SLA Biomedical & Life Sciences Division Blog

Major Developments In Cardiovascular Disease Research : A Quick Survey Based on Some of The Most Highly Cited Studies Published Between 2000-2009

Large Scale, Multifactorial Studies of Risk Factors

Risk factor prevalence  and  any therapeutic and lifestyle alterations that had been undertaken by patients  aged seventy or less in nine European countries were compared over two five year spans, in the EUROASPIRE I  and  EUROASPIRE II study (Kotseva, Wood, DeBacket et al 2001).  Unlike the case in the US, smoking levels  in Europe failed to decline, but as in the US, obesity significantly increased. The taking of aspirin, thiazides, ACE inhibitors, and beta-blockers as cardioprotective  strategies increased, but overall these improvements did not offset persistent adverse  lifestyle trends in terms of  blood pressure and blood chemistry. A EUROASPIRE III update (Kotseva, Wood, DeBacker et al 2009) disclosed that prescriptions taken to reduce high blood pressure and adverse lipid profiles increased significantly, but still brought levels down to acceptable levels in only half the case. Furthermore diabetes prevalence actually increased. 

The INTERHEART study (Yussuf, Hawken, Ounpuu et al 2004) examined 52 countries, including some from every continent. It demonstrated that the same risk factors (particularly an increase in obesity and in smoking) leading to cardiovascular disease and death that applied in economically prosperous portions of the US and Western Europe, existed in both countries  with emerging economies (People’s Republic of China) and Third World states in economic dire straits (Bangladesh) across the globe.

The SCORE project (Conroy, Pyorala , Fitzgerald et al., 2003), which analyzed  the factors contributing to the cardiac-related deaths  of 5652 patients out of a population sample of  200,000 Europeans, canonized the notion that number of years of  duration of a risk factor (five years of being 40 lbs. overweight) , rather than just simply  having a risk factor checked off (40 lbs. overweight today) , was a significantly better predictor of those who would die within a ten-year span.

Specific Risk Factors: Metabolic Syndrome & Diabetes

A  strategic approach to combating a complex condition that encompasses adult onset diabetes and that typically involves obesity with abdominal fat concentration leading to hypertension, coronary artery disease and a propensity toward strokes was formalized under the term “Metabolic Syndrome ‘ (Alberti, Zimmer and Shaw 2006) and prevention guidelines increasingly took this pre-diabetic/pre-cardiovascular disease syndrome into consideration (Ruyden, Standl, Bartnik et al 2007).  Indeed, diabetes was identified as  the greatest single factor  predisposing a patient to atherosclerosis, and since most diabetics actually die from complications of atherosclerosis,  rather than from the diabetes itself, early and aggressive intervention  with the aims of reducing  lower density (LdL) cholesterol and triglyceride levels to stave off  heart attacks  was forcefully recommended  (Beckman, Creager & Libby, 2002). In 2008 (Willer, Sanner, Jackson et al.) an even  stronger  genetic basis that underlies both predisposition to diabetes and higher concentrations of the bad heart-disease-contributing LdL was uncovered via an analysis of  almost 18,000 persons with both   conditions.

However, a more  intense effort to manage insulin and glucose levels after a heart attack, did  not seem to lengthen lives as compared to the standard  metabolic monitoring (Malmberg, Ryden, Wedel et al 2005). However, advantages may still be  realized from an aggressive approach in terms of reduced microvascular damage particularly in the kidneys and retinas (Skyler, Bergenstal, Bonow et al 2009).

Other Risk Factors:

High Blood Pressure, Sleep Apnea, Kidney Disease, Peripheral Artery Disease

In 2003, guidelines for what constitutes high blood pressure that predisposes to elevated risk of cardiovascular disease, particularly in patients 50 and older, were significantly revised downward, suggesting that many more Americans were at risk than was formerly thought (Chobanian, Bakris, Black et al.)

 Sleep apnea, particularly the obstructive type common among the obese and especially among those with metabolic syndrome, has now now officially  been designated another clear warning sign of rising risk for heart attack and stroke (Somers, White, Amin et al 2008).

Kidney disease was not far behind in statements on both predisposition and the need for proactive treatment  (Sarnak, Levey, Schoolwerth et al 2003).  Fowkes, Murray, Butcher et al (2008)  and Smith, Allen, Blair et al ( 2006) added peripheral artery disease and blocked carotids to more generalized atherosclerosis as indicators for stepped up preventive therapy. Patients receiving cancer chemotherapy or suffering from certain immune disorders became a recognized class of at-cardiac-risk patients, often placed in that situation because  drugs used for these conditions impaired heart function (Yeh 2006).

Preventive Measures: Exercise and Omega-3 Fatty Acids

A consensus recommendation for adults 18-65 from cardiologists, exercise physiologists and strength and conditioning trainers for 3-5 days of moderately energetic walking for 30 minutes or aerobics workouts lasting as little as 20 minutes per session emerged as an effective lifestyle strategy to decrease significantly  the chance of heart attack and stroke (Haskell, Lee, Pale et al 2007).  Another consensus finding was that the increased consumption of omega-3 fatty acids (classically available in oily fish, but now widely available in foods engineered for it such as omega-3 eggs and assorted supplements) seems to decrease in a small but a statistically significant way the mortality and admissions of hospital of  patients who already had heart failure ( Tavazzi, Maggioni, Marchioli et al 2008).

The Drive for Evidence-Based Medicine Affects Cardiology Advice

Members of the American Heart Association and the American College of Cardiology have undertaken a thorough review of how many of their 7196 recommendations are based on hard science, and how many are based on well-meaning, ad hoc expert opinion issued in the absence of more rigorous studies, with the goal of increasing the proportion based on the latter (Tricoci, Allen, Kramer et al, 2009).

Heart Failure: The Knife Edge Balance of Good & Bad Inflammation

Heart failure, usually beginning after an infarct, is a progressive, downwardly spiraling disease, and a call for  creative flexibility in treatment  and deeper  insight through basic research was issued (Hunt, Baker, Chin et al 2001).   Cohn, Ferrari and Sharpe et al, 2000, had identified the heart’s  unassisted and sometimes inept attempt at repairing the damaged areas, a process ironically benignly termed “remodeling” as the main culprit. Frangogiannis, Anderson, Benjamin et al (2002) provided  an excellent explanation of why bypass surgery and related artery clearing surgeries work better: A paradoxically beneficial  inflammatory response  is triggered by the surgery, setting off  a cascade of immune responses that ultimately promote the proliferation of fibroblasts and their subsequent conversion into well functioning cardiomyocytes, reducing the amount of necrotic or malfunctioning heart muscle that would be left by “remodeling”  without intervention. Libby and Theroux (2005)  however, demonstrated that ongoing inflammatory processes can lead to a proliferation of plaques elsewhere in the arterials system and that after addressing the initial blockages via bypass, medications that seek to stabilize other high-risk plaques in place, to prevent them from breaking free and causing another infarct,  need to have the highest priority.

A Molecular Level Understanding of

Botched Attempts By the Heart to Repair Itself

& Handle Its Electrochemical Circuits

A key to modulating inflammation and enhancing the outcomes of the heart’s own repair attempts  via reduced modeling appears to lay in a deeper understanding of the Matrix Metalloproteins (MMPs) and the enzymes that control them (Nagase, Visse and Murphy 2006).  Sarbassov, Ali, Sengupta et al (2006) reported on the underlying mechanisms of  a drug (rapamycin) often used in controlling cancer cells through regulating natural cell death (apoptosis) that increasingly serves  a similar role in regulating the factors that lead to adverse cardiac remodeling.

Molecular genetic markers of heart disease, and ion channelpathies were finally introduced into a newly revised classification of heart diseases, a concession to contributions made  using cardiac genomics, proteomics, and cellular level electrophysiology ( Maron, Towbin, Thiene et al 2006).

Comparing Medications to Reduce Blood Pressure

 In a three way comparison (ALLHAT 2002)  among blood-pressure lowering diuretics  (typically thiazides) , Angiotensin-Converting Enzyme inhibitors (ACE inhibitors, e.g. lisinopril), and calcium channel blockers (Beta Blockers)  among  high-risk hypertensive patients,  the thiazides were judged the best first choice for reasons of at least equal efficacy and significantly lower costs, although combination therapies were later to become the norm (Mancia, DeBacker, Dominiczak et al 2007).

In the Losaratan (Cozaar™) Intervention for Endpoint Reduction for Hypertension, best known as the LIFE trial, 8851 patients were monitored for onset on new cases of atrial fibrillation, with the longer-established comparison drug used for prevention and management, atenolol (Tenormin™) coming up on the short side.

 ACE inhibitors (Yusuf, Sleight, Pogue et al 2000)  and beta-blockers showed some  early promise in forestalling  inappropriate remodeling  within the heart in damaged areas  that leads to progressive heart failure (Cohn, Ferrari, Sharpre et al, 2000). ACE inhibitors and angiotensin receptor blockers (ARBs)  appear to prevent atrial fibrillation, particularly in those patients who already have  left ventricular dysfunction or hypertrophy (Healey, Baranchuk, Crystal et al 2005).

“Statin Island”

The use of a wide variety of competing statin (bad-cholesterol and triglyceride lowering) drugs vastly increased in this decade, but results favoring one over another were not always unambiguous.  One of the most anticipated studies of competing drugs intended to lower LdL-C (the bad cholesterol)  involved 8888 patients in northern Europe who had a previous heart attack. This IDEAL study (Pedersen, Faergeman,Kastelein et al 2005) demonstrated that high doses of atorvastatin (aka Lipitor™ ) did lower this bad cholesterol significantly better than simvastatin (aka Zocor™) and  resulted in fewer subsequent nonfatal heart attacks, but there was ultimately no significant difference in death rates from either cardiac or non-cardiac causes. In another study, rosuvastatin (Crestor™) clearly lowered the adverse blood chemistry of patients in heart failure, but that it did not actually lifespan or hospital admission for cardiovascular reasons (Tavazzi, Maggioni, Marchiolo 2008).

Blood Thinners

In the blood thinning drug domain, Yusuf, Zhao, Meta et al (2001) report  that the taking of a combination aspirin and other anti-coagulants, such as clopidogrel ( e.g. Plavix™) worked better than taking either one alone, particularly after any type of cardiac catheterization to avoid blood clots ( Steinhubl, Berger, Mann et al, 2002). The same group (Serebruanny, Steinhubl, Berger et al 2005) was later to develop a laboratory test for predicting which patients taking clopidogrel would underreact with insufficient blood thinning (about 4%)  or overreact with excessively long  clotting times (about 5%).

Avoiding Gastrointestinal Bleeding When on Blood Thinners

Nonetheless concern over limiting gastrointestinal side effects of combinations of aspiring and anticoagulants like clopidogrel have been investigated and the concurrent use of proton pump inhibitors (Prilosec™, Prevacid™) has now been strongly recommended (Bhatt, Scheiman, Abraham et al 2008).

 

Interventional Cardiology Using Catheterization

Atrial fibrillation was better controlled when a catheter, inserted via blood vessels in the groin and then threaded to heart,  was used to sense and then  burn misfiring centers within the heart (Nademanne, McKenzie, Kosar et al. 2004).  Indeed, cardiac catheterization for a wide variety of pathologies had become so very widespread by  the mid-2000s, that new and greatly enlarged guidelines had to be rewritten  (Silber, Albertsson Aviles et al 2005, Silber, Albertsson, Blair et al 2006).

Cardiac Vessel Stents

The use of stents, coiled tubes placed via catheter, to keep open clogged coronary arteries also became commonplace in the early 2000s, particularly those which eluted drugs to control scarring or plaque build up, and promote healing (Woods and Marks 2004) .  Nonetheless, controversies flared over whether plain or drug eluting stents were generally safer (Lagerqvist, James, Stenestrand et al 2007, Moreno, Fernandez, Hernandez et al 2005, Ong, McFadden, Regar et al 2005), and a call for standardization of clinical trials was issued (Cutlip, Windecker, Mehran et al 2007).

Autologous Transplantation of Heart Cells To Stimulate Cardiac Repair

Demonstrating that cardiac repair after a heart attack improves significantly when a plentiful supply of myoblasts is available, Menasche, Hagege, Vilquin et al  provided patients with a transplant of  their own myoblasts, derived from thigh biopsies that were further cultured in the lab,  via injection into heart scar tissue. This procedure, while widely cited,  has not yet become widespread.

The Cabbage  (CABG) Patch

While less invasive procedures predominate today, the thoracic surgical management of heart disease , with Coronary Artery Bypass Graft Surgery, and valve replacement are still common and important procedures (Descoutures, Himbert, Lepage et al 2008, Smith, Allen, Blair et al 2006, Vahannian, Baumgartner, Bax et al 2007, Zeltsman and Acker 2002).

Pacemakers

The use of implanted  devices (both the conventional implantable cardioverter and biventricular cardiac resynchronizers) grew almost exponentially in this decade (Matchett, Sears, Hazelton et al 2009, van Veldhuisen, Maass, Priori et al 2009) but the larger number of cases also disclosed some pitfalls, particularly in the durability of the wire leads (Haqqani and Mond 2009), but expert opinion remains optimistic about newer, electronically simplified models with greater ease of insertion and a single more durable lead (Santini, Cappato, Anfresen et al 2009).

Looking Into the Beating Heart

The most traditional of major instrumental measures of heart function, the echocardiogram, saw further standardization in terms of recommended uses and terminology (Lang, Bierig, Devereux et al 2005).

Leber, Knez, von Ziegler et al (2005) would eventually demonstrate the advantages of  64-slice computer tomography of the heart over  ultrasonic techniques, and a generally upbeat assessment was provided in 2006 (Budoff, Achenbach, Blumenthal et al 2006). Nonetheless, Miller, Rochitte, Dewewy et al (2008)  suggest that it is still essentially on a par with conventional coronary angiography, and owing to a few residual drawbacks, does not clearly replace it. Arad, Goodman, Roth et al (2005) showed that electron beam tomography, a further refinement, was even better for the determination of coronary calcification associated with atherosclerotic cardiovascular events, and had a higher predictive value than tests for C-Reactive Proteins, a common measure of the progression of this disease process. However, it was also determined that the Lifetime Risk Attributable  (LAR)  to any ionizing radiation (e.g. x-rays) during these probes was not negligible, particularly among those at risk of lung and breast cancer already (Einstein, Henzlova and Rajgopalan 2007).  This was not an entirely unsurprising finding, and guidelines that recommended its continued use, with precautions, and that of an emerging technology at that time, cardiac magnetic resonance, which does not involve ionizing radiation,   were issued in 2006 (Hendel, Patel, Kramer et al).

Non-Pedal P.A.D. – Peripheral Artery Disease

(This Time In the Arms Not in the Feet or Legs)

High-resolution  brachial artery ultrasonic imaging  for peripheral artery disease was regarded as particularly promising  but only  if carefully interpreted (Correti, Anderson, Benjamin et al 2002), and its adaptation as a model for clogged coronary arteries progressed (Mintz, Nissen Anderson et al, 2001).

Stroke

Guidelines for stroke prevention were drawn up in 2006 (Goldstein, Adams, Alberts et al). Guidelines for the management of strokes caused by arterial blockages in the brain in the first 48 hours were drawn up in 2007 (Adams, del Zoppo, Alberts et al).

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Malmberg, K., L. Rydén, H. Wedel, K. Birkeland, A. Bootsma, K. Dickstein, S. Efendic, et al. 2005. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): Effects on mortality and morbidity. European Heart Journal 26, (7) (04): 650-61.

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Do Meal Replacements Like Breakfast Bars and Liquid Meals in a Can or Bottle Really Help in Weight Loss?

Meal replacements available from supermarkets, drug and health food stores,  in the form of breakfast or  protein bars  and in cans or bottles that generally feature a kind of flavored milk or milkshake taste and consistency,  have been around for  over half a century. First marketed in 1959, Metrecal,™ a Mead-Johnson product,  was originally formulated as a powder to add to milk, but very quickly sold in the hundreds of millions of units  as a ready mixed beverage in  cans. Ever since then there has been debate as to whether or not these shakes or bars  really work as an aid in losing weight, or in maintaining weight loss.  

Many lingering questions about them have been coming closer to a resolution, and largely in their favor.

Do the bulk of studies confirm that they work?

Overwhelmingly, when taken as a replacement for one or two meals a day -----not for all three meals customarily eaten---- they seem to work by encouraging weight loss through overall caloric reduction, at least as long as the remaining meal or meals is not substantially increased in caloric content as a self-defeating offset (e.g. Egger 2008).

Studies based on replacing three meals a day or the use of VLO (very low calorie) meal replacements are not as often conducted any more, and are not the focus of this report.

Doesn’t simply following a reduced-calorie diet work as well?

In theory, following a healthy reduced calorie diet composed of ordinary food taken in smaller portions should work as well. In practice, however, more dieters stick with their meal replacements in a bar or can longer than other dieters  stick with their healthy reduced calories diets involving reduced portions of  normal food. Some studies (Sarwer, von Sydow, Green et al 2009) show that meal replacement users lose about 10% of their body weight in about the same time as other conventional dieters lose about 5%. Moreover, while virtually all dieters tend to regain much of the weight initially lost, users of meal replacers typically regain less, and regain more slowly.  

Don’t dieters using meal replacement obsess about real food all the time, and in essence, become somehow emotionally unsettled or ineffective in their work or family life?

Studies based on females -----women are by far the biggest purchasers of meal replacement products---- show that in terms of overall mental health and  cognitive functioning, users of replacement meals  tended to be more alike than not   compared to dieters using other methods.  But in a number of cases,  they appear to have gained an advantage in that  meal replacers actually were less likely to engage in “emotional”  binge eating (Annunziato, Timko, Crerand et al 2009, Butryn, Thomas & Lowe 2009).

Aren’t these replacement meal bars or liquids loaded with sugars, including the hated refined carbohydrates and fructose?  What about artificial sweeteners, flavorings, colors,  salt, and preservatives? Aren’t these dangerous for Diabetics, People with High Blood Pressure & Metabolic Syndrome?

Much as organic  food purists and anti-corn syrup activists would wish to the contrary,  the inclusion of sugar or fructose, or of artificial sweeteners, colors flavorings,  preservatives, or salt  in a recipe for meal replacement bars or liquids does not, of itself,  render a meal replacement bar or liquid ineffective or make it unsafe for most overweight people who are otherwise healthy and trying to lose weight. 

People who are already diabetic or who have high blood pressure that appears particularly sensitive to salt may wish to try bars or drinks with less sugar and salt. However, the only things that would make these bars or drinks ineffective in weight loss is if their caloric level as a meal exceeds much more than 20% of the recommended caloric content daily intake   for a person of a given weight and age.

In fact, the fine details of the composition of these bars may be less important than the fact that their lowered caloric content, and the fact that many dieters will stay with them longer,   tends to promote weight loss that demonstrably improves the health of  both diabetics and persons with high blood pressure.

 Indeed, there are numerous positive, statistically  significant studies of the successful use of meal replacements by diabetics and others with chronic diseases or predispositions to them, particularly metabolic syndrome (Cheskin, Mitchell, Jhaveri et al 2008, Gugliucci, Kotani, Taing et al 2009, Konig, Delbert, Frey et al  2006, Sun, Chen, Chen et al  2008, Wadden, West, Neiberg et al 2009).  Ideally, of course,  these bars should have an amount of the vitamins, minerals, and fiber roughly equal to a “normal “ meal.

Should you go with high protein vs. high fiber/high complex carb bars or drinks?

One of the biggest surprises is that, given equal caloric content,  both kinds of bars and drinks  work, and that, in fact, there is some suggestion that dieters stick with high-protein bars and drinks longer than do adherents of the high-fiber, high complex carb meal replacements, and/or may lose more weight (Treyzon, Chen, Hong et al 2008).  Using   high fiber bars or drinks may help foster a healthy reduced energy density eating pattern ------in other words, eating a greater volume of food, but having that food be lower in calories  (Lowe, Tappe, Annunziato et al 2008). But in tests using actual meal replacement users, the addition of naturally derived bulking agents such as beta-glucan or fructooligosaccharide did not stave off hunger any longer than equally caloric replacement bars without these substances (Peters, Boers, Haddeman et al 2009). One study (Kim, Kim, Kim and Lee 2008) found that in meal replacements featuring rice, those that included a mix of whole grain and white rice encouraged somewhat more weight loss than those featuring white rice alone, and had the benefit of a higher proportion of antioxidants.

Should you go with soy-based or whey (milk solids)- based bars or drinks?

The answer is that both sources of protein in meal replacements  seem to work quite well, to the degree that they are equal in calories, for as long as you stick with them. There is some evidence that consumers prefer, and stick with,  the taste of whey-based replacement meals, over mixed whey-and-soy-based meals, and either of them fare better  than those based on soy alone (Child, Yates and Drake 2007)

Which makes you feel fuller longer? Liquids or Bars?

It appears from a small number of studies that solid bars when eaten with some water or  other beverage with a total caloric input equal to a liquid meal replacement, seem to stave off hunger longer (Tieken, Leidy, Stull et al 2007).  Intriguingly enough, one test (Stull, Apolzan, Thalacker et al 2008) was conducted by measuring the amount of oatmeal eaten by dieters using one or the other method, at given intervals after having consumed their replacement meal, with bar users eating less oatmeal before they reported they felt full again.

Will replacement meals work even if all my relatives are fat owing to genetics?

While the genetic relationship involved in obesity are complex, in those few studies where persons known to have genes strongly predisposing them to obesity, used meal replacements as part of their weight management strategy, it appeared to help in more cases than not (Tsuzaki, Kotani, Naigai et al 2009).

Can I use meal replacements even if I  am on prescription diet drugs?

While the number of studies dealing with this are few, (Early, Apovian, Aronne et al 2007, Haddock, Poston, Foreyt et al 2008) users of meal replacements (Medifast™ in one trial, Slim Fast™ in another )who were also taking prescription weight loss medicines did better at weight loss in both the short (12 & 24 weeks in one study ) and the long run (a year in another) than users of either meal replacements,  or prescription weight loss drugs alone.

Do Meal Replacements Works as Well for Men as they Appear to Do for Women?

This was pretty much an open question for a long time, because current purchasers of meal replacement bars and especially drinks are women. But Smith, Sigrist, Bathalon et al ( 2010), in a very recent study involving a majority of men (overweight active duty US Army personnel) demonstrated that users of meal replacements lost more weight, reduced their body fat more, and stayed in weight loss mode longer than those who participated in a traditional educational and counseling program that encouraged changes in their regular diet  largely through portion control.

Won’t you somehow feel weak using meal replacements?

While it is hard to measure how weak one feels on any diet, it is actually possible to measure the strength of muscles and joints. Given that overweight elderly patients with osteoarthritis of the knee  represents the largest pool of knee replacement surgery candidates, it was not too surprising that tests of dieting with meal replacements and exercise demonstrated no loss of strength, indeed, the opposite occurred (Wang, Miller, Messier, Nicklas 2007).

What steps, other than avoiding overeating in the non-replacement meals, can help a meal replacement strategy work better?

One answer is consistently reported:  regular exercise. There is also some evidence that patients who receive some counseling or who belong to voluntary or for-profit  support groups (e.g.  Weight Watchers)  will do better at weight loss.

But a curious  strategy for weight loss that seems to work well with meal replacement is eating more  ready-to-eat cereal as  meals as well (Wal, McBurney, Cho & Dhurandhar 2007).

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Vander Wal, J. S., Michael I. McBurney, Susan Cho, and Nikhil V. Dhurandhar. 2007. Ready-to-eat cereal products as meal replacements for weight loss. International Journal of Food Sciences and Nutrition 58, (5): 331-40.

Vazquez, C., C. Montagna, F. Alcaraz, J. A. Balsa, I. Zamarron, F. Arrieta, and J. I. Botella-Carretero. 2009. Meal replacement with a low-calorie diet formula in weight loss maintenance after weight loss induction with diet alone. European Journal of Clinical Nutrition 63, (10) (Oct): 1226-32.

Vega-Lopez, S., N. R. Matthan, L. M. Ausman, M. Ai, S. Otokozawa, E. J. Schaefer, and A. H. Lichtenstein. 2009. Substitution of vegetable oil for a partially-hydrogenated fat favorably alters cardiovascular disease risk factors in moderately hypercholesterolemic postmenopausal women. Atherosclerosis 207, (1) (Nov): 208-12.

Wadden, T. A., D. S. West, R. H. Neiberg, R. R. Wing, D. H. Ryan, K. C. Johnson, J. P. Foreyt, et al. 2009. One-year weight losses in the look AHEAD study: Factors associated with success. Obesity (Silver Spring, Md.) 17, (4) (Apr): 713-22.

Wal, J. S., M. I. McBurney, S. Cho, and N. V. Dhurandhar. 2007. Ready-to-eat cereal products as meal replacements for weight loss. International Journal of Food Sciences and Nutrition 58, (5) (Aug): 331-40.

Wang, X., G. D. Miller, S. P. Messier, and B. J. Nicklas. 2007. Knee strength maintained despite loss of lean body mass during weight loss in older obese adults with knee osteoarthritis. The Journals of Gerontology.Series A, Biological Sciences and Medical Sciences 62, (8) (Aug): 866-71.

Williams, Gemma, Manny Noakes, Jennifer Keogh, Paul Foster, and Peter Clifton. 2006. High protein high fibre snack bars reduce food intake and improve short term glucose and insulin profiles compared with high fat snack bars. Asia Pacific Journal of Clinical Nutrition 15, (4): 443-50.

Progress & Perils In Adult Stem Cell Research & Therapy: Skin, Hair, Heart, Pancreas, Brain & Spinal Cord

The amount of basic research on stem cells has grown almost exponentially, and some clinical trials are underway. While most of the public has been fairly well informed about the controversial but seemingly endless (and sometimes overhyped) potential of  embryonic stem cells, insight into the surprising level of activity of adult stem cells in the body and their  therapeutic possibilities is less well known.

Stem cells can be described as being healthy  young recruits into the Army  who have completed the basic training phase of their careers,  but who are as yet unassigned to any military specialty school, from which they could graduate, and obtain promotion.   

But as in the Army, there are  a small number of recruits who languish unassigned, and after a while they are deemed irrelevant, because it is thought that whatever their potential was, it had  been wasted through lack of use.  It is often thought that it is better for the Army ----and the human body in times when it is in peril of some disease,  injury, or in aging---- to bring in altogether new recruits, and to ignore the old ones that were somehow  left unassigned.

And such has been the emphasis in stem cell research: Focus on the embryonic ones; underestimate the prospects of the ones that have been in the Army for a long time, but seemingly have not been specially trained or deployed anywhere notably .

WHERE TO FIND WORKING ADULT STEM CELLS?  TRY YOUR SKIN & HAIR!

For a long time it was thought that, at least in humans, adults had relatively few stem cells, in a few locations, and they did not seem to do much.  They were generally thought of as relicts left over from the active growing processes of ourselves as we  developed from embryos to  fetuses to infants.

Part of this view resulted from a failure to see that a variety of seemingly specialized “ body repair tissues”, thought of only in the context of their particular organs systems and in therapies related to them, were in fact, actually stem cells.  

One of the greatest failures of the public imagination and perhaps of science reporting has been to realize that bone marrow transplants, procedures now done for decades, involve what amounts to stem cells.

But this is scarcely the only example of adult stem cells that has been  staring us in the face.

Consider the hair follicle,  one of the subjects of an important review  in a recent issue of Science (Li and Clevers 2010). 

They report that it was not until 2004 that Blainpain et al   were able to demonstrate that the hair follicles and surrounding skin not only contained stem cells, but in fact two different types: the quiescent (the kind of seemingly indolent stem cell we expect to find in adults)  in the bulge  area of the hair follicle, and rather active ones that self-renew their population (in other words, they don’t just sit there, they also provide for their replacement  as undifferentiated cells, before they begin the process of turning themselves into  whatever specialized replacement cell is needed, in other words, when they enter the TA (Transit Amplifying) stage.

Most of the time, this surprising transformation works remarkably well, but  the flip side is evident when this remarkable self-renewal of undifferentiated cells goes awry.

This seems to be the case with the some of the most common (and unfortunately most deadly if untreated) skin cancers melanomas (Cook and Sturm 2008). Their best guess is that beneficial recruitment for skin (and presumably hair) replacement goes bad when a family of cell transcription factors known as POU malfunctions. Not all POU factors are bad, by any means, but the wrong one, or the right one in the wrong place, seems to spell the difference. Marhaba et al (2008) suggest that even adult stem cells that get into a bad neighborhood tend to fall in with a bad crowd: stem cells turn into cancer-initiating cells.

ARE EMBRYONIC CELLS STEM THERAPIES FOR THE HEART LIKELY TO BE THE ONLY WAY TO GO?

There has been significant research on heart attack repair in adult laboratory animals (rats, actually)  using human embryonic stem cells (LaFlamme et al 2007), and general discussion of its use on humans (Leor et al 2007) continues. But in a recent review by  Passier, van Laake and Mummery (2008), it is pointed out that as far back as 2003 Beltrami et al (2003) demonstrated that while the adult heart is overwhelmingly composed of terminally specialized cells, repair after heart attacks involves a residual population of the body’s own adult stem cells.

The preponderance of stem cell studies in connection with heart attack (and stroke) repair is actually with adult bone marrow lines (see  for example, Cesari et al 2010,  Edelberg and Ballard, 2008), with mixed, but generally favorable results Gersh et al (2009), but that the injection of reprogrammed adult fibroblasts  (cells involved in connective tissue, usually obtained from skin snippets) that are treated to become “plenipotentiary” is probably the most exciting (and least controversial) way to go among many competing approaches.

 One possible reason is that while it has not been commonly detected in human trials,  a paradoxical outcome seen in animals of bone marrow transplantation to induce heart attack repair may be good heart repair but increased atherosclerosis (Hristov et al  2008).

OTHER ORGANS, OTHER POSSIBILITES

Quite possibly the two other organ system most involved in stem cell based research are those related to diabetes, and to brain and spinal cord repair.

The pancreas contains two types of cells related to glucose regulation and digestion. By far, the greatest interest has been in the beta cells whose absence or poor function is the cause of diabetes. While, based on  fundamental studies of the embryonic development of the pancreas,  Scharfmann et al (2008) likely represent the majority view that embryonic stem cells hold the greatest promise to enhance the production and performance of these beta cells, Bayens and Bouwens (2008) suggest that pancreatic cells of the other type ----acinar cells----derived from adult cadavers can be reprogrammed into becoming, or at least functioning, like stem cells that will turn into beta cells.

Probably the  most overpromised, under-documented,  and downright shady practice of  stem cell therapy of either embryonic or adult type is done in connection with neurological disorders. Carroll and Borlongan (2008) describe the appalling claims and practices of “stem cell tourist” hotspots that have some bases of operation in the People’s Republic of China, the Carribean, and Eastern Europe. But they also describe their own painstaking progress in the area of using adult stem cells in rodent models, including the surprising finding that a successful experimental therapy that used direct injection into the brain, was actually replicated by using intravenous adult stem cell transplantation.

More work, of course, needs to be done. More work will inevitably be done. But perhaps most intriguingly of all, more of it will involve adult stem cells and their reprogrammed adult cell analogues, than was imagined even a decade ago, when the promise of embryonic stem cells first held our (except for ethical issues) undivided attention.

Tony Stankus, FSLA [email protected] Life Sciences Librarian, Science Coordinator & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

Baeyens, L., and L. Bouwens. 2008. Can beta-cells be derived from exocrine pancreas? Diabetes, Obesity & Metabolism 10 Suppl 4, (11): 170-8.

Beltrami, Antonio P, Laura Barlucchi, Daniele Torella, Mathue Baker, Federica Limana, Stefano Chimenti, Hideko Kasahara, et al. 2003. "Adult cardiac stem cells are multipotent and support myocardial regeneration." Cell 114 (6): 763-776.

Blanpain, Cedric, William E Lowry, Andrea Geoghegan, Lisa Polak, and Elaine Fuchs. 2004. "Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche." Cell 118, (5) : 635-648.

Carroll, James E., and Cesar V. Borlongan. 2008. Adult stem cell therapy for acute brain injury in children. CNS & Neurological Disorders Drug Targets 7, (4) (10): 361-9.

Cesari, Francesca, Patrizia Nencini, Mascia Nesi, Roberto Caporale, Betti Giusti, Rosanna Abbate, Anna Maria Gori, and Domenico Inzitari. 2009. Bone marrow-derived progenitor cells in the early phase of ischemic stroke: Relation with stroke severity and discharge outcome. Journal of Cerebral Blood Flow and Metabolism 29, (12) 1983-90.

Edelberg, Jay M., and Victoria L. T. Ballard. 2008. Stem cell review series: Regulating highly potent stem cells in aging: Environmental influences on plasticity. Aging Cell 7, (4) (08): 599-604.

Elabd, Christian, Chiara Chiellini, Mamen Carmona, Jean Galitzky, Olivia Cochet, Rasmus Petersen, Luc Pénicaud, et al. 2009. Human multipotent adipose-derived stem cells differentiate into functional brown adipocytes. Stem Cells 27, (11): 2753-60.

Gering, Martin, and Roger Patient. 2010. Notch signalling and haematopoietic stem cell formation during embryogenesis. Journal of Cellular Physiology 222, (1) (01): 11-6.

Gersh, Bernard J., Robert D. Simari, Atta Behfar, Carmen M. Terzic, and Andre Terzic. 2009. Cardiac cell repair therapy: A clinical perspective. Mayo Clinic Proceedings.Mayo Clinic 84, (10) (10): 876-92.

Gonzales, Christine, and Thierry Pedrazzini. 2009. Progenitor cell therapy for heart disease. Experimental Cell Research 315, (18) (11/01): 3077-85.

Henriksson, Helena, Maria Thornemo, Camilla Karlsson, Olle Hägg, Katarina Junevik, Anders Lindahl, and Helena Brisby. 2009. Identification of cell proliferation zones, progenitor cells and a potential stem cell niche in the intervertebral disc region: A study in four species. Spine 34, (21) (10/01): 2278-87.

Hristov, Mihail, Alma Zernecke, Andreas Schober, and Christian Weber. 2008. Adult progenitor cells in vascular remodeling during atherosclerosis. Biological Chemistry 389, (7) (07): 837-44.

Ikoma, Tomomi, Satoru Kyo, Yoshiko Maida, Satoru Ozaki, Masahiro Takakura, Shinji Nakao, and Masaki Inoue. 2009. Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. American Journal of Obstetrics and Gynecology 201, (6) (12): 608.e1,608.e8.

Jessberger, Sebastian, Fred H. Gage, Amelia J. Eisch, and Diane C. Lagace. 2009. Making a neuron: Cdk5 in embryonic and adult neurogenesis. Trends in Neurosciences 32, (11) (11): 575-82.

Kaiser, Jocelyn. 2009. Stem cells. CIRM awards seek to move cell therapies to the clinic. Science (New York, N.Y.) 326, (5954) (11/06): 780-1.

Kuhn, Nastaran Z., and Rocky S. Tuan. 2010. Regulation of stemness and stem cell niche of mesenchymal stem cells: Implications in tumorigenesis and metastasis. Journal of Cellular Physiology 222, (2) (02): 268-77.

Laflamme, Michael A, Kent Y Chen, Anna V Naumova, Veronica Muskheli, James A Fugate, Sarah K Dupras, Hans Reinecke, et al. 2007. "Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts." Nature Biotechnology 25, (9) : 1015-1024.

Leor, Jonathan, Sharon Gerecht, Smadar Cohen, Liron Miller, Radka Holbova, Anna Ziskind, Michal Shachar, Micha S Feinberg, Esther Guetta, and Joseph Itskovitz-Eldor. 2007. "Human embryonic stem cell transplantation to repair the infarcted myocardium." Heart 93 (10) : 1278-1284.

Li, Liheng and Hans Clevers. 2010. Coexistence of quiescent and active adult stem cells in mammals. Science 327: 542-545.

Liedtke, Stefanie, Milaid Stephan, and Gesine Kögler. 2008. Oct4 expression revisited: Potential pitfalls for data misinterpretation in stem cell research. Biological Chemistry 389, (7) (07): 845-50.

Lu, Janice, Tina Fan, Qiang Zhao, Wei Zeng, Eva Zaslavsky, John J. Chen, Michael A. Frohman, Marc G. Golightly, Stefan Madajewicz, and Wen-Tien Chen. 2010. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. International Journal of Cancer.126, (3): 669-83.

Marhaba, Rachid, Pamela Klingbeil, Tobias Nuebel, Irina Nazarenko, Markus W. Buechler, and Margot Zoeller. 2008. CD44 and EpCAM: Cancer-initiating cell markers. Current Molecular Medicine 8, (8) (12): 784-804.

McCall, Michael D., Christian Toso, Emmanuel E. Baetge, and A. M. J. Shapiro. 2010. Are stem cells a cure for diabetes? Clinical Science (London, England: 1979) 118, (2) (01): 87-97.

Metzger, Marco, Petra M. Bareiss, Timm Danker, Silvia Wagner, Joerg Hennenlotter, Elke Guenther, Florian Obermayr, et al. 2009. Expansion and differentiation of neural progenitors derived from the human adult enteric nervous system. Gastroenterology 137, (6) (12): 2063,2073.e4.

Passier, Robert, Linda van Laake W., and Christine L. Mummery. 2008. Stem-cell-based therapy and lessons from the heart. Nature 453, (7193) (05/15): 322-9.

Pekovic, Vanja, and Christopher J. Hutchison. 2008. Adult stem cell maintenance and tissue regeneration in the ageing context: The role for A-type lamins as intrinsic modulators of ageing in adult stem cells and their niches. Journal of Anatomy 213, (1) (07): 5-25.

Polak, Dame Julia M. 2009. Regenerative medicine: A primer for paediatricians. Early Human Development 85, (11) (11): 685-9.

Rittié, Laure, Stefan W. Stoll, Sewon Kang, John J. Voorhees, and Gary J. Fisher. 2009. Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skin. Aging Cell 8, (6) 738-51.

Sadri-Ardekani, Hooman, Sefika C. Mizrak, Saskia van Daalen K.M., Cindy M. Korver, Hermien Roepers-Gajadien, Morteza Koruji, Suzanne Hovingh, et al. 2009. Propagation of human spermatogonial stem cells in vitro. JAMA: The Journal of the American Medical Association 302, (19) (11/18): 2127-34.

Salewski, Ryan P. F., Eftekhar Eftekharpour, and Michael G. Fehlings. 2010. Are induced pluripotent stem cells the future of cell-based regenerative therapies for spinal cord injury? Journal of Cellular Physiology 222, (3) 515-21.

Sandy, Ashley R., and Ivan Maillard. 2009. Notch signaling in the hematopoietic system. Expert Opinion on Biological Therapy 9, (11) 1383-98.

Scharfmann, R., B. Duvillie, V. Stetsyuk, M. Attali, G. Filhoulaud, and G. Guillemain. 2008. Beta-cell development: The role of intercellular signals. Diabetes, Obesity & Metabolism 10 Suppl 4, (11): 195-200.

Schöler, Hans,R. 2008. Commentary: Highlight on stem cell research. Biological Chemistry 389, (7) (07): 789-.

Taupin, Philippe. 2009. Adult neurogenesis, neural stem cells and Alzheimer's disease: Developments, limitations, problems and promises. Current Alzheimer Research 6,  (12): 461-70.

Tenzen, Toyoaki, Filip Zembowicz, and Chad A. Cowan. 2010. Genome modification in human embryonic stem cells. Journal of Cellular Physiology 222, (2) (02): 278-81.

Sharma, Shikhar, Theresa K. Kelly, and Peter A. Jones. 2010. Epigenetics in cancer. Carcinogenesis 31, (1) 27-36.

Tenzen, Toyoaki, Filip Zembowicz, and Chad A. Cowan. 2010. Genome modification in human embryonic stem cells. Journal of Cellular Physiology 222, (2) 278-81.

Is Chronic Fatigue Syndrome Triggered By a Virus? If So, Which One(s)?

Chronic fatigue syndrome (CFS)  is an extremely puzzling disease that is reported to affect as high as 2% of the world’s population (Wyller, 2007). Many physicians discount it as a valid diagnosis, or at the very least, as a single, unitary disease. Rather, it is regarded by many of them as being a facet or sequelae of some other disease process. The problem is, no one seems to know with any certainty, which one disease it is, or if many concurrent diseases seem to trigger it (Sanders & Korf, 2009).

CFS Symptoms

The symptomatology usually involves,  more than anything else,  a debilitating lethargy lasting for more than six months.  Sleep disorders, muscle pain, difficulty concentrating on tasks and memory impairment are often seen.

Overwhelmingly, its sufferers are middle-aged women. CFS is often confused with fibromyalgia, rheumatoid arthritis,  and systemic lupus erythematosus, other diseases with similar signs that are also  more common in women than in men.

Clinical depression is so often encountered in CFS patients  that it is not clear to many clinicians if they are not witnessing a case that is primarily a matter of out-of-control depression (or anxiety) with somatic side-effects, rather than vice-versa. In a small, but by no means atypical interview-based study of CFS patients, in this case  Norwegian women aged 25-55,  a number strongly associated its onset with personal dilemmas such as break-ups with boyfriends or conflicts at home  over household  chores or child-rearing (Soderlund & Malterud, 2005).  Some  also expressed a sense of persistent helplessness, indicating that they could not extricate themselves from situations that seemed to trigger the disease, making them feel even more vulnerable to repeated bouts. Almost all patients felt stigmatized as being psychologically,  rather than physically,  ill, and feared being regarded as self-pitying and/or lazy.

Competing Non-Viral Theories of Causation

As with many diseases more common among women than men, an autoimmune basis is often proposed. Elevated levels of markers typical of autoimmune disease inflammation,  such as interleukin-1 are common. Lab work may indicate that T-cell production and function is altered, usually lowered. However,  there are rarely reports of soft or hard tissue involvement that are characteristic of most of the long-lasting autoimmune diseases.

There is also a hormone deficiency, or rather hormone inadequacy theory, of CFS. Cortisol, a natural hormone often produced in response to one’s being physically or mentally challenged by an emotional  situation or difficult task, is thought to be extremely beneficial as part of the body’s coping response. Some studies indicate that CFS patients, on average, have lower amounts of cortisol.  The problems with this hypothesis include the fact that the levels of cortisol are not lower at a statistically significant level, and that injections of cortisol rarely improve CFS symptoms in a sustained manner.

A tendency to low blood pressure or sudden drops in blood pressure, have been reported in some studies of CFS patients, particularly if they are required to stand for longer periods of time. Medications to offset this are under clinical trials, based on those drugs improving the lot of patients with Neurally Mediated Hypotension (NMH), a disease which is better understood than CFS that  nonetheless shares some of the same propensity for one’s feeling faint on standing. It is noteworthy that some CFS patients can be induced into experiencing a rapid drop in blood pressure using tilt tables, in the same manner as NMH patients. Final results are not yet in, but preliminary studies suggest that a small portion of enrolled CFS patients seem to improve with NMH meds, while the majority do not.

There are also reports that silicone breast implants,  hepatitis B vaccinations, and organophosphate insecticides  may trigger CFS (Ortega-Hernandez & Shoenfeld, 2009) , although it is readily apparent that these must be rare cases since most CFS patients have had neither procedure, nor worked in agriculture, and especially few have had both procedures in close temporal proximity while handling substances that are increasingly banned worldwide. Not surprisingly,  implications that vaccinations are involved have been hotly refuted (Zuckerman, 2006).

The Viral Infection Theory

Without doubt, the greatest number of papers dealing with CFS causation involve one or more viruses. These associations of disease with viruses usually come via blood sample analyses or biopsy of tissue, with subsequent detection by some combination of PCR of DNA, gene  sequencing microarrays, tell-tale protein analyses and other markers (Kaushik et al, 2005; Klimas, Koneru & O’Brien, 2007).  Studies typically try to detect the suspect virus within cells, and see if it is being propagated sufficiently to be circulating outside cells in other fluids or tissues, as this could provide a means by which it is transmitted from one person to another.

The problem with viral theories, as in the overall case of CFS causation, is which viruses? No fewer than thirty distinct types have been implicated, with many of them not being structurally related or descended from one another in some obvious way.

The Epstein Barr virus, EBV, associated in the economically developed world with mononucleosis, and in the less developed world with rare cancers like Burkitt’s lymphoma,  seemed the most likely suspect for the 1980s and 1990s. But it is losing prominence as a most-likely-causation to a variety of other viruses, including a broad assortment of other herpes and  parvoviruses in the 2000s (see, for example,  Komaroff, 2006; Grind, 2008; Li et al, 2009; Sejvar et al, 2008; Shapiro, 2009). One of the reasons for EBV’s downfall is that the increased testing for  viruses of many sorts in a wide variety of clinical and research settings disclosed that  as high as 95% of  those subjects tested  had EBV, with the vast majority being asymptomatic for CFS.

XMRV

The late 2000s  saw a flurry of papers implicating gastrointestinal viruses (see, for example  Chia & Chia, 2008; Fremont et al, 2009), but the most intriguing new candidate is Xenotropic Murine Leukemia Related Virus (XMRV).  As its name suggests it was originally found in mice with blood disorders, but it is much more strongly associated in humans with biopsies from prostate cancer patients.

XMRV  was seriously implicated in a study done at the National Cancer Institute, published last October in Science (Lombardi et al, 2009; nicely summarized and put into context by Coffin & Stoye, 2009) in which 67% of 101 patients with CFS had the virus, while in  a matching number of asymptomatic controls  the virus was present in only 4%.  What was particularly intriguing was that not only was the virus readily detectable in cells and tissues, but also in cell-free cultures, indicating a higher potential for person-to-person infectivity.

But as is the case with so many studies of CFS causation, particularly theories of viral causation or triggering, there are conflicting studies, including the most recent (Erlwein et al, 2010), in which there was a complete absence of the virus in 186 known CFS patients living in the UK.  Erlwein et al  do not suggest that this disproves that XMRV causes CFS in Americans, just apparently not in Brits, although the authors note that XMRV is rarely if ever found in prostate cancer biopsies  from any European patients.

This final theory, that different viruses cause essentially the same disease in different continents, does not appear to help the cause of a strictly medical (as opposed to a psychological mood disorder ) causation for CFS, nor does the fact that a virus strongly associated with prostate cancer could be a causative agent make much sense given that ¾ of the patients with CFS have no prostate gland as they are women.  

Nonetheless, the general notion of some sort of viral triggering seems to destigmatize the disease, and is likely to be the wellspring for most ongoing research in the coming year.

Tony Stankus, FSLA, [email protected], Life Sciences Librarian, Science Coordinator, & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

Chia, J. K. S., and A. Y. Chia. 2008. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. Journal of Clinical Pathology 61, (1) (01): 43-8.

Coffin, John M. & Jonathan P. Stoye. 2009. A new virus for old diseases? Science 326: 530-531.

Devanur, L. D., and J. R. Kerr. 2006. Chronic fatigue syndrome.  Journal of Clinical Virology 37, (3) (11): 139-50.

Erlwein, Otto, Steve Kaye, Myra O. McClure, Jonathan Weber, Gillian Wills, David Collier, Simon Wesseley & Anthony Cleare. 2010. Failure to detect novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5, (1), e8519.

Frémont, Marc, Kristine Metzger, Hamada Rady, Jan Hulstaert, and Kenny De Meirleir. 2009. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo  23, (2) (2009): 209-13.

Grinde, Bjørn. 2008. Is chronic fatigue syndrome caused by a rare brain infection of a common, normally benign virus? Medical Hypotheses 71, (2) (08): 270-4.

Hickie, Ian, Tracey Davenport, Denis Wakefield, Ute Vollmer-Conna, Barbara Cameron, Suzanne D. Vernon, William C. Reeves, and Andrew Lloyd. 2006. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: Prospective cohort study. BMJ 333, (7568) (09/16): 575.

Kaushik, N., D. Fear, S. C. M. Richards, C. R. McDermott, E. F. Nuwaysir, P. Kellam, T. J. Harrison, et al. 2005. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. Journal of Clinical Pathology 58, (8) (08): 826-32.

Klimas, Nancy G., and Anne O'Brien Koneru. 2007. Chronic fatigue syndrome: Inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports 9, (6) (12): 482-7.

Komaroff, Anthony L. 2006. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? Journal of Clinical Virology 37 Suppl 1, (12): S39-46.

Lerner, A. M., Safedin H. Beqaj, Robert G. Deeter, and James T. Fitzgerald. 2007. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: Thirty-six months follow-up. In Vivo (Athens, Greece) 21, (5) (2007): 707-13.

Li, Haijing, Shufang Meng, Susan M. Levine, Charles W. Stratton, and Yi-Wei Tang. 2009. Sensitive, qualitative detection of human herpesvirus-6 and simultaneous differentiation of variants A and B. Journal of Clinical Virology 46, (1) (09): 20-3.

Lombardi, Vincent C., Francis W. Ruscetti, Jaydip Das Gupta, Max A. Pfost, Kathryn S. Hagen, Daniel L. Peterson, Sandra K. Ruscetti, et al. 2009. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science (New York, N.Y.) 326, (5952) (10/23): 585-9.

Ortega-Hernandez, Oscar, and Yehuda Shoenfeld. 2009. Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence? Annals of the New York Academy of Sciences 1173, (09): 600-9.

Puri, B. K. 2007. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). Journal of Clinical Pathology 60, (2) (02): 122-4.

Sanders, Patricia, and Jakob Korf. 2008. Neuroaetiology of chronic fatigue syndrome: An overview. The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry 9, (3): 165-71.

Sejvar, James J., Aaron T. Curns, Leonie Welburg, James F. Jones, Louisa M. Lundgren, Lucile Capuron, John Pape, William C. Reeves, and Grant L. Campbel. 2008. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. Journal of Neuropsychology 2, (09): 477-99.

Shapiro, Judith S. 2009. Does varicella-zoster virus infection of the peripheral ganglia cause chronic fatigue syndrome? Medical Hypotheses 73, (5) (11): 728-34.

Soderlund, Atle, and Kirsti Malterud. 2005. Why did I get chronic fatigue syndrome? A qualitative interview study of causal attributions in women patients. Scandinavian Journal of Primary Health Care 23, (4) (12): 242-7.

Wyller, Vegard Bruun. 2007. The chronic fatigue syndrome--an update. Acta Neurologica Scandinavica.Supplementum 187, : 7-14.

Zuckerman, Jane N. 2006. Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines. Journal of Medical Virology 78, (2) (02): 169-77.

Switching Gender: A Surprising Finding About the Lack of Permanency of Gender-Specific Structure & Functioning of Cells Within Adult Sex Organs Once a Genetic Switch That Promotes a Distinctly Female Identity is Turned Off

Recent papers in the prestigious journal Cell (see Sinclair & Smith, 2009; Uhlenhaut et al., 2009) have uncovered a startling phenomenon: The clear differentiation of  most mammalian sexual organ cells into either distinctly male (testicles) or female (ovaries) organs might not be determined once and for all during embryonic development.

It has become a doctrine of faith that except in extremely rare cases of intersex (now preferentially termed as Disorders of Sex Development),  having XX chromosomes led the developing embryo turned fetus  turned newborn baby along a path that led to her having functional ovaries and ova and not testes and sperm. 

This differentiation in the fate of the unspecialized “go-either-way” gonad  was thought to be a self-reinforcing phenomenon. XX chromosomes produced proteins that accelerated early either-one-way-or-the other-way  development towards an irreversibly female mix of circulating hormones, that in turn influenced the formation of distinctly female  sexual  organs  and in most cases, seem to influence the development of  sex differences in the brain in terms of structure and  gender self-identity.  Once the gonads became distinctly female they would be secreting a hormonal mix that was so predominantly  estrogen based that the “pre-ovaries”  not only became mature ovaries, but stayed that way,  and particularly with the onset of puberty, produced  even greater amounts of estrogens which further feminized appearance and function throughout adulthood.

The reverse was also thought to be true: XY chromosomes drove the production of androgens which essentially masculinized the either-or gonads towards maleness. Once the gonads became testicles they would doubtlessly produce male traits that would become even stronger after puberty.

BLAMING MOM FOR CASES OF AMBIGUOUS GENDER

There were a number of  rare exceptions to the rule. Most concerned XY male children with anatomically ambiguous genitalia, and occasionally the reverse: XX females with male-like genitals.   

It was thought that the prenatal level of circulating sex hormones might have an influence  on the  developing embryo   that   blurred distinctions in terms of the absolutely either-or anatomy, physiology and gender identity.  

While gender identity is thought to be far more complex that just having certain chromosomes  and being born with either male or female anatomy,   one of the first strategies in persons born with discordant gender identity , is in fact, hormone manipulation that aims towards the desired gender.

In a sense,  if the  maternal-fetal hormonal environment “made a mistake” then one of the first steps was to reverse it by   tilting the circulating hormone levels. Males who wish to have their bodies match their female identity would be given female hormones, and vice-versa.

At some point in time, the ovaries, testicles, and external sex organs would be removed or surgically repurposed, even as the transgender hormones had to be continued because it was seen as dogma that the gonads could not switch which hormones they were making.

THE PROBLEM OF MENOPAUSE FOR THE CONSENSUS THEORY OF THE IRREVERSIBILITY  OF GONAD DEVELOPMENT & FUNCTION

One other major problem with the theory that gonads were irreversible in gender structure and function is the masculinazation  of post-menopausal females. It was generally thought that the ovaries simply aged out of being efficient producers of female hormones, and the tiny amount of male hormones remaining simply began to circulate and influence the body more towards some masculine traits like hirsutism in particular. But there was no thought that the ovaries could actually become testicles, although in extreme cases of masculinization of secondary sex characteristics, it sometimes appeared that way.

THE INTERPLAY OF SRY, Sox 9, & FOXL2

IN SERTOLI, LEYDIG, GRANULOSA & THECA CELLS

While mice used in the lab are not, of course, human, their sexual anatomy, especially the development of the gonads towards one sex or the other  is highly comparable.

The team of of Uhlenhaut et al.  looked at the intermediate biochemical compounds and pathways that, within both mice and humans,   regulate  two general categories of sexual organ cells  specific to their gender.  These regulated cells are the Sertoli and  Leydig cells for the testicles and the granulosa and theca cells for the development and function of ovaries and ova.

The team   started with a focus on gene-produced complexes known in molecular biology shorthand as  SRY and Sox9.

SRY is basically an initiator of  sexual specialization. Without its action, there is neither female nor male sex cell development. The key is maintaining a certain balance.

When  SRY is uninhibited,  it appears to favor maleness by stimulating Sox9.  SRY’s action is modulated in females before birth by a trio of  other gene-produced complexes acting in concert:  beta-catenin, WNT4, and RSPO1. They  keep down the production of Sox9, leading to femaleness.  

After birth, another complex, known by in molecular biology shorthand as FOXL2, picks up where the trio left off in downregulating Sox9.

HOW A CANCER CHEMOTHERAPY AGENT ALLOWED FOR A SELECTIVE SHUTDOWN OF FOXL2

The team hypothesized that FOXL2 interacts with the classic female hormone estrogen and its receptors in a synergistic way.  More importantly, they  hoped that if they could find an agent that would silence the pro-female FOXL2 complex, they might witness the cessation of at least some female hormone production at the cellular level.  They looked to a drug famous for silencing estrogen receptors in cases of estrogen-driven cancers, particularly breast cancer: Tamoxifen.

The injected  tamoxifen had the desired effect.  Ovaries began to shut down estrogen production, and in particular, they appeared to do so by interfering with FOXL2, just as predicted.

What was unpredicted was that once FOXL2 was blocked, these mature  ovaries cells began to change sex. The female theca cells within them began to morph into male  Leydig cells. The female granulosa cells inside were becoming  male Sertoli cells.  In other words, well past the age of embryos, where maternal environments are thought able to influence gender anatomy, function and identity,  these important sex-specific cells were transgendering long after such a thing was thought possible.

It turns out that without FOXL2, it is conceivable that even mature adult ovaries can essentially become and perhaps act like testicles, and that FOXL2 has to fight off Sox9 throughout the lifespan of the ovary in order for it  to stay an ovary.  

WHY THIS MATTERS

This matters because it gives us an insight how we might better handle   persons with gender identity discordance. It might one day be possible to switch the nature of their gonads by selectively turning off a critical pathway, so that the post-birth ovary can indeed become a testicle and start producing male hormones on its own, as opposed to supplying male hormones and surgically removing ovaries, or vice-versa perhaps for males wishing to become females.  Some surgery and some injected hormone manipulation might still be necessary, but some of it could likely be avoided or minimized.

Perhaps even more importantly to women undergoing menopause, particularly those undergoing unwanted early menopause, insights from this research might find ways to unblock FOXL2, so that it could continue to counterbalance Sox9, and allow ovaries to continue to act like ovaries, and particularly allow for both those younger women who had unusually premature menopause and for  older professional women who had delayed childbirth, now to have children, or offset unwanted effects of female hormone loss without ingested or injected hormones.

Tony Stankus, FSLA [email protected] Life Sciences Librarian, Science Coordinator & Professor

University of Arkansas Libraries MULN-223E

Fayetteville, AR 72701

Voice 479-575-4031

Fax: 479-575-4592.

Amleh, Asma, and Jurrien Dean. 2002. Mouse genetics provides insight into folliculogenesis, fertilization and early embryonic development. Human Reproduction Update 8, (5) (2002): 395-403.

Birnbacher, R., M. Marberger, G. Weissenbacher, E. Schober, and H. Frisch. 1999. Gender identity reversal in an adolescent with mixed gonadal dysgenesis. Journal of Pediatric Endocrinology & Metabolism: JPEM 12, (5) (1999): 687-90.

Diamond, M. 2009. Clinmical implications of the organizational and activational effects of hormones. Hormones & Behavior 55 (5): 621-32.

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Hembree, W.C., P. Cohen-Kettenis, H.A. Delamarre-van de Waal et al. 2009. Endocrine treatment of transsexual persons: An Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism 94: 3132-54.

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The Safety of Beef (Yes, Even of Hamburger!): Constantly Improving Sanitation, Added Natural Products as Protective Agents & New Innoculations Against E. Coli O157:H7

While it may seem contradictory to report that 70,000 people in the US get some food poisoning every year from eating beef (their chances of actually dying from it are slightly less than 1-in-a-1,000), beef is  still  the safest single source of animal protein. A study  by Presi et al, 2009  (cited below) of relative risk  of potential  (not guaranteed!) bacterial contamination of meat gave a score of 6.7,  out of 100 cases,  to chicken products,  4.0 out of 100 cases, to pork products and  0.4%  out of 100 to beef products.

 Does this mean that any of these foods will make you sick once every 18 times (chicken), once every 25 times (pork)  or once every 250 times (beef) that you prepare  or consume it?

The answer is  resoundingly “No,” because consumers can do a great deal to prevent their being food poisoned.

Indeed it is far more likely that most cases of food poisoning are due to mishandling at home than mismanagement at the packing plant or supermarket.

 Simple measures like adequate refrigeration after purchase, washing the meat before cooking it, using clean cutting boards and knives for preparing  the raw meat, thorough cooking, and then using different clean utensils,  cutting boards, and dishes for its carving and serving, have an almost 100% chance of eliminating bacterial food poisoning.

Nonetheless, the safety advantage of beef reported in this study  is well worth exploring further.

THE BEEF INDUSTRY HAS LEARNED FROM ITS SORRY HISTORY

The meatpacking industry got a well-deserved black eye with the 1906 best-selling publication of Upton Sinclair’s novel, The Jungle, in which all manner of food handling filth and cruelty to man and beast were portrayed. It  was  based on the author’s familiarity with exploited Lithuanian workers  in that line of work, and while it contained what some screenwriters today would call “dramatizations”,  the remaining gruesome details were undeniable, despite the industry’s first attempts to cover it all up.

The public outcry  was so striking that President Theodore Roosevelt pressured the industry to the degree that beef industry representatives actually  petitioned Congress for the passage of Meat Inspection Act.  That pressure likely had more  to do with decreased sales of beef than from any genuinely enlightened motives.

Nonetheless, that  pain in the wallet led to quite a change of heart, and today the beef industry is not only in close cooperation with the USDA’s FSIS (Food  Safety & Inspection Service)  in terms of inspection compliance and improved meatpacking plant design and operations,   but is one of the biggest supporters of food protection research at America’s land grant universities (this author’s employer, included).

 

KNOWING THE ENEMY, E.  COLI O157:H7

While a wide variety of bacteria can contaminate  beef products (and vegetarians take note,  just about any other food, including most vegetables and fruits), the particular focus of the beef industry is rightly on E. coli O157:H7.

It is the microbe most often isolated from the sickest food poisoning patients, who are generally children, the elderly, and those with compromised immune systems. 

What distinguishes  this form of E.coli from the hundreds of other E. coli that live peaceably in your own gut is its production of special toxins. These toxins  induce severe cramps and diarrhea, which is often bloody, but notably, they rarely induce high fever ( a peculiar detail that apparently aids doctors in diagnosis)  .

What makes this bacterium hard to eradicate in the food processing chain is that it is unusually cold hardy: it survives the classically frigid meat packing temperatures that arrest the development and inhibit the spread (and sometimes kill outright)  other food-associated bacteria like campylobacter, listeria, and staphylococci.

 

E. COLI O175:H7 HIDES ON THE HIDE

One of the most important pieces of  the fundamental science of E. coli O157:H7 is that it does not naturally invade the muscle tissue -----the part of the animal that we eat----- of a living steer. Rather, after living peaceably (for the steer, that is) within the gut, it is defecated out in what are commonly referred to as cow pies, those multi-pound-weight plops of soft, steamy dung that give the beef and dairy farm its characteristic earthy aroma.

From there, it makes its way onto the hide of the steer through the animal’s walking through or laying onto  these cow pies. Hides from one steer can contaminate another steer’s through brushing against one another or just leaving enough dung in holding pens, feedlot fence rails,  or barn walls, for the E.  coli O157:H7 to be transmitted along with traces of manure.

Indeed,  there are several reports in the US and Canada that children at petting zoos or at state fairs where prize livestock animals are shown  have gotten E. coli O157:H7 quite literally from petting the hides of the living animals, or otherwise putting hands in contact with manure stained fixtures,  and then eating or drinking without washing the hands thoroughly.  

And it should be noted that not only were cows and steers involved, but goats, and even rabbits. And, while there is some controversy as to whether or not alcohol-based hand cleaning solutions work as well as soap and water, there is unanimity that washing one’s hands before eating or drinking is a pretty effective preventative.

WASHING THE BEEF AS WELL AS THE HANDS & CUTTING TOOLS

Today’s best meatpacking practices involve multiple washings, starting with the hides before the meat is processed much beyond euthanizing the steer and making certain primal cuts (decapitation) etc.

Washing works because at this point the E.coli O157:H1 is primarily a “surface of the meat”  invader, and as long and as often as the surface can be washed clean the bacteria can be  killed or at least held at bay. While one cannot add antibiotics to the washes, agents that aid in removal of both the bacteria and residual dirt, essentially anything that could have been left from the hide, are beneficial.

So are washing agents that change the pH of the surface, because research has shown that E. coli O157:H7  has a preferred range of acidity/alkalinity. These agents are, of course, nontoxic to humans, and are generally rinsed away the closer the meat comes to its retail cut.

Scrupulous washing of knives and machine-powered cutting tools is also a must, all along the carcass breaking and cutting line, as  the possibility of even one badly contaminated side of beef making it through can introduce  E. coli O157:H7 to all the subsequent meat processed using the same equipment.

Such is the effectiveness of these washings that intact, solid cuts of meat, for example, a large roast, or even a thick steak, are the very least likely to give one a case of E. coli O157:H7, even if the meat is cooked rare on the inside. 

That is because the exposed surface area of these intact, solid chunks  can be readily washed (eliminating the bulk of the bacteria)  and  then be exposed to high heat (which kills off the remainder) without the interior having to be well-done (Warning: this  observation is accurate but does not reflect  USDA recommendations which basically want all meat cooked medium-well to well-done to err on the side of safety).

THE SPECIAL PROBLEMS OF GROUND BEEF AND HAMBURGER

While ground beef is technically different from hamburger in the sense that ground beef has to be made from a uniform portion of the same animal (i.e. ground sirloin, ground chuck, etc.) while hamburger is made from ground beef to which can be added trimmings from other cuts and carcasses ----- both share a peculiar problem: the process of grinding takes the meat on the surface (meat that potentially has surface dwelling E.  coli O157:H7, and folds it in, again and again, into the interior of the pile of now ground meat, while exposing more and more meat to the surface where it can pick up any environmentally available E. coli O157:H7. 

In a sense, a solid  eye of the round roast that weighs 5 pounds probably has a surface area of around 300 square inches (think one side of three sheets of photocopy paper), but put that same five pounds of meat through a grinder and you have multiplied the proportion of meat that has at least once been exposed to a surface a hundred fold.

Does this mean that hamburger is inherently unsafe to eat?

 

The answer is once again, an emphatic “No.”

 

Basically, cooking your hamburger to about 160 degrees internal temperature (medium well done) means that you are very likely to have a safe hamburger, even if at some point it was exposed to E. coli O157:H7 on some of its original surface area.

Does this mean that those fast food restaurant burgers that are grilled on one side and then flipped to be cooked on the other side are safe to eat? The answer is, in fact, yes, according to Ou and Mittal, 2007 (cited below).  Even when using frozen patties, the heat ultimately penetrates the interior and kills the bacteria.

OTHER MEAT PROCESSESING MEASURES TO CONTROL E. COLI O157:H7

Some of the most innovative steps to control E. coli O157:H7 in hamburger today involve the use of natural food ingredients. While it may seem surprising, ingredients such as dried apple peel powder, tea,  acid from citrus fruits, and even cranberry  and oregano extracts, are in the experimental stage in the US (where the regulations against additives in ground meet and hamburger are quite strict), and may already be coming into use abroad.

In an even more curious finding, lactobacillus bacteria, similar to the type used in yogurt,   seems to inhibit E. coli O157:H7 rather effectively.

Why the use of these products instead of “chemical additives” (even though all “natural” and even all “organic” products are composed of chemicals, of course)?

The answer is at least partly the likelihood that they will have greater consumer acceptance, and partly because these introduced food stuffs are GRAS (Generally Recognized As Safe) by the FDA.

An example of a technology that is very highly effective in controlling E. Coli O157:H7  is meat irradiation, using x-rays, gamma-rays-, or an electron beam. However, consumers mistakenly fear that irradiated meat is somehow  “radioactive,” which is no more true than if you would become radioactive if you as a patient had gotten an x-ray.

Nonetheless, current FDA regulations require that the universal symbol for radioactivity be placed on any package with irradiated beef or hamburger, and this turns off far too many consumers to make this potentially life-saving food technology more widely used.

This is unfortunate, particularly since one legitimate consumer complaint about irradiated beef, off-taste in the fat owing to rapid oxidation, can now be offset with special processing using natural materials.

FIGHTING E. COLI O157:H7 AT ITS SOURCE ON THE FARM

Research on the farm continues apace. There are some suggestions that having too many mixed animals in close proximity to the cattle (for example having pigs nearby) increases the chances of E. Coli O157:H7, because some of these other farm animals also carry the germ.

 Likewise, the long established process of showing one’s livestock appears to spread E. coli O157:H7, in the sense that if one of the cattle is a “super-shedder” (one of a  minority of steers or cows in most herds,  whose cow pies are dramatically  richer in the bacteria), it will spread it to the others who will bring it back to their home herd.  

Finally, there is some controversy over whether or not supplementary diets rich in corn or the use of certain pasture grasses or straw  that may have their own microbial load might not increase the chances, because they somehow alter the gut microbiology of which the E.coli O157:H7 is a part.

Probably the most promising development is the introduction of immunizations against E. coli O157:H7 (see Neuman, 2007, cited below). While they are by no means 100% effective, they seem to have enough power to knock down the ambient numbers of E.coli O157:H7 of even the “super-shedders. ”  .

Because reducing the amount of E. coli O157:H7 that manages to get on the hide seems to be the very best place for the farmer to start, and the practice could become more widespread in the US (it is better established In Canada where a major supplier is based) particularly if beef prices rise enough to cover the $45 per head cost.  Of particular note is that the fact that unlike antibiotics, these inoculations leave absolutely no residues that are passed on to the consumer, because they essentially disappear as they are incorporated into the animals own antibodies.

Tony Stankus, FSLA, [email protected] Life Sciences Librarian, Science Coordinator & Professor

University of Arkansas Libraries MULN 223E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

Arthur, Terrance M., James E. Keen, Joseph M. Bosilevac, Dayna Brichta-Harhay, Norasak Kalchayanand, Steven D. Shackelford, Tommy L. Wheeler, Xiangwu Nou, and Mohammad Koohmaraie. 2009. Longitudinal study of Escherichia coli O157:H7 in a beef cattle feedlot and role of high-level shedders in hide contamination. Applied and Environmental Microbiology 75, (20) (10/14): 6515-23.

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Should You Wait Until You Are 50 to Start Getting Routine Mammograms? Should You Stop Breast Self-Examinations as Well? A Growing Controversy Over New Guidelines from the US Preventive Services Task Force

The US Preventive Services Task Force is an ad hoc  voluntary group of medical experts periodically assigned by  the US Department of Health & Human Services to offer  advice and guidelines on best practices on some topic  in preventive medicine and public health.

 

They are known for their willingness to bring science to discussion tables where emotions have hitherto held sway. Such appears to be the case with  new guidelines which they have announced with regard to the age of onset and frequency of routine mammography.

 

These guidelines, published and discussed in the most recent Annals of Internal Medicine, (cited below under US Preventive Services Task Force, 2009, and accompanying commentaries, and the many citations within all this material,  basically say the following:

 

1. The prior recommendation (US Preventive Services Task Force, 2002) of annual mammographies starting at age 40 as a means of screening for breast cancer was somewhat  ambivalent in terms of the concreteness of its statistical basis and its science, and that the doubters about starting them too soon and having them too often,  were probably right all along.  In their collective, and necessarily hindsight opinion,  those millions of unnecessary mammographies did more  harm to more patients that did not have breast cancer than they did good for the statistically far  fewer patients whose breast cancers were detected.

 

2. The principal harms that occurred were fourfold. First, there were many more unnecessary follow-up mammographies that disclosed no new cancers. Second, there were vastly more breast biopsies (and repeat breast biopsies) , painful and expensive  procedures  that turned out not to have identified an any malignancy. Third, many marginally malignant, or extremely slow-growing cancers, and even altogether non-malignant growths were mistakenly and/or  over-aggressively treated. These treatments, along with the biopsies, opened the door to surgical misadventures, infections, and ironically, unintended initiation of new tumors through  some of the paradoxical side-effects of radiation and chemotherapeutics. Fourth, a great many women were needlessly worried about having a life-threatening disease, when, in fact, they did not.

 

3. Routine breast self examinations for lumps, and even the administration of examinations by trained doctors and nurses in office settings, while not of themselves  having side-effects other than inducing worry, have led to too many biopsies with a potential for adverse side-effects, while disclosing few genuine tumors in individuals relative to the harm collectively caused by teaching and encouraging this procedure. Inevitably, many patients, nurses, and physicians,  will, in fact, find lumps,  which almost inevitably leads to  subsequent, and overwhelmingly unnecessary,  biopsies.

 

4.  There is now more scientifically reliable, statistical evidence that mammograms starting at age fifty, and repeated every other year, will likely detect, more  predictably, lumps and cancers that are actually serious enough actually to warrant biopsy and appropriately aggressive treatment. The risks of false-positives are significantly reduced by waiting until this age range, and  the every other year interval further reduces that risk.

 

5.  This advisory of waiting to age 50, and having every other year intervals, is in no way intended for those with a strong personal case history of breast pathology, or who have predisposing factors such as known familial breast cancer genetic markers.

 

 

There is no evidence that these medical and scientific advisors of the 2009 US Preventive Services Task Force, which included nine men and seven women at the time the recommendation was finalized,  were in the pay of insurance companies that wanted to deny coverage for annual mammograms, or, as has been alleged, they were part of some scheme, inevitable under current proposals for health care reform, to ration health care.

 

Nonetheless, they, and their recommendations have been thoroughly pilloried.

 

And the Secretary of Health & Human Services, Kathleen Sibelius, whose agency requested this very analysis, has beaten a hasty retreat, giving the appearance of leaving her honest analysts out there hanging  defenselessly (See Sack & Kolata, cited below).  

 

Nonetheless, some gutsy support for the new recommendations  can be found in the press. See Controversy over mammograms (2009),  Fink (2009) and Rifkin (2009) cited below.

 

And at least one breast cancer survivor (Collins, 2009) finds this and other blue-ribbon panel medical advisory  flip-flops oddly amusing, once one has gotten past the uglier parts of chemotherapy or radiation.

 

Who Disagrees with Their Expert Opinion? Other Expert Bodies & A Lot Of Breast Cancer Survivors

 

·     The American Cancer Society (see American Cancer Society, 2009, cited below)

·     The American Society of Breast Disease (see Lebovic, 2009, cited below)

·     The American College of Obstetricians and Gynecologists (see American College of Obstetricians and Gynecologists, 2009, cited below)

·     The American College of Radiology (see American College of Radiology, 2009, cited below).    

·     The American Society of Clinical Oncology is less stark in its disagreement, but it clearly thinks that the new recommendations are throwing the baby out with the bath water (see American Society of Clinical Oncology, 2009, cited below).

·     So do a great many women whose lives have been saved by early mammography and breast self-examinations. See the following cited below:  Kearns, (2009); Leveen (2009); Sperber (2009), Swersky (2009).

Is Past Experience with Older Diagnostic Technology & Means of Image & Biopsy Interpretation Necessarily the Best Guideline for a Forward-Looking Recommendation?

 A key question that is not being asked today, is: Whether our retrospective statistical look at false positives caused by the mammographic equipment and older biopsy methods used in the recent past,  and the ways of interpreting the resulting mammograms and tissues excised, will continue to lead to false positives, needless follow-up biopsies, and overtreatment in the years to come?

The advisory as it stands now seems to rule out significant changes in the technology and interpretation of mammograms and biopsies, but any biomedical librarian worth his or her salt will be able to identify a substantial number of papers dealing with new pieces of medical imaging equipment, new combinations of medical imaging equipment and means of taking biopsies, and new algorithms for scanning and interpreting the resulting mammograms and biopsies,  that have been tested and shown to reduce significantly, false positives (Chan et al, 2008; Chawla et al, 2009; Eliahou et al, 2009;  Freixenet et al, 2009; Leff et al, 2008; Llado et al, 2009; Peters et al, 2009; Pfleiderer et al, 2009; Potente et al, 2009; Rojas Dominguez & Nandi, 2008; Salem et al, 2009 ).

 

It might be a good idea to rule out their promise of something better and far more accurate, before ruling out routine annual mammograms for women at 40, with biopsies as needed in the judgment of the physician and patient.

 

Tony Stankus, FSLA, [email protected] Life Sciences Librarian, Science Coordinator & Professor,

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

 Fayetteville, AR 72701-4002

Voice:  479-575-4301

 Fax: 479-575-4592

 

American Cancer Society. (2009).  The American Cancer Society responds to USPSTF Mammography Guidelines. The American Cancer Society guidelines will not change; annual mammography recommended for women 40 and over. http://www.cancer.org/docroot/MED/content/MED_2_1x_American_Cancer_Society_Responds_to_Changes_to_USPSTF_Mammography_Guidelines.asp

American College of Obstetrics and Gynecology. 2009. Response of the American College Of Obstetricians And Gynecologists to new breast cancer screening recommendations from the U.S. Preventive Services Task Force , 2009) http://www.acog.org/from_home/Misc/uspstfResponse.cfm

American College of Radiology. (2009). USPSTF Mammography Recommendations Will Result in Countless Unnecessary Breast Cancer Deaths Each Year. http://www.acr.org/HomePageCategories/News/ACRNewsCenter/USPSTFMammoRecs.aspx

American Society of Clinical Oncology. (2009). Expert Perspective from ASCO on Mammography Screening for Breast Cancer.  http://www.cancer.net/patient/Cancer+News+and+Meetings/Expert+Perspective+on+Cancer+News/Expert+Perspective+from+ASCO+on+Mammography+Screening+for+Breast+Cancer

Belluck, P. (Wednesday, November 18, 2009.)  Responding to new mammogram guidelines: Many physicians aren’t ready to recommend change. New York Times, 159, (54,863), p.A1, continued on p.A22.

Berg, W. A., Blume, J. D., Cormack, J. B., Mendelson, E. B., Lehrer, D., Böhm-Vélez, M., et al. (2008). Combined screening with ultrasound and mammography vs. mammography alone in women at elevated risk of breast cancer. JAMA: The Journal of the American Medical Association, 299(18), 2151-2163.

Brett, J., Bankhead, C., Henderson, B., Watson, E. & Austoker, J. (2005). The psychological impact of mammographic screening. A sustematic review. Psychooncology, 14: 917-938.

Brewer, N.YT., Salz, T., & Lillie, S.E. (2007). Systemastic review: Long term effects of false-positive mammograms. Annals of Internal Medicine, 146, 502-510.

Chan, H., Wei, J., Zhang, Y., Helvie, M. A., Moore, R. H., Sahiner, B., et al. (2008). Computer-aided detection of masses in digital tomosynthesis mammography: Comparison of three approaches. Medical Physics, 35(9), 4087-4095.

Chawla, A. S., Saunders, R. S., Singh, S., Lo, J. Y., & Samei, E. (2009). Towards optimized acquisition scheme for multiprojection correlation imaging of breast cancer. Academic Radiology, 16(4), 456-463.

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Day, N.E. (2005). Overdiagnosis and breast cancer screening. Breast Cancer Research, 7, 228-229.

De Koning, H.J., Draisma, G., Fracheboud, J. & De Bruijn, A. (2006). Overdiagnosis and over treatment of breast cancer: Microsimulation modelling estimates based on observed screen and clinical data. Breast Cancer Research, 7, 285-265.

Duffy, S.W., Agbaje, O., Tabar, L., Vitak, B., Bjurstam, N., Bjorneld, L. et al. (2005). Overdiagnosis and overtreatment of breast cancer: Estimates of overdiagnosis from two tirals of ammographic screening for breast cancer. Breast Cancer Research, 7, 258-265.

Eliahou, R., Sella, T., Allweis, T., Samet, Y., Libson, E., & Sklair-Levy, M. (2009). Magnetic resonance-guided interventional procedures of the breast: Initial experience. The Israel Medical Association Journal: IMAJ, 11(5), 275-279.

Fink, R. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Freixenet, J., Oliver, A., Martí, R., Lladó, X., Pont, J., Pérez, E., et al. (2008). Eigendetection of masses considering false positive reduction and breast density information. Medical Physics, 35(5), 1840-1853.

John, E.M.. Phipps, A.I., Knight, J.A., Milne, R.L., Dite, G.S.  Hopper, J.L., et al. (2005). Medical radiation exposure of mammographic screening: Findings from the Breast Cancer Family Registry. International Journal of Cancer, 121, 386-394.

Kearns, J.M. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Kelikowske, K. (2009). Evidence-based breast cancer prevention: The importance of individual risk. Annals of Internal Medicine, 151, 750-752.

Kirschner, E. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Kolata, G. (Tuesday, November 17, 2009). New guidelines suggest fewer mammograms. New York Times, 159, (54,862), p.A1, continued on p.A17.

Kolata, G. (Friday, Novemebr 20, 2009). Mammogram debate took group off guard. New York Times, 159, p.A22.

Kosters, J.P., & Gotzsche, P.C. (2003). Regular self-examination or clinical examination for early detection of breast cancer? Cochrane Databse Systematic Reviews, CD003373.

Lam, W. W. M., Chan, C. P., Chan, C. F., Mak, C. C. C., Chan, C. F., Chong, K. W. H., et al. (2008). Factors affecting the palpability of breast lesion by self-examination. Singapore Medical Journal, 49(3), 228-232.

Lebovic, G. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Leff, D. R., Warren, O. J., Enfield, L. C., Gibson, A., Athanasiou, T., Patten, D. K., et al. (2008). Diffuse optical imaging of the healthy and diseased breast: A systematic review. Breast Cancer Research and Treatment, 108(1), 9-22.

Leung, G. M., Woo, P. P. S., Cowling, B. J., Tsang, C. S. H., Cheung, A. N. Y., Ngan, H. Y. S., et al. (2008). Who receives, benefits from,  and is harmed,  by cervical and breast cancer screening among Hong Kong Chinese? Journal of Public Health (Oxford, England), 30(3), 282-292.

Leveen, A. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Lladó, X., Oliver, A., Freixenet, J., Martí, R., & Martí, J. (2009). A textural approach for mass false positive reduction in mammography. Computerized Medical Imaging and Graphics: The Official Journal of the Computerized Medical Imaging Society, 33(6), 415-422.

Mandelblatt, J.S. et al. (2009). Clinical guidelines: Effects of ammography screening under different screening schedules: Model estimates of potential benefits and harms. Annals of Internal Medicine, 151, 738-747.

Moss, S. (2005). Overdiagnosis and overtreatment of breast cancer: Overdiagnosis in randomized control trials of breast cancer screening. Breast Cancer Research, 7, 230-234.

Nelson, H.D., Tyne, K., Naik,  A., Bougatsos, C., Chan, B. & Humphrey, L. (2009). Screening for for breast cancer: An Update for the US Preventive Services Task Fioorce.  Annals of Internal Medicine, 151, (10), 727-737.

Olsen, A.H., Agbaje, O.F., Myles, J.P., Lynge, E. & Duffy, S.W. (2006). Overdiagnosis, sojourn time, and sensititivity in the Copenhagen mammography screening program. Breast Journal, 12,338-342.

Paci, E., Miccenesi, G., Puliti, D., Baldazzi, P., DeLisi, V., Falcini, F., et al. (2006).  Estimate of overdiagnosis of breast cancer due to mammography after adjustment for lead time. A service screening study in Italy. Breast Cancer Research, 8, R68.

Peters, N. H. G. M., Meeuwis, C., Bakker, C. J. G., Mali, W. P. T. M., Fernandez-Gallardo, A., van Hillegersberg, R., et al. (2009). Feasibility of MRI-guided large-core-needle biopsy of suspiscious breast lesions at 3 T. European Radiology, 19(7), 1639-1644.

Pfleiderer, S. O. R., Brunzlow, H., Schulz-Wendtland, R., Pamilo, M., Vag, T., Camara, O., et al. (2009). Two-year follow-up of stereotactically guided 9-G breast biopsy: A multicenter evaluation of a self-contained vacuum-assisted device. Clinical Imaging, 33(5), 343-347.

Potente, G., Messineo, D., Maggi, C., & Savelli, S. (2009). Practical application of contrast-enhanced magnetic resonance mammography [CE-MRM] by an algorithm combining morphological and enhancement patterns. Computerized Medical Imaging and Graphics: The Official Journal of the Computerized Medical Imaging Society, 33(2), 83-90.

Rabin, R.C. (Tuesday, November 17, 2009). New guidelines on breast cancer draw opposition. New York Times, 159, (54,862), p.D5.

Rakha, E. A., El-Sayed, M., Reed, J., Lee, A. H. S., Evans, A. J., & Ellis, I. O. (2009). Screen-detected breast lesions with malignant needle core biopsy diagnoses and no malignancy identified in subsequent surgical excision specimens (potential false-positive diagnosis). European Journal of Cancer (Oxford, England: 1990), 45(7), 1162-1167.

Rifkin, W. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

Rojas Domínguez, A., & Nandi, A. K. (2008). Detection of masses in mammograms via statistically based enhancement, multilevel-thresholding segmentation, and region selection. Computerized Medical Imaging and Graphics: The Official Journal of the Computerized Medical Imaging Society, 32(4), 304-315.

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Salem, C., Sakr, R., Chopier, J., Marsault, C., Uzan, S., & Daraï, E. (2009). Accuracy of stereotactic vacuum-assisted breast biopsy with a 10-gauge hand-held system. Breast (Edinburgh, Scotland), 18(3), 178-182.

Seifi, A., Axelrod, H., Nascimento, T., Salam, Z., Karimi, S., Avestimehr, S., et al. (2009). Migration of guidewire after surgical breast biopsy: An unusual case report. Cardiovascular and Interventional Radiology, 32(5), 1087-1090.

Sergentanis, T. N., Zagouri, F., Domeyer, P., Giannakopoulou, G., Tsigris, C., Bramis, J., et al. (2009). Biopsy method: A major predictor of adherence after benign breast biopsy? AJR.American Journal of Roentgenology, 193(5), W452-7.

Sperber, R. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

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Swersky, B. (Wednesday, November 18, 2009). The controversy over mammograms: Letter to the editor. New York Times, 159, (54,863), p.A30.

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Repeated Concussions In Football & The NFL’s Handling Of Them: Does the Ruling on the Field that the League is Fairly Handling Them --- And Retired Players with Chronic Traumatic Encephalopathy Possibly Because of Them --- Need to Be Reviewed?

I am one of the tens of millions of fans of college and professional football. I played football when I was in junior high. (I was a right guard: Not the deodorant, the position!). I watch football religiously on Thursday nights, all-day & evening on Saturdays, Sunday afternoons and evenings,  and Monday nights to boot. I follow the New England Patriots  (my hometown professional franchise), the Holy Cross Crusaders (my undergraduate alma mater) and the University of  Arkansas Razorbacks (the team of my current employer).

 

But I am also a Biomedical librarian with over 35 years of experience, with the duty and competence to identify and supply well-vetted scientific and clinical studies to library patrons, who will go on to use the information in their own professional practice or as part of their ongoing program of study.

 

So it is entirely fair to say that I have conflicted feelings, when comparing the claims of the NFL that repeated concussions  (also known as Mild Brain Traumatic Injuries) have not been shown necessarily to lead prematurely to Chronic Traumatic Encephalopathy ----- persistent cognitive declines,  other neuropsychological effects,  and severe emotional turmoil ----- that emerges later on in the lives of its players, usually after their retirement, sometimes as early as their mid-thirties.

 

I certainly want this denial to be the case, but wanting it to be the case, is not the same as having a preponderance of evidence on one side or the other.

 

Dr. Ira Casson and the NFL team of experts

 

To its great credit, the NFL has started its own “in-house” studies, and these have been generally headed up by Dr. Ira Casson, a board-certified neurologist who has made a career of  studying athletes and brain injuries, particularly concussions. He has frequently worked with other physicians, most commonly  Drs. D.C. Viano, and E.J. Pellman, as part of  a group called ProHEALTH Care Associates, LLP.

 

Dr. Casson  is, in fact, arguably the most published physician in this area. I have identified at least 17 studies, often also involving Viano and Pellman, involving concussion and NFL football players (as well as a few studies of boxers whose record of permanent brain trauma is almost universal). These studies  all appeared in highly reputable journals such as the American Medical Association’s Archives of Neurology, Elsevier’s Physical Medicine and Rehabilitation Clinics of North America and its Neurological Clinics, and perhaps most importantly in the journal, Neurosurgery, a Lippincott, Williams & Wilkins title that is the official voice of the Congress of Neurological Surgeons.

 

Many of his studies are uncontroversial and some results and measures taken by the NFL in response to them, such as the establishment of its official  Mild Traumatic Brain Injury Committee, are undisputed as positive measures in terms of advancing knowledge of concussions and other brain trauma in modern professional football:

 

·     There is now extremely little chance for very severe one-shot head injuries among NFL players. This has already been substantially minimized by intense cooperation between equipment suppliers (particularly of helmets), NFL-retained physicians and trainers, and significant support from science and engineering studies contracted for this purpose.

 

·     There   continues to be a surprising number of ongoing studies that attempt to identify the various dynamic forces in terms of unnatural head and neck deflection and extension with regard to angle of   collision and degree of force behind the collisions. What the auto industry did with respect to auto crashes, seat belts, and air bags, and crash test dummies, is effectively being duplicated in earnest by groups within and without the NFL’s auspices.

 

·     There is a continuous  training program for team physicians and  allied sports professionals to examine and quickly screen for on-field concussions. If the players report them, or show overt symptomatology, they will be closely examined and possibly sent off field for treatment. The NFL has even developed some screening tools to help them overcome the natural reluctance of players who fear losing their starting position, contract renegotiation, or being traded, because they have had one or more concussions and do not want to be considered “whiners who won’t play through the pain.”

 

·     Deliberate helmet-to-helmet collisions in the course of a game now involve, not only a serious 15-yard penalty during the game, but also a stiff fine for the offending player afterwards from the NFL commissioner.

 

·     The NFL has now mandated baseline neurocognitive testing of all incoming NFL players, so as to be able to check not only if there are existing deficits in these players, but more importantly, perhaps, to provide for comparison points between the beginning of a career vs. its immediate end and even the situation several years past retirement. An inventory of facts regarding prior psychiatric issues, chemical dependency, learning disabilities, and some factors of emotional stability is also involved.

 

·     A program of outreach to retired NFL players who are having neurocognitive declines, that includes screening, and follow up for those willing and able to complete any paperwork and to make their own arrangements to come to their facilities.

 

The Criticisms & the Sad, Adverse Case Histories

Dr. Casson and associates are not without critics. Those complaints center around:

·     A lack of independence of the studies from those who paid for the studies. In other words: Is it any surprise that the NFL pays for studies that essentially suggest that the NFL’s current arrangements for handling concussions (i.e. Mild Brain Traumatic Injuries)  are safe and effective in preventing Chronic Traumatic Encephalopathy?

·     Too few subjects within the studies that have been conducted to render scientifically valid results. This is a criticism that the NFL suggests is technical rather than indicative of a lack of good faith on their part. Critics suggest that larger numbers are much more likely to reveal the truth, whatever the intention or motivation of the sponsoring organization.

·     The claims by Casson and others that professional football players who have had a concussion in the course of a game, can often be returned to play very quickly,  often within the same game. It is exactly this accumulation of Mild Brain Traumatic Injuries  that critics suggests leads to Chronic Traumatic Encephalopathy. They say that lack of immediate serious cognitive defects does not preclude long term cumulative damage down the road.

The scientific and clinical ammunition of the opponents is partly statistical and anecdotal of itself. It basically consists of :

·     Bringing to the attention of the media, the U.S. congress, and the public, a growing number of retired NFL players who had experienced multiple concussions and have since undergone drastic declines in their mental faculties and ability to cope with life, far beyond what would be expected for their ages. Their clinical pictures makes them look like they are Alzheimer’s patients in the 70’s as opposed to men in their 40s or 50s.

·     An accumulating body of postmortem brain studies from former NFL players that show that even small concussions, if too many and too often over a career, do result in visible brain damage that cannot be otherwise explained away.

·     Federal support in terms of competitive NIH grants for the Center for the Study of Traumatic Encephalopathy, a collaboration of the not-for-profit (but clearly biased towards the cumulative-effects-leading –to-the-Chronic-Traumatic-Encephalopathy viewpoint)  Sports Legacy Institute and the Boston University School of Medicine. While paper of Dr. Anne McKee and her own team of experts, cited below, is clearly outnumbered by the studies of Casson, Viano and Pellman, it is no less prestigious in terms of its venue, the Journal of Neuropathology and Experimental Neurology.

Congress Throws the Red Flag

In professional football, the coach of a team who wishes a reexamination of a call adverse to that team that has been made by the referees on the field, has the limited right to throw a red flag on the field. This causes the play to be reviewed using additional replays based on multiple camera angles, which supply different perspectives, and which have the potential for overturning that ruling. On Thursday, October 26, 2009, members of congress, during special hearings, clearly threw their flag, and were especially not pleased with the absence of the head referee, Dr. Ira Casson,  who was presumably going to be asked to review the call on the field. While other physicians and league officials were there, and gave testimony and answers as best they could,  it seemed that no conclusive result could be reached in his absence.

In the interest of football and football players, both current and retired from the NFL players, plus the players in college, high school, and even journal high schools who learn how to play, by watching the pros, it might well be that it really is time for someone else other than the NFL’s own experts “to review the tapes” either to confirm or overturn the current ruling on the field concerning whether or not current leagues practices relating to concussions really do avoid or minimize the chances of chronic traumatic encephalopathy, and whether or not the league owes even more to its brain-damaged veterans.

Tony Stankus, FSLA [email protected] Life Sciences Librarian, Science Coordinator  & Professor

University of Arkansas Libraries MULN 223E

365 North McIlroy Avenue

Fayetteville AR  72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

Cao, C., Tutwiler, R. L., & Slobounov, S. (2008). Automatic classification of athletes with residual functional deficits following concussion by means of EEG signal using support vector machine. IEEE Transactions on Neural Systems and Rehabilitation Engineering: A Publication of the IEEE Engineering in Medicine and Biology Society, 16(4), 327-335.

Casson, I. R., Sham, R., Campbell, E. A., Tarlau, M., & Didomenico, A. (1982). Neurological and CT evaluation of knocked-out boxers. Journal of Neurology, Neurosurgery, and Psychiatry, 45(2), 170-174.

Casson, I. R., Siegel, O., Sham, R., Campbell, E. A., Tarlau, M., & DiDomenico, A. (1984). Brain damage in modern boxers. JAMA: The Journal of the American Medical Association, 251(20), 2663-2667.

Casson, I. R., Pellman, E. J., & Viano, D. C. (2006). Chronic traumatic encephalopathy in a National Football League player. Neurosurgery, 59(5), E1152-E1152.

Casson, I. R., Pellman, E. J., & Viano, D. C. (2006). Chronic traumatic encephalopathy in a national football league player. Neurosurgery, 58(5), discussion e1003.

Casson, I. R., Pellman, E. J., & Viano, D. C. (2008). Concussion in the national football league: An overview for neurologists. Neurologic Clinics, 26(1), 217-41.

Casson, I. R., Pellman, E. J., & Viano, D. C. (2009). Concussion in the National Football League: An overview for neurologists. Physical Medicine and Rehabilitation Clinics of North America, 20(1), 195.

Casson, I. R., Pellman, E. J., & Viano, D. C. (2009). National Football League experiences with return to play after concussion. Archives of Neurology, 66(3), 419-420.

Casson, I. R., Viano, D. C., & Pellman, E. J. (2008). Synopsis of the National Football League player health and safety meeting: Chicago, Illinois, june 19, 2007. Neurosurgery, 62(1), 204.

Fréchède, B., & McIntosh, A. S. (2009). Numerical reconstruction of real-life concussive football impacts. Medicine and Science in Sports and Exercise, 41(2), 390-398.

Goldberg, D. S. (2008). Concussions, professional sports, and conflicts of interest: Why the National Football League's current policies are bad for its (players') health. HEC Forum: An Interdisciplinary Journal on Hospitals' Ethical and Legal Issues, 20(4), 337-355.

Greenwald, R. M., Gwin, J. T., Chu, J. J., & Crisco, J. J. (2008). Head impact severity measures for evaluating mild traumatic brain injury risk exposure. Neurosurgery, 62(4), 789.

Lau, B., Lovell, M. R., Collins, M. W., & Pardini, J. (2009). Neurocognitive and symptom predictors of recovery in high school athletes. Clinical Journal of Sport Medicine: Official Journal of the Canadian Academy of Sport Medicine, 19(3), 216-221.

McKee, A. C., Cantu, R. C., Nowinski, C. J., Hedley-Whyte, E., Gavett, B. E., Budson, A. E., et al. (2009). Chronic traumatic encephalopathy in athletes: Progressive tauopathy after repetitive head injury. Journal of Neuropathology and Experimental Neurology, 68(7), 709-735.

Mello, M. J., Myers, R., Christian, J. B., Palmisciano, L., & Linakis, J. G. (2009). Injuries in youth football: National emergency department visits during 2001-2005 for young and adolescent players. Academic Emergency Medicine: Official Journal of the Society for Academic Emergency Medicine, 16(3), 243-248.

Miller, G. (2009). Neuropathology. A late hit for pro football players. Science (New York, N.Y.), 325(5941), 670-672.

Pellman, E. J., Lovell, M. R., Viano, D. C., & Casson, I. R. (2006). Concussion in professional football: Recovery of NFL and high school athletes assessed by computerized neuropsychological testing--part 12. Neurosurgery, 58(2), 263.

Pellman, E. J., Lovell, M. R., Viano, D. C., Casson, I. R., & Tucker, A. M. (2004). Concussion in professional football: Neuropsychological testing--part 6. Neurosurgery, 55(6), 1290.

Pellman, E. J., Powell, J. W., Viano, D. C., Casson, I. R., Tucker, A. M., Feuer, H., et al. (2004). Concussion in professional football: Epidemiological features of game injuries and review of the literature--part 3. Neurosurgery, 54(1), 81.

Pellman, E. J., Viano, D. C., Casson, I. R., Arfken, C., & Feuer, H. (2005). Concussion in professional football: Players returning to the same game--part 7. Neurosurgery, 56(1), 79.

Pellman, E. J., Viano, D. C., Casson, I. R., Arfken, C., & Powell, J. (2004). Concussion in professional football: Injuries involving 7 or more days out--part 5. Neurosurgery, 55(5), 1100-1119.

Pellman, E. J., Viano, D. C., Casson, I. R., Tucker, A. M., Waeckerle, J. F., Powell, J. W., et al. (2004). Concussion in professional football: Repeat injuries--part 4. Neurosurgery, 55(4), 860.

Pellman, E. J., Viano, D. C., Tucker, A. M., Casson, I. R., & Waeckerle, J. F. (2003). Concussion in professional football: Reconstruction of game impacts and injuries. Neurosurgery, 53(4), 799.

Randolph, C., & Kirkwood, M. W. (2009). What are the real risks of sport-related concussion, and are they modifiable? Journal of the International Neuropsychological Society: JINS, 15(4), 512-520.

Ross, R. J., Casson, I. R., Siegel, O., & Cole, M. (1987). Boxing injuries: Neurologic, radiologic, and neuropsychologic evaluation. Clinics in Sports Medicine, 6(1), 41-51.

Rowson, S., Brolinson, G., Goforth, M., Dietter, D., & Duma, S. (2009). Linear and angular head acceleration measurements in collegiate football. Journal of Biomechanical Engineering, 131(6), 061016.

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Tsushima, W. T., Oshiro, R., & Zimbra, D. (2008). Neuropsychological test performance of Hawai'i high school athletes: Hawai'i ImPACT normative data. Hawaii Medical Journal, 67(4), 93-95.

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Viano, D. C., Casson, I. R., Pellman, E. J., Bir, C. A., Zhang, L., Sherman, D. C., et al. (2005). Concussion in professional football: Comparison with boxing head impacts--part 10. Neurosurgery, 57(6), 1154.

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Prescription Paradoxes : How the Drugs of Choice for Treating Primary ADHD May Not Be Best for Drug Addicts or BiPolar Patients Who Also Have ADHD, and that Drugs of Choice for BiPolar Disorder & Even For Adult Onset Diabetes, May Promote Weight Gain

In prescribing treatments for a variety of ailments, it sometimes seems as if no good deed goes unpunished.  The September, 2009 issue of the journal Postgraduate Medicine,  presents us with a number of excellent papers that show that some remedies for one illness,  have potential for causing others, or at least, for requiring more vigilance  for co-morbidity, the presence of two diseases in the same patient at once.

Indeed,  paradoxes abound, and those physicians and pharmacological researchers who try to navigate between the “rock and the hard place” are to be credited as often as they succeed, because the path is by no means clear for all the affected patients.

Is There A Relationship  Between Adult ADHD And Adult Substance Use  Disorders?

There has been a longstanding   supposition that a link exists between the onset of   Attention Deficit Hyperactivity Disorder (ADHD)  and Substance  Use Disorder (SUD usually involving generally street drug addiction).

Demographic studies of adults  based on interviews of individuals living in the community (or on the streets),  have usually been conducted by  walk-in or outpatient clinics. Their results   in reporting their rates for separate and   simultaneous incidence of both conditions  have fluctuated, in part because it is hard to follow up on patients or to retest them to assure reliability.

This uncertainty of a connection, or of the frequency of having both conditions at the same time,  has been considerably reduced via a study at  Odyssey House, an in-patient, residential treatment facility in New York City (See Adler et al, 2009 below).  

 It involved a very  large group ( 1064) of  in-patients, where  no subjects had to be excluded for lack of reliability of background information or unwillingness or unavailability to take a series of diagnostic tests, and no patients  dropped out, conditions almost never attainable in community-based studies.  

The end result is that patients with drug abuse  problems had reliably diagnosed ADHD at twice the rate (~7+%) of the “normal” population (~4%), but not necessarily  the 25%+ rates seen in other studies.

The paradox in treating the ADHD of these patients who also had drug abuse problems will crop up shortly in this essay.

Is There A Relationship Between ADHD and Patients with Major Mood Disorders Including Bipolar?

Of course, drug abuse is not the only co-morbidity associated with  adult ADHD.

 Mood disorders, particularly major depression and bipolar disease,  also have a connection .  

A paper By Goodman & Thase (2009, cited below) reports that 13% of patients presenting primarily for treatment for  mood disorders also turn out to have ADHD, and 38% of patients presenting primarily for treatment of ADHD turn out to have major depression or bipolar disorder.  

While a wide variety of treatment strategies are suggested to attack this problem, one of them, and quite frankly, the first line of defense, are prescription medications, and these two present prescribers with a paradox.

First Paradox: The Overall  Drug of Choice for Primary ADHD is Not Likely to Be the Safest  Drug of Choice for Substance Abuse Disorder or BiPolar Patients With Co-morbid ADHD. It’s Enough To Give Some Patients Heartburn

This  is where the first in a string of paradoxes  comes in.

One salient problem in the case of both studies is that the drug of choice for treating ADHD is “speed”, more technically,  amphetamines.

It is not clear that one wishes to give drug addicts a drug, which if they take in doses beyond the prescribed low levels ( a common behavior among addicts, and also among many ADHD patients) will lead to yet another addiction.

It may also be very unwise to use amphetamines, which do have the potential for causing over-excited behavior and a general feeling of edginess to bipolar patients who are entering their manic phase.

In a further complication,  some controlled release versions of mixed amphetamine salts, developed in part because their more gradual pharmacokinetics make them less likely to cause a “speed buzz”, are rendered less predictable in their ability to gradually enter the body.

This is due to certain prescribed and over the counter medications (the best-selling of which is omeprazole, brand name Prilosec) designed to control acid reflux (also a common condition shared by both adult ADHD and bipolar patients).

Omeprazole  changes the chemical environment of the gut in a manner that has the potential in some patients to subvert the designed rate of release of the mixed amphetamine salts.  (See Haffey et al., cited below.)

In about half the cases in this study, the mixed amphetamine salts in controlled released, reached peak saturation significantly sooner, with the dosage tailing off towards the end of the individual   dose.

This may leave some patients with the choice to stick with their controlled-release  mixedamphetamine salts medication  for ADHD and to try and  ignore the heartburn, or perhaps switch to the fast-acting  amphetamines, without the risk of heart burn because the omeprazole could still be taken, but with the risk of abuse of the fast-acting variety.

(Fortunately lisdexanfetamine, an alternative for some ADHD patients, seems unaffected by omeprazole, but it is not clear whether this drug will work as well for all  patients well-controlled with mixed amphetamine salts.)

Second Paradox: The Drugs of Choice for Adult BiPolar Disorder Patients May Predispose them to Weight Gain, Metabolic Syndrome, and Adult Onset Diabetes

If the drug of choice for  treating mixed bipolar disorder and ADHD is yet to be identified (with or without acid reflux or heartburn) there is no lack of choice in treating the more severe forms of primary bipolar disorder.

Clozapine (brand name Clozaril), Olanzapine (brand name Zyprexa), Risperidone(brand name Risperdal), Quetiapine (brand name Seroquel), Aripiprazole  (brand name Abilify) and Ziprasidone (brand name Geodon) have all been used with significant success in literally millions of patients. 

What’s the catch?

According to a paper by Bell, McKenna & Roscoe (2009, cited below) the first four of these are associated with patient weight gain and adverse blood lipid profiles (too much of the wrong kinds of cholesterol, less of the good kind, and overall, higher triglyceride levels.)  

All six are associated with increased diabetes risk.  

Most psychiatric providers do not, however, suggest that these drugs be discontinued, but rather, they recommend trying to change the patient’s health affecting behaviors in a positive way.

Having said this, they also warn that  this is extremely difficult with many bipolar patients, many of whom will go off on their anti-bipolar drugs because, like many “normal people,”  they too disdain getting fat (sadly, more so than they fear severe mood swings).

Third Paradox: Many of the Drugs Designed to Stave Off Adult Onset Diabetes Have An Ironic Propensity to Promote Weight Gain

A review by Pi-Sunyer (2009, cited below) of 15 major agents to control the early stages of adult onset diabetes, discloses that most of them paradoxically promote weight gain and sometimes adverse blood profiles, independent factors in increasing the propensity for diabetes and heart disease.

Nonetheless, very few physicians  recommend forgoing the glucose control drugs despite this paradox .

The trick, according to the author is to find out which drugs (or injections) account for the least amount of weight gain, because his research shows once again, that many patients will stop taking the prescribed drugs or injecting themselves, if they  find themselves gaining weight.

A Fourth & Final Paradox:  Taking Capsules Filled with Oil Every Day, Without Otherwise Adjusting Your Diet, Does Not Gain You 4-5 Extra Pounds a Year, If those Oils are Omega-3 Fatty Acids (Or Maybe Even Just Corn Oil)

Finally, not all paradoxes work against the prescribing physician and his or her patient. In a study by Bays et al (2009, cited below) patients with dangerously high triglycerides, a category of fatty substances in the blood associated in many cases with patients who have high intakes of calories and especially of fats and oils, were prescribed Lovaza capsules, the brand name for a highly concentrated form of omega-3 fatty acids in oil form.

While a wide variety of health claims have been made for omega-3 fatty acids over the last few decades, there is somewhat greater certainty that these can help control high triglyceride levels.

They took these capsules  in conjunction with fenofibrate (brand name Antara) another agent proposed to help reduce high triglyceride levels.

They compared the “fat-adding” potential of the Lovaza capsule with a capsule containing the caloric equivalent in corn oil.

The results  contained two surprises, one of them more surprising than the other.

It was really no surprise that the levels of triglycerides decreased more significantly with the Lovaza+fenofibrate than it did with the corn oil +fenofibrate.

The real surprise is that neither oil-containing capsule, taken in the amounts prescribed, caused significant weight gain!

 

Tony Stankus, FSLA, [email protected], Life Sciences Librarian, Science Coordinator & Professor

University of Arkansas Libraries MULN 223 –E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

 

Adler, L.A., Guida, F., Rotrosen, J. & O’Donneel, M.A. (2009).  Screening and imputed prevalence of ADHD in adult patients with comorbid substance use disorder at a residential treatment facility. Postgraduate Medicine, 121(5),7-10.

Bays, H.E., Maki, K.C., Doyle, R.T.  &  Stein, E. (2009). The effect of prescription omega-3 fatty acids on body weight after 8 to 16 weeks of treatment for very high triglyceride levels. Postgraduate Medicine, 121(5), 145-150.

Bell, P. F., McKenna, J. P., & Roscoe, B. M. (2009). Treatment of bipolar disorders and metabolic syndrome: Implications for primary care. Postgraduate Medicine, 121(5), 140-144.

Brunton, S. (2009). Beyond glycemic control: Treating the entire type 2 diabetes disorder. Postgraduate Medicine, 121(5), 68-81.

Haffey MB, R., Buckwalter, M., Zhang, P., Homolka, R., Martin, P., Lasseter, K. C., et al. (2009). Effects of omeprazole on the pharmacokinetic profiles of lisdexamfetamine dimesylate and extended-release mixed amphetamine salts in adults. Postgraduate Medicine, 121(5), 11-19.

Pi-Sunyer, F. X. (2009). The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus. Postgraduate Medicine, 121(5), 94-107.

Influenza A (H1N1) 2009 Update: Vaccines, Rates of Contagion in Homes and Schools, the Flu Experiences of Mexico & Australia, the Role of Antibiotics for Infections Secondary to the Flu

Effective Vaccines Are on The Way

 

Two developments, worlds apart, have been very positive, for a simplified vaccination program, that would require a single injection.  CSL of Australia, that country’s largest  biotech firm, tested their vaccine on 175 volunteers.  Half got  a single injection. Half received a second injection, on one of the following days: 7, 14, or 21.

 

Tests showed that the second injection conferred no particular advantage. The initial injection seemed quite sufficient to stimulate the protective immune reaction. This was very much the result in England at the University of Leicester as well, although the test group included 100.

 

There were some  side-effects.  For some, there was pain at the injection site.  A small percentage had a headache or short term fever. All side-effects were rated as mild to moderate, and were considered quite tolerable when compared to getting the flu itself.

 

Will They Arrive in Time?

 

Two important studies suggest that while the vaccines may arrive in mid-to-late October, the flu could peak in some areas by early-to-mid October, essentially beating the vaccines. In addition, it takes about 14 days after vaccination for immunization   truly to take effect.

 

Does this mean that  the vaccines will have represented a waste of time and effort?

 

The answer is no for two reasons.

 

First, the flu is emerging in different areas, such as individual states within the US, at different rates. This means that the peak in one state will be different from another.  There will be some states that have been heavily hit; while the numbers of the sick in others will be quite small. 

Second, the definition of peak   generally means that half the cases that will occur,  have occurred. This means that as many as half the potential victims  have not yet been infected.  Immunizations are quite likely to help those patients.

 

What are the Odds of Someone Getting the Flu?

 

If someone in your household has the flu there is about a 27% chance of your getting the flu, according to a University of Washington study. If a kid in your child’s class gets the flu,  the chances are  that the sick kid will spread it to two or three other kids.  The lag times between  exposure and symptomatology in the new flu patients are between two and one half to three days.  At that time, the new flu patients will  themselves possibly spread the flu.  This is not inevitable if the families of the affected family initiate good hygiene.

 

Two Countries with Extensive H1N1 Flu Experience

 

Mexico has been the country hardest hit by the flu thus far, and bears the unfortunate stigma of having “seeded the virus” through immigrants and travelers to other countries. An analysis  by the Harvard School of Public Health offers a paradox.  They estimate that there were between twice and three times as many H1N1 flu cases in Mexico during the study period as were officially reported, seemingly a grim statistic. However, the number of deaths that were the result of the flu, remained the same. In other words,  the percentage of people who actually had the flu and died of the flu  is actually only half to a third of the official estimate. The flu, in other words, even in a hard hit country, is a lot less lethal than was generally thought.

 

Australia has also seen many cases of flu. What tends to make their experience unique is that they had many more experiences with official quarantines.  While the clinical success of these quarantines was mixed, they had a profound effect on public opinion, which   in polls indicated that they were highly effective (and of which they were generally in favor). Likewise, the Australians had high hopes for eventual protection from vaccines (given the very recent success of CSL with their vaccine trials, this was not entirely without basis). Most Australians  felt that they would not be very seriously  affected by the virus. Unfortunately, few Australians seemed aware, or had a strong personal belief  even if aware, that hand washing and similar preventive measures like restraining coughs, sneezes, etc.,  with disposable tisues, as opposed with bare hands that were subsequently not washed --- ironically,  practices with demonstrable efficacy  were at least as important as quarantines or vaccinations in reducing the spread of the flu.

 

It’s Sometimes Not Just the Flu that Happens When You Get the Flu

 

It is not unusual for some flu patients, particularly those with pre-existing respiratory or immunological problems, to get bacterial infections in addition.  It is generally policy in the UK, that these secondary complications be treated aggressively according to nationally published guidelines. However, there has  been a general protest by antibiotics specialists (see Barlow below) that their  use  should be much more judicious and  varied, with a number of alternatives strongly recommended.  The  fear of these  protesting doctors is that in the course of treating complicated flu patients,  the existing policy exposes the patients to CDAD (Clostridium difficile diarrhea ) and MRSA (Methicillin Resistant Staphylococcus aureus), which have a higher fatality rate than even complicated H1N1.

 

Tony Stankus, [email protected] FSLA, Professor, Life Sciences Librarian & Science Coordinator

 University of Arkansas Libraries MULN 223 E 

365 North McIlroy Avenue Fayetteville AR 72701-4002 

Voice 479-409-0021 

Fax: 479-575-4952

 

Balcan, D., Hu, H., Goncalves, B., Bajardi, P., Poletto, Ramasco, J.J., Paolotti, D., Perra, N., Tizzoni, M., Van den Broeck, W., Colizza, V., & Vespignani, A. (2009).  Seasonal transmission potential and activity peaks of the new influenza A(H1N1): A Monte Carol likelihood analysis based on human mobility. BMC Medicine, 7, (1), article 45.

 

Barlow, G.D., on behalf of the BSAC Council. (2009). Swine flu and antibiotics.  Journal of Antimicrobial Chemotherapy, epub ahead of print.

 

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Clark, T.W., Pareek, M., Hoschler, K., Dillon, H., Nicholson, K.G., Groth, N., & Stephenson, I. (2009). Trial of influenza A (H1N1) 2009 monovalent MF59-Adjuvenated Vaccine --- Preliminary Report.  New England Journal of Medicine, epub ahead of print.

 

Cohen, J.  (2009).  Public Health: A race against time to vaccinate against novel H1N1 virus. Science, 325, (5946), 1328-1329.

 

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Greenberg, M.E., Lai, M.H., Hartel, G.F., Wichems, C.H., Gittleson, C., Bennet, J., Dawson, G., Hu, W., Leggio, C., Washington, D., & Basser, R.L. (2009). Response after one dose of a monovalent influenza A (H1N1) 2009 Vaccine --- Preliminary Report.  New England Journal of Medicine, epub ahead of print.

 

Hancock, K., Veguilla, V., Lu, X., Zhong, W., Butler, E.N., Sun, H., Liu, F., Dong, L., Devos, J.R., Gargiullo, P.M., Brammer, T.L., Cox, N.J., Tumpey, T.M., & Katz, J.M. (2009). New  England Journal of Medicine, epub ahead of print.

 

Lipsitch, M., Lajous, M., O’Hagan, J.J., Cohen, T., Miller, J.C., Goldstein, E., Danon, L., Wallinga, J.J., Rilsey, S., Dowell, S.F., Reed, C., & McCarron, M. (2009).  Use of cumulative incidence of novel influenza A/H1N1 in foreign travelers to estimate lower bounds on cumulative incidence in Mexico.  PLoS ONE, 4, (9), article 6895.

 

Seale, H., McLaws, M.L., Heywood, A.E., Ward, K.F., LOwbridge, C.P., Van, D., Gralton, J., & Macintyre,  C.R. (2009).  The community’s attititude towards swine flu and pandemic diseases.  Medical Journal of Australia, 191, (5), 267-269.

 

Yang, Y., Sugimoto, J.D., Halloran, Basta, N.E., Chao, D.L., Matrajt, L., Potter, G., Kenah, E., & Longini, I.M.Jr. (2009).  The transmissibility and control of pandemic influenza A (H1N1) virus. Science, epub ahead of print.