SLA Biomedical & Life Sciences Division Blog

What's The Point(s)? Is Weight Watchers Shift to the New ProPoints Plan Based on Good Science?

What has been the biggest health-effecting news thus far in 2011?  A cure for some form of cancer? Declines in AIDS, TB, or malaria?  Side-effect-free new drugs for schizophrenia and bipolar disorder? No, given the fact that it will actually affect multiple millions of overweight people, who might otherwise drift sooner rather than later into adult onset diabetes, knee and hip replacements, heart disease, and stroke,  arguably it’s the fact that in the US, Weight Watchers International, has shifted their famed Points counting system to the “PointsPlus” program, following its adoption in Europe.

This has been much discussed in the New York Times (Gootman 2011), Time magazine (Sachs 2011), USA Today (Hellmich 2011), the Herald Sun in Melbourne,  Australia (Herald Sun 2011), the Daily Mail in London (Keeling 2010), and many other publications,  and actually made the cover of Environmental Nutrition (Environmental Nutrition editors 2011).

In the interest of full disclosure, I am actually a member of Weight Watchers, and at one point in my life (circa 2000) actually lost 150 pounds (which took me 10 years to gain back, although I have re-lost 35 over the last several months). Nonetheless, I own no stock in the company and expect no free membership or other payback for this blog.

Did the old points counting system not succeed?

No, it succeeded for millions of people, overwhelmingly women, although it certainly can work for men.  The old Weight Watchers  point scheme has generally faired at least as well, and often marginally better than other major commercially backed diet programs in a   rather large number of scientific and clinical comparison studies  as well as in advisories or editorials found in health related publications (Brown et al 2009,  Dansiger et al 2005, Futtterman 2006, Hunt & Poulter 2007, Jolly et al 2010, Ma et al 2007, Morgan et al 2009, Scarff 2008, Truby et al 2006, Tsai & Wadden 2006. Witherspoon & Rosenzweig 2004) although some critics suggest that the evidence for most commercial programs is not particularly strong  (Weaver 2005), while others argue that it is too expensive, although the most recent study figures in transportation costs to meetings, which suggests that if the overweight people were not going to meetings they would not be going anywhere, as opposed to incorporating  their trip to Weight Watchers, with something likely to be necessary at least once a week, like shopping for food or going to and from work (Cobiac, Vos & Veerman 2010). To some degree this can also be overcome by participating in Weight Watchers online, albeit not all the people of modest means addressed in that study were as likely as the general populace in having personal computers or internet access.

In comparison with the purported “scientific” or “clinical”  studies at unnamed “leading medical universities” vaguely alluded to in late night cable or supermarket tabloids  ads for miracle pills, capsules, or “nutritional supplements” the factual basis for Weight Watchers, as well as for many of its honorable competitors, is overwhelming.

This relatively consistent positive showing by Weight Watchers is not surprising because the plan is actually based on a combination of mindful eating habits, good nutrition, upbeat group psychology, and a model for customer satisfaction and mutual support that is effective and widely admired in business circles (Tax, Colgate & Bowen 2006, Vignali & Henderson 2008) .

Basically, like many of its competitors, Weight Watchers counsels caloric restriction &  portion control, encourages exercise, is forgiving of occasional backsliding, and encourages the client to rethink their eating habits and attitudes towards food, particularly in social situations or at times of stress or personal disappointment.

Weight Watcher’s genius in the caloric restriction area has been to substitute for laborious calorie counting the idea of given foods having a certain number of “points” which can be readily looked up in one of their print publications and/or online guides.

Historically on Weight Watchers, one could eat pretty much what one wanted and expect to lose weight most weeks  if they adhered to their points allotment for the week.  In other words, if you chose to eat half your points allotment in potato chips ------not something they would then or now recommend------you could nonetheless expect to lose weight.

Allotments were based on the client’s current weight, age, gender, and as one lost weight, the points allotment actually went down.

One could consume a somewhat greater points allotment by engaging in a wide variety of physical activities which also were assigned a Points value, which could be subtracted from an overage of food points consumed.

This is not to say that Weight Watchers has not consistently encouraged eating a wide variety of fruits and vegetables, whole grains, etc. It just did not make following that particular aspect an absolute.

                        Why fool around with such a winning program?

I suspect that Weight Watchers changed their Points counting system for the some of the same reasons that science textbook publishers frequently change editions: There is always some new wrinkle  in science that, while not overthrowing the laws of the universe,  changes things up somewhat, and new editions which  incorporate these changes tend to reduce or stop resale of used textbooks already in circulation from which the publisher no longer profits,  from cutting into the steady sales of new textbooks.  Or as one perceptive analyst, Ruth Mortimer (2010)of Marketing Week, noted:

 

“A brilliant move by WeightWatchers is to make sure its eating systems are just complicated enough that its followers have to buy into the company’s products. If the diet plan was easy to follow without any guidance, why would anyone need Weight Watchers?”  

What is this new science?

Weight Watchers has apparently incorporated more of the glycemic index in the Points counting scheme, but not uncritically so. A glycemic index  approach is not particularly new (Bellisle et al 2007, Thomas, Elliott & Baur 2007), and certainly not a discovery unique to, or even pioneered by,  Weight Watchers.

According to the Mayo Clinic:

 “A glycemic index diet is a general term for a weight-loss diet that's based on choosing foods and beverages that are thought to prevent rapid increases in your blood sugar level. Glycemic index diets are based on the idea that controlling blood sugar levels leads to weight loss (Mayo Clinic staff 2011).”

The difference is that while many glycemic index diets do not have one count calories, they require the dieter to be aware of which foods have a high glycemic index (raising blood  glucose levels rapidly) and generally to avoid them. Examples include white bread and spaghetti.  Dieters are advised to eat more readily those foods with a moderate glycemic index rating: corn and bananas .  And they are urged to eat low glycemic rating foods abundantly: these include many fruits and vegetables. Portion control is not a big feature of most glycemic index diets, as long as the portions are of low glycemic index foods.

How far is Weight Watchers going with this? In terms of points counting, members are getting a free pass on many very low glycemic index fruits and vegetables (Gootman 2010). Unfortunately for lovers of refined carbs like baked goods that are without enormous  fiber content, and other higher glycemic index  foods (including many potato and rice dishes), their points values  have gone up. Beer, wine, and alcoholic beverages also seem to have accreted extra points.

Surprisingly, so have many juices. Orange juice is up, and so are my personal favorites, tomato juice and V-8. However, under the new PointsPlus counting scheme,  if one were to eat the oranges or tomatoes or the mixed vegetables that go into V-8, instead of their  juices, there would be zero, or only a very few points.

Presumably, eating the raw materials, so to speak, does not spike blood sugar levels, and there is probably a natural stomach-filling aspect to packing in those bulky, more solid foods, that inhibits eating too many of them, or perhaps forestalls the desire or ability subsequently to eat  higher glycemic index foods.

And to be fair, Weight Watchers has increased the Points allotment for virtually all of their clients, so the transition should not be entirely discomfiting.

This free-for-all for many fruits and vegetables, is not entirely a departure for Weight Watchers. There have always been a fairly extensive list of foods that, in customary portions, did not count against one’s Points allotment. This included cabbage, radishes, lettuce, scallions, green and wax beans,  beets, asparagus, broccoli, summer squash, spinach and zucchini, to name a few.

In a very real sense, Weight Watchers is now entirely in line with the new Food Pyramid modeled by the FDA, which as the Harvard School of Public Health Nutrition Source succinctly states (2011):

“Most people should aim for at least nine servings (at least 4½ cups) of vegetables and fruits a day, and potatoes don't count.”

Conclusions

Ultimately, the question that each overweight person must ask themselves, however, is not when they should begin  a program of corrective diet and exercise, it’s when they wish to get used to having insulin shots, knee or hip replacements, heart attacks or strokes.  Making the first determination  is not a guarantee that the second outcome will not happen, but one improves the odds of it not happening,  or not happening as soon as it might otherwise.  And while handling the “new math” ProPoints plan on Weight Watchers is annoying to those of us who lost weight on the old one, it’s not as annoying as  figuring out if your savings account has enough money for those copayments that will very likely come if you do nothing to change the way you eat and exercise (or don’t).  And, yes, there is good science behind the change, even if this was not necessarily the sole reason the change was made.

Long term Weight Watchers adherents significantly reduce  adverse triglyceride levels, decrease low density cholesterol, increase high density cholesterol, and decrease C-Reactive protein levels, considered by some a precursor or predictor of cardiovascular disease, and weight loss is probably the greatest single slower of weight-bearing joint deterioration there is, particularly in conjunction with non-jolting, non-joint-pounding exercise.  It is not the only way all this can be accomplished, but it is a way that has worked, sometimes modestly, sometimes manifestly, for literally millions.

 

Tony Stankus, FSLA, 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

 

Alderman, Lesley. 2010. Four recommended apps. The New York Times, July 17, 2010, sec B; Business/Financial Desk.

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Jolly, Kate, Amanda Daley, Peymane Adab, Amanda Lewis, John Denley, Jane Beach, and Paul Aveyard. 2010. A randomised controlled trial to compare a range of commercial or primary care led weight reduction programmes with a minimal intervention control for weight loss in obesity: The Lighten Up trial. BMC Public Health 10 (07/27): 439-.

Keeling, Judith. 2010. Weight Watchers is a byword for dieting success. So why, this week, has it completely changed its approach? DAILY MAIL (London), November 4, 2010.

Lambert, L., M. Raidl, S. Safaii, C. Conner, E. J. Geary, and S. Ault. 2005. Perceived benefits and barriers related to postpartum weight loss of overweight/obese postpartum WIC participants. Topics in Clinical Nutrition 20 (1) (2005): 16-27.

Lowe, Michael R., Tanja V. E. Kral, and Karen Miller-Kovach. 2008. Weight-loss maintenance 1, 2 and 5 years after successful completion of a weight-loss programme. The British Journal of Nutrition 99 (4) (04): 925-30.

Ma, Yunsheng, Sherry L. Pagoto, Jennifer A. Griffith, Philip A. Merriam, Ira S. Ockene, Andrea R. Hafner, and Barbara C. Olendzki. 2007. A dietary quality comparison of popular weight-loss plans. Journal of the American Dietetic Association 107 (10) (10): 1786-91.

Mata, Jutta, Peter M. Todd, and Sonia Lippke. 2010. When weight management lasts. Lower perceived rule complexity increases adherence. Appetite 54 (1) (02): 37-43.

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Morgan, L. M., B. A. Griffin, D. J. Millward, A. DeLooy, K. R. Fox, S. Baic, M. P. Bonham, et al. 2009. Comparison of the effects of four commercially available weight-loss programmes on lipid-based cardiovascular risk factors. Public Health Nutrition 12 (6) (06): 799-807.

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Sachs, Andrea. 2011. "Dieters' Free Lunch." Time 177, no. 3: 49-50.

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Southerners In The Stroke Belt Eat A Lot of Fried Fish And Have A Lot Of Strokes: Is It The Fish? The Frying Of It? Both? Neither? Or Actually Not a Bad Choice of A Meal Compared to Common Southern Alternatives?

 

Clinical researchers (AHRQ 1998, Borhani 1965, Clinical Advisor for Nurse Practitioners 2006 ) have long been calling much of the Southeastern United States, including  Alabama, Arkansas, Louisiana, Mississippi,  (and more recently East Texas-----see Ramshaw 2011) as part of a stroke belt, and the medical literature has long used the term “the Stroke Belt Buckle” for both North & South Carolina and Georgia.  

But now, stories in the New York Times (Rabin 2009) and USA Today (Brophy Marcus 2010) , have heightened public awareness of that Stroke Belt & Belt Buckle, particularly with regard to the eating of fried fish (Bakalar 2011) as possibly a contributing dietary factor.

Are Stroke Belt Dwellers Not Getting Enough Fish-Provided Omega-3 Fatty Acids?

The key study (Nahab et al 2011) places no clear cut blame on any particular type of fish, but suggests that  of the 21,675 study participants,  only 5,022 ate the recommended two servings per week of fish high in omega-3 fatty acids, a nutraceutical associated with good cardiovascular health.

 

By this,  the authors imply that the majority of Southerners were  not eating  fish like mackerel, herring, salmon (coldwater ocean-going species for the most part, which were cited as examples of fish one should eat to obtain omega-3s). This is not surprising since none are particularly common to Southern cuisine, nor are they quite as available in supermarkets,  and in the case of salmon, not  as affordable relative to alternative fish.

Additionally one feature of those Southerners  with a higher rate of stroke was that many had two or more servings of other fried fish not so notably rich in omega-3s.  

Where  are Stroke Belt Dwelling Fried Fish Eaters Eating Their Fried Fish Meals?

To most people in the Stroke Belt ( I now count myself among their numbers)  it would seem  important for any study to be more definitive to distinguish between home-cooked and restaurant-cooked, in determining which fish are most likely to be involved in any study implicating fried fish, although it is not clear that the authors  did this with the survey instrument that they used. The reason that "where the fish is typically eaten",  is important is that both the type of fish and the type of frying vary, sometimes dramatically between home-cooked and restaurant-cooked, here in the South.

Are The Freshwater Fish Favored By Those In the Stroke Belt Somehow at Fault?

 Home-cooked fish in the South means predominantly freshwater fish. First and foremost, it’s farm-raised catfish, then farm-raised tilapia, followed by sport-fished, wild-caught  crappie or bass. Along the Gulf Coast, home-cooked saltwater fish like red snapper is also common.

 Restaurant-cooked fish in the South vary further by whether one is eating at a large, generally nationwide chain, or at a locally-owned or regionally-concentrated operation.

The overall fisheries marketing consideration  here in the South (and actually increasingly for the rest of the US),   is that there is a strong preference among restaurant-goers for fish whose flesh is white and whose taste, unlike the taste of herring, mackerel, and sometimes salmon, is mild.  

Fishy tastes and oily, dark flesh do not sell well in the South, and indeed, have been bred out of today’s farm-raised catfish, one of the reasons for its sustained popularity. Unfortunately, perhaps, oily, dark-fleshed fish are usually very rich in omega-3s.

But The Stroke Belt is Not the Only Place in the Country Where Fried Fish Relatively Lower In Omega-3s is Frequently Eaten

The local/regional fish found in the restaurants of the Stroke Belt  are today overwhelmingly farmed catfish and farmed tilapia.

Wild-caught cod,  haddock, and pollock,  are sometimes available but are expensive and far more characteristic of homes and restaurants New England, New York, & New Jersey, than the South. (I lived my first 56 years in New England, so I know whereof I speak).

However, today’s restaurant pollock and haddock, whether served at local, regional, or national restaurants---- outside of the local, coastal New England market------  is  much more likely to come from Alaskan waters than from New England, today).

Judging from their corporate websites,  it is sometimes possible to sort trying to sort out which “mild, white fish” is used for larger restaurant chains. Given that “mild white fish” can vary quite a bit in terms of their omega-3 levels, it  ought to make a difference if it is the omega-3s that matter the most.

Unfortunately for our purposes in tacking down which fish was in the “fish-wich,” so to speak, many national chains,  particularly outside the South,  use a number of differing fish interchangeably without necessarily cueing the consumer.

 None of the following is to be taken as indicative of a lack of concern on the part of the restaurant chain for the wholesomeness of whatever fish it is. There is no proof that any of the species discussed is unsafe to eat, just that some fish have more omega-3s than others.

Denny’s appears to use an assortment of fish including pollock and “pangasius” (generally these are farmed catfish-like fish imported from Vietnam or the People’s Republic of China, but are not to be confused with the arguably much  more closely monitored, more  quality-controlled US farm-raised catfish.) Denny's also sometimes uses haddock.

Long John Silvers uses a similar variety of white, mild fish, but also include hake ( a relative of the cod family), and tilapia.

Wendy’s uses primarily cod.

Ruby Tuesdays uses the usual assortment of white fish, but has premium seafood entries that include farmed salmon and farmed trout. Of those, only the salmon and the trout would have notably higher omega-3 levels.

Are All Types of Frying Equally Bad, Assuming That It’s the Frying That’s the Problem?

The study’s authors  suggest that frying seems to reduce or destroy natural omega-3 levels in the fish. But there  is no indication if by "frying"  the authors mean deep-fat frying, like French fries and donuts, or pan-frying as in pork chops or bacon.

As a practical matter in Southern kitchens, most home-cooked fish is likely  to be shallow-pan-fried, and most restaurant fish is likely to be battered and deep-fat fried, although grilled fish is coming on strong, particularly at eat-in restaurants in national chains.

Do the Cooking Fats & Oils Matter More than the Fish Within Which They Were Fried?

In any case, if the infusion of oil caused by deep fat frying  is the culprit, then this should be explicitly mentioned or separately analyzed.

It should be understood, however, that battered and deep-fried fish probably has a lot less penetration of the cooking oil into the fish than might be imagined, because the oil, if sufficiently hot when the battered fish is placed in it, quickly seals off  the fish.  

Nor do we know which homes or restaurants use butter, lard, partially hydrogenated semi-solid shortening oils (similar to Crisco) or polyunsaturated oils in liquid form.

This is likely to be a significant matter since, at various times, a number of these fats have been implicated as being unhealthy for the heart, while others (typically olive oil, sunflower oil, and safflower oil and certain other more exotic types, are regarded as downright heart-healthy).

Omega-3 Levels vs. Arachidonic Acid Levels In Fish

There is, an as yet, unresolved debate as to whether eating some fish with lower levels of omega-3 fatty acids but possibly higher levels of a somewhat similar fatty acid, called arachidonic acid (ARA) is as “heart healthy” as eating only high omega-3 fish.

Some farmed fish, particularly catfish and tilapia, have a higher ratio of ARA to omega-3s. Some authors (Weaver et al. 2008) suggest that ARA may promote inflammatory responses within the body, and that may have some implications for cardiovascular disease processes, although the experimental animals on which this position is based is the African green monkey (Parks et al 1990)  whose physiology provides a  good, but scarcely infallible road map to likely human consequences.   

But other authors (Clandinin et al 2005) point out that ARA is demonstrably crucial to the development of infants and is actually added to infant formula.

Tests of significantly larger amounts of ARA in the diet of healthy adults showed no adverse consequences (Brenna & Diau 2007, Nelson et al 1997).

ARA seems to promote healthy immune responses (Kelley et al 1997)  and cell and tissue repair (Bonnans & Levy 2007).

In a study of Japanese fishermen, who not only ate fish, but were  given additional ARA  (Kusumoto et al 2007) there was some adverse blood and platelet chemistry, but this was a rather extreme situation.

 By extreme we mean that one would have to eat about five times as much US farm-raised tilapia, or eight times as much US farm-raised catfish, to get even close to the levels of ARA in the Japanese study (Nettleton 2008).

But this debate may be best resolved by a compromise suggested by Chilton (2008) one of the authors of the “fear of ARA ratios in some fish paper,” in answering a critique of that study. Perhaps, Chilton notes, there are simply certain people with chronic inflammatory diseases that might be specially advised to avoid certain fish, (or for purposes of our discussion, certain fish fried in some particular way), while the vast majority of people may eat fried fish gladly, particularly in preference to “bacon, hamburgers, or doughnuts.”

If Farmed Freshwater Fish Are the Problem, Can the Fish Be Farmed In A Different Way?

The answer is yes, if the fish  is actually the problem, which is by no means clear. Including certain dried algae (Menghe et al 2009) in catfish feed would improve their lipid profiles beneficially, but whether or not this is commercially feasible in an industry that already has problems with its feed costs (Stankus 2010) or if the supply of the dried algae is sufficient has not yet been determined.

What Factors, Other Than Fried Fish,  Might Be Involved in Making the Stroke Belt the Stroke Belt?

The answer is: There are so many posible confounding factors, in the study and in the Stroke Belt, that it would be hard to know when to stop counting.

Lower levels of education and income are also associated with the South and with strokes.

High blood pressure is associated with strokes and higher blood pressure is more common in the South.

Consumption of high saturated fats (particularly lard, pork, ham, bacon, etc.) is common in the South.

As is a high rate of diabetes, obesity, cigarette smoking, and salt consumption

Geography itself in some way, seems to play a persistent role in the incidence of stroke. People who are born in the South but live as adults in other parts of the country seem to have a persistently higher rate of stroke anyway (El-Saed & Kuller 2007, Glymour, Avendaño & Berkman 2007 ) and adults who were born and raised elsewhere who move to the South (much like myself) also have a raised probability of having a stroke (Glymour, Kosheleva & Boden-Albala 2009).

But we should not be too quick to blame somehow being in the Southern United States for causing strokes.

The US Stroke Belt is scarcely the only one in the world: Andalusia in Spain (Castilla Guerra, Del Fern & Marín-Martín 2010) has one of its own, and there is no evidence whatsoever that fried fish, farmed, freshwater, omega-3 poor or arachidonic acid high, has anything to do with it, even as many of the other factors discussed in the latter portion of this blog seem to come together, much as they do in the American South.  

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

University of Arkansas Libraries MULN 233 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

 

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Allen, Norrina B., Theodore R. Holford, Michael B. Bracken, Larry B. Goldstein, George Howard, Yun Wang, and Judith H. Lichtman. 2010. Trends in one-year recurrent ischemic stroke among the elderly in the USA: 1994-2002. Cerebrovascular Diseases 30 (5) (10): 525-32.

Bakalar, Nicholas. 2011. Diet: Fried fish is seen as a 'stroke belt' culprit. New York Times (01/04): 6.

Bonnans, C. & B.D. Levy. 2007. Lipid mediators as agonists for the resolution of acute lung inflammation and injury. American Journal of Respiration: Cellular & Molecular Biology 36: 201-205.

Brenna, J.T., & G.-Y. Diau. 2007. The influence of docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition. Prostaglandins, Leukotrienes & Essential Fatty Acids 77: 247-250.

Brenner, D. A., R. M. Zweifler, C. R. Gomez, B. M. Kissela, D. Levine, G. Howard, B. Coull, and V. J. Howard. 2010. Awareness, treatment, and control of vascular risk factors among stroke survivors. Journal of Stroke & Cerebrovascular Diseases 19 (4) (2010): 311-20.

Brophy Marchus, Mary. 2010 (December 23, 2010). Strokes deaths higher where there’s fried fish aplenty. USA Today,  Section: Life. p.4d.

Castilla Guerra, Luis, Carmen del Fern, and Jorge Marín-Martín. 2010. Factors explaining excess stroke prevalence: The Spanish stroke belt. Stroke; a Journal of Cerebral Circulation 41 (2) (02): e114.

Chilton, F.H. 2008. Authors response. Journal of the American Dietetic Association 108: 1831-1832.

Clandinin, M.T., J.E. Van Aerde, K.L. Merkel, et al. 2005. Growth and development of preterm infants fed infant formulas  containing docosahexaenoic acid and arachidonic acid. Journal of Pediatrics 146: 461-468.

Cleary, J. D., M. Pearson, J. Oliver, and S. W. Chapman. 2008. Association between histoplasma exposure and stroke. Journal of Stroke & Cerebrovascular Diseases 17 (5) (2008): 312-9.

Clinical Advisor for Nurse Practitioners. United States still plagued with a "stroke belt". 2006. Clinical Advisor for Nurse Practitioners 9 (4) (04): 11.

 

Cushman, M., R. A. Cantrell, L. A. McClure, G. Howard, R. J. Prineas, C. S. Moy, E. M. Temple, and V. J. Howard. 2008. Estimated 10-year stroke risk by region and race in the United States: Geographic and racial differences in stroke risk. Annals of Neurology 64 (5) (11): 507-13.

Edelson, Ed. 2009. Birth in South raises stroke risk for life. Health Day Consumer News Service (12/01).

El-Saed, A., and L. H. Kuller. 2007. Is the stroke belt worn from childhood?: Current knowledge and future directions. Stroke; a Journal of Cerebral Circulation 38 (9) (09): 2415-21.

Glymour, M. M., A. Kosheleva, and B. Boden-Albala. 2009. Birth and adult residence in the stroke belt independently predict stroke mortality. Neurology 73 (22) (2009): 1858-65.

Goldstein, L. B., L. A. Hey, and R. Laney. 1998. North Carolina stroke prevention and treatment facilities survey: RtPA therapy for acute stroke. Stroke; a Journal of Cerebral Circulation 29 (5) (05): 1171-8.

Howard, Virginia J., Robert F. Woolson, Brent M. Egan, Joyce S. Nicholas, Robert J. Adams, George Howard, and Daniel T. Lackland. 2010. Prevalence of hypertension by duration and age at exposure to the stroke belt. Journal of the American Society of Hypertension: JASH 4 (1) (2010): 32-41.

Kelley, D.S., P.C. Taylor, G.J. Nelson et al. 1997. Effects of dietary arachidonic acid on human response. Lipids 32: 449-456.

Knox, M. L., and J. Nussbaum. 1998. South Carolina: In the middle of the stroke belt. South Carolina Nurse 5 (1) (1998): 16-8.

Kusumoto, A., Y. Ishikura, H. Kawashima et al. 2008. Effects of arachidonic-enriched triacylglycerols supplementation on serum fatty acids and platelet aggregation in healthy male subjects with a fish diet. British Journal of Nutrition 98: 626-635.

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Maestre-Moreno, Jos. 2010. [Mortality in the Spanish 'stroke belt': Some key points in andalusia]. Revista De Neurologia 51 (6) (09/16): 383.

Manning, B. B., H. Li Menghe, E. H. Robinson, and B. C. Peterson. 2006. Enrichment of channel catfish (ictalurus punctatus) fillets with conjugated linoleic acid and omega-3 fatty acids by dietary manipulation. Aquaculture 261 (1) (01/01): 337-42.

Mary, Brophy Marcus. Date. Stroke deaths higher where there's fried fish aplenty. USA Today. 

Menghe, H. Li, E. H. Robinson, C. S. Tucker, B. B. Manning, and L. Khoo. 2009. Effects of dried algae schizochytrium sp., a rich source of docosahexaenoic acid, on growth, fatty acid composition, and sensory quality of channel catfish ictalurus punctatus. Aquaculture 292 (3-) (01/01): 232-6.

Meschia, J. F., P. Merrill, E. Z. Soliman, V. J. Howard, K. M. Barrett, N. A. Zakai, D. Kleindorfer, M. Safford, and G. Howard. 2010. Racial disparities in awareness and treatment of atrial fibrillation: The Reasons for geographic and racial differences in stroke (REGARDS) study. Stroke; a Journal of Cerebral Circulation 41end_of_the_skype_highlighting (4) (04): 581-7.

Nahab, F., A. Le, S. Judd, M. R. Frankel, J. Ard, P. K. Newby, and V. J. Howard. 2011. Racial and geographic differences in fish consumption: The REGARDS study. Neurology 76 (2) (01/11): 154-8.

Nelson, G.J., P.C. Schmidt, G. Bartolini et al. 1997. The effect of dietary arachidonic acid on platelet function, platelet fatty acid compositin, and blood coagulation in humans. Lipids 32: 421-425.

Nettleton, J.A. 2008. Concerning PUFA in fish. Journal of the American Dietetic Association 108: 1830-1832.

Nettleton, J. A., W. H. Allen J., L. V. Klatt, W. M. N. Ratnayake, and R. G. Ackman. 1990. Nutrients and chemical residues in one- to two-pound Mississippi farm-raised channel catfish (ictalurus punctatus). Journal of Food Science 55 (4) (01/01): 954-8.

Ozogul, Y., F. Ozogul, and S. Alagoz. 2007. Fatty acid profiles and fat contents of commercially important seawater and freshwater fish species of Turkey: A comparative study. Food Chemistry 103 (1) (01/01): 217-23.

Parks, J.S., J. Sawyer-Kaduck, B.C. Bullock & L.L. Rudel. 1990. Effect of dietary fish oil on coronary artery and aortic atherosclerosis in African green monkeys. Arteriorsclerosis 10: 1102-1112.

Pullicino, P. M., V. G. Wadley, L. A. McClure, M. M. Safford, R. M. Lazar, M. Klapholz, A. Ahmed, V. J. Howard, and G. Howard. 2008. Factors contributing to global cognitive impairment in heart failure: Results from a population-based cohort. Journal of Cardiac Failure 14 (4) (05): 290-5.

Rabin, Roni Caryn. 2009. Risks: Leaving stroke zone but not the dangers. New York Times (12/08): 6.

Ranshaw, Emily. 2011. Life Expectancy; East Texans' bad health and bad habits promote a 'stroke belt'. New York Times (01/14): 21A.

Ross, Joseph S., Ethan A. Halm, and Dawn M. Bravata. 2009. Use of stroke secondary prevention services: Are there disparities in care? Stroke; a Journal of Cerebral Circulation 40 (5) (05): 1811-9.

Sallar, Anthony M., P. B. Williams, Ademola M. Omishakin, and Debra Patton Lloyd. 2010. Stroke prevention: Awareness of risk factors for stroke among African-American residents in the Mississippi Delta Region. Journal of the National Medical Association 102 (2) (02): 84-94.

Sergeev, A. V. 2010. Stroke mortality outside the stroke belt: Analysis of racial and rural-urban disparities. Vol. 20.

Stankus, Tony. 2010. U.S. farm-raised catfish. Journal of Agricultural & Food Information 11 (3): 176-184.

Story, L., S. Mayfield-Johnson, L. H. Downey, C. Anderson-Lewis, R. Young, and P. Day. 2010. Getting on target with community health advisors (GOTCHA): An innovative stroke prevention project. Nursing Inquiry 17 (4) (12): 373-84.

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When your university’s school of nursing does not have all the resources of a national leader, what’s a defensible, reasonable expectation for the number and kinds of journals which might appear on your CV?

While there are actually many (617) Associate Degree and some (59) Hospital School Diploma programs enabling their graduates to take the NCLEX exam leading to licensure as a Registered Nurse, the clear trend over the last 30 years has been for the bachelor’s degree, granted by one of the nation’s 259 four-year college or university schools or departments of Nursing  to be regarded as the most desirable entry level credential for professional nurses today. 

There are therefore now literally thousands of Nursing faculty at bachelor-degree granting institutions who have faculty status with the possibility of tenure and promotion.

With that status has come increasing pressure for them to publish on a regular basis, much as is required of faculty in other academic department or schools on campus. The problem is that there have traditionally been few rubrics on what constitutes a reasonable expectation in terms of the number of articles and the reputational ranking of the journals within which they might appear.

 

The Old General Rules

 

To a great degree, Nursing had long gotten a pass on some of the stricter norms for scholarly productivity and consideration of the relative prestige of journal venues that one would expect of the Chemistry department in the College of Arts & Sciences, the College of Engineering, or even the School of Medicine, the field closest to it in shared concerns.  This is an unspoken exemption that  at some universities  the School of Nursing  shares  with Schools of Education, Social Work, Home Economics (now better known as Human Environmental Sciences), or even Library & Information Science.

These are all, for better or worse, and mostly for worse in terms of prestige and campus funding, “women’s” service professions  traditionally featuring faculty with  heavy classroom teaching loads and after-class oversight scheduling and coordination duties in sometimes far-flung hospitals and clinics. The terminal degree awarded to their students would typically be a bachelor’s or a master’s degree at best. Course content was simply assumed by higher academic authorities on campus to be based largely on knowledge derived from other more scholarly or higher order professional  fields (i.e. on medicine in the case of Nursing) and that such papers as appeared in the appropriate  journals might best be based merely on years of experience, consensus of practitioners, and fairly simple and typically small-scale empirical work.  

Criteria for what counted as scholarly communication for tenure and promotion purposes was often rather generous (conference talks, poster sessions, book reviews, local or state Nursing newsletter notices) and when articles in journals were considered, it was often enough just to say that they were “Peer-reviewed, “ and let it go at that.

The tenure process generally involved getting the chair of the Nursing Department or School to sign off on the affirmative vote of the already tenured instructors concerning a tenure candidate, and submit this to the Dean, Provost, President or Board of Trustees. The document would somewhere vouch  that the candidate’s publication record in terms of quantity and quality met with the traditions of the Nursing profession as best decided internally by the Nursing faculty themselves.  

Occasionally  a  nominally independent verification of this claim for research sufficiency would be sought from a  small selection of external reviewers. However, these were almost always  from regional peer  Nursing schools selected by members of the local Nursing faculty,  whose reviewers  would frankly be expected to affirm  what the local faculty had to say. Consequently, barring any other independent source of information or advice, the top academic official on campus had little choice or grounds to do anything but sign off on the local faculty vote.

But no more.

The New Order

With time, and as college deans, university provosts, and presidents or chancellors have changed over recent decades, they have been made more and more aware of powerful new online tools that allow them at least some independent bases of comparison of faculty outputs, including those of the departments and colleges of Nursing on their campus with other campuses.

Principal among these are the ability to retrieve online the list of publications in Nursing journals from other institutions (even if could not read the papers with understanding,   these senior academic administrators could certainly count them) and they could even make some reasonably valid use of Thomson-Reuters Journal Citation Reports Impact Factors to see which schools had the highest percentage of articles in journals with the best rankings.

Even if those particular rankings are acknowledged to be imperfect, they are almost always used in the absence of anything else. There is nothing else yet that is  so widely publicized and applied so near universally. (There are for example, over 105 articles in the literature of  my profession, Library & Information Science that involve them in some meaningful way.)

In addition, senior academic officials who evaluate dossiers in scientific and clinical fields have not only developed a pretty good feel over time for which are prominent and reputable publishers, but they can refresh their memories of “who publishes what” with a few mouse clicks without ever leaving their desktops.

Deans, Provosts, Presidents and Chancellors are scarcely alone in adopting and adapting these online finding tools to build up a certain independent level of expertise. They have been joined by people who publish reputational rankings, like the staff of the US News & World Report , and a great many external funding agencies and foundations who wanted to be sure to back winners with their bucks.

To a great degree this new sophistication in discernment of research output  comes at a time when the very newest Nursing faculty members are being judged by the senior members of  departments or schools of Nursing who published little or not at all when they came up, many years ago, and even now  they are uncertain as to how to respond reasonably for verification of the competitive standing of journals, given that many of them still may not be publishing within them frequently.

In short, it can be a confusing time for top academic administrators, senior faculty members of Nursing Schools, and Nurses coming up for tenure or promotion.

The Two Great Questions

 

This confluence of  old  habits and new information  technology has led to the two great questions of the day.

From the Provost or other senior academic officer we get the key credibility question:

“How can I believe your simply saying that a Nursing journal is peer-reviewed,  even with the concurrence of your colleagues at nearby universities that this is so,  conveys  enough information to help me make an informed judgment on your judgment, instead of just rubber stamping it, when I see other programs across the country doing a lot more?”

From the candidate for tenure or promotion we get the key fairness question:

“How can you expect me to publish as many papers and in the same places as  a professor at a top ten school when I have more contact hours, more students, more committees, less internal seed money, no nearby collaborators with research experience, no major teaching hospital or medical school affiliation, no graduate programs here, etc.”

The answers to both questions may provide one very good  solution:

The pattern  of  the national leaders can affirm the basic quality of regional peer output even if the first still numerically overwhelms the second.

A compromise position is actually possible, at least in terms of the journal quality control dilemma, if not in the quotas of articles published. This can be done by comparing the patterns of some of the national leaders against that of regional peers, and looking primarily at the number of schools in either group that publish in the same journals with some frequency. (It’s important that just cherry picking one school out of either group does not allow for good standards setting, because even some nationally prominent schools are eccentric in their emphasis on some journal-----an emphasis that is not shared when other equally prominent schools are added to the mix.)

I first chose ten university-based Nursing schools out of the top twenty from the last US News & World Report ratings (2007), which it must be explained all had  graduate as well as baccalaureate programs, and were based in the same city (and often on the same campus) as their  medical school and their major cooperating  teaching hospitals,  with which they often also offered Advanced Practitioner certification programs.

These programs tended to have larger facilities and faculties than most “ordinary” collegiate Nursing schools, and included endowed chairs in some cases, and major journal editors in all cases. 

These prominent programs  were at universities that generally had national reputations as research leaders in virtually all the fields in which they offered degrees. In short, it was no surprise that these schools were so highly regarded.

I then chose a regional peer group that would be appropriate for much of the Midwest and South, but which pointedly did not include any members of the national top ten group. 

These nursing programs were all accredited and generally based at the flagship or other large campuses of their state university system, but not located within any medical school complex (which typically was located in the largest city or cities in the state away  from the Nursing campus).

While some of these regional peer schools offered graduate degrees in Nursing and Advanced Practice certification programs, others did not.

While some of the programs were parts of identifiably independent Colleges of Nursing nominally co-equal to the College of Education or Arts & Sciences in terms of campus organization and hierarchies, other programs were subsumed into colleges of education or human services or some other cluster of fields.

What best characterized this field was the heterogeneity of the status, size, facilities, staffing,  and enrollment of these schools, a situation which is actually much closer to the reality of the mosaic of collegiate nursing programs today.

Using the Web of Science (WoS) database, I approximated  the 2001-2010 output of Nursing faculty (generally as primary authors)  in what were clearly Nursing journals (as opposed to their coauthored output in journals of medicine, public health, primary or high school health teaching, etc.). I  entered “Nursing”  in a Topic search box, then the  appropriate abbreviation for the school (obtainable from  their clickable online list of approved abbreviations) in an “Address”  search box, and the desired  period from the “Timespan”  boxes. When the results came up, I once again clicked on the “Refine Subject Areas” box for “Nursing”  journals only to keep sharp the focus on Nursing journals alone. I then clicked on the “Refine Source Titles” box to provide “more options/values…” which gave me a most-to-least frequency rank-ordered list of specifically Nursing journals to analyze.

While noting the total journal output for each Nursing program, I decided to focus on comparisons of the more general journals of nursing and nursing education, taking particular note of the top 10 of these for each school,  rather than on parsing out specialty journals such as those devoted more narrowly to cancer,  mental health, or obstetrics nursing, etc.

This was done for  two  reasons:

First, while both groups of schools had both general Nursing journals and some Nursing specialty journals, the types of specialties represented varied greatly, with some specialties absent altogether from regional peer programs making comparisons with national top ten schools problematic.  (On the whole top national top ten Nursing schools featured a higher proportion of its output, up to half, in Nursing specialty journals while regional peers, often lacking access to all the Medical & Nursing specialty services in large teaching hospitals and medical schools, rarely are able to  contribute as high as one third of their output  to similar specialty journals.

Second,   Impact Factor data is  really fair only when all the journals have a similar subject scope (It’s fair to compare one general Nursing journal with another general Nursing journal, but unfair to call, for example, the American Journal of Critical Care a better Nursing journal than the American Journal of Nursing because the two journals  have  significantly different scopes and audiences.)  

So How Did the National Top Ten Do Relative to the Regional Peer Group?

Unsurprisingly, the top ten national leaders published many more articles than the regional peer group: 1415 vs. 614 in the same time frame. What was somewhat unexpected was that while  the top ten general Nursing journals from each group were somewhat different in rank order, they  shared six of the same core titles.

The Six Shared Journals

In alphabetical order we had: the American Journal of Nursing, the Journal of Advanced Nursing,  the Journal of Nursing Education, the Journal of Professional Nursing,  Nursing Outlook, and Nursing Research.

What else do the shared six share?

They are in fact, all refereed.

They are all published by well-known firms and societies.

Wiley has the Journal of Advanced Nursing.

Slack ------well known in Nursing if not in many other fields-------has the Journal of Nursing Education.

Elsevier is represented by Nursing Outlook which it publishes on behalf of the American Academy of Nursing, as well as the Journal of Professional Nursing, issued in cooperation with the American Association of Colleges of Nursing.

Wolters  Kluwer Health, still much better known as Lippincott, Williams & Wilkins, issues Nursing Research in conjunction with the Eastern Nursing Research Society and the Western Institute of Nursing.

Lippincott, Williams & Wilkins also  publishes the American Journal of Nursing, voted by over three quarters of the members of the Biomedical and Life Sciences Division of the Special Libraries Association ------the sponsors of this blog--------- as the single most influential journal of Nursing  of the twentieth century.

How do these six differ among themselves?

Most notably they appear to be all over the map in terms of relative Impact Factors, but this requires some caution before leaping to conclusions.

While two titles, the Journal of Advanced Nursing and  Nursing Research, are clearly among the  most cited general nursing research  venues,  three others are mid-range, Nursing Outlook, the Journal of Nursing Education, and the American Journal of Nursing.

One holds markedly lower rank, the Journal of Professional Nursing, according to the latest JCR rankings to which I have access (2008, the 2009s are out but not yet available to me).  However, even this last title is much better in Impact Factors that might be imagined because the difference in calculations is only a matter of a few tenths of a point between it and the three mid-range journals just mentioned.

 The fact of the matter is that while Impact Factors among Nursing journals give you a good idea of which  five to ten  journals are at the very top or at the very bottom of the approximately 60-70 titles being compared each year , they disclose that almost 40  other Nursing journals are bunched rather closely together, with statistically weak justification for ranking  them in any hard and fast order, other than being in the mainstream,  if not the headwaters or the backwaters of Nursing publications.

What they these Impact Factors nonetheless do is to provide proof that the articles in these journals are cited by other Nursing researchers around the world, at least  to some degree, and are not just local venues of convenience for lesser papers.

What about the journals that are prominent among the top ten national schools but not in the top ten among the regional peers?

There are four journals more prominent among the top ten national programs that do not frequently appear in the top ten lists of the regional peers. (Some authors from the regional peer groups appear in them, but not frequently enough to make the journal one of their top ten titles.)  Which are these, and what can be said about them?

First, all of them are peer-reviewed.

The International Journal of Nursing Studies is published by Elsevier. It is at the very top of general Nursing journals in Impact Factors. It is British-based and has a great many editors from the UK, Canada, Australia and New Zealand in addition to four of whom are senior faculty at US top 10 Nursing programs.

The Journal of Clinical Nursing is published by Wiley. Like the International Journal mentioned above, a journal with which it directly competes,  it is UK based but has an even  broader  representation of editors from the former British Commonwealth the European Union, as well as a few  from notable programs in the US. It is not quite at the top, but in the top quarter in terms of Impact Factors.

The Journal of Nursing Scholarship is published by Wiley on behalf of Sigma Theta Tau,  the US national Nursing honors society. It ranks in the middle of the field in Impact Factors.

The Western Journal of Nursing Research is published by Sage Press, a notable firm in the Social Sciences and Education, on behalf of the Midwestern Nursing Research Society. It ranks in the middle of the field in Impact Factors.

In sum, all four are very sound journals at the top or mid-range of Nursing in prestige and Impact factors. Two are clearly more cosmopolitan in authorship and readership than most titles favored by our regional peer group faculty.     

What about the journals that are prominent among the  regional peer schools but not in the top ten among the national top ten schools?

There are four journals more prominent among the regional peer programs that do not frequently appear in the top ten lists of the national top ten schools. (Some authors from the top ten schools appear in them, but not frequently enough to make the journal  one of their top ten titles.)  Which are these, and what can be said about them?

Two of these journals are theme-issue based, meaning that the journal editor or a guest editor assembles a panel of expert authors on a single topic on which each article focuses. Publishers are fans of this journal format, because it frequently generates extra sales of  individual issues as a kind of topical best practices collection, or state of the art review. It is clear that some editing of submitted manuscripts must be involved but it seems that the crucial point in quality control, may not be traditional double blind peer review, but rather getting the issue theme and its author team approved fairly early on in the process.

It is not surprising that the two journals involved, Nursing Clinics of North America and Advances in Nursing Science are direct competitors. Nursing Clinics comes from Elsevier, while Advances is a Lippincott, Williams and Wilkins title. Nursing Clinics fares rather poorly in Impact Factors while the Advances are in the top quarter by that measure.

The two other titles where regional peers appear quite often are Nursing Education Perspectives from the National League of Nursing, and Nurse Educator from Lippincott, Williams & Wilkins. Both are peer-reviewed in the more traditional sense,  but both titles fares poorly in Impact Factors.

Does the presence of these regional peer four titles tell us much vis-à-vis the four titles of the top ten schools?

I think it is safe to say that overall, the higher level of research  may be found in the top ten school four than the regional peer four, but that the regional peer four titles make more sense for Nursing professors who still view their jobs primarily as teachers.  Two of their titles are clearly focused on methods and trends in teaching Nursing, while the remaining two provide in effect, high-level course packs quite literally authored by teams of invited experts for upper division and graduate courses.

What is the consensus opinion of medical librarians on this?

The closest thing that my profession has to say on this, apart from voting the American Journal of Nursing the most influential of the 20^th century,  comes from a continuation of the old Brandon-Hill List, published and republished in a number of places, but most pertinently for our purposes in Nursing Outlook 2002; 50:100-113. It names the following journals discussed in this blog as essential to any Nursing collection: Advances in Nursing Science, American Journal of Nursing, Journal of Nursing Education, Journal of Nursing Scholarship, Journal of Professional Nursing, Nursing Clinics of North America, Nursing Education Perspectives, Nursing Outlook, and Nursing Research. It considers the following to be genuinely reputable, sound journals  that would be good additions to any Nursing collections, after the essentials were already in place: Journal of Advanced Nursing, Nurse Educator,  and the Western Journal of Nursing Research.

 I suspect that the marginally lower rating given to the Journal of Advanced Nursing, might provide us with an explanation of why the International Journal of Nursing Studies and the Journal of Clinical Nursing were not included: the list is slanted to stocking the small US hospital library  and favored journals that had a higher proportion of American research or researchers, and was not necessarily a reflection on their quality as venues for scholarly work on the whole.

Indeed, the biggest surprise for those who are too ardent in using Impact Factors without considering other factors, is that one title identified by two expert librarians as essential, the Nursing Clinics of North America,  is ranked so poorly, while the people who most closely monitor journal use in terms of what circulates or is read-online, the remaining community of medical librarians, are very likely to second Brandon-Hill’s high regard for it.

Advice to provosts and nursing faculty seeking tenure & promotion, neither of whom are not at a top ten university school of nursing .

Regional Peer School Provosts, if your candidates manages to publish about half as many papers as their peers in a top ten school, they are probably doing quite well with the resources you are able to provide them. You are going to have to give them more to get more out of them. Impact factors are one tool for you to use, but not the only tool in making your evaluation. Do  not expect all of their  papers, now and even in the future,  to appear in journals ranking in the top quarter in Impact Factors.  But by the same token  be very leery of an assortment of papers in which few if any come from that Impact Factor level, particularly if there are no top ten school authors in the journals in which your own faculty publish  for prolonged stretches of time. (If no top ten schools publish in a journal over the course of a year, be suspicious and ask for explanations.) Look for the usual  statements of peer-review and rely on the reputation and longevity of the publishers behind the journal. They did not get to be “venerable robber barons”  by selling their principal buyers (medical librarians, as it turns out) unadulterated tripe. They have built their demand by being in their own way very demanding of their editors and authors.

Nursing Faculty Members At Regional Peer Schools: Choose more wisely than ever the journals within which you send your manuscripts. Getting at least some of your papers into some of the shared six titles in this paper, is probably a very good idea, both because it is routinely done by the very talented, very driven, very hard-working scholars in top ten schools ------and because it has demonstrably been done by your regional peers at least some of the time. Do not, however, be ashamed of being primarily a Nurse educator. You may well not have as much ready access to specialty research teams at a medical school or its teaching hospital and few if any of your colleagues are likely to be major Nursing journal editors, but you do have at least as much access (and probably much more contact time) as well as a great responsibility to the kids in front of you and the patients that will one day be in their charge. Studies involving understanding their pre-Nursing  backgrounds and abilities, improving their understanding of Nursing concepts and procedures, and the monitoring of their follow-on careers and needs for continuing education, remain important to both your career and to the profession at  large. Nonetheless, when the opportunity presents itself, to do work that leads to publication in Nursing specialty journals, jump on it. It will be a good way to distinguish yourself and promote diversity of expertise in your own Nursing school or department.

 

 

 

 

 

 

 

 

Cholera

It is almost exactly a year ago that perhaps the most wide-ranging review of the state of our knowledge on vibrio cholera was published in the prestigious journal Nature Reviews Microbiology  by Nelson et al (2009).  Given that Haiti is experiencing an incipient epidemic (see McNeil & Sontag 2010), it might prove useful to review the facts.

• Cholera is spread primarily by water contaminated by bacteria  known as Vibrio cholerae, although contaminated seafood, especially raw shellfish,  will give it to you as well.

 

• Cholera is overwhelmingly a disease of Third World countries with  overcrowded populations with poor isolation of water for drinking and cooking apart from water used to flush feces and wash clothes soiled by diarrhea.  Cholera is very frequent in Bangladesh (Emch et al 2010), southern India (Das 2010),  southeast Asia (Lenglet et al 2010) certain sub-Saharan African cities (Lusaka, see Gettlemen 2009), and parts of Latin America (Alamet et al 2010).  Eastern Europe and Russia are also susceptible when water and sewer infrastructure  crumbles  owing to age or poor maintenance (Cromley 2010). Crowding alone rarely provides sufficient conditions for cholera. Hong Kong & Singapore are tremendously crowded places, but sanitary systems have been updated and made robust enough to withstand certain shocks, so chances for cholera outbreaks there are reduced. Despite being located on a peninsula where cholera is endemic, Singapore, a city-state of 4.8 million people,  had only 7 cases of vibrio cholera  in 2007, and to the degree it can be confirmed, raw seafood seemed to be the primary culprit although contaminated beverages were also implicated  in one case (Wong, James & Goh 2010).

 

 

• Cholera is considered to be a perfect model for public health experts and mathematically inclined epidemiologists (Azaele et al 2010) to use to predict and map epidemics, owing to its having had repeated outbreaks over long periods of time, many of which were well  documented in terms of the number of victims, locations, weather conditions, and demographics (Bertuzzo et al 2010, Ruiz-Moreno et al 2010). Three factors in addition to poverty and overcrowding almost mathematically tend to predict outbreaks. 1.  Unusually heavy rains, which cause sewage and drinking water to mix (Sasaki et al 2009)  2. Spikes of high temperatures which favor the multiplication of the bacterium (Islam et al 2009).  3. Physical shocks such as earthquakes, volcanoes, tsunamis, and floods so deep that buried pipelines are crushed from overhead weight and/or dams break (Guha-Sapir & Gijsbert van Panhuis 2009). It is sadly  no surprise that earthquake-damaged Haiti is experiencing an epidemic, but almost astonishing  that cholera has not broken out to any extent in vastly more flooded Pakistan, which has experienced  many of these contributing factors but fortunately temperatures there are heading downwards in a way that may limit vibrio proliferation.

 

• Vibrio cholera typically has a sort of bullet-shaped or elliptical body, often developing  a whipping tail or flagellum that propels it. It uses the flagellum to penetrate membranes, and seems to thrive in those slick aquatic (but occasionally visceral) scummy surfaces that are called biofilms (Kamruzzaman et al 2010).

 

 

• The bacterium  otherwise has what amounts to a two step life cycle. It lives and reproduces relatively slowly in sewage-type water, but once a patient ingests as little a single glass of this sort of water  (unwittingly containing  millions to billions of unseen particles), it can begin a new and hyper-virulent  life cycle in the body, if it beats certain of the body’s defenses.

 

• Curiously the biggest initial defense is stomach acid (Nalin et al 1978). There is some evidence that a diet high in certain acidic foods or acidic natural products confers some disease resistance (Rahim et al 2010).

 

•  Once the bacteria survives to make it to the small intestine, it uses its flagella to propel the head of the bacterium into the lining of the small intestine. There  the bacterium’s “head”  release some toxins. These toxins cause the cells  lining the intestine to rupture and release free floating proteins, fats & carbohydrates,  which enable  the bacterium to feed and multiply very rapidly. In fact, once  the vibrio sustain an intestinal presence not only does the patient become very sick, but the bacteria that emanates from his or her stool become hyper-infectious, reproducing much more rapidly than in ordinarily contaminated water, and causing person-to-person transmission to happen more quickly and resulting  in the most severe of symptoms (Merrell et al 2002).

 

 

• Intestinal tissue damage, from marauding vibrio, however,  is not the immediate cause of death. Rather it is the massive diarrhea of a consistency and appearance of  what is typically described in the medical literature as “rice water:” i.e. Water that looks like it was left over after you had boiled rice in it. What that water contains, besides tens of  trillions of hyper-infectious vibrio is a great quantity of electrolytes (dissolved salts and trace minerals) without which the body cannot function, as well as vast quantities of water (sometimes quarts at a time) that have to be replaced or the patient will die of dehydration, which is ironic since it often seems as if the patients  are practically swimming in their own watery waste. 

 

• While antibiotics will help a patient, particularly if the right ones are matched to the right subtypes of cholera, the patient must first survive the onslaught of their  fluid and electrolyte loss through the immediate force-feeding of  oral rehydration therapy. The composition of the remedial solutions often consists of fairly simple concoction of water, salt, sugar, and well-cooked rice. The chances for recovery go  up from around 50% to as high as 99% if the patient is well hydrated through a crisis period lasting several days (Atia & Buchman 2010). It’s key, of course, that the water used to make these is uncontaminated!

 

• Certain age groups and people with certain blood types seem to have a special propensity for bad outcomes during cholera epidemics. Children under the age of 5 (Bryce et al 2005) , and people with blood type O are especially hard hit (e.g. Swerdlow et al 2005).

 

• What can be done to limit the spread or damage caused by vibrio cholera? While most vaccines developed to date are of limited effectiveness, a certain level of immunity is conferred if everyone is vaccinated in an endemic area, at least as long as the locally infective subtype does not mutate greatly ( Ali et al 2005).  The idea that we could release viruses that feed on vibrio into the local water supplies of an area undergoing an epidemic has some merit, since it has been found that seasonal outbreaks of cholera tend to be quashed when the viruses that feed on them also multiply to such a degree that they damp down the epidemic (Faruque et al 2005). But ultimately the most effective “cure”  for cholera is most likely to be industrialization which increases incomes for individuals and budgets for the local authorities while it  improves water supplies primarily for reasons of manufacturing, with its side benefit of building durable  separate  systems  for piping in and storing drinking water and processing and piping away urine and feces contaminated waste water  (Hamlin 2009). This complex, indirect, and largely capitalist approach surprisingly better explains long term successes in controlling outbreaks than theories of popular uproar, reform movements,  and grass roots public health outreach.


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 

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Atia, A, and A L Buchman. 2010. Treatment of cholera-like diarrhoea with oral rehydration. Annals Of Tropical Medicine And Parasitology 104 (6): 465-474.

Azaele, Sandro, Amos Maritan, Enrico Bertuzzo, Ignacio Rodriguez-Iturbe, and Andrea Rinaldo. 2010. Stochastic dynamics of cholera epidemics. Physical Review.E, Statistical, Nonlinear, and Soft Matter Physics 81 (5) (05): 051901-.

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Bryce, J., C. Boschi-Pinto, K. Shibuya, & R./E. Black. 2005. WHO estimates of the causes of death in children. The Lancet 365: 1147-1152.

Cariri, F. A. M. O., A. P. R. Costa, C. C. Melo, G. N. D. Theophilo, E. Hofer, Melo Neto de, and N. C. Leal. 2010. Characterization of potentially virulent non-O1/non-O139 Vibrio cholerae strains isolated from human patients. Clinical Microbiology & Infection 16 (1) (01): 62-7.

Chowdhury, N., M. Asakura, S. B. Neogi, A. Hinenoya, S. Haldar, T. Ramamurthy, B. L. Sarkar, S. M. Faruque, and S. Yamasaki. 2010. Development of simple and rapid PCR-fingerprinting methods for Vibrio cholerae on the basis of genetic diversity of the superintegron. Journal of Applied Microbiology 109 (1) (07): 304-12.

Cromley, Ellen K. 2010. Pandemic disease in Russia: From black death to AIDS. Eurasian Geography & Economics 51 (2) (Mar): 184-202.

Das, Amitav, P. Manickam, Yvan Hutin, B. B. Pal, G. P. Chhotray, S. K. Kar, and M. D. Gupte. 2009. An outbreak of cholera associated with an unprotected well in Parbatia, Orissa, Eastern India. Journal of Health, Population, & Nutrition 27 (5) (10): 646-51.

Emch, Michael, Mohammad Yunus, Veronica Escamilla, Caryl Feldacker, and Mohammad Ali. 2010. Local population and regional environmental drivers of cholera in Bangladesh. Environmental Health: A Global Access Science Source 9 : 2.

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Guha-Sapir, Debarati, and Willem Gijsbert van Panhuis. 2009. Health impact of the 2004 Andaman Nicobar earthquake and tsunami in Indonesia. Prehospital and Disaster Medicine: The Official Journal of the National Association of EMS Physicians and the World Association for Emergency and Disaster Medicine in Association with the Acute Care Foundation 24 (6) (2009): 493-9.

Hamlin, Christopher. 2009. "Cholera forcing". American Journal of Public Health 99 (11) (11): 1946-54.

Islam, M. S., M. A. Y. Sharker, S. Rheman, S. Hossain, Z. H. Mahmud, M. S. Islam, A. M. K. Uddin, et al. 2009. Effects of local climate variability on transmission dynamics of cholera in Matlab, Bangladesh. Transactions of the Royal Society of Tropical Medicine and Hygiene 103 (11) (11): 1165-70.

Kamruzzaman, M., S. M. N. Udden, D. E. Cameron, Stephen B. Calderwood, G. B. Nair, John J. Mekalanos, and Shah M. Faruque. 2010. Quorum-regulated biofilms enhance the development of conditionally viable, environmental Vibrio cholerae. Proceedings of the National Academy of Sciences of the United States of America 107 (4) (01/26): 1588-93.

Lenglet, Annick, Bouaphanh Khamphaphongphane, Phetsamay Thebvongsa, Phengta Vongprachanh, Noikaseumsy Sithivong, Chitsavang Chantavisouk, and Reiko Tsuyuoka. 2010. A cholera epidemic in Sekong Province, Lao People's Democratic Republic, December 2007-January 2008. Japanese Journal Of Infectious Diseases 63, (3): 204-207.

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McNeil, Donald G., and contributed reporting by Deborah Sontag. 2010. Cholera outbreak kills 150 in Haiti, raising fears of epidemic in crowded camps. New York Times (10/23): 5.

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The Bisphosphonates: Fosamax™, Actonel™, Actonel with Calcium ™, Boniva™, Atelvia™ , Reclast™, Skelid™ & Zometa™. Vastly more helpful for millions by reducing the threat of osteoporosis than surely more harmful for a very few

 

What are the bisphosphonates?

The bisphosphonates are a class of drugs that are generally prescribed, primarily for women who are late pre-menopausal, menopausal or post-menopausal to reduce and possibly reverse the demineralization of bone through calcium loss, usually targeting the two areas of the body where calcium loss causes the most damage: the spinal column (vertebrae) and the hip and thigh. They are also prescribed for certain cancers (mostly myeolomas, but also metastases from breast cancer in women and prostate cancer in men ), and diseases (Paget’s Disease, Osteogenesis Imperfecta,  AIDS, certain types of renal failure) which have the direct unfortunate effect of inducing bone thinning and fractures  of themselves, or which involve treatments that have those adverse side effects.

Why are these drugs  in the news?

On October 13, 2010, the US Food & Drug Administration added some new information to be given to patients taking these medications, as well as to their prescribing physicians. It concerns a potential for a somewhat higher statistical chance for certain rare types of hip and thigh bone fractures for those who have been taking bisphosphonates for several years vs. the overall incidence of vertebral, hip and thigh fractures.

Why would this be news?

It most likely became news primarily because we as a public in the United States and perhaps elsewhere in the developed world, have become almost paranoid about drug recalls, and are often morbidly entertained by conspiracy thinking about “Big Pharma” and doctors who prescribe drugs allegedly because they are incentivized with free vacations, subsidized continuing medical education junkets, or some other type of underhanded inducements. Less than a month earlier, Avandia™ , a drug given to diabetics to forestall heart disease (ironically diabetes is not the direct cause of death for the vast majority of diabetics, the number one direct killer of diabetics is actually heart disease) counter-intuitively actually increased the chances of a small, but significant number of Avandia™-taking patients, to develop heart disease, and therefore was severely restricted.

What actually did the FDA advisory say to patients about these bisphosphonates?

On its website, www.fda.gov/Drugs/DrugSafety/ucm229009.htm the FDA advises patients to:

• Continue to take your medication unless you are told to stop by your healthcare professional.

 

• Talk to your healthcare professional if you develop new hip or thigh pain (commonly described as dull or aching pain), or have any concerns  with your medications.

 

• Report any side effects with your bisphosphonate medication to FDA’s Medwatch program using the information at the bottom of the page in the “Contact Us” box.  

 

What did the FDA advisory say to Doctors about these bisphosphonates?

On its website, www.fda.gov/Drugs/DrugSafety/ucm229009.htm the “FDA recommends that healthcare professionals should:

• Be aware of the possible risk of atypical subtrochanteric and diaphyseal femur fractures in patients taking bisphosphonates.

 

• Continue to follow the recommendations in the drug label when prescribing bisphosphonates.

 

 

• Discuss the known benefits and potential risks of using bisphosphonates with patients.

 

 

• Evaluate any patient who presents with new thigh or groin pain to rule out a femoral fracture.

 

 

• Discontinue potent antiresorptive medications (including bisphosphonates) in patients who have evidence of a femoral shaft fracture.

 

 

• Consider periodic reevalutation of the need for continued bisphosphonate therapy, particularly in patients who have been treated for over 5 years.

 

 

• Report any adverse events with the use of bisphosphonates to FDA’s MedWatch program using the information at the bottom of the page in the “Contact Us” box.

 

Any information provided to MedWatch should be as detailed as possible and include information concerning fracture location/configuration, magnitude of trauma, fracture details (complete or incomplete, bilateral, or comminuted), presence and duration of prodromal thigh or groin pain, duration of bisphosphonate use, relevant medical history, and concomitant use of other medications. “

What is the key point involved in these advisories?

There appears to be a tiny  increase in the relative (but not necessarily absolute) number of subtrochanteric and femoral shaft fractures, largely  in elderly women taking one of the bisphosphonates for several years. Depending on your means of calculating odds with the worst case statistics, this means that there is a worst case possibility that 3%-5% of all the patients at high risk for an osteoporosis-related fracture might get a different and fairly rare (“atypical” is the term used) fracture farther down the thigh than the usual location for such fractures, and it would be wise to monitor them for dull pain in the thigh and/or groin  if they have been taking bisphosphonates for a long time (several years), because most patients (70%) who eventually have such a fracture had this tell-tale symptom first.

Does this mean that not taking bisphosphonates actually decreases your chance of getting a vertebral, hip  & thigh fracture?

Absolutely not! Probably the best estimate, taken from  Shane et al (2010) is that prescription bisphosphonates cut the number of vertebral fractures by 1000/10,000 patient years and the number of hip and thigh fractures by 700/10,000 patient years. This is an astonishingly positive  benefit to risk ratio. Quite literally millions of people have benefited from taking these drugs, while at the worst perhaps 300-400  cases drawn from about 170 pooled articles,  have been documented in the medical literature as having these rare fractures or other complications, in conjunction with their taking bisphosphonates .

Are there any confounding conditions connected with the women taking bisphosphonates and subsequently having one of these atypical fractures?

Yes, while the number of studies and case reports are scattered and do not all follow the same protocols for diagnosis and classification of these traumas, it appears, that a  fair number were older and  in generally poorer health, had been using proton pump inhibitors for gastric reflux,  had a history of osteoarthritis, had previous bone fractures and in some cases had taken cancer chemotherapeutic or immunosuppressive drugs. In other words, they had rather lengthy prior histories of medical importance. There is also some suggestion that Asian women were at greater risk.  However, other studies of women without all these complications or predispositions, or with matching records of having them to the same degree,  still show some increased risk of having these atypical fractures. There is little doubt that the risk of these atypical fractures is real, but significant doubt as to just how small the number of affected individuals might be when compared to the overall pool of people at risk for osteoporosis-related fractures: 5%?, 4%, 3%?, 2%?, 1%?,  0.1%, 0.01%? To determine better just what the odds are, and to track what happens when the bisphophonates are discontinued at the earliest signs of trouble, a registry of cases is being proposed (Shane et al 2010). Nonetheless, no fewer than 20 of the articles cited below still regard prescription bisphosphonates as the strategy of choice for patients seriously at risk for osteoporosis-related fractures.

What about bisphosphonates might be causing this small number of atypical fractures?

Fractures from osteoporosis related  causes tend to be  owing to the thinning  of the cortical (outermost) structural layer of bone, and/or from accumulating defects in the microarchitecture of the minerals in the bone. Bisphosphonates may be better at strengthening the cortical thickening than they are at repairing microarchitecture, or the methods or route  by which they strengthen the cortex has the unintended side-effect of further weakening the microarchitecture.  This microarchitecture  weakness would make help us make sense of the tiny minority of patients who also have a necrotic reaction to bisphosphonates that manifests itself in the jaw to the degree that it causes the drug’s discontinuance, and makes dental procedures problematic.  (But even in the cases of jaw misadventure, the patients are older, poorer, and sicker on average). In other words, bisphosphonates may not be the perfect medicine for this condition, albeit they are the best we currently have in production and have been proven safe and effective for millions thus far.

So, should we not be glad that the FDA stopped this "Big Pharma" conspiracy?

Well, even the worse conspiracy theorists would be dumbfounded when they learn that 21 of the 23 researchers involved in the key  Task Force of the American Society for Bone and Mineral Research overview (Shane et al 2010) on which the FDA’s modified patient and physician advisories were based,  either worked for, or had taken funding from, those allegedly evil folks in Big Pharma. It is little understood by many in the investigative reporting business that sometimes the greatest pool of expertise really does come from people who do research within or are funded by,   businesses who generally make our lives much better, because developing new drugs that help us manage or cure diseases is pretty much their life’s work.

What would be the most likely health outcomes if people were scared off taking their bisphosphonates by overhyped media reports?

Funny that you should ask, because a study of this has already been done in Australia where medical and prescription drug records are available to researchers owing to governmental benefits programs. According to Sambook et al 2010, adverse media reports on the side effects and risks for bisphosphonates appearing in Australia last year probably resulted in the ensuing nine months in 70 more hip fractures, 60 more other fractures (largely vertebral) and 14 more deaths, than would have occurred if the patients had simply stuck to taking them.

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

Editor-in-Chief of Science & Technology Libraries

University of Arkansas Libraries MULN 233 E

365 North McIroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

Antoniazzi, Franco, Elena Monti, Giacomo Venturi, Roberto Franceschi, Francesco Doro, Davide Gatti, Giorgio Zamboni, and Luciano Tatò. 2010. GH in combination with bisphosphonate treatment in Osteogenesis Imperfecta. European Journal of Endocrinology / European Federation of Endocrine Societies 163 (3) (09): 479-87.

Baqain, Zaid H., Faleh A. Sawair, Zaid Tamimi, Nazzal Bsoul, Ghazi Al Edwan, Jamal K. Almasad, and Abdalla A. Abbadi. 2010. Osteonecrosis of jaws related to intravenous bisphosphonates: The experience of a Jordanian teaching hospital. Annals of the Royal College of Surgeons of England 92 (6) (09): 489-94.

Barney, Rocky J., Brian M. Wasko, Amel Dudakovic, Raymond J. Hohl, and David F. Wiemer. 2010. Synthesis and biological evaluation of a series of aromatic bisphosphonates. Bioorganic & Medicinal Chemistry 18 (20) (10/15): 7212-20.

Beukelman, T., K. G. Saag, J. R. Curtis, M. L. Kilgore, and M. Pisu. 2010. Cost-effectiveness of multifaceted evidence implementation programs for the prevention of glucocorticoid-induced osteoporosis. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (9) (09): 1573-84.

Bladé, J., M. T. Cibeira, de Larrea Fernández, and L. Rosiñol. 2010. Multiple myeloma. Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO 21 Suppl 7 (10): vii313-9.

Bleicher, Kerrin, Vasi Naganathan, Robert G. Cumming, Markus J. Seibel, Philip N. Sambrook, Fiona M. Blyth, David Le Couteur G., David J. Handelsman, Louise M. Waite, and Helen M. Creasey. 2010. Prevalence and treatment of osteoporosis in older Australian men: Findings from the CHAMP study. The Medical Journal of Australia 193 (7) (10/04): 387-91.

Body, J-J. 2010. Prevention and treatment of side-effects of systemic treatment: Bone loss. Annals of Oncology: Official Journal of the European Society for Medical Oncology / ESMO 21 Suppl 7 (10): vii180-5.

Brandi, Maria Luisa. 2010. Current treatment approaches for Paget's Disease of Bone. Discovery Medicine 10 (52) (09): 209-12.

Brown, Janet E., and Sheryl Sim. 2010. Evolving role of bone biomarkers in castration-resistant prostate cancer. Neoplasia (New York, N.Y.) 12 (9) (09): 685-96.

Canoui-Poitrine, F., S. Jaglal, R. Chapurlat, V. Tainturier, C. Colin, and A. M. Schott. 2010. Has reimbursement of bone mineral density testing and anti-osteoporotic treatments improved management of osteoporosis in France? Bone 47 (4) (10): 790-4.

Cardwell, Chris R., Christian C. Abnet, Marie M. Cantwell, and Liam J. Murray. 2010. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA: The Journal of the American Medical Association 304 (6) (08/11): 657-63.

Castellví, Ivan, Maria Bonet, Jose Narváez A., and Jose Molina-Hinojosa. 2010. Successful treatment of SAPHO syndrome with adalimumab: A case report. Clinical Rheumatology 29 (10) (10): 1205-7.

D'Amelio, P., A. Grimaldi, M. A. Cristofaro, M. Ravazzoli, P. A. Molinatti, G. P. Pescarmona, and G. C. Isaia. 2010. Alendronate reduces osteoclast precursors in osteoporosis. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (10) (10): 1741-50.

Diel, Ingo J., Andreas H. A. Kurth, Hans-Bernd Sittig, Harald Meden, Michael Maasberg, Andreas Sandermann, and Raoul Bergner. 2010. Bone pain reduction in patients with metastatic breast cancer treated with ibandronate-results from a post-marketing surveillance study. Supportive Care in Cancer: Official Journal of the Multinational Association of Supportive Care in Cancer 18 (10) (10): 1305-12.

Dissette, Valeria, Pietro Bozzi, Carlo Alberto Bignozzi, Alessandro Dalpiaz, Luca Ferraro, Sarah Beggiato, Eliana Leo, Eleonora Vighi, and Luisa Pasti. 2010. Particulate adducts based on sodium risedronate and titanium dioxide for the bioavailability enhancement of oral administered bisphosphonates. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences 41 (2) (10/09): 328-36.

Duque, Gustavo, Jacqueline J. Close, Julien de Jager P., Peter R. Ebeling, Charles Inderjeeth, Stephen Lord, Andrew J. McLachlan, Ian R. Reid, Bruce R. Troen, and Philip N. Sambrook. 2010. Treatment for osteoporosis in Australian residential aged care facilities: Consensus recommendations for fracture prevention. The Medical Journal of Australia 193 (3) (08/02): 173-9.

Epstein-Barash, Hila, Dikla Gutman, Ela Markovsky, Galit Mishan-Eisenberg, Nickolay Koroukhov, Janos Szebeni, and Gershon Golomb. 2010. Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: Internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death. Journal of Controlled Release: Official Journal of the Controlled Release Society 146 (2) (09/01): 182-95.

Garg, Arun. 2010. News on bisphosphonates: But will patterns of use change? Dental Implantology Update 21 (9) (09): 71-2.

Gimsing, Peter, Kristina Carlson, Ingemar Turesson, Peter Fayers, Anders Waage, Annette Vangsted, Anne Mylin, et al. 2010. Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): A double-blind, randomised controlled trial. The Lancet Oncology 11 (10) (10): 973-82.

Giovannini, Monica, Daniela Aldrighetti, Patrizia Zucchinelli, Carmen Belli, and Eugenio Villa. 2010. Antiangiogenic strategies in breast cancer management. Critical Reviews in oncology/hematology 76 (1) (10): 13-35.

Guañabens, Núria, and Albert Parés. 2010. Liver and bone. Archives of Biochemistry and Biophysics 503 (1) (11/01): 84-94.

Harel, Ran, and Lilyana Angelov. 2010. Spine metastases: Current treatments and future directions. European Journal of Cancer (Oxford, England: 1990) 46 (15) (10): 2696-707.

Haworth, Charles S. 2010. Impact of cystic fibrosis on bone health. Current Opinion in Pulmonary Medicine 16 (6) (11): 616-22.

Hofbauer, Lorenz C., Franz Jakob, and Dieter Felsenberg. 2010. Bisphosphonates and atypical femoral fractures. The New England Journal of Medicine 363 (11) (09/09): 1084; author reply 1084-5.

Holmberg, Anders R., Ulf H. Lerner, Ayodele A. Alayia, Mai Al-Mohanna, Chaker Adra, Marcela Marquez, Lennart Meurling, and Sten Nilsson. 2010. Development of a novel poly bisphosphonate conjugate for treatment of skeletal metastasis and osteoporosis. International Journal of Oncology 37 (3) (09): 563-7.

Iguchi, Kazuhiro, Yoshiki Tatsuda, Shigeyuki Usui, and Kazuyuki Hirano. 2010. Pamidronate inhibits antiapoptotic bcl-2 expression through inhibition of the mevalonate pathway in prostate cancer PC-3 cells. European Journal of Pharmacology 641 (1) (09/01): 35-40.

Imaz, I., P. Zegarra, J. González-Enríquez, B. Rubio, R. Alcazar, and J. M. Amate. 2010. Poor bisphosphonate adherence for treatment of osteoporosis increases fracture risk: Systematic review and meta-analysis. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (11) (11): 1943-51.

Jones, Michael D., Charles W. Tran, Guang Li, Walter P. Maksymowych, Ronald F. Zernicke, and Michael R. Doschak. 2010. In vivo microfocal computed tomography and micro-magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat. Arthritis and Rheumatism 62 (9) (09): 2726-35.

Jules, Joel, Jason W. Ashley, and Xu Feng. 2010. Selective targeting of RANK signaling pathways as new therapeutic strategies for osteoporosis. Expert Opinion on Therapeutic Targets 14 (9) (09): 923-34.

Kaji, H., Y. Kuroki, Y. Murakawa, I. Funakawa, Y. Funasaka, F. Kanda, and T. Sugimoto. 2010. Effect of alendronate on bone metabolic indices and bone mineral density in patients treated with high-dose glucocorticoid: A prospective study. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (9) (09): 1565-71.

Karosas, Ann O. 2010. Ewing's sarcoma. American Journal of Health-System Pharmacy: AJHP: Official Journal of the American Society of Health-System Pharmacists 67 (19) (10/01): 1599-605.

Katsumi, Hidemasa, Kosuke Kusamori, Toshiyasu Sakane, and Akira Yamamoto. 2010. Development of delivery system of bisphosphonates for the treatment of osteoporosis. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan 130 (9) (09): 1129-33.

Lamberg, A. L., E. Horvath-Puho, S. Christensen, and Sørensen H.T. 2010. Use of oral bisphosphonates and risk of venous thromboembolism: A population-based case-control study. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (11) (11): 1911-7.

Lazarovici, Towy Sorel, Shlomit Mesilaty-Gross, Iris Vered, Clara Pariente, Hannah Kanety, Navot Givol, Ran Yahalom, Shlomo Taicher, and Noam Yarom. 2010. Serologic bone markers for predicting development of osteonecrosis of the jaw in patients receiving bisphosphonates. Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons 68 (9) (09): 2241-7.

Lipton, Allan. 2010. New approaches to treating and preventing bone metastases. Current Opinion in Supportive and Palliative Care 4 (3) (09): 178-81.

López-Jornet, Pía, Fabio Camacho-Alonso, Francisco Molina-Miñano, Francisco Gómez-García, and Vicente Vicente-Ortega. 2010. An experimental study of bisphosphonate-induced jaws osteonecrosis in sprague-dawley rats. Journal of Oral Pathology & Medicine: Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 39 (9) (10): 697-702.

Lyritis, George P., Thomas Georgoulas, and Christos P. Zafeiris. 2010. Bone anabolic versus bone anticatabolic treatment of postmenopausal osteoporosis. Annals of the New York Academy of Sciences 1205 (1) (09): 277-83.

Magrey, Marina, and Muhammad Asim Khan. 2010. Osteoporosis in ankylosing spondylitis. Current Rheumatology Reports 12 (5) (10): 332-6.

Mahtani, Reshma, and Mohammad Jahanzeb. 2010. Bisphosphonates as anticancer therapy for early breast cancer. Clinical Breast Cancer 10 (5) (10/01): 359-66.

Maricic, Michael. 2010. The role of zoledronic acid in the management of osteoporosis. Clinical Rheumatology 29 (10) (10): 1079-84.

McKague, Meredith, Derek Jorgenson, and Kelly A. Buxton. 2010. Ocular side effects of bisphosphonates: A case report and literature review. Canadian Family Physician Médecin De Famille Canadien 56 (10) (10): 1015-7.

Mehanna, P., and R. Goddard. 2010. Bisphosphonate associated osteonecrosis: An unusual case. Australian Dental Journal 55 (3) (09): 311-3.

Miller, P. D., and R. J. Derman. 2010. What is the best balance of benefits and risks among anti-resorptive therapies for postmenopausal osteoporosis? Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 21 (11) (11): 1793-802.

Odri, Guillaume A., Sophie Dumoucel, Gaëlle Picarda, Sé Battaglia, François Lamoureux, Nadège Corradini, Julie Rousseau, et al. 2010. Zoledronic acid as a new adjuvant therapeutic strategy for Ewing's Sarcoma patients. Cancer Research 70 (19) (10/01): 7610-9.

Oldfield, Eric. 2010. Targeting isoprenoid biosynthesis for drug discovery: Bench to bedside. Accounts of Chemical Research 43 (9) (09/21): 1216-26.

Panzavolta, S., P. Torricelli, B. Bracci, M. Fini, and A. Bigi. 2010. Functionalization of biomimetic calcium phosphate bone cements with alendronate. Journal of Inorganic Biochemistry 104 (10) (10): 1099-106.

Pozzi, Samantha, and Noopur Raje. 2010. Bisphosphonates and atypical femoral fractures. The New England Journal of Medicine 363 (11) (09/09): 1083-4.

Rao, Shobha S., Nitin Budhwar, and Ambreen Ashfaque. 2010. Osteoporosis in men. American Family Physician 82 (5) (09/01): 503-8.

Reid, I. R., G. D. Gamble, P. Mesenbrink, P. Lakatos, and D. M. Black. 2010. Characterization of and risk factors for the acute-phase response after zoledronic acid. The Journal of Clinical Endocrinology and Metabolism 95 (9) (09): 4380-7.

Resnick, J., N. Gupta, J. Wagner, G. Costa, R. J. Cruz J., L. Martin, D. A. Koritsky, et al. 2010. Skeletal integrity and visceral transplantation. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons 10 (10) (10): 2331-40.

Sambrook, Philip N., Jiang S. Chen, Judy M. Simpson, and Lyn M. March. 2010. Impact of adverse news media on prescriptions for osteoporosis: Effect on fractures and mortality. The Medical Journal of Australia 193 (3) (08/02): 154-6.

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Sellmeyer, Deborah E. 2010. Atypical fractures as a potential complication of long-term bisphosphonate therapy. JAMA: The Journal of the American Medical Association 304 (13) (10/06): 1480-4.

Shabestari, Ghasem Omati, Yadollah Soleimani Shayesteh, Arash Khojasteh, Marzieh Alikhasi, Neda Moslemi, Amin Aminian, Reza Masaeli, Behnam Eslami, and Nathaniel S. Treister. 2010. Implant placement in patients with oral bisphosphonate therapy: A case series. Clinical Implant Dentistry and Related Research 12 (3) (09): 175-80.

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Shiraki, Masataka, Yasushi Yamazaki, Yumiko Shiraki, Takayuki Hosoi, Naoko Tsugawa, and Toshio Okano. 2010. High level of serum undercarboxylated osteocalcin in patients with incident fractures during bisphosphonate treatment. Journal of Bone and Mineral Metabolism 28 (5) (09): 578-84.

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Stagi, Stefano, Laura Masi, Serena Capannini, Rolando Cimaz, Giulia Tonini, Marco Matucci-Cerinic, Maurizio de Martino, and Fernanda Falcini. 2010. Cross-sectional and longitudinal evaluation of bone mass in children and young adults with juvenile idiopathic arthritis: The role of bone mass determinants in a large cohort of patients. The Journal of Rheumatology 37 (9) (09): 1935-43.

Ueda, Takeshi, Yusuke Imamura, Atsushi Komaru, Satoshi Fukasawa, Tomokazu Sazuka, Takahito Suyama, Yukio Naya, Naoki Nihei, Tomohiko Ichikawa, and Masayuki Maruoka. 2010. Treatment outcomes of sorafenib for first line or cytokinerefractory advanced renal cell carcinoma in Japanese patients. International Journal of Urology: Official Journal of the Japanese Urological Association 17 (9) (09): 811-5.

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Tuberculosis, TB, is on the Rise Again

If there was a celebrity cause of death of the last millennium, it was probably tuberculosis. According to an unsigned, but rather exhaustive inventory,  matter-of-factly entitled "List of tuberculosis victims" http://en.wikipedia.org/wiki/List_of_tuberculosis_victims, which I fact-checked for  two dozen or so names,  it does seem likely that all of the following died of TB or its complications: John Calvin, Cardinal & Regent of France Richelieu,  Saint Theresa and Saint Bernadette Soubirous of Lourdes, all of the Bronte sisters, Elizabeth Barrett Browning, John Keats, Eugene O’Neill, William Somerset Maugham, D.H. Lawrence, George Orwell, Alexander Pope, Washington Irving, Moliere, Sir Walter Scott, Laurence Sterne, Henry David Thoreau, Robert Louis Stevenson, Jean-Jacques Rousseau, Frederic Chopin, Igor Stravinsky, Anton Chekhov, Maxim Gorky, Simon Bolivar, President James Monroe, Eleanor Roosevelt, Alexander Graham Bell, Louis Braille,  Immanuel Kant, Florence Nightingale, Baruch Spinoza, Ho Chin Mihn & W.C. Fields. But TB is scarcely a “dead disease. ”  Every year over 9,000,000 new cases are reported and 2,000,000 die from it. (Das & Horton 2010, Lonnroth et al. 2010). This is in contrast to the numbers who died during the recent, much more highly publicized H1N1 misnamed “swine flu and/or bird flu” epidemic: 14,286, according to the European Centers for Disease Control & Prevention.

 

Who Gets TB Today?

 

While anyone can conceivably get TB today,  the following are among the most likely victims today. Poor urban dwellers (Cantwell et al 1998) with a history of alcoholism (see, for example Mathew et al 2010) and smoking (see for example  Silva et al 2010)……although neither poverty nor alcohol nor tobacco use cause TB of themselves). Recent immigrants to developed Western countries from underdeveloped countries in Africa, the Middle East & Central Asia, or South East Asia (see for example Buu et al 2010, Menzies et al 2010), where TB is much more common. Certain isolated indigenous peoples, including some Native American Indian tribes (Breault & Hoffman 1997) .  Dairy herdsmen and slaughterhouse workers, veterinarians,  doctors, nurses, dentists (see for example Cadmus et al 2010) workers and the very people who fight TB the most: Public Health workers (Hanscheid & Grobusch 2010, Jong Lee et al 2010,  Ling & Menzies 2010). And just about anyone with HIV, particularly in Sub-Saharan Africa. TB hits children (Marais & Schaff 2010)  and the elderly (Mori & Leung 2010) much harder than adults.

 

From What, Where or Whom Do They Get TB?

 

Well over 90% of TB is transmitted from person-to-person. In other words if you have been exposed to people who are in their active stage of  TB, people whose  levels of Mycobacteria tuberculosis bacteria are such that they are abundant in their sputum which is sprayed about mostly through coughing and sneezing, long enough or in the right close circumstances, you can contract TB. Single digit percentages of TB are contracted from animals or animal products: most commonly through consuming unpasteurized dairy products and occasionally red meat. The causative agent is Mycobacterium bovis (so-called bovine or zoonotic TB).  (Chickens can get their own form of TB, but transmission of that type to humans is not common, although chickens can give it to cows, where it causes Johne’s Disease).  

 

However, TB is an equal opportunity disease: people can get it from their relatives, their cows, dairy products, and even from wildlife, and can give it right back to the sources they got it from or their uninfected  herd or pack mates (Rock et al 2009)! Humans can infect cattle, whose excreta infects wildlife (in the US mostly deer, in the UK mostly badgers, in Africa wild buffalos and wildebeest, and anything that eat the wildlife or the cattle,   so that wolves, lynxes, lions can get it and give it back too through saliva and excreta.) Humans can transmit the bovine form just as well as they can the more common M. tuberculosis form to other humans or to animals, and animals can give humans either type as well. Indeed, the best theory of TB origins have it arising from mutations of very tough soil-born versions which became capable of infecting  livestock which in turn infected herdsmen.  North Africa, Europe and Asia seemed to have developed both human and bovine types before the disease spread to Australia or the Americas. Indeed, traces of TB have been found in wooly mammoth and ancient musk oxen and bison  frozen remains and bones on both sides of the Bering Strait, with a trail running down through the west coast of the US (Rothschild & Martin 2006).

 

Given that TB seems so infectious, why don’t more people have it?

 

The short answer in the western world of North America and most of Europe, is that more people used to have it, but three developments halted its more rapid spread, and knocked down its numbers dramatically.  First, TB patients were very often quarantined in sanatoriums, cutting down on further person-to-person transmission, although health care workers at those facilities even now have elevated chances.  Second, dairy products overwhelmingly  became sold to the public only after pasteurization – a heating process which kills the bacteria. Cows that tested positive for TB in their milk were often put down or successfully treated with antibiotics until the infection cleared and even the antibiotics that cured them also cleared from appearance in the milk. Third, a number of drugs were developed that knocked down or completely eliminated the Mycobacteria in both humans and livestock. A fourth factor is now clear: some people and animals have an unusual genetic propensity for resisting the disease, while others have heightened genetic susceptibility (Allen et al 2010).

 

Can’t people be easily diagnosed, take their medicines, and get cured?

 

The diagnosis of TB is usual done by a tuberculin skin text (the PPD) and/or chest x-rays. While the PPD is still usually quite reliable, it does give out a small number of false negatives and false positives. One reason for the false positive, is that foreign-born patients may have received doses of BCG vaccine, which triggers this result. These vaccines are commonly used in an attempt to prevent TB in Europe, Africa and parts of Asia, but owing to limited effectiveness, are  rarely used in the US.  Chest x-rays however, seem to be even less useful on close examination than were previously thought (Eisenberg & Pollock 2010), although they are still frequently required as a condition of employment, of  attending college, or joining the military, a practice going back to the times of WWII. More sophisticated tests are constantly being developed, but most are  more expensive and less widely distributed than  their predecessors (see for example Chen et al 2010, Graham 2010,  Idh et al 2010).

 

The real problem with medications is two-fold: Many patients are non-compliant because the course of drug treatment can be months long, and they start feeling better sooner than the mycobacteria are totally eliminated. Patients with the quiescent “latent” form of TB often have no symptoms at all, and only know that they have TB owing to a PPD test, and resent having being forced to take medications, particularly after they are reassured that they are unlikely to be able to give anyone else TB while the disease is in its latent stage……the problem is that a number of other medical crises can precipitate the development of active TB disease, and that they become quite infectious to others and very sick themselves.   While many governments subsidize the cost of these medications, they are  not always free. Furthermore, in western societies, many immigrants of uncertain legality are leery about complying with  government agencies for fear that they will be deported (see for example Kulane, Ahlberg & Berggren 2010).

 

Perhaps an even larger problem is the development of resistance to standard drugs of choice like Isoniazid (INH) and Rifampin (RIF) and a few other analogues that have served us well for several generations. Multiple Drug Resistance (MDR -----resistant to two standard drug types ) and Extensive Drug Resistance (XDR ----- resistant to all four standard drug types) are becoming a problem for hundreds of thousands (Dheda et al 2010, Hasan et al 2010,  Metcalfe et al 2010). Most of these patients will either become stabilized for short periods of time on ever more exotic combinations of drugs taken on a trial basis,  with the hope that their disease reverts to latency. But many more will die.

 

What can be done now?

 

• Immigrants from countries where TB is endemic need to be screened using more sophisticated tests such as the QuantiFERON®-TB Gold (QFT-G), QuantiFERON®-TB Gold In-Tube test (QFT-GIT); and T-Spot®.TB test. They are only moderately more expensive and show good results (Idh et al 2010). These test must be  administered with scrupulous oversight and integrity of recordkeeping in settings that include modern instrumentation (Nkengasong et al 2010). Patients who test positive should be thoroughly treated before being allowed to immigrate. The developed world to which these unfortunate people wish to move must underwrite the higher cost of better diagnosis and treatment as being in its own enlightened self-interest.

 

• As suggested by practical trials in places like Taiwan (Tsai et al 2010), paying patients financial incentives for compliance with long term drug treatments for latent TB may be more effective and cheaper than police pursuit or treating full-blown TB cases that emerge from untreated latent TB.

 

• Drug research into new anti-TB agents must continue apace. (see for example Patel, Khani & Rajani 2010).

 

• Research into treatments for AIDS is in many cases also preventive or concurrent for  dealing with TB, so that advances in one almost always aid the other (Pathak, Wentzel-Larsen & Asju 2010, VanZyl-Smit et al 2010.

 

• Continued vigilance concerning  Mycobacterium bovis in farm animals, farm products and wildlife, is a relatively low-cost means of holding down  to about 60,000 deaths annually this form of TB. Providing the means for  immunizing and treating animals and/or absolute guarantees of compensation for putting down  infected animals are at this time the best that can be done, and barring a foolish abandonment of pasteurization and a generalized return to raw milk products, likely to succeed (see for example Wee et all 2010) and perhaps even reduce those numbers. For an exhaustive overview of this story see the forthcoming Hardin, Crandall & Stankus (2010).

 

• Fundamental research into the cooption of the host  immune system and the drug resistance bacterial genetics of Mycobacteria will likely give us the best long term outcome, while we fight on public health and pharmacological fronts for now (Behar, Devangai & Remold 2010).

 

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

University of Arkansas Libraries MULN 223 E

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Fayetteville AR 72701-4002

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Allan, K. M., E. Murphy, and J. G. Ayres. 2010. Assessment of respiratory health surveillance for laboratory animal workers. Occupational Medicine (Oxford, England) 60 (6) (09): 458-63.

 

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Andersen, B. M., G. Syversen, H. Thoresen, M. Rasch, K. Hochlin, B. Seljordslia, I. Snevold, and E. Berg. 2010. Failure of dry mist of hydrogen peroxide 5% to kill Mycobacterium tuberculosis. The Journal of Hospital Infection 76 (1) (09): 80-3.

 

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Buu, Tran N., Dick van Soolingen, Mai N. T. Huyen, Nguyen N. T. Lan, Hoang T. Quy, Edine W. Tiemersma, Martien W. Borgdorff, and Frank G. J. Cobelens. 2010. Tuberculosis acquired outside of households, rural Vietnam. Emerging Infectious Diseases 16 (9) (09): 1466-8.

 

Cadmus, Simeon I., Victoria N. Okoje, Babafemi O. Taiwo, and Dick van Soolingen. 2010. Exposure of dentists to Mycobacterium tuberculosis, Ibadan, Nigeria. Emerging Infectious Diseases 16 (9) (09): 1479-81.

 

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Chen, Ru, Yingzuo Bi, Guohai Yang, Zhiling Liu, Zhihui Liu, Bijian Zeng, and Tiezhu Tong. 2010. Development of a fluorescent microsphere-based multiplex assay for simultaneous rapid detection of mycobacterium tuberculosis complex and differentiation of M. tuberculosis and M. bovis in clinical samples. Diagnostic Molecular Pathology: The American Journal of Surgical Pathology, Part B 19 (3) (09): 172-9.

 

Das, P., and R. Horton.  2010.  Tuberculosis-time to accelerate progress.  The Lancet 375 (9728):  1755-1756.

de Klerk, Lin-Mari, Anita L. Michel, Roy G. Bengis, Nicolaas P. J. Kriek, and Jacques Godfroid. 2010. BCG vaccination failed to protect yearling African buffaloes (Syncerus caffer) against experimental intratonsilar challenge with Mycobacterium bovis. Veterinary Immunology and Immunopathology 137 (1-2) (09/15): 84-92.

 

De Schutter, Iris, Kinda Schepers, Mahavir Singh, Françoise Mascart, and Anne Malfroot. 2010. Latent tuberculosis in a newborn: Diagnostic challenges. European Journal of Pediatrics 169 (9) (09): 1155-8.

 

Dheda, Keertan, Robin M. Warren, Alimuddin Zumla, and Martin P. Grobusch. 2010. Extensively drug-resistant tuberculosis: Epidemiology and management challenges. Infectious Disease Clinics of North America 24 (3) (09): 705-25.

 

Eisenberg, Ronald L., and Nira R. Pollock. 2010. Low yield of chest radiography in a large tuberculosis screening program. Radiology 256 (3) (09): 998-1004.

Graham, Stephen Michael. 2010. Research into tuberculosis diagnosis in children. The Lancet Infectious Diseases 10 (9) (09): 581-2.

 

Hänscheid, Thomas, and Martin Peter Grobusch. 2010. Biosafety and tuberculosis laboratories in Africa. The Lancet Infectious Diseases 10 (9) (09): 582-3.

 

Hardin, Amy, Philip Crandall & Tony Stankus. 2010. The zoonotic tuberculosis syndemic:  A literature review & analysis of the scientific journals covering a multidisciplinary field that includes clinical medicine, animal science, wildlife management, bacterial evolution & food safety. Science & Technology Libraries, 29 (4): in press.

 

Hasan, Rumina, Kauser Jabeen, Asho Ali, Yasraba Rafiq, Rabia Laiq, Babar Malik, Mahnaz Tanveer, et al. 2010. Extensively drug-resistant tuberculosis, Pakistan. Emerging Infectious Diseases 16 (9) (09): 1473-5.

 

Idh, Jonna, Ebba Abate, Anna Westman, Daniel Elias, Helena Janols, Aschalew Gelaw, Assefa Getachew, et al. 2010. Kinetics of the QuantiFERON((R))-TB gold in-tube test during treatment of patients with sputum smear-positive tuberculosis in relation to initial TST result and severity of disease. Scandinavian Journal of Infectious Diseases 42 (9) (09): 650-7.

 

Jong Lee, Kyung, Young Ae Kang, Young Mi Kim, Sang-Nae Cho, Jin Wook Moon, Moo Suk Park, Se Kyu Kim, Joon Chang, and Young Sam Kim. 2010. Screening for latent tuberculosis infection in South Korean healthcare workers using a tuberculin skin test and whole blood interferon-gamma assay. Scandinavian Journal of Infectious Diseases 42 (9) (09): 672-8.

 

Kolattukudy, P. E., N. D. Fernandes, A. K. Azad, A. M. Fitzmaurice, and T. D. Sirakova.  1997.  Biochemistry and molecular genetics of cell wall lipid biosynthesis in mycobacteria.  Molecular Microbiology 24 (2):  263-270.

 

Kulane, Asli, Beth M. Ahlberg, and Ingela Berggren. 2010. "It is more than the issue of taking tablets": The interplay between migration policies and TB control in Sweden. Health Policy (Amsterdam, Netherlands) 97 (1) (09): 26-31.

 

Ling, Daphne, and Dick Menzies. 2010. Occupation-related respiratory infections revisited. Infectious Disease Clinics of North America 24 (3) (09): 655-80.

 

Lönnroth, K., K. G. Castro, J. M. Chakaya, L. S. Chauhan, K. Floyd, P. Glaziou, and M. C. Raviglione.  2010.  Tuberculosis control and elimination 2010-2050:  Cure, care, and social development.  The Lancet 357 (9728):  1814-1829.

 

Maragou, Chrysoula, Nadia Theologie-Lygidakis, Panayotis Ioannidis, Antonia Stenou, Sophia Kanavaki, Ioannis Iatrou, and Maria N. Tsolia. 2010. Primary tooth abscess caused by Mycobacterium bovis in an immunocompetent child. European Journal of Pediatrics 169 (9) (09): 1143-5.

 

 

Mathew, Trini A, Alan L Shields, Aizhan Imasheva, Sonya S Shin, Sergey P Mishustin, Gennady G Peremitin, Aivar K Strelis, Galina V Yanova, Shelly F Greenfield, and Jennifer J Furin. 2009. Knowledge, attitudes, and practices of physicians in Tomsk Oblast tuberculosis services regarding alcohol use among tuberculosis patients in Tomsk, Russia. Culture, Medicine And Psychiatry 33 (4): 523-537.

 

Marais, Ben J., and H. S. Schaaf. 2010. Childhood tuberculosis: An emerging and previously neglected problem. Infectious Disease Clinics of North America 24 (3) (09): 727-49.

 

Menzies, Heather J., Carla A. Winston, Timothy H. Holtz, Kevin P. Cain, and William Mac Kenzie R. 2010. Epidemiology of tuberculosis among US- and foreign-born children and adolescents in the United States, 1994-2007. American Journal of Public Health 100 (9) (09): 1724-9.

 

Metcalfe, John Z., Elizabeth Y. Kim, Grace Lin S.Y., Adithya Cattamanchi, Peter Oh, Jennifer Flood, Philip C. Hopewell, and Midori Kato-Maeda. 2010. Determinants of multidrug-resistant tuberculosis clusters, California, USA, 2004-2007. Emerging Infectious Diseases 16 (9) (09): 1403-9.

 

Mori, Toru, and Chi Chiu Leung. 2010. Tuberculosis in the global aging population. Infectious Disease Clinics of North America 24 (3) (09): 751-68.

 

Nkengasong, John N., Peter Nsubuga, Okey Nwanyanwu, Guy Gershy-Damet, Giorgio Roscigno, Marc Bulterys, Barry Schoub, Kevin M. DeCock, and Deborah Birx. 2010. Laboratory systems and services are critical in global health: Time to end the neglect? American Journal of Clinical Pathology 134 (3) (09): 368-73.

 

 

Patel, Navin B., Imran H. Khan, and Smita D. Rajani. 2010. Pharmacological evaluation and characterizations of newly synthesized 1,2,4-triazoles. European Journal of Medicinal Chemistry 45 (9) (09): 4293-9.

 

Pathak, Sharad, Tore Wentzel-Larsen, and Birgitta Asjö. 2010. Effects of in vitro HIV-1 infection on mycobacterial growth in peripheral blood monocyte-derived macrophages. Infection and Immunity 78 (9) (09): 4022-32.

 

Reuter, Morgan A., Nicole D. Pecora, Clifford V. Harding, David H. Canaday, and David McDonald. 2010. Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells. Journal of Virology 84 (17) (09): 8549-60.

 

Rock, M., B. J. Buntain, J. M. Hatfield, and B. Hallgrimsson.  2009.  Animal-human connections, "one health," and the syndemic approach to prevention.  Social Science and Medicine 68 (6):  991-995.

 

Rothschild, B. M., and L. D. Martin.  2006.  Did ice-age bovids spread tuberculosis?  Naturwissenschaften 93 (11):  565-569

 

Silin, Muriel, Fabienne Laraque, Sonal S. Munsiff, Aldo Crossa, and Tiffany G. Harris. 2010. The impact of monitoring tuberculosis reporting delays in New York City. Journal of Public Health Management and Practice: JPHMP 16 (5) (2010): E09-17.

 

Silva, Denise Rossato, Diego Millán Menegotto, Luis Fernando Schulz, Marcelo Basso Gazzana, and Paulo de Tarso Roth Dalcin. 2010. Factors associated with mortality in hospitalized patients with newly diagnosed tuberculosis. Lung 188, (1): 33-41.

 

Tsai, Wen-Chen, Pei-Tseng Kung, Mahmud Khan, Claudia Campbell, Wen-Ta Yang, Tsuey-Fong Lee, and Ya-Hsin Li. 2010. Effects of pay-for-performance system on tuberculosis default cases control and treatment in Taiwan. The Journal Of Infection 61 (3) (09): 235-43.

 

van Zyl-Smit, Richard,N., Laurence Brunet, Madhukar Pai, and Wing-Wai Yew. 2010. The convergence of the global smoking, COPD, tuberculosis, HIV, and respiratory infection epidemics. Infectious Disease Clinics of North America 24 (3) (09): 693-703.

 

Wee, Sung-Hwan, Cheol-Hee Kim, Simon J. More, and Hyang Mi Nam. 2010. Mycobacterium bovis in Korea: An update. Veterinary Journal (London, England: 1997) 185 (3) (09): 347-50.

Eggs: Safer for You Than You’d Think Given Recent Stories in the News

They’re recalling  up to 500,000,000 eggs?   Isn’t this an indictment of the U.S. egg industry as a whole?

It might be if that were the total production of the US, but it’s not even close. Last year, according to the U.S. Dept. of Agriculture’s National Agriculture Statistical Service,  the 337, 000,000 laying hens living in the US produced 90,400,000,000 eggs (about 269 eggs per layer, by the way). The recalled number of eggs is less than 1% of the national output, and even among those 500,000,000, it is likely that only a tiny percentage are actually infected. Statistically, the odds are about 1 egg out of 20,000 eggs is infected. ( www.eggsafety.org )

I hear that thousands of people have been made ill from these eggs: what are my chances that I will get salmonella from eating eggs?

As a rule, you are right in thinking that it is possible to get salmonella from eating undercooked eggs, and this is unfortunately one of the most common ways to get salmonella. However the odds are vastly on your  side as opposed to being on salmonella’s. In a 2008 paper (Davis et al, cited below) the odds were given as 1 or 2 people out of 100,000 will get salmonella from undercooked eggs.) This seems a tad too rare, so let’s  divide up the estimated 2010 population of the U.S., 308,000,000,  by the FDA’s estimate that there are 142,000 cases  annually of salmonella caused by eating undercooked  eggs.   This gives you a 1 in 2168  chance of getting undercooked-egg-induced salmonella. That’s cases of illness, not fatalities. Out of this small number, your chances of  actually dying admittedly increase if you are elderly, an infant, or immunocompromised, and pasteurized egg products available to foodservice providers are recommended for venues where large numbers of these groups are served. But remember, the odds of becoming ill or dying from salmonella derived from eggs would be  essentially zero if the eggs were cooked thoroughly, by the way.

What causes this contamination?

A strain of bacteria called Salmonella enteritidis.

Where does that bacterium come from?

It can come from soil, water, or feed, but is found today mostly in poultry manure. It appears to have migrated from rats and mice to poultry a few decades ago. Egg producers and government scientists and health officials have since placed a premium on detecting any signs of rodents in egg producing operations, and in eliminating the vermin, but to some extent the bad genie is out of the bottle. Rodent control still limits the chances of new acute outbreaks of subtypes that have yet to infect layers or show up in eggs.

How does the salmonella get into the egg?

Salmonella enteritidis most commonly lives in the reproductive and intestinal tracts of layers . Eggs are made “inside out” in the sense that whatever pathogens live inside the hen can be transmitted to the eggs growing inside her during egg formation and laying.

Are all parts of the egg equally “dangerous.”

As a practical matter, given that eggs come out of the hen from the same place as her manure, the shell is by far, the most likely part to be contaminated, as it traverses this shared route. This is followed at a great statistical distance  by the egg white, which just happens to have naturally produced inhibitors of the further growth of salmonella (Humphrey & Whitehead 1993) and then, accounting for an  even tinier percentage, would be the yolk.

What do egg producers do to make sure the eggs are safe?

First and foremost, eggs and flocks are tested on a regular basis  and layers known to be salmonella carriers are taken out of production, and their eggs stopped from entering the market.  In some cases, the layers will be given antibiotics until the infection clears. (In other cases, the layers will be destroyed outright.) Any eggs from those layers will be discarded, and even when the infection has passed in successfully treated layers,  the eggs will not be put back into the food supply until the eggs themselves have tested free of antibiotics.

The day-to-day processing of eggs also involves a number of important, practical safety steps. All shell  eggs are thoroughly washed to remove fecal traces. New procedures involving ozone (Perry, Rodriguez-Romo & Yousef 2008), and microwaves (Lakins et al 2008) are being developed as boosters in egg contaminant removal.  Eggs are kept constantly chilled, a seemingly simple step that greatly retards the growth of virtually all bacterial pathogens, including salmonella.

The living conditions of the hens are also continuously inspected and cleaned. The chicken feed and water supply are examined. In all cases of conscientious egg production, the goal is to get the fecal matter away  from the birds and the newly laid eggs as often as possible.

I hear that many US Producers do not vaccinate their hens, while this is done routinely in other countries.  What gives?

A New York Times story headlined “U.S. Rejected Hen Vaccine Despite British Success,” and reported by William Neuman on August 25, 2010, called into question the fact that many U.S. egg producers do not vaccinate their hens in the same way that British egg producers did, virtually eliminating egg-associated salmonella cases over there. But a more careful reading of the story also indicated that the FDA had considered it, but decided that the evidence was not so clear cut as to mandate it nationally. (It’s important to note that the Brits still find salmonella within their hen houses and on the grounds of their farms, and even in some chickens and eggs, and about 500 cases of egg-associated salmonella in humans still crop up annually, although that number   represents a dramatic drop off .) The FDA had  already mandated a number of enhanced hygiene practices on July 9, 2010,  for the egg industry before the outbreak, so it is not as if, the agency has been asleep at the switch. The FDA and the industry’s leading trade organization, the United Egg Producers,  have been partners in safety for decades, according to the FDA’s own  pronouncements.  A recent review of Britain’s success (Snow et al. 2010) cited vaccination as one of the likely reasons, but it also cited washing and disinfecting the hen house, providing cleansing pools of disinfectant  and scrub brushes so that workers could  remove poultry manure from their shoes and boots, using a commercial chicken feed supplier as opposed to a home-grown mixture , and the presence of cats and dogs  to keep the rodent population down as other contributors. While it is not clear whether or not the much larger US egg production facilities use cats and dogs to hunt rodents on site, measure like these are already standard here.

US egg-producing facilities are gigantic and involve caged-birds, and operations like this are banned in Europe,  including within the UK. Will freeing the layers free us from salmonella in their eggs?

According to an  August 25, 2010 column by Angela Wu  in Newsweek entitled “Are Free-Range Eggs Safer: Factory farming has its problems, but evidence is unclear about whether local food is better,”  the story is complicated and the evidence contradictory.  The problem is that the FDA has found salmonella outbreaks at the largest factory farms and at some of the smallest free-range operations, as well as in those mid-sized operations in between. Two pieces of evidence will surprise the back-to-nature enthusiasts: In large caged bird operations, by their very design, manure removal is done more often and much more efficiently: the birds don’t get to soil themselves or the eggs to the same degree. Second, free-range, “pastured” poultry actually has a higher rate of parasitic infections,  so one might wish not to trade the devil you know (salmonella) for the devil you don’t.

Should I give up eating eggs until this is all over?

If you did, you would be giving up one of the most economical, nutritious, and still generally very safe sources of protein, vitamins, minerals, and nutraceuticals. Much wiser might be following the recommendations of a paper by Davis et al 2008, in which they compare common means of cooking eggs at home  in terms of their ability to kill off salmonella (which, ironically because they could not find enough naturally infected eggs, with which to conduct this experiment, they had to go out and artificially infect them). They concluded that hard-boiled, soft-boiled, and eggs poached in dimpled pan suspended over the boiling water and/or steam were safest. Over-easy and scrambled eggs were reasonably safe, with longer cooking times adding to the margin of safety. “Dropped poached eggs,” meaning those let freely slip into simmering boiling or near/boiling water were safe but only if they were immersed for at least  5 minutes. Sunny side eggs, were,  alas, the least safe, although increased cooking time (until the yolk is firmly set) and the use of a pan cover or basting of the yolk with hot cooking oil or grease was thought to be helpful to get the top of the yolk to cook through.

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: 479-575-0966

Fax: 479-409-0021

Almonacid, S., R. Simpson, and A. Teixeira. 2007. Heat transfer models for predicting Salmonella enteritidis in shell eggs through supply chain distribution. Journal of Food Science 72 (9): E508-17.

Davis, A. L., P. A. Curtis, D. E. Conner, S. R. McKee, and L. K. Kerth. 2008. Validation of cooking methods using shell eggs inoculated with Salmonella serotypes enteritidis and Heidelberg. Poultry Science 87 (8): 1637-42.

Gurtler, J. B., and D. E. Conner. 2009. Survival and growth of Salmonella enteritidis in liquid egg products varying by temperature, product composition, and carbon dioxide concentration. Foodborne Pathogens and Disease 6 (5): 561-7.

Humphrey, T.J. & A Whitehead. 1993. Egg age and the growth of Salmonella enteritidis. Epidemiology & Infection. 111: 209-291.

Jones, D. R., and M. T. Musgrove. 2007. Pathogen prevalence and microbial levels associated with restricted shell eggs. Journal of Food Protection 70 (9): 2004-7.

Kretzschmar-Mccluskey, V., P. A. Curtis, K. E. Anderson, L. K. Kerth, and W. D. Berry. 2008. Influence of hen age and molting treatments on shell egg exterior, interior, and contents microflora and Salmonella prevalence during a second production cycle. Poultry Science 87 (10): 2146-51.

Lakins, D. G., C. Z. Alvarado, L. D. Thompson, M. T. Brashears, J. C. Brooks, and M. M. Brashears. 2008. Reduction of Salmonella enteritidis in shell eggs using directional microwave technology. Poultry Science 87 (5): 985-91.

Little, C. L., J. R. Rhoades, L. Hucklesby, M. Greenwood, S. Surman-Lee, F. J. Bolton, R. Meldrum, et al. 2008. Survey of Salmonella contamination of raw shell eggs used in food service premises in the United Kingdom, 2005 through 2006. Journal of Food Protection 71 (1): 19-26.

Murchie, L., Xia Bin, R. H. Madden, P. Whyte, and L. Kelly. 2008. Qualitative exposure assessment for Salmonella spp. in shell eggs produced on the island of Ireland. International Journal of Food Microbiology 125 (3): 308-19.

Musgrove, M. T., J. K. Northcutt, D. R. Jones, N. A. Cox, and M. A. Harrison. 2008. Enterobacteriaceae and related organisms isolated from shell eggs collected during commercial processing. Poultry Science 87 (6): 1211-8.

Perry, J. J., L. Rodriguez-Romo, and A. E. Yousef. 2008. Inactivation of Salmonella enterica serovar enteritidis in shell eggs by sequential application of heat and ozone. Letters in Applied Microbiology 46 (6): 620-5.

Roberts-Witteveen, A., B. A. Campbell, T. D. Merritt, P. D. Massey, C. T. Shadbolt, and D. N. Durrheim. 2009. Egg-associated salmonella outbreak in an aged care facility, New South Wales, 2008. Communicable Diseases Intelligence 33 (1): 49-52.

Snow, L.C., R.H. Davies, K.H. Christiansen, J.J. Carrique-Mas, A.J. Cook & S.J. Evans. 2010. Investigation of risk factors for Salmonella on commercial egg-laying farms in Greta Britain, 2004-2005. Veterinary Record 166 (19): 579-586.

Wu, Angela. 2010. Are free-range eggs safer? Newsweek (August 25, 2010). www.newsweek.com/2010/08/25/are-free-range-eggs-safer-.print.html

Cancer Research & Treatment 2000-2009: A Listing of Some of the Most Cited Articles of that Decade & Highlights of Some of their Findings

By 2005, as expressed in a major review by Adams and Weiner,  it  had become clear that monoclonal antibodies have proven to be one of the most promising of new biological chemotherapies.  That term may seem an oxymoron in the old dichotomy which separated biologicals (such as vaccines derived from sera or killed cells) from chemotherapeutic agents (which were synthesized from common chemicals usually derived from petrochemicals or alcohols). But the new usage indicates that they are derived from cell culture methods and are then chemically stabilized so as to be able to be administered in reliable dosages.) The key to the effectiveness of monoclonal antibodies appears to be their ability dock onto receptors that are needed for cancer cells or tumors to thrive. In doing so, they displace growth factors or hormones, often leading to tumor regression. In addition, monoclonal antibodies often can be used with traditional cytotoxic chemotherapies, or radiation,  without interfering with their effects.

Epidermal growth factor receptors (EGFR) have been found in excess in a number of tumor classes, and drugs targeted against them ( e.g  erlotinib, Tarceva™) have worked with spotty success among some non-small-cell cancers of the lung or pancreas. But there  were no standards for pre-testing tissues to see if the tumors were, in fact, susceptible. This was an omission corrected by an expert panel (Eberhard, Giaccone and Johnson 2008) who were setting up clinical trials and needed to have benchmarks.

One of the happy but still puzzling situations encountered in oncology are a small number of types of  cancers that start out aggressively growing but then spontaneously become self limiting. A 2007 review by Bartek, Bartkova and Lukas discussed the DDR (DNA damage response)  with the idea that a new line of therapy might well involve, instead of trying with limited success to kill off all cancer cells, stimulating surviving cancer cells to initiate this DDR-induced quiescence.

Telomeres and telomerases were profiled in 2008 by the French team of DeCian, Lacroix, Douarre et al,   as representing a good therapeutic target because it is thought that many cancers result from a decrease in the ability of chromosome basically to keep  the ends of their chromosomes (their telomeres)  intact, or at least forestall the rate at which they fray and shrink.

Along similar lines, it was suggested in a 2005 review by Dean, Fojo, and Bates that the resilient pluripotential stem cells we virtually worship in biotechnology  as the hope for replacing many damaged cells and tissues in diseases like Parkinsonism, have a darker side, and it might be warranted to target them in some forms of cancer. The very traits that make them able to survive undifferentiated and less vulnerable, and then  later  to  take on many identities,  tend in cases like hematopoietic cancers (leukemia, lymphoma and multiple myeloma)  to  protect them from being killed during chemotherapy. Those stem cells may contain what the authors call an overabundance of adenosine trisphophate (ABC)  cassettes.  In some cases, ABC cassettes  promote resistance to chemotherapeutic agents by literally pumping them out of the stem cells  which, once the existing cancer cells have been killed off, may replace them as cancer cells, instead of as healthy tissue.

Transforming Growth Factor beta (TGF-beta) is an essential component of normal activities that involve the growth and branching out of healthy human cells into tissues and then into organs. In particular, helps them develop their own localized blood supply to keep them going. A 2005 study by Elliott and Blobe suggests that unfortunately very high levels of TGF-beta are  detectable in early cancer biopsies, and that monitoring these could help in staging cancers, and disrupting them, may cut off their growth.

While CAT scans and MRIs had long  become effective and routine in the diagnosis and staging of cancers, arguably the fastest rising technology of the 2000s  was F18- FDG PET (Fluorodeoxyglucose Positron Emission Tomography). The combination of trace radioactivity and glucose function enable not only a 3D visualization of location, but also provide information on metabolism at the site. According to Fletcher, Djulbegovic, Benjamin et al it served as an excellent tool for initial diagnosis of cancers of the head and neck, pancreas and unknown primary tumors, and was a good measure for scoring the staging or recurrence of breast, colon, esophageal, and other tumors initially diagnosed by other means.

 

Breast Cancer

Given the major advances made in understanding and treating several estrogen receptor (ER) dependent breast cancers, it surprised many that even  as  the decade waned that there was still a great deal of  tumor resistance to the usual hormone receptor blocking therapies. The thinking was that without these hormones having a home at which they could lodge, that the stimulus they provided to further breast tissue growth would be shut down and tumors would shrink and perhaps disappear. But in 2008  Arpino, Wiechman, Osborn and Schiff  explored  how human epithelial growth receptors  (HER)    provided what they termed  “cross-talk” with estrogens in search of a place to go, leading to  alternative pathways for  these  hormones to dock despite the shut down of ER.  This study  led towards further recognition of  an important subtype of breast cancer  ( HER-susceptible) requiring an alternative treatment with  newer drugs like transtuzumab (Herceptin™) to cut off that alternate route.

One of the most effective families of breast cancer chemotherapeutic agents, are the anthracyclines,  with doxorubicin, (Adriamycin™) probably being the best known. Nonetheless one of the most successful new class of breast cancer drugs of the 1980s and 1990s, particularly in the more aggressive breast cancers  have been the taxanes  (historically derived from rather rare yew bark, but now made by semi-synthetic methods that did not endanger the species and have since reduced their costs) . These taxanes were often administered only after the anthracyclines seemed to stop working, and the disease returned.  A 2008 meta-analysis by DeLaurentis, Cancello, D’Agostino et al, demonstrated that a concurrent combination therapy of anthracyclines and taxanes (as opposed to a sequential one) increased the intervals when  patients with  early but aggressive breast cancers patient  stayed in remission and raised their overall survival.

Colorectal Cancer

Testing the character of a tumor to determine the right course of treatment is standard for a wide variety of tumors, and two of the most common are IHC (ImmunoHistoCompatability) complex and its more recently developed competitor FISH (Fluorescent In-Situ Hybridization) are sometimes used for biopsies. In some cases, such as breast and lung cancers, a positive test on the IHC  is automatically sent for confirmation by the FISH, but it is not unknown for the two test to conflict on whether or not a therapeutic  attack based on the biopsy indicating a high level of Epidermal Growth Factor Receptors (EGFR) would be the best course. A 2005 study by Chung, Shia, Kemeny et al determined that no matter whether the IHC test was positive or negative, once a course of a more conventional chemotherapeutic agent such as iriniotecan (Camptesar™) had failed, then progression towards one of the newer EGFR inhibitors, such as cetuximab (Erbitux™) seems warranted, because many IHC negative tumors seemed to have responded to the Erbitux ™ despite that test.

In a 2007 paper Giantonio, Catalano, Meropol et al trialed three courses of treatment for colorectal cancer. One plan involved a traditional cocktail of oxaliplatin (Eloxatin™), Fluouracil (Adrucil™ and Fluoroplex™) and folinic acid (Leucovorin™), a combination known in chemotherapy circles as FOLFOX4. The second plan involved the use of newer anti-angiogenic drug bevacizumtab (Avastin™) on its own. A third plan combined FOLFOX4 and Avastin ™. The Best outcomes came form the addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin. This four-way combination   improves survival duration for patients with previously treated metastatic colorectal cancer, although as with many chemotherapeutic regiments: nausea, hypertension and some rectal bleding were side-effects that had to be managed.

 

Gastrointestinal  Cancer

One of the most common of stomach tumors as the gastrointestinal stromal tumors (the GISTs). GISTs are often  detected only when they become rather large by which time they tend to displace the alignment and sometimes the smooth function of  nearby organs in the area. While usually treated by surgical removal, and often with good results, they have long resisted follow-up chemotherapy. But by 2005, a consensus recommendation of European sarcoma societies had endorsed imatinib (Gleevec™) a drug previously used with some success in chronic myelogenous leukemia,  known to be a disruptor of tyrosine kinase, an enzyme absolutely essential to the progression of the cancer, as a post-surgical treatment.

Cancers of the Head and Neck

In 2008, Argiris, Karamouzis, Raben and Ferris reviewed the current state of sqamous cell head and neck cancer etiology and treatment. Certain traditional contributing factors such as tobacco use and heavy (and often concurrent) alcohol intake remained  at the top of the list, but human papilloma viruses became more and more often implicated, and became formalized as an important subtype. While a variety of traditional chemotherapeutic agents and radiation therapy continued  to be the first line of treatment (Fakhry, Westra, Cmelak et al 2008)  epidermal growth factor receptor inhibitors (e.g. cetuximab, Erbitux™,  showed increasing promise (Bonner, Harari, Giralt et al 2006, Burtness, Goldwasser, Flood et al 2005).   

 

Liver Lancer

In the western world, most liver cancer has been secondary to prolonged alcoholism, but in the Far East, where hepatitis remains especially endemic a substantial number of patients seem to develop it  after chronic viral infection. A  2009 protocol has been reported by Cheng, Kang, Chen et al for the prolonging of life of patients with advanced hepatocellular cancer ,  with a  drug that had previously been shown to have good results against kidney cancers,  sorafenib (Nexavar™). While the life extension offered is still only about  six months, this is an improvement over the 4 months common with placebo, or other therapies in use, with a relatively tolerable incidence of side-effects. 

A greater life extension was achieved in patients with gastroeneteropancreatic cancers. While slow-growing, most patients die within four years. But a radioactively labeled growth stopper, a somatostatin analog called lanreotide (Somatuline™) has extended the life of some patients up to six.

Lung Cancer

Lung cancers have a spotty record in terms of which drugs will lengthen life with the fewest side-effects, and most patients die within a fairly short time despite treatment. But in 2006, Cappuzzo, Hirsch, Rossi et al and in 2008, Hirsch, Herbst, Olsen et al reported that when patients with non-small-cell lung cancer (NSCLC)  had biopsies that included a fluorescent in-situ hybridization (FISH) test of the tissue, those patients who were positive for epidermal growth factor receptors (EGFR) could be treated better with cetuximab (Erbitux™) a drug otherwise used successfully for  colorectal and head and neck cancers. EGFR positive patients  whose treatment included Erbitux™ tended to live eight months longer than patients negative for EGFR treated with  a similar regimen.

Ovarian Cancer

Apart from the  Pap smear early detection method, ovarian cancer  has traditionally been found only when it had become painful, usually at an advanced stage with a  poor prognosis, and an uncertain chemotherapeutic path. In 2008, however, Garcia, Hirte, Fleming et al advanced the idea that a combination therapy of a very traditional (1950s) alkylating agent cyclophosphamide (Cytoxan™) and a newer monoclonal antibody bevacizumab (Avastin™)  that blocked angiogenesis in tumors (cutting off their blood supply) in colorectal cancers had excellent results blocking ovarian cancer recurrences and was well worth further exploration. A 2006 study in the New England Journal of Medicine  by Armstrong, Bundy, Wang et al reported that the use of a combination of some traditional chemotherapeutic agents delivered through differing routes can have significantly different results. As compared with the traditional administration of  paclitaxel and cisplatin via the intravenous route, intravenous paclitaxel plus direct intraperitoneal injections of cisplatin and paclitaxel improves survival in patients with optimally debulked stage III ovarian cancer, by a period of several months to years. This effect held true even though many patients disliked and even discontinued the direct injections owing to greater pain, nausea and other side effects.  The longer after the treatments concluded the more that patients reported that these side-effects dissipated, and in retrospect, seemed to make worthwhile their initial suffering.

Pancreatic Cancer

Pancreatic cancers have a very poor prognosis and most chemotherapeutic strategies have very limited life-prolonging potential. In 2008, Kulke, Lenz, Meropol et al  tried using sunitinib (Sutent™)  a drug that targets VEGF (vascular endothelial growth factors and their receptors) and PDGF (platelet derived growth factors) and which had  previously shown good results in fighting gastrointestinal stromal tumors and in renal cell carcinonoma. It  extended the life of pancreatic cancer patients whose tumors were of the neuroendocrine type for a whole year.  It has shown less promise in dealing with carcinoid tumors of the pancreas, but these began showing good response to somatostatin analogs like lanreotide (Somatuline™) as noted earlier.

Prostate Cancer

Most prostate cancers are slow moving, but certain subtypes become more aggressive and require treatment sooner than the norm. The treatment regimes often  include some combination of surgery, cytotoxic chemotherapy, radiation, and increasingly,  male hormone suppression.  While none of these treatments is without the potential for incontinence and impotence, androgen suppression has the added problem of a certain feminization of features and in some cases cognitive declines, bone thinning and increased cardiovacular risk A 2008 analysis by D’Amico, Chen, Renshaw et al reported  that in a study of 206 men with localized but unfavorable risk prostate cancer,  that androgen suppression did not markedly preserve life notably longer, and might be omitted if its addition to side-effects seemed to onerous for the patient to bear.

Skin Cancer

Melanomas are among the most common cancers, and they can become fatally invasive, if left untreated. Fortunately they can often be cut, frozen or burned off the skin, but the question remains whether or not the melanoma will recur despite what appears to be “clean edges.” Stage III melanomas are fairly advanced, and have a high rate of recurrence,  but there has been no consensus as to the best follow-up after surgical removal, and doing nothing but watchful waiting has been shown to be about as effective as other more aggressive therapies. Eggermont, Suciu, Santinami et al demonstrated in 2008 that a post melanoma removal treatment plan that included pegylated interferon alfa-2b (Peg Intron™) substantially increased recurrence-free survival rates.

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

University of Arkansas Libraries 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

Adams, G. P., and L. M. Weiner. 2005. Monoclonal antibody therapy of cancer. Nature Biotechnology 23 (9) (SEP): 1147-57.

Ajani, Jaffer A., Kathryn A. Winter, Leonard L. Gunderson, John Pedersen, Benson,Al B.,,III, Charles R. Thomas Jr., Robert J. Mayer, Michael G. Haddock, Tyvin A. Rich, and Christopher Willett. 2008. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal - A randomized controlled trial. JAMA-Journal of the American Medical Association 299 (16) (APR 23): 1914-21.

Allegra, Carmen J., J. Milburn Jessup, Mark R. Somerfield, Stanley R. Hamilton, Elizabeth H. Hammond, Daniel F. Hayes, Pamela K. McAllister, Roscoe F. Morton, and Richard L. Schilsky. 2009. American society of clinical oncology provisional clinical opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. Journal of Clinical Oncology 27 (12) (APR 20): 2091-6.

Argiris, Athanassios, Michalis V. Karamouzis, David Raben, and Robert L. Ferris. 2008. Head and neck cancer. Lancet 371 (9625) (MAY 17): 1695-709.

Armstrong, D. K., B. Bundy, L. Wenzel, H. Q. Huang, R. Baergen, S. Lele, L. J. Copeland, J. L. Walker, R. A. Burger, and Gynecologic Oncology Grp. 2006. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine 354 (1) (JAN 5): 34-43.

Arpino, Grazia, Lisa Wiechmann, C. Kent Osborne, and Rachel Schiff. 2008. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: Molecular mechanism and clinical implications for endocrine therapy resistance. Endocrine Reviews 29 (2) (APR): 217-33.

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Scagliotti, Giorgio Vittorio, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, et al. 2008. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. Journal of Clinical Oncology 26 (21) (JUL 20): 3543-51.

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Shepherd, F. A., J. Dancey, R. Ramlau, K. Mattson, R. Gralla, M. O'Rourke, N. Levitan, et al. 2000. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. Journal of Clinical Oncology 18 (10) (MAY): 2095-103.

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Slovak, M. L., K. J. Kopecky, P. A. Cassileth, D. H. Harrington, K. S. Theil, A. Mohamed, E. Paietta, et al. 2000. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: A southwest oncology Group/Eastern cooperative oncology group study. Blood 96 (13) (DEC 15): 4075-83.

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2000-2009: A Quick Review of Progress in Psychiatry & Addictions Treatment Based on Some of that Decade’s Most Cited Papers

Genetic Propensities for Mental Illness in General

The year 2009 saw the emergence of a network of GWAS (Genome Wide Association Studies) of mental illnesses. Cichon, Craddock, Daly et al. reported that taken together, these GWAS will include 59,000 case studies, 7700 family trios, and more than 40 billion genotypes, all done  for the purpose of documenting correlations between diagnosed mental illnesses and specific genetic sequences.

If Mental Illness Makes You Less Fit To Survive, Why Is It that the Numbers of People with Mental Illnesses  Does Not Seen to Be Declining Over the Course of Decades & Centuries?

Nesse & Stearns (2009) supply an  answer to an age-old dilemma in the intergenerational demographics of mental illnesses: If mental illness puts its patients at such a disadvantage evolutionarily when competing against people without mental illness, why don’t the numbers  of the mentally ill in successive  generations decline so that people with mental illness become, for lack of a better word, extinct? They argue that our bodies, including  our minds which function as part of them, are not optimized over the course of evolution for perfection in all things, but rather, primarily in ways that ensure that whatever else happens to us, or is wrong with us, we  persist in striving  to reproduce and pass on our genes. As long as persons with genetic propensities towards various mental illnesses are able to have children that survive to their own reproductive age, genes for mental illnesses and inevitably persons with mental illnesses will reappear again and again. This is not, however, a simplistic call for eugenics, since not all persons with such genes, nor their offspring that have these genes, will become mentally ill. And,  some people with as yet undiscovered genetic propensities will become mentally ill, despite not having anyone in generations near them with a mental illness. Furthermore, as reported by Sweatt (2009) in the journal Biological Psychiatry it is now undeniable that sometimes, even in adults whose brain structure and function is not thought of as being particularly amenable to remodeling,  positive changes in their environments (and yes, even psychotherapy), seem to change their neurochemistry in such a way that the malignant production of adverse proteins or other brain active factors by mental illness genes is offset or silenced, a finding that one would never have found in this journal as recently as ten years ago.  As such, mentally ill patients who go even temporarily into recovery, are also available for reproduction, although  one cannot guarantee that their offspring will experience a similar mental health improving environment.

Accelerating Findings from Basic Science into Treatment Plans for the Mentally Ill

Insel (2009) announced new initiatives in funding  granted by the National Institutes of Mental Health with the idea of translating many, isolated but reliably factual studies from  many different disciplines dealing with mental illnesses,  into coherent  evidence-based protocols which mental health practitioners can apply with some confidence.  Ultimately the NIMH hopes, wherever possible,  that we try  to preempt genetic predisposition to mental illness, or barring that, slow its development or ultimate severity in patients. NIMH funding will also promote the provision of  more widely available clinical services so that the mentally ill are in fact,  as well as in law, treated in a timely manner and  on an equal basis with those with non-mental somatic disorders.

Does the Process of Medical School Education Favor the Development of Empathy in Physicians for their Patients, including the Mentally Ill?

An analysis of the genuine, visceral empathy levels of medical students choosing different medical specialties was measured annually over four years in a class of medical students using a standardized test, the Balanced Emotional Empathy Scale.  While  overall empathy levels scores trended  relentlessly downward compared to class scores at the  start of medical school, even among those students who chose psychiatry as their specialty, a field in which empathy is thought to be crucial, it did so to varying degrees of severity. The process of accelerating empathy erosion over the course of medical school seemed to correlate and perhaps even assist students in sorting out which fields were best for them. Not too surprisingly,  students who  opted for specialties with non-recurring or reduced personal contact with sick patients: most surgeons, radiologists, pathologists, etc., annually typically scored the lowest, while those whose future practices involved a great deal of  personal familiarity  with their patients, such as pediatricians and  primary care providing adult internists generally scored higher. There were some notable gender differences. Most men on entering medical school actually scored well above the norm in empathy on the test, but their empathy levels continued to decline reaching their lowest levels after the third year, while It took women, who generally scored at or only slightly above the norm for empathy upon admission to school, only two years to descend to their empathy nadir.

Schizophrenia:  Progression of Impairments, Treatment, & the Question of Remission

A year 2000 study by Green, Kern, Braff et al pointed out that while deficits in secondary verbal memory, immediate memory, executive function, and the overall ability to pay attention for sustained periods to incoming information are characteristic of the long term outcomes of schizophrenics, the ongoing management of schizophrenic patients, has relied on too few tests and measurements, particularly card sorting. These tests do not tell us as much about abilities at onset as about them at endpoint. The authors argued for the incorporation of more recently developed  tests of cognitive function and indicate that these may well help  measure  progression of disease.   

A year 2000 paper by Manoach, Gollub Benson et al demonstrated that functional magnetic resonance (fMRI) clearly pointed to aberrant activation of the prefrontal cortex and basal ganglia during the performance of tasks involving working memory, explaining part of the results reviewed by Green, Kern and Braff above. In addition, a 2005 paper by Lewis, Hashimoto and Volk characterized   the decline in other cognitive functions in patients with schizophrenia in terms of the failure of TRkB receptors. As receptor function declines, so does the amount of GABA (gamma amino butyric acid)  synthesized within the brain. The loss of cognitive function is gradual because other brain cells try to make up for the GABA shortfall, but ultimately fall  behind, and a certain synchronicity of neuron firing necessary for learning fails more and more often, leading to progressive cognitive decline. 

One of the key problems with the declining physical health of patients with schizophrenia  is that taking their prescribed medications leads a significant number of them to gain weight, develop diabetes, incur cardiovascular problems, and  often develop drooling, facial ticks, tremors, and eccentric gait. (Unfortunately not taking these medications tends to cause a rebound in their symptoms, particularly in psychosis).  It had been hoped that the disadvantages of the first generation antipsychotic drugs (e.g. haloperidol, Haldol™) would be  overcome by so-called second generation medications (detailed in the next study). However a 2006 study in Britain by Jones, Barnes, Davies et al. demonstrated that at least at the one year mark, patients randomly assigned either type had similar rates in Quality of Life measures and in rates of compliance in taking their medications. This put the less expensive first-generation drugs at an advantage, particularly in the UK’s National Health system.

 Whether the 12 month end point was sufficiently long  to determine when American patients typically discontinued taking their schizophrenia mediations , was determined  in part by a  2005 study of 1432 patients randomized  into taking one of four competing “second generation” medicines, published   in the New England Journal of Medicine (Lieberman, Stroup, McEvoy et al).  They exhaustively documented what many clinicians already intuitively surmised: 74% of patients quit taking their prescriptions within 18 months, largely because they felt the side effects were intolerable relative to the benefit they received from them. Patients tended to stay with their medication longest with olanzapine (Zyprexa™), followed by perphenazine (Trilafon™), followed by quetiapine (Seroquel™)  and then by risperidone (Risperdal™). 

A tie breaker in whether or not less expensive first generation drugs should be the first choice was likely exploded by 2005 study by Lieberman, Tollefson, Charles et al. Even after a single course of treatment for a first time outbreak of psychosis, . Haloperidol (Haldol™), the archetypal first generation drug,  significantly decreased  gray matter volume while olanzapine (Zyprexa™), its second generation counterpart,  did not, although a neurochemical pathway that would explain how this shrinkage happened has yet to be discovered..

Along similar lines,  it was strongly recommended  in 2005 by Glassman that schizophrenia patients be assessed for cardiovascular health before so called “atypical anti-psychotic agents” (e.g. ziprasidone, Geodon™)  are prescribed, not because they directly cause torsades de pointes arrhythmias, but because there is an unexplained increase in undiagnosed asymptomatic patients who may have some propensity.

Cross over drugs are becoming far more common in the treatment of schizophrenia. In 2003 Meltzer, Li, Kaneda et al forecast an increase in the use of drugs that dock at multiple categories of receptor sites within the brain (e.g. the so-called 5-HT series in addition to the “D” series) rather than target  just one type. A prominent example discussed was Ariprazole (Abilify™)  which was initially developed for bipolar disorders, and now has not only cross over use for schizophrenia but also major depression. 

In 2005,  Andreasen, Carpenter, Kane et al put forward a set of criteria that could be used internationally to standardize the notion of when a patient might be regarded to be in remission from schizophrenia, as a lack of consistency in what constituted remission made it very hard to determine how often it happened and whether or not rates or patterns differed by treatment plans or geographic and demographic groups. This need was reinforced in 2006 in another influential paper by Van Os, Burns, Cavallaro et al.

Schizophrenia: Heritability & Genetic Markers

Arguably the most influential   paper of the decade  for the systematization of genetic predispositions inclining one towards schizophrenia was by Gottesman and Gould in 2003.  They suggested that a number of criteria be met before a characteristic mental illness or important predisposing physiological factor  could be truly said to be genetic in nature.  The marker or “endophenotype”   being characterized must be clear cut, not of itself, some combination of vaguely  interacting factors.  Ideally,  the endophenotype  should not be based on an overall impression of the patient, but be measurable and recognizable by multiple raters working independently who were looking for that marker, and would not know whether or not the patients had an active mental illness. The endophenotype should be found readily in  other members of the family of a patient with an overt illness whether or not those other family members  overtly  have the illness, and finally the endophenotype should be significantly more common among persons with the illness and their families than in the general population. 

A small scale study of Icelandic families which had members who had schizophrenia seemed to have anticipated the Gottesman  and Gould criteria and localized abnormalities in a high proportion of affected family members in the 8p  chromosome. This gene regulates NRG1 (neuregulin 1) which controls glutamate receptors whose malfunctioning is thought to be a contributor to schizophrenia. This elegant study  included the observation that clozapine, a drug of last resort for severe schizophrenia (owing to cardiovascular and hematological complications) but also a drug possessing a very high degree of effectiveness in the worst cases, specifically works by counteracting  malfunctioning glutamate receptors.

One of  the largest studies  on genetic propensity for schizophrenia was published in 2009 by Lichetenstein, Yip,  Bjork et al in The Lancet.  Using the exhaustively complete medical records of over 2 million families in Sweden, they were able to trace patients with either schizophrenia or bipolar disorder, and compare their mental health with those of their parents, siblings, and children. The authors  were able to chart a direct correlation for the likelihood of developing the disease based on parent-to-child transmission, in the sense that children who had two parents who were both schizophrenic had about double the risk of children who had only one parent so affected, and even this lowered risk was 100 fold the risk in the normal population. This relationship held even when the children were raised apart from their biological parents, negating the notion that environmental factors caused by living in the home with schizophrenic parents are what triggered the child’s schizophrenia. One stunning surprise was that couples with one or both parents having  bipolar disorders had about the same high probability of having children with schizophrenia as they did of their developing bipolar disorder, suggesting that the shared genetic predisposition for two diseases thought to be separate entities may indicate that they are closer in molecular and cellular cause than previously thought.  This finding was a direct challenge to a 2001 postmortem analysis by Rajowska, Halaris and Selemon, of the brains of persons with bipolar disorder  when compared to those of schizophrenics. Bipolar patients have markedly decreased neuronal and glial density when compared to  normals, while schizophrenics have markedly increased neuronal and glial density, relative to both groups. In 2006, evidence for a shared genetic propensity for bipolar disorder and schizophrenia grew even stronger according to a review by Craddock, O’Donovan and Owen.

A 2001 paper in the Proceedings of the National Academy of Sciences demonstrated that in a small but significant number of cases, a common functional polymorphism (i.e. genetic variation) termed Va-108/158-Met that regulated dopamine, was a good predictor of those at risk of some familial forms of schizophrenia (Egan, Goldberg, Kolachana et al).   A 2005 paper by Harrison and Weinberger suggested that seven other susceptibility genes have also  been clearly identified, and that these express proteins that confound the normal cytoarchitecture at the synaptic and other microcircuitry levels.

Schizophrenia:  Correlation Between Imaging Studies and Molecular Theories

Three of the very most cited papers of the decade, particularly by schizophrenia researchers,  were the 2000 study by Ashburner and Friston, and the 2001 reviews  by  Liberman, Chakos, Wu et al and Shenton, Dickey, Frumon et al,  and  the 2008 study by Meisenzahl, Koutsouleris, Gaser et al, in which they reviewed the use of voxel-based morphometry, in which the size of brain structures  and volume of gray matter in the brain is rather precisely imaged and calculated, with the idea of comparing the size volumes of living normals with those diagnosed, or thought to be at risk for, major mental disorders.

Nonetheless, the dominant theory of schizophrenia,  according to Howes & Kapur (2009) continues to be based on errors of dopamine handling by the brain. They argue that a wide array of analyses of risk factors associated with patients who become schizophrenic, including birth defects and in-utero stresses, a history of traumatic experiences, drug abuse, and genomic studies in which dopamine function is also measured,  are now being confirmed by fMRI and PET scans that trace dopamine levels, localization and activation. Ultimately an excess of dopamine activity in the presynaptic  striata appears to cause abnormal cognitive salience, or in lay terms, disproportionate and discordant  (i.e. exaggerated and odd) fixations in one’s paying attention and processing information flowing before the patient from the world outside.

One of the few causation studies of mental illness that did not emphasize heritability and yet attracted significant attention throughout the decade appeared in 2000 in the American Journal of Psychiatry. There,  Kronfol and Remick suggested that while correlations between large molecular weight hormones secreted by specific organs and brain function are increasingly well understood, we have not focused the same attention on brain function and cytokines, lower weight molecular compounds that are produced within cells in many areas of the body (including the brain)  and which effect cell-to-cell communication. They note that most studies of cytokines have  concerned their role in immune responses to infection or cancer, but that, to date,  few researchers have tied the symptoms of mental illness often exhibited by  patients who are flooded with cytokines because they are seriously ill with infections or with cancers, with mentally ill people without these infections or cancer but who display the same behaviors and may have similarly high levels of certain cytokines.

Mood disorders: Theories of Causation

A number of new models for the biological basis of depression, anxiety and bipolar disorder  were introduced during the decade.

In 2000, Jacobs, Praag and Gage put forward a theory that reduced or absent development of new neurons in the dentate gyrus of the hippocampus may be a cause of depression. Their model correlates with  events witnessed in the clinical management of depression. First, stressful episodes in patient’s  lives trigger a flood of stress hormones which reduce neurogenesis  as well as trigger depression. Second,  after successful drug or talk therapy, serotonin levels notably increase and neurogenesis once again resumes.

In 2001,  Pariante and Miller put the focus, instead, on glucocorticoid receptors (GRs) . They argued that patients with major depression have demonstrably  reduced GR function  and note that a number of antidepressants increase GR function, even though this had not been thought of as their primary mode of action.

A 2008 study by Chen, Lawler and Lewis exploded a favored  theory: that genetically determined  BDNF (Brain-Derived Neurotrophic Factor)  levels were the root cause or at least played a significant role in mood disorders, finding no statistically significant correlation.  This contradicted at least in part a heavily cited  2003 study suggesting the opposite by Egan, Kojima, Callicott et al, whose study featured some confirmation in fMRIs. And it failed to account for the 2003 observation by Shi and He that antidepressants reverse the low levels of BDNF in patients who recover from their depression.

Mood disorders: The Centrality of Hypervigilance & the Amygdala

Many more studies of mood disorders like depression, anxiety, bipolar, and even PTSD, in this decade however, focused on what might be regarded as the takeover of the brain’s environmental safety assessment by an overactive or dominant amygdala.

In 2000,  in a functional magnetic resonance imaging study,  Rauch, Whalen Shin et al demonstrated that combat veterans with PTSD patients have markedly higher rates of amygdala arousal to flashed images of fearful faces, than do veterans with similar levels of combat experience without PTSD.  In 2001, Shin, Whalen, Pitman et al extended this work to show via fMRI that anterior cingulate function, which serves to dampen down and manage frightful stimuli, is weak in PTSD combat veterans relative to combat veterans without PTSD.   In 2001 Sheline, Barch, Donnelly et al extended this fMRI study  to patients with major depression, and noted the same exaggerated amygdala stimulation, but these investigators went on to  report that after treatment, their levels of amygdala activation to fearful faces matched those of normal patients.

Functional abnormalities in the “affective chronometry”  of the  amygdala  and prefrontal cortex were pinpointed in a 2002 study of anxiety by Davidson. In patients with high anxiety, coming to a faster conclusion based almost solely on what the amygdala “had to say”  about potential danger  at the expense of  further consideration by the prefrontal cortex,   yielded disproportionally negative judgments, even if it also served to warn them against real threats sooner. In other words the car far down the road might not stop in time; it may even pick up speed,  so let’s not cross the street now and maybe never, because you might get run over. 

This over dependence in anxiety-ridden people on part of the amygdala’s warnings at the expense of reasonable risk taking was to receive some confirmation in 2003,  when Hariri, Mattay, Tessitore et al,  using fMRI were able to observe, by contrast,  the normal conscious modulation by the prefrontal and anterior cingulated cortices of patients viewing angry of fearful images  after the initial  instantaneous unconscious warning firing of the amygdala. In other words, the investigators  were able to see the cycle by which we dampen down our initial response to frightful stimuli by subsequent activation of the brain circuits and  areas involved in processing information and making judgments. 

This  two-track theory of visual information capture and processing was also  in line with a 2002 study by Haxby, Hoffman and Gobbini, which indicated  once again that two different brain circuits were activated for the two roles in processing of human faces, with one circuit  attempting to identify the person based on memory, while the other gauges the “state of mind”  or mood of the person  from noticing facial expressions.

Finally  a  paper late in the decade (Phillips, Ladoucerur and Drevets, 2008) proposed  a similar anatomical theory of bipolar disorder in which two brain circuits, one described as “feedforward” and the other as “feedback”  work simultaneously at cross purposes. Findings from fMRI imaging indicate that anatomic regions of automatic emotion processing (dominated by the amygdale but also including certain pleasure centers) override those of  voluntary emotion management (prefrontal cortex and related areas).

Mood disorders: Treatment

In 2008, Bandelow, Zohar,  Hollander et al proposed a three tiered sequence of drugs of choice for anxiety, obsessive compulsive order and PTSD. Typical serotonin reuptake inhibitors (such as fluoxetine, Prozac™, citalopram, Celexa™, paroxetine Paxil™, sertaline Zoloft™)  represent first choices. Next come serotonin norepinephrine uptake inhibitors (such as velafaxine, Effexor™, desvenlafaxine, Pristiq™, and duloxetine, Cymbalta™). Pregabalin (Lyrica™) is used largely in the US to treat fibromyalgia, and  sometimes recommended as a third choice. Farther down the road are more traditional tricyclics, benzodiazepines, and others.

New World Federation of Biological Psychiatry guidelines were published in 2007 (Bauer, Bschor Pfennig et al.) Based on a systematic review of  treatments for unipolar depressive disorders (i.e. depression) they overwhelming recommend a variety of antidepressants, and in a very small number of sever cases, electroconvulsive therapy, and by contrast in some mild disorders, such as seasonal affective disorder and low intensity depression, light (photo) therapy.

A 2006 study compared two older means of treating patients with major depression with a review to avoiding relapse: an old cocktail of lithium and tricyclics and electroconvulsive therapy (ECT) .  Both worked about equally well, although ECT-treated patients who relapsed had longer intervals before relapse.

A  definitive 2008 meta-analysis of 23 studies involving 1053 patients by Leichsenring and Rabung documented something that many clinical psychologists and social workers have long advocated, despite serious doubts on the part of many in the neuropsychopharmacology field: Long term talk therapy demonstrably improves the lives and well being of  patients with  complex mental disorders including chronic anxiety and depression. In addition they showed that brief, short term psychotherapy, often advocated by insurance companies who find it less expensive, simply does  not have any way near as good a track record with the worst off patients.

A novel and still not widely used (nor FDA-approved for general use) treatment for depression is repetitive transcranial magnetic stimulation (rTMS). Patients who have not had good results using conventional drug therapy or talk therapy are sometimes referred to centers where an electromagnetic device position on top of the head against the hair and scalp essentially sends pulses which appear to depolarize or otherwise alter certain brain circuits.  While most of these devices penetrate only a centime or two, newer models are claimed to get perform this “rebooting” in the deeper limbic system where depression, anxiety, and pleasure centers are thought to be at least partly based. A meta-analysis by Gross, Nakamura, Pascula-Leone & Fregni (2007)  discloses that in contrast with earlier evaluative reviews, which showed modest if still somewhat ambiguous improvement in depressive symptoms, more recent studies have shown a larger antidepressant effect, although by no means a decisive one.

Attention Deficit Hyperactivity Disorder

Even before the onset on the 2000s decade, the pharmacology of ADHD in children seemed greatly advanced by the advent of atomoxetine (Strattera™). By 2003, it had been clearly proven by Michaelson, Adler, Spencer et al. efficacious and nonaddictive  for adults as well.

Addictions: General Theory

The 2000s were a golden era for the appreciation of addicts as  patients more effectively treated based on a better understanding of their altered brain function,  than by moral hectoring about losing their souls.

There was absolutely no shortage of authoritative reviews, most sharing many of the same viewpoints.

In 2001, Bechara, Dolan, Denburg et al   published a video gambling experiment where  alcoholics, speed addicts participated along with two control groups.  The first control group were normals but the second, intriguingly, consisted of  persons with brain damage from accidents, surgeries, strokes or other causes that excluded addictions,  that  was known to be centered on their ventromedial prefrontal cortex, an area  that governs the ability to  foresee  adverse consequences of  high risk actions.   Cards could be drawn from any of  four decks, with the object of accumulating the highest total  points.  The decks differed in their proportions  of point-gaining  and point-penalizing  cards.  Normals quickly learned which decks appeared to have the most penalty cards, and not only avoided drawing from them, but even had a measurable  increase in physiological indicators of  fear or alarm whenever their pointer even got near them on the way towards selecting from the more favorable decks. A significant number of alcoholics and speed addicts, however,  performed exactly like those   patients whose brain damage had eliminated their aversion to  risk. They showed  no fear or physiological alarm indicators when going near and/or selecting from,  descs that carried the highest rates of negative consequences.    

In 2007, Kauer and Malenka, zeroed in on the mesolimbic dopamine system, as a  location where at least in new drug abusers, the drugs literally hijack the firing mechanisms of synapses, resulting in  memories of pleasure that are so intense that new addicts will do whatever it takes to relive them again. However, as far back as 2001,  Drevets, Gautier, Price et al and Volkow and Fowler, and again in 2006, Hyman, Malenka and Nestler, emphasized that long term drug abusers have altered forebrain circuits that processes the experience of drug taking in much the same way that normals process the experience of euphoria upon attaining hard won  rewards (such as  winning an Olympic medal or  getting an 800 on an SAT). They found that even after the ability to obtain a pleasurable experience of getting high or drunk has long been  negated through habituation, and even after dire physical illnesses concomitant with long term drug abuse have taken hold, the orbitofrontal cortex circuits that produce the false feeling of having achieved  something  of consequence continue to function in response to the drugs of abuse and therefore implausibly continue to drive the drug abuse. 

Addictions: Cocaine and Methamphetamines

In 2006, Volkow, Wang, Telang et al published  one of the  more clever tests of cocaine addicted persons to determine who would likely undergo the greatest severity of withdrawal symptoms, and have the highest risk of relapse. It  involved showing the patients videos of  people using drugs versus videos of persons and scenery not involving drug use, while monitoring them with PET (Positron Emission Spectroscopy) for dopamine activity. Those addicts whose dopamine levels were  most radically changed just by viewing the drug use scenes  turned out to be those who would have the greatest difficulty kicking their drugs and have the highest relapse rate. This dopamine dependent result is largely in concurrence with observations made back as 2000 by Robinson and Berridge.

Most adolescent users of marijuana do not become schizophrenics or have frequent hallucinations as adults, but a notable subset with a genetic propensity was finally identified in 2005 by Caspi, Moffitt, Cannon et al.

Addictions: Nicotine

The knowledge of the underlying mechanism of nicotine use, largely through smoking, progressed dramatically, and 2008 was a banner year.

In 2008 Benowitz addressed the issue of whether all smokers have the same likelihood of a genetic linkage to their  nicotine addiction, or whether there were subgroups of smokers that had a greater or less likelihood of an inherited disposition to smoke. He articulated the  notion that situational differences in when  a subject is most likely to be smoking  and the number of cigarettes smoked at that time are not too surprisingly good predictors of those whose addictions which have the strongest genetic  basis.  Those who smoke many cigarettes  during stressful situations or during the use or withdrawal from other drugs or alcohol have the highest inheritability. Those who smoke fewer cigarettes, usually smoke  in the context of  upbeat social situations,  have the lowest inheritability.

 A 2008 study by Gonzales, Rennard, Nides et al. showed that varenicline (Chantix™) was significantly more effective  after either a 12 or 24 week course of treatment than placebo or the hitherto standard prescription, buproprion (Wellbutrin™)..

A 2008 meta-analysis  by Stead, Perera, Mant et al, reported that all over-the-counter  forms of NRT (Nicotine Replacement Therapy) gums, patches, lozenges, inhaler, and nasal spray significantly (50%-70%) reduced rates of quitting smoking.

Finally, Cahill, Stead and Lancaster published a 2008 review which gave a slight advantage for varenicline (Chantix™) over NRT. Interestingly a related drug derived from a number of different plants, cytosine (Tabex™)  has some potential in this area but greater concerns have been expressed over potential side-effects.

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

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Highlights of Medical Research In Clinical Endocrinology & Metabolism with an Emphasis on Diabetes & Obesity: A Quick Survey Based On Some of the Most Cited Papers 2000-2009

A widely cited 2001 review by Atkinson and Eisenbarth set the agenda for diabetes care for the remainder of the decade with a prediction, since borne out, that genetically engineered insulins (particularly glargine, see Lepore et al  2000) and every more accurate and inexpensive glucose monitors would play a significant role in improving the lot of diabetics. Norris, Engelgau and Narayan in 2001 and Bodenheimer, Loring, Holman and Grumbach in 2002 pointed out that patients who had been given significant training in handling the fluctuations in their  chronic disease  on their own, at least in the short run, actually had better outcomes than those who were well-informed but instructed not to make any adjustments independent of their physician’s advice. 

The Causes & Costs of Poor Patient Compliance with Diabetes Management Regimes

Making diabetic patients more self-confident in managing their diabetes may require overcoming some psychological barriers. A 2000 analysis by Ciechanowski, Katon and Russo and a 2001 study by Anderson, Freedland, Clouse and Lustman found that overall, diabetics were twice as likely as nondiabetics to suffer clinical depression. Rates among women and those whose diabetes was poorly controlled were even higher. Not surprisingly, these are the patients with the poorest diets and lowest medication adherence, the cost of whose emergency treatment disproportionately impacted  the overall healthcare budget. Krinsley reported in a 2004 paper in the Mayo Clinic Proceedings that the use of protocol he designed and the set aside of a small number of beds for patients in diabetic crisis, helped mitigate those costs by reducing length of hospital stays in the ICU by 10% , decreased need (19%) for packed red blood cell transfusions,  a 75% reduction in renal failure, and most important, 29% fewer deaths on the floor.

The Longer a Diabetic Lives, the More Important Cardiovascular Care Becomes

 One mixed blessing of the extended lives of diabetics, however,  is that according to major 2002 review by Beckman, Creager and Libby most of them now die of cardiovascular disease, and so as to stave off these for as long as possible, prescription diuretics, ACE inhibitors, statins and anticoagulants should be considered in virtually all cases of adult diabetes management. By 2007, Dahlof et al. reported a major refinement to the traditional mix of blood pressure medications for diabetics , favoring a combination of amlopidine with perindopril as needed over atenolol and bendroflumethiazide as needed.

Diabetes & Metabolic Syndrome

Diabetes research became inextricably linked focused on the tremendous rise in the  numbers of patients with metabolic syndrome, a symptomatic cluster involving  visceral fat deposits around the stomach, high blood pressure, often with a number of circulating markers of  ongoing inflammatory processes.  Patients with metabolic syndrome are extraordinarily prone to type 2 diabetes and heart disease.  In 2003, Park, Zhu, Palaniappan et al reported that a six year survey disclosed that  almost one in four adults in the United States now showed signs of  metabolic syndrome, and in 2005 the American Heart Association and the National Heart, Lung,  and Blood Institute issued comprehensive new guidelines for its diagnosis and management (See Grundy et al). In 2006, Nathan et al published a consensus algorithm for the initiation and adjustment of hyperglycemia for the many new cases of type 2 diabetes emerging.

Diabetes & Inflammatory Processes

 A 2003 review by Fernandez-Real and Ricart provides additional support  for an inflammatory basis for chronic diseases via their survey of the actions of  two proinflammatory cytokines, TNF-alpha (Tumor Necrosis Factor alpha) and IL-6 (Interleukin 6). Both substances turn out to be  heavily involved in both type 2 diabetes, and in atherosclerosis.

A further linkage of diabetes with inflammatory processes at the molecular and cellular level was found in a 2007 study  by Lumeng, Bodzin and Saltiel. They discovered that cells designed to fight off infection in fat tissue, macrophages, undergo an unfavorable  change in their surface polarization  that increases with high-fat feeding. Instead of being protective, they become inflammatory and contribute to insulin resistance, a pattern seen time and again in metabolic syndrome.

The Boom in Genetic Studies of Type 2 Diabetes

While the genetics of type 1 diabetes  have long been very  well understood, the 2000s saw greater insights into type 2 susceptibility, and a contributing cofactor, high triglyceride levels. A vast team headed up by Saxena, Voight, Lyssenko et al analyzed 386,731 genetic variants found among 1464 patients with type 2 diabetes and matched them against an approximately equal number of normals. In a 2007 paper reported in Science, they uncovered significant  six  new variants, five related to the diabetes and one related to the triglyceriedes.

Programmed Cell Death & Diabetes

In 2003, a proposal by Butler, Janson, Bonner-Weir et al  to start targeting the type 2 diabetic’s shortfall in beta cells in pancreatic tissue, by reducing the premature and excessive apoptosis (natural cell death)  gained traction as a pro-active measure, since stopping their death seemed a better strategy than just trying to compensate for it after the fact.

Obesity: An Increased Emphasis on Childhood & Adolescence

A 2005 review in The Lancet by Haslam and James set the stage for the rest of the decade: Adult and childhood obesity had now become the sixth most common disease worldwide. A 2006 analysis by Wang and Lobstein reported that after reviewing results  from 25 countries, that obesity among school-aged children  increased between 1980 to 2010 in 23 of 25 countries, the exceptions being Russia and to some extent Poland, during the collapse of state socialism and the current market economies. A contrarian view was reported in a 2008 study by Ogden, Carroll & Flegal. The increase in the prevalence of high BMI for age among US children that was previously seen in large-scale US surveys between 1988-2004 was not observed between 2003-2004 and 2005-2006. Even at the highest BMI for age level, no change in prevalence was found between 2003-2004 and 2005-2006, either overall or by racial/ethnic group. In other words, we have a lot of fat kids, but their numbers are not growing as fast as earlier professional and popular media reports suggest.

In 2007, an expert committee of specialists in childhood obesity, headed by Sarah Barlow,  substantially revised their guidelines for the diagnosis and management of  the condition in children and adolescents, devising a four step program with the hopes of arresting the condition before it carried over into adulthood.

Weight-Loss Surgery

A 2007 analysis in the New England Journal of Medicine (Adams, Gress, Smith et al)  demonstrated that patients who had undergone gastric bypass surgery dramatically decreased their risk of dying from diabetes, heart disease and cancer, relative to matching groups of obese persons not having the surgery and against normals who had surgeries other than bypass. Also in 2007, a Swedish study in the New England Journal of Medicine (Sjostrom, Narbro, Sjostrom et al) compared roughly 4,000 obese patients, half of whom had weight loss surgery while the other half had treatment involving counseling, dieting and exercise. Patients who had gastric bypass, vertical-banded gastroplasty, or banding did significantly better in the ensuing years. While 13 would go on to die of heart disease, and 29 fell to cancer, those treated with more conventional methods had a greater number of deaths from both heart disease (25) and cancer (47). The researchers highlight the fact that those nutritionally counseled, who dieted and exercised ultimately weighed plus or minus two percent of their original obese level weight.

Fat-Bypass Drugs

Nonetheless, there is still a ray of hope for patients (typically women) who would prefer to try one of the fat-bypass drugs, such as orlistat (beter known by its trademarked names of prescription strength= Xenical, over-the-counter = Alli )  on the market as well as a reduced calorie diet, as opposed to by-pass surgery. A 2009 Turkish study by Ulusoy et al shows a clear cut improvement in cardiovascular risk factors and cardiac function.

Obesity as a Social Contagion

An intriguing hypothesis was put forward in 2007 by Christakis and Fowler: That obesity was a kind of contagious  social disease. Their observation of 12,067 members of the Framingham Heart Study showed that not only did non-obese siblings subsequently increase their chances of becoming obese  (+40% ) if  a sibling subsequently became obese, but also if they married  (+37%) or befriended (+57%) a person who became  obese.  While the data that supports this conclusion is unassailable, implementation of  its practical preventive follow-up, viz. ostracizing fat people, seems unlikely to gain widespread support.

The Genetics of Obesity

A more conventional insight into the roots of obesity  was found in the 2007 papers of Dina, Meyre, Galina et al, Frayling, and Frayling, Timpson, Weedon et al. They reported that variations in FTO  (fat mass and obesity associated) genes not only predict 22% of the increased of obesity in children and adults of European ancestry but also tie in with conditions leading to type 2 diabetes. An even more extensive analysis, also in 2007, by Scuteri, Sanna, Chen et al found genetic markers that tied in with BMI (body-mass index) numbers, hip circumference, and overall body weight. 

Are Your Gut Microbes Making You Fat? Or Is Your Being Fat, Making Better Microbes Leave Your Colonic Neighborhood?

A 2006 theory published in two papers by Nature by Ley, Turnbaugh, Klein and Gordon, and Ley, Turnbaugh, Mahowald et al, that sounded  absurd, but which gained a great deal of evidence to support it is that obese people have intestinal microflora -----notably a higher ratio of firmicutes----- that promotes obesity, while thin individuals have intestinal microflora -------notably a higher ratio of bacteroidetes------that actually promotes leaness. The mechanism by which bacteria alter the body’s intake of nutrients  is not unlike that of the cow with its abundance of microbes in its four-chambered stomach, excepting that instead of having the bacteria primarily processing cellulose from grass,  hay or grains  so as to make it a bioavailable  energy source with trace amounts of protein and fat, bacteria in the human intestines like the firmicutes excel in extracting fats from the passing food stream for deposition in the human body.  Turnbaugh, Hamady, Yatsunenko et al would subsequently provide a 2009 refinement of the theory: The difference between lean and obese individuals in terms of their gut microflora is that the obese have a far less diverse array of bacteria, rendering  the earlier observation of an imbalance in favor of firmicutes, accurate but incomplete because the remaining population of non-firmincutes which are not bacteroides, is also sparse, and symptomatic of a genuine lack of species richness.

Other Issues in Metabolism: Fasting Blood Tests & Tests of Body Fluids in General

A cardinal practice, the use of a fasting period before  measurement of blood chemistry, particularly of triglycerides, came under close scrutiny. Based on the observation that postprandial triglycerides are typically elevated relative to fasting levels, and that it is exactly this elevation that might contribute the most to heart disease, Bansal, Buring, Rifai et al studied a group of approximately 27,000 women, who had triglyceride tests of either type, with some of either type of test takers  subsequently having had heart attacks. Those whose triglyceride tests were taken after meals, and who showed  a high triglyceride level, were, in retrospect,  by far  more likely to have a subsequent heart attack,  making postprandial tests a superior prognostic  indicator. The heart attacks of fasting-triglyceride-test- taking women  were not predicted any way nearly as  often  because these tests essentially gave a false-negative results that  did not show that tell-tale  spike in triglycerides. 

In 2007 Wishart, Tzur, Eisner et al announced the construction of the HMDB, the Human Metabolome Database, a searchable online resource,  reporting on the properties and range of concentrations in bodily fluids of over 2000 human metabolites derived from scans of the existing scientific literature. The collection includes a great many linkages to genetic data, related enzymes, disease associations, and spectroscopic profiles.

Does Red Wine Really Help Your Obesity, Cholesterol, Triglycerides?

A 2006 laboratory animal study in Cell by Lagouge, Argmann, Gerhart-Hines et al, provided a significant ray of hope for the ingestion of resveratrol, a compound widely associated with red wines and the French advantage in longevity and lower cardiovascular disease, despite a diet rich in saturated fats and cholesterol. While claims that its efficacy in humans is clear cut and that it extends the life of all creatures are still unproven, it does have a high degree of potential in delaying the onset of Metabolic Syndrome, and has been shown to reduce the development of beta-amyloid plaques found in Alzheimer’s Disease

Post-Menopausal Bone-Loss Breakthroughs

Treatment for post menopausal bone loss saw its greatest advance in a 2007 paper in the New England Journal of Medicine by Black, Delmas, Eastell et al. Zoledronic acid, an IV-administered  medicine to fight the loss of bone in certain cancers and in Paget’s Disease  (and for those purposes marketed  under the trade name Zometa) was approved for the more common condition of the prevention of limb or joint breakage owing to bone thinning and weakening in women in their 50s and above. While it was later shown to be strongly counterindicated in patients with kidney disease and certain  jaw bone or dental problems, its once-a-year administration under the trademarked brand name Reclast, has proven to be of significant benefit, even for women who have already had a fracture.

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

University of Arkansas Libraries MULN 223 E

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