluation and treatment and you aren't on his side or on the insurance company's side. Get that in the open -- especially among those patients who are assigned to see you."
"These thoughts about killing a doctor or suing him are part of the ripple effect caused by chronic pain," said Rollin Gallagher, M.D., a clinical professor of psychiatry and anesthesiology at the University of Pennsylvania. "These patients may be more inclined to sue and may harbor wishes of violence if they have pain and are in litigation."
Dr. Gallagher, who was not part of the studies, said that pain patients tend to be frustrated and have loss of hope, problems that doctors need to address and be aware of when they are treating these individuals.
He also said the study points out the need for further education of doctors on the complexity of chronic pain and "emphasizes the need for the timely referral of patients to pain specialists."
Dr. Fishbain disclosed possible financial conflicts of interest with Lilly; Dr. Gallagher reported no financial conflicts of interest. The studies were funded through Pearson Assessments.
Primary source: American Academy of Pain MedicineSource reference:Fishbain D, et al "What are the variables that are associated with the patient's wish to sue his physician in patients with acute and chronic pain?" AAMP Meeting 2008; Abstract 102.

Updated Osteoporosis Guideline Addresses a Broader Population

By John Gever
WASHINGTON, Feb. 22 -- Non-Caucasian women and men over 50 are covered for the first time in new guidelines for prevention and treatment of osteoporosis issued here by the National Osteoporosis Foundation.
The new guide also substantially bumps up the recommended daily intake of vitamin D3 -- to 800 to 1,000 IU from 400 to 600 -- for most people over 50.
The new version includes the following specific recommendations for identifying postmenopausal women and men age 50 and over who should be treated:
A hip or vertebral (clinical or morphometric) fracture
Other prior fractures and low bone mass (bone mineral density T-score from -1.0 to -2.5 at the femoral neck, total hip, or spine)
T-score < -2.5 at the femoral neck, total hip or spine after appropriate evaluation to exclude secondary causes
Low bone mass (T-score from -1.0 to -2.5 at the femoral neck, total hip, or spine) and secondary causes associated with high risk of fracture (such as glucocorticoid use or total immobilization)
Low bone mass (T-score from -1.0 to -2.5 at the femoral neck, total hip, or spine) and 10-year probability of hip fracture ≥3% or a 10-year probability of any major osteoporosis-related fracture ≥ 20% based on the World Health Organization's FRAX model for evaluating 10-year fracture risk, adapted for U.S. women.
WHO's model is based on bone mineral density and nine specific clinical risk factors for osteoporosis and related fractures.
They include age, gender, fracture history, parental hip fracture history, oral steroid therapy, low body mass index, femoral neck bone mineral density, secondary osteoporosis, current smoking, and alcohol intake of at least three drinks daily.
In a press release, the foundation said that dual-energy x-ray absorptionometry instruments now in development will incorporate software to analyze these factors in conjunction with bone mineral density readings. These devices are expected to produce instant reports on patients' 10-year fracture risk.
Currently, clinicians can use an online calculator at the following website: www.shef.ac.uk/FRAX/
Clinicians should note that the WHO model applies only to patients previously untreated for osteoporosis, according to the foundation.
The foundation's guideline development committee, chaired by Bess Dawson-Hughes, M.D., of Tufts University in Boston, adapted this algorithm for the United States to incorporate fracture outcome and mortality data for U.S. women and men as well as a cost-effectiveness analysis to determine when it makes sense to prescribe osteoporosis medications.
Two position papers published online in Osteoporosis International provide details on the adaptation. In them, Dr. Dawson-Hughes and colleagues explained that osteoporosis treatment became cost-effective when the 10-year probability of hip fracture according to the WHO model was at least 3%.
For patients in their 70s and 80s, 10-year fracture risk probability had to surpass about 4% to be cost-effective.
The threshold did not vary substantially between genders or among racial and ethnic groups, although it tended to be slightly higher for men than for women, the researchers said.
The calculation was based on an estimated drug cost of $600 per year for five years with a 35% reduction in fracture rate. The maximum cutoff for cost-effectiveness was set at $60,000 per quality-adjusted life-year gained.
Putting the algorithm at the heart of the new guide "dramatically alters the approach to assessing fracture and risk treatment," Dr. Dawson-Hughes said.
"It provides evidence-based recommendations to help healthcare providers better identify people at high risk for developing osteoporosis and fractures and assures that those at highest risk are recommended for treatment to lower that risk."
The new guide also adds zoledronate (Reclast) to the list of available bisphosphonate drugs. Additionally, it adds two medications now available in Europe, strontium ranelate and parathyroid hormone 1-84PTH to its list of drugs that physicians may consider prescribing off-label.
It also covers prevention steps, including recommended calcium and vitamin D intake, exercise, tobacco cessation, and alcohol reduction.
The new guide and supporting documents, including the Osteoporosis International papers, can be downloaded at the foundation's website: www.nof.org/professionals/Clinicians_Guide.htm
The guidelines were prepared in collaborated with physician representatives of 18 medical societies, including the American Association of Clinical Endocrinologists, the American College of Radiology, the American Orthopaedic Association, and the International Society for Physical Medicine and Rehabilitation.
Development of the guidelines was funded by the National Osteoporosis Foundation.
The research published in Osteoporosis International was funded by the National Osteoporosis Foundation and the National Institutes of Health.
Members of the guideline development committee reported no potential conflicts of interest.
Primary source: National Osteoporosis FoundationSource reference:National Osteoporosis Foundation "Clinician's guide to prevention and treatment of osteoporosis" 2008. Additional source: Osteoporosis InternationalSource reference: Tosteson A, et al., "Cost-effective osteoporosis treatment thresholds: the U.S. perspective from the National Osteoporosis Foundation Guide Committee" Osteoporosis International 2008; DOI:1007/s00198-007-0544-4. Additional source: Osteoporosis InternationalSource reference: Dawson-Hughes B, et al., "Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the U.S." Osteoporosis International 2008; DOI: 10.1007/s000198-007-0559-5.

WHO Finds Global Drug-Resistant TB at Record Levels

By Peggy Peck
GENEVA, Feb. 27 -- Cases of multidrug-resistant tuberculosis have reached record levels worldwide and extensively drug-resistant tuberculosis (XDR-TB) has spread to 45 countries, according to the World Health Organization.
In its first major TB report in four years, the WHO estimated the global proportion of drug-resistant TB at 4.6%. China and India are estimated to account for 50% of the global burden of drug-resistant cases with the Russian Federation adding a further 7%.
The WHO findings were derived from data collected from 2002 through 2006 on 90,000 TB patients in 81 countries.
These survey data mark the first time that the global analysis included information about XDR-TB, but because few countries are currently equipped to diagnose this emerging disease, limited data were available for the report.
On the basis of the survey data, the WHO estimates there are nearly half a million new cases of MDR-TB a year, or about 5% of the nine million new TB cases of all types.
The highest rate was recorded in Baku, the capital of Azerbaijan, where nearly a quarter of all new TB cases were reported as multidrug-resistant.
Proportions of MDR-TB among new TB cases were 19.4% in Moldova, 16% in Donetsk in Ukraine, 15% in Tomsk Oblast in the Russian Federation, and 14.8% in Tashkent in Uzbekistan.
These rates surpass the highest levels of drug resistance published in the previous WHO report in 2004. Surveys in China also suggest that MDR-TB is widespread there.
But the true scale of the problem is unknown because few countries at risk have the needed surveillance programs, said Abigail Wright, M.P.H., a WHO TB expert who was the lead author of the report.
For example, only six countries in Africa -- the region with the highest occurrence rate of TB in the world -- were able to provide drug-resistance data. Other countries in the region could not conduct surveys because they lack the equipment and trained personnel needed to identify drug-resistant TB.
"Without these data, it is difficult to estimate the true burden and trends of MDR-TB and XDR-TB in the region," Wright said. "It is likely there are outbreaks of drug resistance going unnoticed and undetected."
The WHO also identified a link between HIV infection and MDR-TB in Latvia and Ukraine, where HIV-infected TB patients were twice as likely to have MDR-TB as patients who were not HIV-positive.
According to WHO, effective control of TB in low and middle-income countries would cost $4.8-billion in 2008, with $1-billion of that earmarked for MDR-TB and XDR-TB control. But the said current funding for TB control is $2.5-billion short of the needed amount.
Mario Raviglione, M.D., director of the WHO Stop TB Department, said fighting the growth of resistant TB strains requires "a frontal assault. If countries and the international community fail to address it aggressively now, we will lose this battle."

Analysis Gives Venlafaxine Slender Edge Over SSRIs

By Charles Bankhead
ATLANTA, Feb. 27 -- For achieving major depression remission, a dual neurotransmitter reuptake inhibitor has a thin advantage over selective serotonin reuptake inhibitors, found a meta-analysis. Slightly more patients with major depression went into remission with venlafaxine (Effexor), the dual neurotransmitter reuptake inhibitor, than did those taking SSRIs. But the clinical significance of the difference remained unclear. Venlafaxine demonstrated a 5.9% advantage in remission rates in direct clinical comparisons with SSRIs, Charles Nemeroff, M.D., Ph.D., of Emory University, and colleagues, reported in the Feb. 15 issue of Biological Psychiatry. In a small number of trials that included a placebo arm, venlafaxine achieved a 13% difference in remission rates compared with a 6% difference between SSRIs and placebo.
"One would expect to treat approximately 17 patients with venlafaxine to see one more success than if all had been treated with another SSRI," the authors said. "Although this difference was reliable and would be important if applied to populations of depressed patients, it is also true that it is modest and might not e noticed by clinicians in everyday practice."
"Nonetheless, a number needed to treat of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder," they added.
The approved antidepressants are widely perceived as having similar efficacy, the authors said. However, few individual studies of newer antidepressants have had sufficient statistical power to demonstrate a difference in efficacy between effective therapies.
A meta-analytical approach offers the potential to reveal meaningful differences that individual randomized controlled trials could not, the authors continued. Previous meta-analyses have suggested that venlafaxine, which inhibits reuptake of serotonin and norepinephrine, has an efficacy advantage over SSRIs.
The current study, funded by Wyeth, continued the meta-analytical approach and involved two strategies for analyzing the data. One meta-analysis included all double-blind Wyeth-sponsored trials comparing venlafaxine and SSRIs. The authors said the limited analysis was undertaken to ensure access to individual patient data.
For the second analysis, the investigators used a funnel plot analysis to extend the primary dataset by including data from all studies in the public domain. The funnel plot analysis was based on 48 studies, including 14 additional studies, 11 of which were not funded by Wyeth. No evidence of statistically significant selection bias was observed in the updated analysis of 48 studies, suggesting to the authors that study sponsorship did not significantly influence outcomes.
The study included 34 randomized, double-blind studies of 4,191patients treated with venlafaxine or 3,621 given an SSRI. Nine studies with 932 patients also included a placebo control arm. The primary outcome was intent-to-treat remission rates at week eight, as defined by a Hamilton Rating Scale score of ≤7.
The overall difference between venlafaxine and the SSRIs as a class was statistically significant (P<0.001). When the SSRIs were considered separately, venlafaxine had a statistically significant advantage only versus fluoxetine (6.6%, 95% CI 0.030 to 0.095). Significantly more patients withdrew because of adverse events with venlafaxine than with SSRIs (11% versus 9%, P=0.0011).
Acknowledging limitations of the study, the authors said the generalizability of the findings to clinical practice is unknown as patients with more complex conditions were excluded from the trials. The trials involved short-term treatment, and the possibility of SSRI "catch up" with longer treatment could not be ruled out. They also acknowledged potential questions about the validity of combining all the SSRIs into a single group for the analysis.
Dr. Nemeroff had a lengthy list of financial disclosures that included relationships with Wyeth, which sponsored the study.
Primary source: Biological PsychiatrySource reference:Nemeroff CB, et al "Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs" Biol Psychiatry 2008; 63: 424-434.

Prognosis: Large Social Networks May Help Surgical Patients

By NICHOLAS BAKALAR
Having a large network of friends and family, a new study suggests, may help surgical patients experience less anxiety and pain before their operations and a quicker recovery afterward.
Researchers studied 605 people scheduled for chest or abdominal operations. They estimated their social connectedness by determining how many close friends and relatives each had, and how often they attended social functions. Using well-validated scales, the patients rated their levels of pain and anxiety before and after their operations.
The one-fifth of patients with the smallest social networks reported almost twice as much postoperative pain intensity as the one-fifth with the largest. Smaller social networks were also associated with longer hospital stays.
The authors, writing in the February issue of The Journal of the American College of Surgeons, say it is not clear from their data whether poor social connectedness is a cause or a result of increased postoperative pain. But when they adjusted for preoperative pain level, the effect of social connectedness on postoperative pain disappeared. This suggests a strong association between social network size and preoperative pain levels, which may be the reason for the easier postoperative recovery.
“The average physician, when he takes a social history, asks about smoking and drugs and not the real social situation of the patient,” said Dr. Daniel B. Hinshaw, the senior author and a professor of surgery at the University of Michigan. “And yet it looks like this is a real marker for problems.”

Gentlemen, 5 Easy Steps to Living Long and Well

By NICHOLAS BAKALAR
Living past 90, and living well, may be more than a matter of good genes and good luck. Five behaviors in elderly men are associated not only with living into extreme old age, a new study has found, but also with good health and independent functioning.
The behaviors are abstaining from smoking, weight management, blood pressure control, regular exercise and avoiding diabetes. The study reports that all are significantly correlated with healthy survival after 90.
While it is hardly astonishing that choices like not smoking are associated with longer life, it is significant that these behaviors in the early elderly years — all of them modifiable — so strongly predict survival into extreme old age.
“The take-home message,” said Dr. Laurel B. Yates, a geriatric specialist at Brigham and Women’s Hospital in Boston who was the lead author of the study, “is that an individual does have some control over his destiny in terms of what he can do to improve the probability that not only might he live a long time, but also have good health and good function in those older years.”
The study followed more than 2,300 healthy men for as long as a quarter-century. When it began, in 1981, the subjects’ average age was 72. The men responded to yearly questionnaires about changes in health and lifestyle, and researchers tested their mental and physical functioning. At the end of the study, which was published Feb. 11 in The Archives of Internal Medicine, 970 men had survived into their 90s.
There was no less chronic illness among survivors than among those who died before 90. But after controlling for other variables, smokers had double the risk of death before 90 compared with nonsmokers, those with diabetes increased their risk of death by 86 percent, obese men by 44 percent, and those with high blood pressure by 28 percent. Compared with men who never exercised, those who did reduced their risk of death by 20 percent to 30 percent, depending on how often and how vigorously they worked out.
Even though each of these five behaviors was independently significant after controlling for age and other variables, studies have shown that many other factors may affect longevity, including level of education and degree of social isolation. They were not measured in this study.
Although some previous studies have found that high cholesterol is associated with earlier death, and moderate alcohol consumption with longer survival, this study confirmed neither of those findings.
A second study in the same issue of the journal suggests that some of the oldest of the old survive not because they avoid illness, but because they live well despite disease.
The study of 523 women and 216 men ranging in age from 97 to 119 showed that a large proportion of people who lived that long and lived with minimal or no assistance did so despite long-term chronic illness. In other words, instead of delaying disease, they delay disability.
Dr. Dellara F. Terry, the lead author and an assistant professor of medicine at Boston University, said the study showed that old age and chronic illness were no reason to stop providing thorough treatment. “We should look at the individual in making treatment decisions,” Dr. Terry said, “and not base our decisions solely on chronological age.”

China: Rise in AIDS and Syphilis

China disclosed a large percentage rise for 2007 in diseases transmitted sexually or via blood, including AIDS and syphilis, without reporting exact figures. The number of new AIDS cases rose 45 percent in 2007 from the year before and new syphilis cases rose 24 percent, the Health Ministry said on its Web site. It did not elaborate. China has been battling an acknowledged rise in cases of AIDS and H.I.V., the virus that causes AIDS, now mainly sexually transmitted, though it had said before that the overall rate was slowing. In the past, most cases were caused by intravenous drug use. The government said last year that it estimated that about 700,000 people had H.I.V. or AIDS.

For the Very Old, a Dose of ‘Slow Medicine’

By ABIGAIL ZUGER, M.D.
My Mother, Your MotherEmbracing "Slow Medicine," the Compassionate Approach to Caring for Your Aging Loved Ones. By Dennis McCullough, M.D. HarperCollins. 263 pages. $25.95
It was two decades ago that a group of culinary mavericks took a giant step backward down the evolutionary trail with the “slow food” movement. Instead of fast food produced by the assembly lines of giant consortiums, they championed products of small-scale agriculture — time-consuming to prepare, beautiful to behold, very good for you.
Now (and, some might add, at last) doctors are following suit, rejecting the assembly line of modern medical care for older, gentler options. The substituted menu is not for all patients — at least not yet. For the very elderly, however, most agree the usual tough love of modern medicine in all its hospital-based, medication-obsessed, high-tech impersonality may hurt more than it helps.
In its place, doctors like Dennis McCullough, a family physician and geriatrician at Dartmouth Medical School, suggest “slow medicine” — as he puts it, “a family-centered, less expensive way.”
This medicine is specifically not intended to save lives or to restore youthful vigor, but to ease the inevitable irreversible decline of the very old.
Dr. McCullough directs his book to the children of elderly parents, and he pegs it to the story of his mother. She evolved from a vital, healthy 85-year-old retiree to a feeble 92-year-old dying in hospice care, not from any particular disease so much as the aggressive frailty common among the oldest of old people.
His bottom line is this: It is up to friends and relatives to rescue the elderly from standard medical care. And slow medicine, like slow food, involves a lot of hard work. Readers who sign on will acquire a staggering list of tasks to perform, some of which may be just as tiring and tear-producing as chopping onions.
First, while the aging parent is still vital and lively, children must not fool themselves that this happy situation will last forever. This is the time, Dr. McCullough suggests, to reinsert themselves back into the parent’s life, to show up at doctor visits and to raise unpleasant topics like advance directives and health proxies.
After few more years, it is time to address the “Should you still drive?” and “Can you still manage at home?” issues, and to help create routines that compensate for a slipping memory and slightly wobbly balance.
Medical crises will inevitably arise; the child must be vigilant for a hospital’s bad habits when caring for elderly patients. An “advocacy team” of friends and relatives should be mustered to help protect the hospitalized parent; a wider “circle of concern” should be tapped for moral support.
Still down the road is the complex world of rehabilitation, either home-based or institutional, and the even more complex spectrum of available nursing options for the slightly impaired, the seriously impaired and those near death.
All the while, medical care for the parent should favor the tried and true over the high tech. For instance, Dr. McCullough points out that instead of a yearly mammogram, a manual breast exam may suffice for the very old, and home tests for blood in the stool may replace the draining routine of a colonoscopy.
The parent’s doctors should be nudged to justify flashy but exhausting diagnostic tests, and to constantly re-evaluate medication regimens. The high-blood-pressure pills that are life-saving at 75 may cause problems at 95, and paid companionship or a roster of visitors may prove to be antidepressants at least as effective as any drug.
The pace of care should be slowed to a crawl. For doctors, that means starting medications at low doses and increasing them gradually. For children, that means learning not to panic and yell for an ambulance on every bad day. And for a good overall picture of a parent’s condition, a child is well advised to ignore the usual medical and nursing jargon and to focus instead on the sound of the parent’s own voice. “No one,” Dr. McCullough says, “can be a bigger expert on a parent’s voice than a former teenager trained in the same household.”
Some standard self-help muzziness creeps around the edges of this book, with reflections on the value of scrapbooks to preserve family memories and admonitions that “it is always the right time to say ‘thank you’ and ‘I love you.’ ” Dr. McCullough’s decision to call each stage of old age a “station” (as in “The Station of Crisis,” “The Station of Decline” and “The Station of Prelude to Dying”) may be a little too religious for some and far too reminiscent for others of the food stations at large catered events.
Instead, he might have steeled the book’s spine with a few hard-headed tips for those who would valiantly try to slow the twin Mack trucks of the modern doctor and the modern hospital. How should relatives go about applying the brakes to their fast doctors without alienating them or earning for themselves the label of troublemaker? Dr. McCullough, by his own report, works in something of a paradise when it comes to geriatric care, but in many medical venues the phrase “slow down” is an obscenity.
Still, he has written a valuable book, chilling and comforting in equal measure. A similar book directed at fast doctors, fast hospital administrators and fast insurers might be the next welcome stride backward down the path.

Just 1 in 4 know heart attack signs

By MIKE STOBBE,
Only about 1 in 4 Americans know the warning signs of a heart attack and what to do first, according to a new government report. That's a decline in knowledge since the last survey in 2001, which showed nearly 1 in 3 to be well informed.
The study's lead author, Dr. Jing Fang, called public awareness in the new survey "alarmingly low." Fang is with the Centers for Disease Control and Prevention, which surveyed residents of 13 states and the District of Columbia.
Heart attack warning signs can include one or more of the following five symptoms: shortness of breath; pain or discomfort in the chest; discomfort in the arms or shoulder; a feeling of weakness or lightheadedness; and discomfort in the jaw, neck or back.
Chest pain is the most common symptom. Women are more likely than men to experience some of the other symptoms, particularly shortness of breath and back or jaw pain, according to the American Heart Association.
Anyone experiencing these symptoms should call 911, the heart association advises.
The groups best informed of heart attack warning signs and what to do about them tended to be white, highly educated, and women. Also scoring well were residents of West Virginia, which has some of the nation's highest heart attack death rates.
Each year more than 900,000 Americans suffer a heart attack, and about 157,000 of them are fatal. About half the deaths occur within an hour of symptoms occurring, experts say.
Because different people experience different symptoms, it's important to be aware of all of them, doctors say.
"It's not always massive chest pain," said Wayne Rosamond, a University of North Carolina epidemiology professor and expert on heart disease statistics.
Of course, knowing is not the same as doing: Although most of those who got the heart attack symptoms right said they would call 911, other studies show that only about half of heart attack victims go to a hospital by ambulance, Rosamond noted.
Patients' concerns about lack of health insurance status or other matters may explain why so few go to a hospital, said Rosamond, who was not involved in the new study.
The CDC's findings were based on a random-digit-dial telephone survey of about 72,000 people in 2005.
In West Virginia, more than 35 percent of respondents from that state knew all five warning signs and that they should call 911, compared with 27 percent in the overall study population.
Iowa and Minnesota also were at the top of the list. The gap between West Virginia and the two other states was not statistically significant.
West Virginia consistently ranks among the states with the highest heart attack deaths rates, and also is a leader in smoking, obesity, high cholesterol and other heart disease risk factors. But it's not clear whether personal experience was the reason the state's residents were so well informed. Public health education campaigns or other factors may also explain the result, experts said.

Chinese woman dies of bird flu


A migrant worker has died of the H5N1 virus in southern China, the Hong Kong government said Tuesday, as the country confirmed its fourth outbreak of bird flu among poultry this year.
The woman who died Monday in Shanwei, a coastal city in eastern Guangdong province, tested positive for the deadly H5N1 avian flu virus, Hong Kong's Health Department said in a statement issued after receiving confirmation from China's Health Ministry.
Her death marked the country's 20th fatality from the deadly H5N1 virus and its third this year.
The woman had been in contact with dead poultry before becoming sick Feb. 16, a statement on the Web site of Guangdong's Health Department said Monday.
Meanwhile, China confirmed its fourth outbreak of bird flu among poultry this year but said it had been effectively contained.
Nearly 4,000 poultry were killed by the H5N1 virus in southwestern China's Guizhou province, the Agriculture Ministry said on its Web site Monday. Another 240,000 were culled to contain the outbreak.
China, which raises more poultry than any other country in the world, has vowed to aggressively fight H5N1, which has killed 232 people worldwide, according to the World Health Organization.
Bird flu remains hard for people to catch, but health experts worry the virus could mutate into a form that passes easily among humans, sparking a pandemic. So far, most human cases have been traced to contact with infected birds.
China has already reported two human deaths from H5N1 this year. Since 2003 when the virus began ravaging poultry stocks in Asia, the country has had 19 human deaths from bird flu, the WHO says.
Three outbreaks of bird flu in poultry were reported in China in 2008, two in the far western region of Tibet and another in the northwestern region of Xinjiang.