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Content 7


The Doctor and the Pharmacist

Radio Show Articles:
March 16, 2013

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Is Sugar Intake Specifically Driving the Diabetes Epidemic?
Mediterranean Diet Lowers Rates of Adverse Cardiovascular Events
Coronary Disease's Long History — Ask the Pharaohs
Vitamin D and Calcium Supplementation in Women: Making Sense of Conflicting Data
Vitamin D and Calcium: What Women Need at Midlife and After
Treatment of Preschool-Age Children with ADHD: A Cautionary Note
Azithromycin: FDA Issues Cardiac Warning
Agricultural Antibiotic Use and Antibiotic Resistance
Breast Irradiation and Increased Risk for Ischemic Heart Disease: New Data Emerge
Circulating Tumor DNA Tracks Metastatic Breast Cancer in Proof-of-Concept Study
Big Price Tag on Smallpox Antiviral Stockpile
Quitting Smoking Lowers CV Risk, Regardless of Weight Gain
Breast-Feeding Intervention Doesn't Reduce Childhood Obesity
Most Women Aren't Receiving the Best Treatments for Ovarian Cancer
Intranasal Ketamine for a Neuropsychiatric Condition
About a Quarter of Screening Colonoscopies in U.S. Elderly Seem Inappropriate
Can Maternal Folic Acid Supplementation Prevent Autism?

MM: The title and even the abstract of this article can be very misleading. It took reading the original report that truly clarified that High Fructose Corn Syrup (HFCS) was the main culprit in this global epidemic. Unfortunately there is often "spin" in the medical literature as there is in so many other areas. Many regions of the world that have had cane or beet sugar as the primary form of sweetener are now using the prolifically available and inexpensive HFCS alternative and this seems to be directly related to the increasing obesity and diabetes epidemic.
PLoS ONE 2013 Feb 27; 8:e57873
Is Sugar Intake Specifically Driving the Diabetes Epidemic?
In a country-by-country analysis, sugar availability is related to prevalence of diabetes.
Multiple factors, including overweight and obesity, are associated strongly with diabetes. Yet, in individuals and in population-based studies, the correlation is far from perfect: We see both thin diabetic patients and people with marked obesity but normal blood glucose levels. In addition, some countries have high rates of obesity but low prevalence of diabetes, and some have the reverse.
In a new study, researchers in California examined cross-sectional data from 175 countries. After controlling for the availability of food types, weight, age, income, and urbanization, the investigators found that the availability of sugar (and no other food) correlated strongly with prevalence of diabetes. The availability of calories from all types of foods had a weak positive correlation with prevalence of diabetes, but the availability of calories specifically from sugar had a strong positive correlation: For every 150 kcal/person/day increase in sugar availability, national prevalence of diabetes increased by 1.1%. The duration and degree of sugar availability correlated with diabetes in a dose-dependent manner.
Comment: This study provides evidence that intake of sugar, more than isocaloric intake of other foods, might be an important factor driving the diabetes epidemic. However, an ecological study such as this cannot prove that the association is causal. Also, an important potential confounder — levels of exercise — was not tested robustly.
Anthony L. Komaroff, MD  Published in Journal Watch General Medicine March 12, 2013
Citation(s): Basu S et al. The relationship of sugar to population-level diabetes prevalence: An econometric analysis of repeated cross-sectional data. PLoS ONE 2013 Feb 27; 8:e57873.
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MM: The use of a Mediterranean Diet appears to lead to more of a Quality of Life (QOL) issue rather than an actual lengthening of life since there is such a significant effect on stroke risk.
N Engl J Med 2013 Feb 25
Mediterranean Diet Lowers Rates of Adverse Cardiovascular Events
In a primary prevention trial, this diet modestly outperformed a low-fat diet.
The so-called Mediterranean diet is thought, mostly on the basis of observational studies, to confer cardiovascular benefit. Now, Spanish researchers have put this diet to the ultimate test — a large, randomized, primary-prevention trial.
About 7500 people (age range, 55–80) without known cardiovascular disease but with either diabetes or ≥3 nondiabetes cardiac risk factors were randomized to one of three diets:

During average follow-up of 5 years, the primary composite outcome (myocardial infarction, stroke, or cardiovascular-related death) occurred significantly less often in the two Mediterranean-diet groups than in the control group (8 per 1000 person-years in each Mediterranean group vs. 11 per 1000 person-years in the control group). Among the three components of the primary endpoint, only stroke was significantly lower in the intervention groups. The two Mediterranean diets did not lower all-cause mortality significantly.
Comment: In this primary-prevention trial, two Mediterranean diets were associated with lower rates of cardiovascular events — about three fewer events per 1000 person-years — compared with a standard low-fat diet. Although some of the publicity surrounding this trial emphasized the merits of supplemental extra-virgin olive oil and nuts, we should note that the underlying diets differed: For example, wine with meals and legumes were recommended in the Mediterranean diets, whereas low-fat dairy products, bread, pasta, and potatoes were recommended in the control diet.
Allan S. Brett, MD  Published in Journal Watch General Medicine March 12, 2013
Citation(s): Estruch R et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013 Feb 25; [e-pub ahead of print].
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Coronary Disease's Long History — Ask the Pharaohs
Heart disease apparently has been plaguing humankind for thousands of years, according to a study in the Lancet. Whole-body CT scans of 137 mummies from four distinct geographical regions — including ancient Egypt and Peru — found probable or definite atherosclerosis in 34%. How'd they keep this under wraps for so long?
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MM: I still maintain that the IOM's Vitamin D recommendations are too low and too conservative but at least they are moving in the proper direction. Increased awareness of calcium requirements and sources of this mineral is a real eye opener. I have questioned calcium supplements for almost 20 years and it is nice to know that my concerns were valid. The reality is that calcium in our diet is superior form than high dose supplements.
Vitamin D and Calcium Supplementation in Women: Making Sense of
Conflicting Data

Most women should strive to eat a diet rich in these nutrients and consider supplements only if necessary to meet the RDA.
Many clinicians are confused about the benefits and risks of vitamin D and calcium supplementation for midlife and older women. We offer guidance on the appropriate use of these supplements.


Long recognized as important for skeletal health, vitamin D has garnered recent interest for its possible nonskeletal benefits. This vitamin is synthesized in the skin in response to sunlight and can also be ingested as vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol). Natural dietary sources of vitamin D are few and include fatty fish and egg yolks. Vitamin D is also commonly added to milk and some other dairy products, cereals, and orange juice. Vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D], the major circulating metabolite, and is then further converted to 1,25-dihydroxyvitamin D (calcitriol).
A recent evidence-based Institute of Medicine (IOM) report1,2 provides guidelines about the amount of vitamin D that most North American women should consume. The IOM's review confirmed that vitamin D clearly confers bone benefits, but found that current data are insufficient to conclude that it lowers risk for nonskeletal diseases (e.g., cardiovascular disease [CVD], diabetes, cancer); thus, the IOM based its recommendations only on the amount required for bone health:

Because the IOM assumed little to no sun exposure, these guidelines apply even to individuals living in northern latitudes during the winter.
The IOM also reviewed safety data on high-dose vitamin D supplements and set the tolerable upper level of daily intake at 4000 IU (previously 2000 IU). Extremely high intakes can lead to hypercalcemia, thereby damaging the kidneys and heart, but data are lacking about the long-term safety of intakes above the RDA. Several ongoing randomized trials should clarify the benefit-risk balance of such doses. For example, in the large, 5-year VITamin D and OmegA-3 TriaL (VITAL), researchers are testing 2000-IU daily supplemental vitamin D3 for primary prevention of cancer and CVD.3
The IOM's recommendations reflect a population-level, public-health orientation and are intended to complement but not replace individualized clinical decision making. Clinical guidelines that combine both perspectives are useful.4 Per the IOM, most healthy individuals should do their best to meet the aforementioned RDAs and do not need routine 25(OH)D testing. However, for individuals with risk factors for, or clinical conditions associated with, vitamin D insufficiency (e.g., malabsorption, osteoporosis), 25(OH)D measurement is prudent. If the level is <20 ng/mL, two approaches to vitamin D therapy are as follows:

Roughly speaking, 25(OH)D increases by 6 to 10 ng/mL for each additional 1000 IU daily of supplemental vitamin D3.4 Reassessing 25(OH)D is necessary about 3 months after a dose change to check that the target level has been attained. Some organizations recommend maintenance levels >30 ng/mL for "at-risk" individuals. The IOM recommends avoiding 25(OH)D levels >50 ng/mL, as some research suggests excess risk for CVD,1 pancreatic cancer,5 all-cause mortality,6 and even fractures7 at these levels.


The IOM also conducted a parallel assessment of calcium and concluded that this nutrient provides critical bone benefits.1,2 The Women's Health Initiative (WHI), a randomized trial of the benefits and risks of daily calcium (1000 mg) and low-dose vitamin D (400 IU) supplements in 36,282 postmenopausal women (age range, 50–79), showed that treatment led to significantly less bone loss at the hip and a 12% reduction in hip fracture rate.8 Although the latter figure was lower than expected and not statistically significant, it was one of the findings that led to the influential U.S. Preventive Services Task Force's 2013 assertion that this treatment is ineffective for fracture prevention at midlife and beyond.9 However, among WHI participants aged ≥60 — the age group most likely to sustain osteoporotic fractures — the intervention was associated with a larger, statistically significant 21% reduction in hip fracture rate.8 Moreover, among participants who took their study pills regularly and were not already taking supplements, the intervention was associated with a still larger, statistically significant 30% reduction in hip fracture rate.8 Participants with intakes ≥1200 mg/daily at baseline did not clearly benefit from the intervention, suggesting that "more is not necessarily better." The evidence as a whole points to the need for sufficient calcium to ensure bone health and prevent fractures.1,2,10
The IOM set the current RDA for calcium (from food plus supplements) at 1000 mg for women aged ≤50 and 1200 mg for those aged >50. Many women are consuming unnecessarily high doses of supplemental calcium. Instead, they should aim to meet the RDA by eating calcium-rich foods (e.g., milk, yogurt, cheese, and other dairy foods; fish such as sardines or salmon; tofu; calcium-fortified juice and cereals; broccoli, collard greens, and kale) and consider supplements only if their diet does not provide the recommended amount of calcium. Given that the median daily dietary calcium intake of midlife and older women is about 700 mg1 (equivalent to 2–3 servings of the above foods), many women need no more than about 500 mg daily in calcium supplements to meet the RDA.10
Calcium from food does not seem to raise CVD risk (indeed, observational data suggest that the opposite may be true11), but calcium supplements may raise blood calcium levels more rapidly than dietary calcium, thereby boosting risk for heart disease. This hypothesis, however, remains unproven.10 In the WHI, no overall elevation in myocardial infarction (MI) or stroke risk occurred,12 although a 22% increase in MI risk was noted among participants who first began taking calcium supplements as part of the trial (but not among those already taking them at baseline).13 However, the supplements did not increase coronary artery calcification at trial's end.14 Also, a review of randomized trials showed that, compared with placebo, calcium supplements (whether alone or with vitamin D) were not linked to CVD risk.11 Nevertheless, striving to obtain calcium from food rather than from supplements — while ensuring adequate concurrent vitamin D intake — is wise.
Regarding other clinical outcomes in the WHI, a significant 17% increase in risk for kidney stones was noted,8 but the background intake of calcium was high. Total mortality was reduced by 9% (a finding of borderline statistical significance),15 and risk for total, colorectal, or breast cancer was unaffected.16 Overall, the findings suggest that calcium supplementation to bring the total intake of this nutrient to the RDA level — but not to exceed it — can lower risk for hip fracture without raising risk for CVD or other major adverse events.10


To maintain bone health, current recommendations for daily vitamin D intake call for 600 IU for women aged ≤70 and 800 IU for those aged >70, and recommendations for daily calcium intake are 1000 mg for women aged ≤50 and 1200 mg for those aged >50. The benefit–risk balance of long-term supplementation with doses of vitamin D and/or calcium that exceed the RDA is the subject of ongoing research. Most women should endeavor to eat a diet rich in these nutrients and consider supplements only if necessary to meet the RDA.
— JoAnn E. Manson, MD, DrPH, and Shari S. Bassuk, ScD  Dr. Manson is Professor of Medicine and Chief, Division of Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital; and a WHI principal investigator. Dr. Bassuk is an epidemiologist and science writer at Brigham and Women's Hospital.
Published in Journal Watch Women's Health February 28, 2013
1. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. The National Academies Press; 2011.
2. Ross AC et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab 2011 Jan; 96:53.
3. Manson JE et al. The VITamin D and OmegA-3 TriaL (VITAL): Rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 2012 Jan; 33:159.
4. Szmuilowicz ED and Manson JE. How much vitamin D should you recommend to your nonpregnant patients? OBG Management 2011 Jul; 23:45.
5. Stolzenberg-Solomon RZ et al. Serum vitamin D and risk of pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Screening Trial. Cancer Res 2009 Feb 15; 69:1439.
6. Melamed ML et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008 Aug 11; 168:1629.
7. Sanders KM et al. Annual high-dose oral vitamin D and falls and fractures in older women: A randomized controlled trial. JAMA 2010 May 12; 303:1815.
8. Jackson RD et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006 Feb 16; 354:669.
9. U.S. Preventive Services Task Force. Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement.
10. Manson JE and Bassuk SS. Calcium supplements: Do they help or harm? North American Menopause Society (NAMS) Practice Pearl September 6 , 2012.
11. Wang L et al. Calcium intake and risk of cardiovascular disease: A review of prospective studies and randomized clinical trials. Am J Cardiovasc Drugs 2012 Apr 1; 12:105.
12. Hsia J et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 2007 Feb 20; 115:846.
13. Bolland MJ et al. Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ 2011 Apr 19; 342:d2040.
14. Manson JE et al. Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative. Menopause 2010 Jul; 17:683.
15. LaCroix AZ et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: The Women's Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 2009 May; 64:559.
16. Manson JE et al. Vitamin D and prevention of cancer — ready for prime time? N Engl J Med 2011 Apr 14; 364:1385.
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Vitamin D and Calcium: What Women Need at Midlife and After
Both nutrients are important for bone health.
With conflicting nutritional information available from multiple sources, it's hard to decide not only what to eat, but what, if any, supplements to take. It's commonly recommended that women — especially as they get older — should take calcium and vitamin D supplements to help strengthen bones and protect against future fractures (broken bones). However, the U.S. Preventive Services Task Force (USPSTF) recently concluded that there isn't enough proof that taking these supplements before or after menopause prevents fractures in women who never had fractures before, and that the possible harm supplements may cause is unknown.
So what should you do? Here's what we know right now about calcium and vitamin D for midlife and older women.


What It Is: Vitamin D is not a true vitamin. It's considered a "prohormone," a substance from which hormones are made. It comes in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). If you are buying a vitamin D supplement, you may see both forms on the shelf. Unlike other vitamins, vitamin D can be made by the body: Your skin manufactures it when exposed to sunlight.
What It Does: Vitamin D works in the small intestine to help absorb calcium into the bloodstream, so that the calcium can help build bone. Vitamin D also helps strengthen muscles and the immune system and helps reduce inflammation. The bone-health benefits of vitamin D have been clearly shown. Some studies have suggested that vitamin D plays a role in preventing cardiovascular disease or some cancers. However, there is not yet enough information to prove that any dose of vitamin D can protect against these conditions, and its use for this purpose is not recommended.
How Much You Need: If you are regularly exposed to sunlight even for a short amount of time (as little as 15–30 minutes twice a week), you might have enough vitamin D. However, as you age, your body may be less efficient at making vitamin D; also, many women avoid sun exposure to protect against skin cancer and wrinkling. The recommended daily amount of vitamin D is:

A blood test can determine if you are getting an adequate amount of vitamin D (or too much). This test is not routinely recommended but can be helpful if you have malabsorption (decreased ability to absorb nutrients), osteoporosis, fractures, or another condition that makes having adequate vitamin D especially important. Your clinician (doctor, nurse practitioner, nurse midwife, or physician assistant) might have an individualized recommendation about vitamin D for you if you have certain health conditions.
How Much Is Too Much: Very high doses of vitamin D can increase calcium levels in the blood, causing kidney and heart damage. Unlike many other vitamins, D can build up in the body over time. Some ongoing studies are looking at exactly how much vitamin D is too much; for now, it is recommended that you not use supplements over 4000 IU for an extended period. If you are taking several different dietary supplements, check the labels on all of them to be sure you are not overdoing it. Don't worry about getting too much vitamin D from sun exposure or foods; that's not likely to happen.
How to Get It: Vitamin D occurs naturally in very few foods: egg yolks, fatty fish (mackerel, salmon, tuna), and beef liver. Some foods are fortified with vitamin D (and say so on the label): milk and other dairy products, cereals and grains, orange juice. If you can't get enough vitamin D from sunshine and your diet, many forms of nonprescription vitamin D supplements are available in various doses; some calcium supplements have vitamin D added as well. Many regular daily multiple vitamin supplements contain the recommended amounts of vitamin D, so check the label. As with all vitamins, inexpensive generic vitamin D supplements purchased at a pharmacy or grocery store work just as well as expensive name-brand ones advertised as "natural" or in some way superior. Look for "USP verified" on the label. Manufacturers of supplements are not required to follow the same strict guidelines as for prescription drugs. However, they may choose to have the USP agency check their products. "USP verified" means the supplement actually contains the ingredients on the label, does not contain harmful chemicals, will be released into the body in a specified amount of time, and has been manufactured according to strict guidelines.
For your body to absorb vitamin D well, take it with a meal that contains some fat — preferably "good fats" found in avocados, olive oil, fatty fish, or nuts.


What It Is: Calcium is a mineral that is essential to health in many ways.
What It Does: Calcium makes up most of your bones and teeth. It also plays a role in clotting blood and helping nerves, muscles, and the heart to work properly. Getting an adequate amount of calcium is necessary for bone health. Some studies have suggested that calcium, like vitamin D, may play a role in preventing some cancers or cardiovascular disease, but it's too early to say whether this is true.
How Much You Need: The recommended daily amount of calcium from food and — if necessary — supplements, is:

How Much Is Too Much: Taking too much calcium from supplements can cause kidney stones and heart disease. Don't worry about getting too much calcium from your diet, though; this does not seem to be a health problem and in fact might be beneficial. If you're using supplements, don't take more than the recommended amount.
How to Get It: Calcium is found in many foods, such as dairy products (milk, yogurt, cheese), some fish (such as sardines and salmon), tofu, calcium-fortified juices, and some dark green vegetables. If you eat three to four 8-ounce servings of dairy products a day, you are probably getting enough calcium from your diet. If you don't get enough dietary calcium, consider a supplement only to bring the total amount up to the recommended level. Supplements are available in various forms, including tablets, capsules, liquids, and candy-like chews. Some calcium supplements also contain vitamin D. As with vitamin D, inexpensive generic supplements are just as effective as expensive, well-advertised name brands, but look for the term "USP verified" on the label.


Vitamin D and calcium are essential to bone health. If possible, get adequate amounts from your diet and, for vitamin D, from sun exposure. Talk with your clinician or a nutritionist about supplements and bone health. If you have health problems that affect your ability to absorb nutrients, to get sun exposure, or to eat foods containing calcium and vitamin D — or if you are taking medications that affect your bone health or you have already had a fracture — different guidelines may apply to you.
And, of course, don't forget that a healthful diet, regular exercise, and good habits such as avoiding or quitting smoking and excessive alcohol also contribute to your overall wellbeing.
Food Sources of Vitamin D and Calcium
U.S. Preventive Services Task Force Information on Vitamin D and Calcium
Choosing and Using Supplements
Diane E. Judge, APN/CNP
Published in Journal Watch Women's Health February 28, 2013
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J Am Acad Child Adolesc Psychiatry 2013 Mar; 52:264
Treatment of Preschool-Age Children with ADHD: A Cautionary Note
Most preschool children with moderate-to-severe ADHD continue a chronic course with substantial symptom severity even with treatment.
In 2006, the first randomized placebo-controlled trial of preschool children (age range, 3.0–5.5 years) with moderate-to-severe attention-deficit/hyperactivity disorder (ADHD) demonstrated short-term effectiveness and long-term (40 week) safety of methylphenidate (MPH; JW Pediatr Adolesc Med Jan 10 2007). Now, investigators report 6-year follow-up in 207 children (68% of original cohort; 75% male) at a mean age of 10 years. During follow-up, medications and other therapies were prescribed by community clinicians outside of the study protocol; about 60% were receiving MPH at years 3 and 6.
Parent and teacher rating scales documented a sustained decrease in symptom severity at year 3, but symptoms remained stable in the moderate-to-severe range through year 6. Symptoms in girls were more severe than in boys. At 6 years, 89% of children met diagnostic criteria for ADHD; symptom severity was similar for inattentiveness and hyperactivity/impulsivity. Co-existing conditions (i.e., oppositional defiant disorder and conduct disorder) were associated with greater risk for ADHD at year 6. Medication status (on vs. off) did not predict symptom severity from years 3 to 6.
Comment: These disappointing results indicate that for most preschool children with moderate-severe ADHD, the course is chronic with significant symptom severity, even after medication and parent training. Although the study has limitations (no comparison group, uncontrolled treatment during the 6-year follow-up, and variability in provider practices and experience) and the children in this cohort had more severe symptoms than most preschool-age children with ADHD cared for by primary care clinicians, the findings demonstrate the challenge of both diagnosis and treatment of ADHD in very young children. The take home message to me is that clinical management of children with ADHD must remain as rigorous and evidenced-based as in the original PATS study to achieve a significant reduction in symptoms and impairment. We also need more nonpharmacological treatments for ADHD such as the intense parent training of the evidence-based Webster-Stratton model (J Clin Child Adolesc Psychol 2011; 40:191).
Martin T. Stein, MD  Published in Journal Watch Pediatrics and Adolescent Medicine March 13, 2013
Citation(s): Riddle MA et al. The Preschool Attention-Deficit/Hyperactivity Disorder Treatment Study (PATS) 6-year follow-up. J Am Acad Child Adolesc Psychiatry 2013 Mar; 52:264.
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Azithromycin: FDA Issues Cardiac Warning
By Kelly Young
The antibiotic azithromycin (Zithromax and Zmax) can cause QT interval prolongation and torsades de pointes, the FDA warned on Tuesday.
The agency says that healthcare providers should consider risk for fatal heart rhythms when treating patients already at high cardiovascular risk, including people with known prolongation of the QT interval, torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure; patients taking drugs that prolong the QT interval; and patients with proarrhythmic conditions (e.g., uncorrected hypokalemia). Older patients and patients with cardiac disease may also be at higher risk.
The warning follows a New England Journal of Medicine study last year that found a higher rate of cardiovascular and all-cause mortality in patients who took 5 days of azithromycin, compared with other antibiotics.


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MM: Superbugs are a danger to us all and the increasing prevalence of Chinese products in our grocery stores and subsequently in our homes makes this article that much more important.
Proc Natl Acad Sci U S A 2013 Feb 26; 110:3435
Agricultural Antibiotic Use and Antibiotic Resistance
Numerous unique antibiotic-resistance genes were abundant in manure and soil samples from Chinese swine farms.
China is now the largest worldwide producer and consumer of antibiotics. In 2007, 46% of what was produced was used in the livestock industry. To explore the potential effect of this antibiotic usage, a multinational team of researchers assessed bacterial antibiotic-resistance genes (ARGs) in samples from manure, as well as manure compost and soil receiving manure compost, at three large-scale commercial swine farms in different regions of China.
Tetracyclines, sulfonamides, and fluoroquinolones were all present in the farm samples. In addition, the samples yielded 149 unique microbial ARGs, encompassing the three major resistance mechanisms — efflux pump, antibiotic deactivation, and cellular protection — and potentially conferring resistance to aminoglycosides, β-lactams, fluoroquinolones, macrolides, tetracyclines, chloramphenicol, and vancomycin. Compared with control samples from pigs never fed antibiotics and soil from a pristine forest, the farm samples showed marked enrichment of ARGs, with maximum enrichment seen in a manure sample from one farm (121,000-fold) and a compost sample from another (57,000-fold). Sixty-three unique ARGs were significantly enriched in at least one farm sample, for an overall median enrichment of 192-fold across all farm samples. Transposases (which mediate gene transfer) were also enriched up to 90,000-fold in manure samples and up to 1000-fold in soil samples from the commercial farms.
Comment: Although several recent studies have suggested that ARGs predate the modern use of antibiotics (JW Infect Dis Sep 14 2011), this work clearly shows that agricultural antibiotic usage can greatly amplify their presence in the environment. Given the concern that antibiotic-resistant bacteria are now one of our greatest public health threats, international efforts are needed to eliminate antibiotic use for growth promotion in the livestock industry.
Richard T. Ellison III, MD  Published in Journal Watch Infectious Diseases March 13, 2013
Citation(s): Zhu Y-G et al. Diverse and abundant antibiotic resistance genes in Chinese swine farms. Proc Natl Acad Sci U S A 2013 Feb 26; 110:3435.
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Breast Irradiation and Increased Risk for Ischemic Heart Disease:
New Data Emerge

By Amy Orciari Herman
A case-control study in the New England Journal of Medicine provides new information on the link between breast irradiation and increased risk for ischemic heart disease.
Using national registries, researchers in Sweden and Denmark studied nearly 2200 women who underwent radiotherapy for breast cancer between 1958 and 2001; roughly 1000 who subsequently had a major coronary event were matched with 1200 controls.
The rate of coronary events increased with the mean estimated dose of radiation to the heart. The risk increase was observed within 5 years after treatment and lasted for at least 20 years. The absolute risk for coronary events was particularly high for women who had preexisting cardiac risk factors.
In Journal Watch Oncology and Hematology, William Gradishar concludes: "Efforts to provide women with the option of breast conservation should not be abandoned, but for select women with very significant cardiac risk factors ... a mastectomy might be a better option."
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Circulating Tumor DNA Tracks Metastatic Breast Cancer in
Proof-of-Concept Study

By Joe Elia
A small study — deemed "more encouraging than definitive" by commentators — shows that circulating DNA from breast tumors can be used to track progression in metastatic breast cancer.
Researchers monitored the tumor burden of 30 women with metastatic disease with use of radiographic imaging plus assays of circulating tumor DNA, circulating tumor cells, and the cancer antigen CA 15-3.
Circulating tumor DNA was found in 29 of the 30 women with identifiable mutations. The sensitivity of the assays for CA 15-3 (78%) and circulating tumor cells (87%) was lower. Increasing levels of circulating DNA and tumor cells both correlated with inferior survival.
Writing in the New England Journal of Medicine, editorialists say the work "provides proof of the concept that circulating tumor DNA represents a sensitive biomarker of tumor burden" — and call for further studies.
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MM: Make the argument any way that you want, this is a boondoggle and a mis-appropriation of public funds. The article in the New York Times opens our eyes to how special interest groups are contributing to our increasing deficit and mortgaging the future of our children.
Big Price Tag on Smallpox Antiviral Stockpile
The U.S. Department of Health and Human Services is overseeing the $450 million purchase of a smallpox antiviral, Arestvyr, in quantities sufficient to treat 2 million people, the New York Times reports. That works out to more than $200 per treatment.
Smallpox was eradicated by 1980, but U.S. and Russian government labs have stocks of the virus. Vaccines are available and are effective even if given 3 days after exposure in, for example, a bioterror attack.
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Quitting Smoking Lowers CV Risk, Regardless of Weight Gain
By Amy Orciari Herman
Adults who quit smoking are at lower cardiovascular risk than those who continue to smoke, even if they gain weight in the post-cessation period, according to a JAMA study.
Researchers studied nearly 3300 adults from the Framingham Offspring Study who didn't have cardiovascular disease at baseline. During 25 years' follow-up, some 630 CVD events occurred.
Among participants without diabetes, those who quit smoking during the study had about half the CVD risk as those who continued to smoke, even when weight gain was taken into account. Findings were similar among diabetic patients who quit smoking, although the risk reduction was not statistically significant.
Editorialists point out that the study could not assess the effect of weight gain over 10 kg. Nonetheless, they conclude that the findings "can be used to reassure patients concerned about the health effects of cessation-related weight gain."
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Breast-Feeding Intervention Doesn't Reduce Childhood Obesity
By Kelly Young
Efforts to promote breast-feeding are not associated with lower BMIs later in childhood, according to a JAMA study.
Researchers randomized some 30 maternity hospitals and outpatient clinics in Belarus to continue their usual breast-feeding policies or to adopt an intervention to promote breast-feeding. At 3 months, infants in the intervention group were more likely to be exclusively breast-fed (43% vs. 6%). But at age 11.5 years, there were no differences between the groups in terms of BMI, other measures of adiposity, or levels of insulin-like growth factor I.
The authors conclude: "Although breastfeeding is unlikely to stem the current obesity epidemic, its other advantages are amply sufficient to justify continued public health efforts to promote, protect, and support it."
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Most Women Aren't Receiving the Best Treatments for Ovarian Cancer
By Joe Elia
Two out of three women with ovarian cancer don't receive treatment in accordance with National Comprehensive Cancer Network guidelines, according to a meeting presentation that's getting New York Times coverage.
Using the California Cancer Registry, researchers identified some 13,000 patients who underwent oophorectomy for epithelial ovarian cancer between 1999 and 2006. Only 37% received NCCN-adherent care. Hospitals and surgeons with the highest case volumes were more likely than low-volume providers to deliver adherent care, and their patients were more likely to have better survival.
The work was presented in Los Angeles at the Society of Gynecologic Oncology's annual meeting on women's cancer.
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Neurology 2013 Jan 30
Intranasal Ketamine for a Neuropsychiatric Condition
It decreases severity of migraine aura — could this formulation also be used for depression?
Researchers have begun examining the antidepressant effect of intravenous ketamine, an N-methyl-D-aspartate glutamate receptor antagonist and anesthetic (JW Psychiatry Jul 9 2012). Thus, research into potential additional therapeutic uses, especially with an easier-to-administer formulation, is of interest. This controlled, double-blind study examined the effect of intranasal ketamine in prolonged aura in migraine. The investigators hypothesized that cortical spreading depression — thought to be the basis of migraine auras — may have a glutamatergic basis and could be blocked by ketamine.
Twenty-nine patients with migraine and prolonged aura (range, 3 hours–1 week) were randomized to intranasal ketamine 25 mg or midazolam 2 mg. Participants were asked to treat three attacks and to record data on these and on three additional, untreated attacks.
Only 18 subjects completed the study (4 men). Both drugs reduced the median duration of aura by 3 hours, and ketamine reduced aura severity. Five patients taking ketamine reported transient (30–45 minutes) feelings of unreality, euphoria, or giddiness.
Comment: This small study both suggests some efficacy for intranasal ketamine in reducing the severity of migraine aura and details an interesting alternative route for administration that could be given chronically. The dosage seemed to be tolerated. If this nasal spray has the same efficacy for depression as does the intravenous route, a practical therapy for ketamine could be developed.
Jonathan Silver, MD Published in Journal Watch Psychiatry March 4, 2013
Citation(s): Afridi SK et al. A randomized controlled trial of intranasal ketamine in migraine with prolonged aura. Neurology 2013 Jan 30; [e-pub ahead of print].
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About a Quarter of Screening Colonoscopies in U.S. Elderly Seem Inappropriate
By Joe Elia
Roughly 25% of screening colonoscopies done among the elderly may be inappropriate, according to a JAMA Internal Medicine study of Medicare data.
Researchers examined claims data on some 75,000 Texas Medicare recipients aged 70 or older who underwent complete colonoscopy in a 1-year period starting in 2008. Procedures that were repeated early without a clear indication, or those that were done contrary to published guidelines with regard to age, were considered possibly inappropriate. In addition, a 5% national Medicare sample was also examined.
Overall, 23.4% of the cohort were found to have undergone a potentially inappropriate procedure. There was marked variation geographically both within Texas and the U.S., as well as among colonoscopists, some of whom had rates of potentially inappropriate colonoscopies above 45% (they tended to be surgeons and graduates of U.S. medical schools).
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JAMA 2013 Feb 13; 309:570
Can Maternal Folic Acid Supplementation Prevent Autism?
Periconceptional folate supplementation was associated with lower risk for autism spectrum disorders in a nationwide Norwegian cohort.
The prevalence of autism spectrum disorders (ASDs) is rising, but no effective preventive measures have yet been demonstrated. Periconceptional folic acid supplementation protects against neural tube defects and more recently has been associated with lower occurrence of other neurodevelopmental disorders (JW Womens Health Oct 27 2011). Investigators used data from a Norwegian nationwide cohort of >85,000 children born during a 10-year period to explore the association between periconceptional folate intake and ASD risk.
ASDs were diagnosed in 270 (0.32%) of the children. Questionnaire-based reports of maternal folic acid supplementation varied throughout pregnancy: 33% of women reported use before conception, 71% during gestational weeks 9 to 12, and 46% during weeks 13 to 16. Autistic disorder (the most severe form of ASD) was present in 0.10% of children whose mothers used supplemental folate from 4 weeks before to 8 weeks after the start of pregnancy and in 0.21% of those whose mothers did not (adjusted odds ratio, 0.61). In analyses designed to minimize confounding, neither folate supplementation during week 22 nor periconceptional fish oil supplementation (likely to be used by more health-conscious women) affected risk for autistic disorder. Folate use was not significantly associated with Asperger syndrome or other forms of ASD.
Comment: This well-conducted observational study supports the proposition that the benefits of periconceptional folic acid extend beyond prevention of neural tube defects. Replication of these findings in other populations — for example, those with higher prevalence of autism spectrum disorders or with mandatory folate fortification of grain products — will be valuable. In the meantime, given the woefully low rates of periconceptional supplement use and high rates of unintended pregnancy, clinicians and policymakers must endeavor to ensure that all women with childbearing potential have access to this well-tolerated, inexpensive dietary supplement, which is available in appropriate doses in most multivitamins.
Allison Bryant, MD, MPH  Published in Journal Watch Women's Health March 14, 2013
Citation(s): Surén P et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA 2013 Feb 13; 309:570.

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