SLA Biomedical & Life Sciences Division Blog

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

Octopus Behavior, Intelligence, Learning, Personality, Problem Solving & Consciousness

In a German aquarium this summer, Paul the Octopus, successfully picked the winner of 2010 FIFA World Cup soccer matches being held in South Africa  eight times in a row, including correctly noting an upset win by Serbia over Germany, but then subsequently predicting Germany’s rebound to winning ways until eventually Germany lost to Spain, the ultimate world cup winner, an outcome Paul had also predicted. Click on the following for a picture of Paul and a story entitled “Germany's 'Octopus oracle' keeps perfect record,”  on the official FIFA website.

www.fifa.com/worldcup/news/newsid=1270308/index.html

Paul’s method of prediction was to select a clam from  one of two underwater boxes in one of two adjacent tanks. Each tank was labeled with the national flag of one or the other of opposing soccer teams.  Confounding logic, many German fans felt that the pregame choice by the octopus somehow subsequently caused Germany’s defeat, and monitors of German Internet usage showed heightened activity related to  researching octopus recipes. The Prime Minister of Spain, in response, promised to send his nation’s equivalent of the US Secret Service to guard Paul and keep him from becoming someone’s dinner. The Russians, out of contention for the World Cup early on, demonstrated greater common sense. The state-supported gaming industry offered 100,000 euros for Paul’s services so as to enable them more scientifically to set odds in international sporting contests. The aquarium,  in reaction to all this, announced that Paul would now be going into retirement from sports prognostications, and perhaps would begin a career as a teacher of other young octopuses. This would seem ludicrous, excepting that there have been some papers, in journals as prestigious as Nature,  that indicated that octopuses can learn from one another, just by watching the trial and error procedures of one of their kind (Fiorito & Scotto 1992) .  Could a weekly column in Sports Illustrated or pr pre-game appearances on ESPN be in the works?  Or perhaps has Paul the Octopus all his hands full already.

How Smart Are Octopuses?

There is a general consensus that octopuses are the smartest of invertebrates, and indeed, they may be smarter than many vertebrates. They can negotiate mazes, and retain a memory of successful vs. blocked pathways (Hvorecny et al 2007). The can learn the location of a suitable hideaway in an experimental tank, be  transferred from the tank to another for a week, and then instantly find the hideaway in the original tank when they are returned to it.  Should this hideaway be closed to them, the octopuses  can then be taught a new hideaway’s location, and retain a subsequent memory of it (Boal et al. 2000).

Octopuses have definite favorites in the types of clams or mussels they eat, but it is conditional, with the principal determinant being the degree of difficulty in getting the shell opened or otherwise penetrated (Anderson & Mather 2007).  In a three way choice, the easiest to open bivalves were consistently the most eaten, the next easiest to open were second, and the most difficult to open were last. However, food preferences for these same octopuses flipped when all three bivalves were presented in equal numbers in an already-opened state. One of the more difficult-to-open species became the new favorite. However, when ordinarily easy-to-open clams or mussels are glued and wired shut experimentally, octopuses once again shift their preferences in order to minimize effort. What’s important is that they appear to generalize from initial trials in each round of changed circumstances. When they encounter types that they find that are hard to open in a particular round, they avoid them subsequently during that round, saving their energy by redirecting their foraging to easier types.

To bolster the argument for octopuses making conscious adjustments and generalizing knowledge from specific examples, it was found that octopuses switched strategies for getting at the actual meat in a clam or mussel: sometimes pulling the shell apart, sometimes smashing the shell, sometimes drilling through the shell and at other times chipping away at the shell’s rim. All of these represented shifts in tactics to difficulties encountered.  When one method did not work for a particular species of clam  or mussel, another method might be tried, and once one method proved to be the right tactic for a particular species, that  method of penetration became associated with that species. Indeed, in a final grace note to the argument, octopuses apparently learned to target where to drill their holes so as to get to the most vital internal organs of the clam or mussel most directly, so that their  subsequent injection of poison would cause the shellfish to open up most quickly.

Can Octopuses Use Tools?

One popular video currently making the rounds  on YouTube, entitled “Coconut-Carrying Octopus” www.youtube.com/watch?v=1DoWdHOtlrk and backed by a scientific article in Current Biology  (Finn, Tregenza & Norman 2009) shows that octopuses “claim” coconut shells that have been split apart as part of copra processing and been cast into the sea. They have developed a way of stilt walking across the ocean floor with the shell hanging beneath them, so as to transport the half-shells rather long distances to a preferred site, and then fashioned them into rather safe shelters. 

Some critics have argued that the use of “found objects” like these shells is not the same as fashioning them into tools, but they have yet to explain away the peculiar habit of octopuses for quite literally playing with Lego toys in aquaria (Kuba et al. 2006) . These toys are in no way food-like objects, nor do they represent  prey or serve as practice dummies for hunting. In fact, they resemble nothing in their natural environment, and yet, they become objects of continuing interest in both adult and juvenile octopuses. Octopuses have even  learned on their own, how to unscrew jars and bottles.

“Hand-Eye”  Coordination & Specialization within the Octopus Brain

One of the relatively recent findings in studies of octopus capabilities is the fact that although they do not have specialized tentacles like squid for trapping prey, they do develop special abilities within their otherwise anatomically identical legs or arms, and that this seems to be done in conjunction with having a favored eye they use for specific tasks. In a series of papers (Byrne, Kuba & Meisel 2004, Byrne et al 2006a, 2006b) it was clearly shown that octopuses have a preferred eye that they use more often than its opposite counterpart, and this seems to correlate with tasks routinely assigned to a given arm or set of arms. Anterior arms were used to probe and reach out for novel objects. Octopuses also seemed to favor a particular arm when trying to negotiate a maze. Moreover some octopuses used different legs or arms for sidewise motion, versus back and forwards, despite the fact that it would take little energy to rotate their bodies and choose a different sequence. This all points to an eye-to-brain-to-arm (or leg) circuitry that indicates that the octopus is capable of designating particular parts of their very large brains to serve differentially, specific functions, much as mammals do.

Do Octopuses Have Distinct Personalities Or Temperaments?

There have been many proponents of the theory that individual octopuses do, in fact, have different personalities. The most vocal in support of this notion are the many aquarium personnel who have observed that some octopuses of the same species are aggressive and easy to anger, while others are shy and gentle. Some are quick learners  who love to play while others are  seemingly annoyed by changes in routine and defensive about new objects in their watery domains. Some come out from hiding in their aquarium tanks to look right back at the people who are looking at them. Some get along with other octopuses in large tanks while others view  others of their kind as intruders that have to be put in their place.  Most remarkable are octopuses who habitually break out of their own tanks, traverse the floor to another tank they have been eyeing, enter that tank, and consume all the crabs or clams to be had there, before moving on to another tank or returning to their assigned one.

By far, the most heavily published of experts in areas of octopus intelligence, behavior and temperament is the Canadian researcher Jennifer Mather of the University of Lethbridge, in Alberta,  ironically  a  province that does not even have access to an ocean (She has repeatedly acknowledged the generous access she has been granted over the years to the Seattle Aquarium). This landlocked academic appointment has not stopped her from making the case rather convincingly that individual octopuses develop their personalities or temperaments over time, that genetically related octopuses tend to have similar behavioral traits, and that  at least some  invertebrates, particularly the category of cephalopods (octopuses, squid and cuttlefish) which have very large brains, use them to explore their environments in a conscious manner,   solving  problems, and building  a memory bank of experiences on which they will depend to improve their lives…….and yes, to have a little fun, now and again.

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 USA

Voice: 479-409-0021

Fax: 479-575-4592

 Anderson, Roland C., and Jennifer A. Mather. 2007. The packaging problem: Bivalve prey selection and prey entry techniques of the Octopus enteroctopus dofleini. Journal of Comparative Psychology 121 (3) (08): 300-5.

Boal, Jean Geary, Andrew W. Dunham, Kevin T. Williams, and Roger T. Hanlon. 2000. Experimental evidence for spatial learning in octopuses (Octopus bimaculoides). Journal of Comparative Psychology 114 (3) (09): 246-52.

Byrne, Ruth A., Michael J. Kuba, and Daniela V. Meisel. 2004. Lateralized eye use in Octopus vulgaris shows antisymmetrical distribution. Animal Behaviour 68 (5) (11): 1107-14.

Byrne, Ruth A., Michael J. Kuba, Daniela V. Meisel, Ulrike Griebel, and Jennifer A. Mather. 2006. Does Octopus vulgaris have preferred arms? Journal of Comparative Psychology 120 (3) (08): 198-204.

Byrne, Ruth A., Michael J. Kuba, Daniela V. Meisel, Ulrike Griebel, and Jennifer A. Mather. 2006. Octopus arm choice is strongly influenced by eye use. Behavioural Brain Research 172 (2) (07): 195-201.

Byrne, Ruth A., Michael Kuba, and Ulrike Griebel. 2002. Lateral asymmetry of eye use in Octopus vulgaris. Animal Behaviour 64 (3) (09): 461-8.

Cheng, Mary W., and Roy L. Caldwell. 2000. Sex identification and mating in the blue-ringed octopus, Hapalochlaena lunulata. Animal Behaviour 60 (1) (07): 27-33.

Edelman, David B., Bernard J. Baars, and Anil K. Seth. 2005. Identifying hallmarks of consciousness in non-mammalian species. Consciousness and Cognition: An International Journal 14 (1) (03): 169-87.

Finn, J.K., T.Tregenza & Mark D. Norman. 2009. Defensive tool-use in a coconut-carrying octopus. Current Biology 19 (23): R1069-R1070.

Fiorito, Graziano; and Pietro Scotto. 1992. Observational learning in Octopus vulgaris. Science. Vol. 256(5056), 545-547.

Glanzman, D.L. Octopus conditioning: A multi-armed approach to the LTP- learning question. Current Biology 18 (2): R527-R530.

Gosling, Samuel D., and Oliver P. John. 1999. Personality dimensions in nonhuman animals: A cross-species review. Current Directions in Psychological Science 8 (3) (06): 69-75.

Hochner, Binyamin, Euan R. Brown, Marina Langella, Tal Shomrat, and Graziano Fiorito. 2003. A learning and memory area in the octopus brain manifests a vertebrate- like long-term potentiation. Journal of Neurophysiology 90 (5) (11): 3547-54.

Huffard, Christine L., Roy L. Caldwell, and Farnis Boneka. 2010. Male-male and male-female aggression may influence mating associations in wild octopuses (Abdopus aculeatus). Journal of Comparative Psychology 124 (1) (02): 38-46.

Hvorecny, Lauren M., Jessica L. Grudowski, Carrie J. Blakeslee, Tiffany L. Simmons, Paula R. Roy, Jennifer A. Brooks, Rachel M. Hanner, et al. 2007. Octopuses (Octopus bimaculoides) and cuttlefishes (Sepia pharaonis, S. officinalis) can conditionally discriminate. Animal Cognition 10 (4) (10): 449-59.

Ikeda, Yuzuru. 2009. A perspective on the study of cognition and sociality of cephalopod mollusks, a group of intelligent marine invertebrates. Japanese Psychological Research 51 (3) (09): 146-53.

Kuba, Michael J., Ruth A. Byrne, Daniela V. Meisel, and Jennifer A. Mather. 2006. When do octopuses play? Effects of repeated testing, object type, age, and food deprivation on object play in Octopus vulgaris. Journal of Comparative Psychology 120 (3) (08): 184-90.

Mather, Jennifer A. 2008. Cephalopod consciousness: Behavioural evidence. Consciousness and Cognition: An International Journal 17 (1) (03): 37-48.

Mather, Jennifer . 2006. Behaviour development: A cephalopod perspective. International Journal of Comparative Psychology 19 (1): 98-115.

Mather, Jennifer A., and Roland C. Anderson. 1999. Exploration, play, and habituation in octopuses (Octopus dofleini). Journal of Comparative Psychology 113 (3) (9): 333-8.

Mather, Jennifer A., and Roland C. Anderson. 1993. Personalities of octopuses (Octopus rubescens). Journal of Comparative Psychology 107 (3) (09): 336-40.

Mather, Jennifer A. 2008. To boldly go where no mollusk has gone before: Personality, play, thinking, and consciousness in cephalopods. American Malacological Bulletin 24 (1/2): 51-58.

Meisel, Daniela V., Ruth A. Byrne, Michael Kuba, Jennifer Mather, Werner Ploberger, and Erhard Reschenhofer. 2006. Contrasting activity patterns of two related octopus species, Octopus macropus and Octopus vulgaris. Journal of Comparative Psychology 120 (3) (08): 191-7.

Minakata, H., S. Shigeno, N. Kano, S. Haraguchi, T. Osugi, and K. Tsutsui. 2009. Octopus gonadotrophin-releasing hormone: A multifunctional peptide in the endocrine and nervous systems of the cephalopod. Journal of Neuroendocrinology 21 (4) (04): 322-6.

Shomrat, T. I. Zarrella, G. Fiorito, & B. Hochner. 2008. The octopus vertical lobe modulates short-term learning rate and uses LTP to acquire long-term memory. Current Biology 18 (5): 337-342.

Sinn, David L., Nancy A. Perrin, Jennifer A. Mather, and Roland C. Anderson. 2001. Early temperamental traits in an octopus (Octopus bimaculoides). Journal of Comparative Psychology 115 (4) (12): 351-64.

Wood, James B., and Roland C. Anderson. 2004. Interspecific evaluation of octopus escape behavior. Journal of Applied Animal Welfare Science 7 (2): 95-106.

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.

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Roach,Mack,,III, Gerald Hanks, Howard Thames Jr., Paul Schellhammer, William U. Shipley, Gerald H. Sokol, and Howard Sandler. 2006. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO phoenix consensus conference. International Journal of Radiation Oncology Biology Physics 65 (4) (JUL 15): 965-74.

Ross, Jeffrey S., Christos Hatzis, W. Fraser Symmans, Lajos Pusztai, and Gabriel N. Hortobagyi. 2008. Commercialized multigene predictors of clinical outcome for breast cancer. Oncologist 13 (5) (MAY): 477-93.

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Roukos, Dimitrios H. 2008. Innovative genomic-based model for personalized treatment of gastric cancer: Integrating current standards and new technologies. Expert Review of Molecular Diagnostics 8 (1) (JAN): 29-39.

Saltz, L. B., N. J. Meropol, P. J. Loehrer, M. N. Needle, J. Kopit, and R. J. Mayer. 2004. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. Journal of Clinical Oncology 22 (7) (APR 1): 1201-8.

Sandler, Alan, Robert Gray, Michael C. Perry, Julie Brahmer, Joan H. Schiller, Afshin Dowlati, Rogerio Lilenbaum, and David H. Johnson. 2006. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New England Journal of Medicine 355 (24) (DEC 14): 2542-50.

Sarbassov, D. D., S. M. Ali, S. Sengupta, J. H. Sheen, P. P. Hsu, A. F. Bagley, A. L. Markhard, and D. M. Sabatini. 2006. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell 22 (2) (APR 21): 159-68.

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.

Schiller, J. H., D. Harrington, C. P. Belani, C. Langer, A. Sandler, J. Krook, J. M. Zhu, D. H. Johnson, and Eastern Cooperative Oncology Grp. 2002. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New England Journal of Medicine 346 (2) (JAN 10): 92-8.

Sequist, Lecia V., Renato G. Martins, David Spigel, Steven M. Grunberg, Alexander Spira, Pasi A. Jaenne, Victoria A. Joshi, et al. 2008. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. Journal of Clinical Oncology 26 (15) (MAY 20): 2442-9.

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

University of Arkansas Libraries MULN 233 E

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Insel, Thomas R. 2009. Translating scientific opportunity into public health impact A strategic plan for research on mental illness. Archives of General Psychiatry 66 (2) (FEB): 128-33.

Jacobs, B. L., H. Praag, and F. H. Gage. 2000. Adult brain neurogenesis and psychiatry: A novel theory of depression. Molecular Psychiatry 5 (3) (05): 262-9.

Jaffee, S. R., and T. S. Price. 2007. Gene-environment correlations: A review of the evidence and implications for prevention of mental illness. Molecular Psychiatry 12 (5) (MAY): 432-42.

Jones, Peter B., Thomas R. E. Barnes, Linda Davies, Graham Dunn, Helen Lloyd, Karen P. Hayhurst, Robin M. Murray, Alison Markwick, and Shon W. Lewis. 2006. Randomized controlled trial of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia - cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Archives of General Psychiatry 63 (10) (OCT): 1079-U6.

Kauer, Julie A., and Robert C. Malenka. 2007. Synaptic plasticity and addiction. Nature Reviews Neuroscience 8 (11) (NOV): 844-58.

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Lewis, D. A., T. Hashimoto, and D. W. Volk. 2005. Cortical inhibitory neurons and schizophrenia. Nature Reviews Neuroscience 6 (4) (APR): 312-24.

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Lieberman, J. A., T. S. Stroup, J. P. McEvoy, M. S. Swartz, R. A. Rosenheck, D. O. Perkins, R. S. E. Keefe, et al. 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine 353 (12) (SEP 22): 1209-23.

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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

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Ebola and Marburg: Two Closely Related, Highly Lethal Viruses that Cause Hemorrhagic Fever in Africa and May Still Be Being Sought By Terrorists and Rogue States To Weaponize and Attack Anywhere

Two of the most dreaded illnesses in the world are Ebola and Marburg. The names for these syndromes involves some medical geography;   in the first case, a river in Uganda (the Ebola) and in the second,  a city in Germany (Marburg),  where each of these hemorrhagic fevers was first detected in human patients.   

What is a hemorrhagic fever?

Hemorrhagic diseases are, by definition, characterized by profuse bleeding, internally or externally, and often both ways, and both Ebola and Marburg certainly qualify, although the panoply of other accompanying signs varies. (For a complete roster of possible symptoms, see Pittalis et al 2009 below )   Both Ebola and Marburg, are, however, in the early stages, primarily characterized by fever, exhaustion, and confusion in the patient. The hemorrhagic aspect is more obvious only in later stages.  Patients may develop dark-blister-like growths on their face and body where blood has pooled from broken capillaries.  They may then begin bleeding from the mouth, eyes, or ears. They almost always develop breakdowns in coagulation that leads to multiple sites of internal bleeding in a number of organs, leading further to localized tissue destruction. Eventually, the overall loss of sufficient internal blood supply can lead  to shock and death. Fortunately for the patients suffering, they often die only after they have gone into a coma.

How lethal are these two diseases?

While there are some less deadly strains (“Sudan” and “Bundibugyo” see Gupta et al 2010 below), Ebola and Marburg  kill off as high as 90% of infected patients, usually within three weeks of their contracting the responsible virus. The remaining patients of course, recover, although it is not always certain why they did so, when so many others have died.

From where did these diseases come?

They really both come from Africa, and all major outbreaks, and most individual cases, almost always are found there only, except  for patients  traveling to more developed countries seeking  diagnosis or treatment,  and medical researchers working with the virus in western countries. In addition to Uganda, Ebola has primarily broken out in Gabon, Sudan, and the Congo, with isolated cases elsewhere, including South Africa.  That Marburg is connected with a town in Germany has to do with laboratories there that make vaccines. (Two other European outbreaks  are based on similar circumstances.)  Lab workers  in Marburg  had routinely been importing  African green monkeys, but eventually unawares took in an infected  shipment which  gave this new disease to their handlers and research scientists.  Natural, as opposed to laboratory,  outbreaks of Marburg have occurred primarily  in Angola, Congo, Kenya, South Africa and Zimbabwe.

If this disease is so deadly, why hasn’t it already wiped out large portions of sub-Saharan Africa?

The disease breaks out most often in very isolated parts of the particular countries involved. There tends to be a steeply rising number of local cases for  several weeks to a few months, with a corresponding crescendo of deaths, and then a tapering off, with higher survival rates among later contractors of the virus. It is absolutely clear that quarantining patients and observing extreme measures to protect health providers, other patients and any family visitors, from contact with infective fluids, etc. is prudent and has done much to restrain the spread of outbreaks.  But Ebola and Marburg, often disappear altogether from a region as suddenly and unexpectedly as they erupted.

Avoidance strategies

Avoidance of Ebola and Marburg is much like avoiding running out of doors when there is a lightning storm.  It’s a very good idea, but of itself does not confer immunity. Avoidance does not seem to protect you from getting the disease unexpectedly elsewhere in sub-Saharan Africa, any more than avoiding one place where lightning has struck in the past will confer immunity to thunderbolts should a storm  break out elsewhere and you get caught there by surprise.

Where does the disease lurk, then, between outbreaks?

There is little doubt that these diseases persist in wild animals, where they do not necessarily make  all of their natural hosts fatally sick. Rodents, bats, and various small monkeys have been implicated as natural reservoirs (See for example Leroy et al 2009 below). By contrast, chimpanzees and gorillas are known to contract Marburg and Ebola, but seem to die off very quickly much like humans do in response to infection, so they do not seem to be a likely vector, except when their dead carcasses are eaten as bush meat by native peoples. (See Bermejo et al. 2006 below).   But those animals which do survive and harbor the virus, in  their feces, urine, saliva, blood, and perhaps other body parts or fluids apparently contaminate the food, water, or air that is taken in by nearby humans. While vermin eradication, particularly of rodents, is recommended as a possible preventive strategy to reduce the chances of a community developing an outbreak of Ebola or Marburg, there is not a great deal of evidence that reintroduction of vermin predators (such as the revival of cat ownership which had the effect of reducing rats with bubonic plague carrying fleas)  or even chemical extermination of pests  has stopped an ongoing outbreak, quite possibly because, with few exceptions, (such as an Angolan episode of Marburg)  they tend to be short term any way.   Current laboratory experiments in search of effective therapies generally use infected lab mice, rats, guinea pigs, or monkeys. Some of these experimental animals are more disease tolerant than others, and the point of using them is to see what contributes to that tolerance. Other laboratory animals are designed to get sick and die pretty much as a model for the human experience of these diseases. There is a peculiar case in the Philippines where a variant of Ebola called Ebola-Reston (after Reston, Virginia, where a shipment of crab-eating monkeys sent to a medical research lab was found to have Ebola) has infected pigs and pig farmers near Manila, but the pigs seem not to die off quickly, and the farmers do not get sick at all, despite the fact that blood tests show that  both animals and men have definitely had some sort of immune reaction indicating some level of infection (See Normile 2009 below).

What currently can be done for patients?

Patients are typically placed in medical isolation wards whenever possible, and given comfort care. They have fluid replacement, pain and fever reducers, but often do not get whole blood transfusions because these simply bleed out so rapidly.  

What do we know about the viruses responsible for Ebola and Marburg ?

The structure of both Ebola and Marburg viruses has been very well studied (See, for example, Hartman, Tower & Nichol 2010 or Noda et al 2010 below ) and they are  virtually identical, although they trigger slightly different immunological responses and have slightly different means of attacking cells (See Valmas et al 2010 below).  These viruses consist of a surprisingly long (for a virus) strand of RNA coated largely with lipids, with fairly short protein prongs alongside.  We can detect when and how they begin to penetrate cells (See Lipkin, Paacio & Briese 2009 or Tscherne, Manicassamy & Garcia-Sastre 2010  below ) and can now visualize how these  viruses bud (See Liu et al 2010, Mateo et al 2010 and Welsch et al 2010 below).  We have a pretty good idea of how  they evade the body’s immune defenses (See Basler & Amarasinghe 2009 and  Mohamadzadeh 2009 below ) yet provoke fevers that should otherwise have helped kill them off  nonetheless (See Okumura et al 2010 below), even as they induce immune cell death (See Bradfute et al 2010 below).

What are the current strategies for fighting Ebola and Marburg?

Vaccines seem to be the route of choice (See Bausch et al 2008 ,  Geisbert et al 2009, and Olinger et al 2009  below), in part because it does seem that the small percentage of survivors of  Ebola and Marburg have developed some immunological means of fighting off the remnant viruses (See Wauquier et al 2009 below) and this suggests that the right antigen triggers will generate a survival response similar to that of these patients. Nonetheless the Food and Drug Administration has relaxed the strict rules for claims of efficacy in humans by allowing initially for a greater reliance on animal models, largely because typical Ebola (and Marburg) outbreaks are extremely unpredictable and very often short-lived  and most often happen in poorly equipped remote jungle areas where  the numbers of patients fluctuate wildly and setting up rigid double-blind trials is simply unworkable (See Sullivan et al 2009 below).

Some vaccine prototypes are based on evoking natural immune responses to natural Ebola strains or  chemically altered Ebola mutants whose ability to replicate wildly and endanger the patient has  been tamed (See Halfmann et al 2009 and Prins et al 2010 below), although using specially tailored viruses more commonly associated with the common cold or flu also seems promising (See Bukreyev et al 2010 and Pratt et al 2010 below ).

Attacking proteins necessary for cellular invasion and/or replication is a common theme (See Hood et al 2010 below), as is disrupting RNAs making proteins using antisense morpholino  oligomers (See Swenson et al 2009 below) or microencapsulated “small interfering” RNA (Geisbert et al 2010) both of which block off key sites, while other approaches basically allow the viruses to enter some cells but then trap them there by halting the budding process (See Harty 2009 below).

Nightmare scenarios: Weaponization of Marburg and Ebola by the Soviets  and reported attempts by terrorists to acquire it

Several websites, including that of the highly respected Federation of American Scientists (http://www.fas.org/programs/bio/factsheets/ebola.html ) give credence to the notion that some form of the Ebola virus was developed as biological weapon of mass destruction by the Soviets, and  a book coauthored by a former Soviet bioweapons expert, Ken Alibek (see Alibek & Handelman 1999 below)  who is currently a well-respected  U.S. based bioterrorism medical expert (see Weinstein & Alibek 2003 below ) also documents the use of the Marburg virus in a similar context. Other credible websites assert that terrorists and doomsday religious cults, most notably the Japanese  group Aum Shinrikyo (http://www.globalsecurity.org/wmd/intro/bio_ebola.htm ) have sought to acquire and exploit hemorrhagic viruses. (They instead, released Sarin gas in an attack on the Tokyo subway system, killing 13, wounding 50, and temporarily blinding thousands.) Preparation for medical responses to the use of Ebola and Marburg in terrorist attacks is, alas, not taken as a matter of science fiction or television action and adventure thriller episodes any longer (see DuPuy & Schmaljohn 2009 and Goffman 2010 below).

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

University of Arkansas Libraries MULN 223 E

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Alibek, Ken, and Stephen Handelman. 1999. Biohazard: the chilling true story of the largest covert biological weapons program in the world, told from the inside by the man who ran it. New York: Random House.

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Basler, Christopher F., and Gaya K. Amarasinghe. 2009. Evasion of interferon responses by Ebola and Marburg viruses. Journal of Interferon & Cytokine Research  29, (9) (09): 511-20.

Bausch, D.G., A/G. Sprecher, B. Jeffs & P. Boumandouki. 2008. Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions. Antiviral Research 78 (1): 150-60.

Bermejo, M. J.D. Rodrieguez-Teijero, G. Illera, A. Barroso, C. Villa, & P.D. Walsh. 2006. Ebola outbreak kills 5,000 gorillas. Science 314: 1564.

Bhattacharyya, Suchita, Kelly L. Warfield, Gordon Ruthel, Sina Bavari, M. J. Aman, and Thomas J. Hope. 2010. Ebola virus uses clathrin-mediated endocytosis as an entry pathway. Virology 401, (1) (05/25): 18-28.

Bradfute, Steven B., Paul E. Swanson, Mark A. Smith, Eizo Watanabe, Jonathan E. McDunn, Richard S. Hotchkiss, and Sina Bavari. 2010. Mechanisms and consequences of Ebolavirus-induced lymphocyte apoptosis. Journal of Immunology 184, (1) (01/01): 327-35.

Bukreyev, Alexander A., Joshua M. Dinapoli, Lijuan Yang, Brian R. Murphy, and Peter L. Collins. 2010. Mucosal parainfluenza virus-vectored vaccine against Ebola virus replicates in the respiratory tract of vector-immune monkeys and is immunogenic. Virology 399, (2) (04/10): 290-8.

Dias, M. B., Leonardo Reyes-Gonzalez, Francisco M. Veloso, and Elizabeth A. Casman. 2010. Effects of the USA Patriot Act and the 2002 Bioterrorism Preparedness Act on select agent research in the United States. Proceedings of the National Academy of Sciences of the United States of America 107, (21) (05/25): 9556-61.

Douglas, Janet L., Jean K. Gustin, Kasinath Viswanathan, Mandana Mansouri, Ashlee V. Moses, and Klaus Früh. 2010. The great escape: Viral strategies to counter BST-2/tetherin. Plos Pathogens 6, (5): e1000913-.

Dupuy, Lesley C., and Connie S. Schmaljohn. 2009. DNA vaccines for biodefense. Expert Review of Vaccines 8, (12) (12): 1739-54.

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Feldmann, Heinz. 2010. Are we any closer to combating Ebola infections? Lancet 375, (9729) (05/29): 1850-2.

Geisbert, Thomas W., Joan B. Geisbert, Anders Leung, Kathleen Daddario-DiCaprio, Lisa E. Hensley, Allen Grolla, and Heinz Feldmann. 2009. Single-injection vaccine protects nonhuman primates against infection with Marburg virus and three species of Ebola virus. Journal of Virology 83, (14) (07): 7296-304.

Geisbert, Thomas W., Amy C. H. Lee, Marjorie Robbins, Joan B. Geisbert, Anna N. Honko, Vandana Sood, Joshua C. Johnson, et al. 2010. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: A proof-of-concept study. Lancet 375, (9729) (05/29): 1896-905.

Goffman, Thomas E. 2010. Bioterrorism: What might be walking into the ED? The American Journal of Emergency Medicine 28, (4) (05): 515-8.

Gupta, Manisha, Cynthia S. Goldsmith, Maureen G. Metcalfe, Christina F. Spipopoulou, and Pierre E. Rollin. 2010. Reduced virus replication, proinflammatory cytokine production, and delayed macrophage cell death in human PBMCs infected with the newly discovered Bundibugyo Ebolavirus relative to Zaire Ebolavirus. Virology 402, (1) (06/20): 203-8.

Halfmann, Peter, Hideki Ebihara, Andrea Marzi, Yasuko Hatta, Shinji Watanabe, M. Suresh, Gabriele Neumann, Heinz Feldmann, and Yoshihiro Kawaoka. 2009. Replication-deficient Ebolavirus as a vaccine candidate. Journal of Virology 83, (8) (04): 3810-5.

Hartman, Amy L., Jonathan S. Towner, and Stuart T. Nichol. 2010. Ebola and Marburg hemorrhagic fever. Clinics in Laboratory Medicine 30, (1) (03): 161-77.

Hartshorn, Kevan L. 2010. Role of surfactant protein A and D (SP-A and SP-D) in human antiviral host defense. Frontiers in Bioscience (Scholar Edition) 2, : 527-46.

Harty, R.N. 2009. No exit: Targeting the budding process to inhibit filovirus replication. Antiviral Research 81 (3): 189-97.

Hoenen, T., S. Jung, A. Herwig, A. Groseth, and S. Becker. 2010. Both matrix proteins of Ebola virus contribute to the regulation of viral genome replication and transcription. Virology 403, (1) (07/20): 56-66.

Hood, Chantelle L., Jonathan Abraham, Jeffrey C. Boyington, Kwanyee Leung, Peter D. Kwong, and Gary J. Nabel. 2010. Biochemical and structural characterization of cathepsin L-processed Ebola virus glycoprotein: Implications for viral entry and immunogenicity. Journal of Virology 84, (6) (03): 2972-82.

Leroy, Eric M., Alain Epelboin, Vital Mondonge, Xavier Pourrut, Jean-Paul Gonzalez, Jean Muyembe-Tamfum, and Pierre Formenty. 2009. Human Ebola outbreak resulting from direct exposure to fruit bats in Luebo, Democratic Republic of Congo, 2007. Vector Borne and Zoonotic Diseases (Larchmont, N.Y.) 9, (6) (12): 723-8.

Leung, Daisy W., Dominika Borek, Mina Farahbakhsh, Parameshwaran Ramanan, Jay C. Nix, Tianjiao Wang, Kathleen C. Prins, et al. 2010. Crystallization and preliminary X-ray analysis of Ebola VP35 interferon inhibitory domain mutant proteins. Acta Crystallographica.Section F, Structural Biology and Crystallization Communications 66, (06/01): 689-92.

Leung, Daisy W., Kathleen C. Prins, Dominika M. Borek, Mina Farahbakhsh, JoAnn M. Tufariello, Parameshwaran Ramanan, Jay C. Nix, et al. 2010. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. Nature Structural & Molecular Biology 17, (2) (02): 165-72.

Lipkin, W. I., Gustavo Palacios, and Thomas Briese. 2009. Diagnostics and discovery in viral hemorrhagic fevers. Annals of the New York Academy of Sciences 1171 Suppl 1, (09): E6-E11.

Liu, Yuliang, Luis Cocka, Atsushi Okumura, Yong-An Zhang, J. O. Sunyer, and Ronald N. Harty. 2010. Conserved motifs within Ebola and Marburg virus VP40 proteins are important for stability, localization, and subsequent budding of virus-like particles. Journal of Virology 84, (5) (03): 2294-303.

Mateo, Mathieu, St Patrick Reid, Lawrence W. Leung, Christopher F. Basler, and Viktor E. Volchkov. 2010. Ebolavirus VP24 binding to karyopherins is required for inhibition of interferon signaling. Journal of Virology 84, (2) (01): 1169-75.

Mohamadzadeh, Mansour. 2009. Potential factors induced by filoviruses that lead to immune supression. Current Molecular Medicine 9, (2) (03): 174-85.

Noda, Takeshi, Kyoji Hagiwara, Hiroshi Sagara, and Yoshihiro Kawaoka. 2010. Characterization of the Ebola virus nucleoprotein-RNA complex. The Journal of General Virology 91, (06): 1478-83.

Normile, Dennis. 2009. Emerging infectious diseases. Scientists puzzle over Ebola-Reston virus in pigs. Science 323, (5913) (01/23): 451-.

Okumura, Atsushi, Paula M. Pitha, Akihiko Yoshimura, and Ronald N. Harty. 2010. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. Journal of Virology 84, (1) (01): 27-33.

Olinger Gene G., Julia E. Biggins, Vanessa R. Melanson, Victoria Wahl-Jensen Victoria,  Thomas W. Geisbert, and Lisa E. Hensley. 2009. Drug targets in infections with Ebola and Marburg viruses. Infectious Disorders Drug Targets 9, (2) (04): 191-200.

Pittalis, Silvia, Francesco Maria Fusco, Simone Lanini, Carla Nisii, Vincenzo Puro, Francesco Nicola Lauria, and Giuseppe Ippolito. 2009. Case definition for Ebola and Marburg haemorrhagic fevers: A complex challenge for epidemiologists and clinicians. The New Microbiologica: Official Journal of the Italian Society for Medical, Odontoiatric, and Clinical Microbiology (SIMMOC) 32, (4) (10): 359-67.

Pratt, William D., Danher Wang, Donald K. Nichols, Min Luo, Jan Woraratanadharm, John M. Dye, David H. Holman, and John Y. Dong. 2010. Protection of nonhuman primates against two species of Ebola virus infection with a single complex adenovirus vector. Clinical and Vaccine Immunology: CVI 17, (4) (04): 572-81.

Prins, Kathleen C., Sebastien Delpeut, Daisy W. Leung, Olivier Reynard, Valentina A. Volchkova, St Patrick Reid, Parameshwaran Ramanan, et al. 2010. Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs. Journal of Virology 84, (6) (03): 3004-15.

Raabe, Vanessa N., Imaam Mutyaba, Paul Roddy, Julius J. Lutwama, Wenzel Geissler, and Matthias Borchert. 2010. Infection control during filoviral hemorrhagic fever outbreaks: Preferences of community members and health workers in Masindi, Uganda. Transactions of the Royal Society of Tropical Medicine and Hygiene 104, (1) (01): 48-50.

Shedlock, Devon J., Michael A. Bailey, Paul M. Popernack, James M. Cunningham, Dennis R. Burton, and Nancy J. Sullivan. 2010. Antibody-mediated neutralization of Ebola virus can occur by two distinct mechanisms. Virology 401, (2) (06/05): 228-35.

Stanwell-Smith, R. 2009. When nature turns cook: An epidemiological feast: Report of the John Snow Society Pumphandle Lecture 2009, delivered by Dr David Heymann. Public Health 123, (12) (12): 814-6.

Sullivan, Nancy J., Julie E. Martin, Barney S. Graham, and Gary J. Nabel. 2009. Correlates of protective immunity for Ebola vaccines: Implications for regulatory approval by the animal rule. Nature Reviews. Microbiology 7, (5) (05): 393-400.

Swenson, Dana L., Kelly L. Warfield, Travis K. Warren, Candace Lovejoy, Jed N. Hassinger, Gordon Ruthel, Robert E. Blouch, et al. 2009. Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection. Antimicrobial Agents and Chemotherapy 53, (5) (05): 2089-99.

Trombley, Adrienne R., Leslie Wachter, Jeffrey Garrison, Valerie Buckley-Beason, Jordan Jahrling, Lisa E. Hensley, Randal J. Schoepp, et al. 2010. Comprehensive panel of real-time TaqMan polymerase chain reaction assays for detection and absolute quantification of filoviruses, arenaviruses, and New World hantaviruses. The American Journal of Tropical Medicine and Hygiene 82, (5) (05): 954-60.

Tscherne, Donna M., Balaji Manicassamy, and Adolfo García-Sastre. 2010. An enzymatic virus-like particle assay for sensitive detection of virus entry. Journal of Virological Methods 163, (2) (02): 336-43.

Urata, Shuzo, and Jiro Yasuda. 2010. Regulation of Marburg virus (MARV) budding by Nedd4.1: A different WW domain of Nedd4.1 is critical for binding to MARV and Ebola virus VP40. The Journal of General Virology 91, (01): 228-34.

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

Large Scale, Multifactorial Studies of Risk Factors

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

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

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

Specific Risk Factors: Metabolic Syndrome & Diabetes

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

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

Other Risk Factors:

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

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

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

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

Preventive Measures: Exercise and Omega-3 Fatty Acids

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

The Drive for Evidence-Based Medicine Affects Cardiology Advice

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

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

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

A Molecular Level Understanding of

Botched Attempts By the Heart to Repair Itself

& Handle Its Electrochemical Circuits

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

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

Comparing Medications to Reduce Blood Pressure

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

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

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

“Statin Island”

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

Blood Thinners

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

Avoiding Gastrointestinal Bleeding When on Blood Thinners

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

 

Interventional Cardiology Using Catheterization

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

Cardiac Vessel Stents

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

Autologous Transplantation of Heart Cells To Stimulate Cardiac Repair

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

The Cabbage  (CABG) Patch

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

Pacemakers

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

Looking Into the Beating Heart

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

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

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

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

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

Stroke

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

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Craig Venter & The Cell With A Synthetic Genome: Taking Your Car in for a New Battery and Coming Back to Find That the Mechanic Has Substituted Homemade Replacement Parts for Everything Under the Hood

The Thursday night, May 14^th, 2010, early release of a paper in the journal Science by Craig Venter’s team (See Gibson, Glass, Lartigue et al 2010) set off a tsunami of headlines suggesting that scientists had finally created artificial life.

What Venter’s team did, after many false starts and a great many successful preliminary studies (Benders, Noskov, Denisova et al 2010, Gibson, Benders, Andrews-Pfannoch et al 2008, Gibson, Benders, Axelrod et al 2008), was to map and then effectively duplicate most of  the DNA sequence of a very simple microorganism Mycoplasma mycoides using an electromechanical  assembler of small units of DNA (oligonucleotides) , called an oligonucleotide synthesizer. 

What’s important to recognize in this step is that the team did not snip up the microorganism’s own natural DNA and let some particularly desired portion multiply itself using the Polymerase Chain Reaction, the way most genetic engineers proceed when they want to obtain  some desired DNA for later  insertion into some other target organism’s genome.

 Rather, the team decoded the entire  sequence, and essentially placed that sequence into the equivalent of a cookbook that could be scanned by a robotic cook who worked from simple molecular ingredients, following one step after another.

The robot cook took baked some short segments,  then it assembled them into longer segments (Gibson, Young, Chang et al 2009),  and then ultimately linked the longer segments into a giant loop, the way the natural DNA within the microorganism is organized.

Technically they took the synthetically recreated giant loop of  Mycoplasma mycoides DNA and put it into the pre-existing cellular vesicle of a Mycoides capricolum, after they had taken out the pre-existing DNA of the Mycoides capricolum that had been “living” there.

The Mycoides capricolum provided a more robust housing that apparently reproduced itself better. In a sense the natural Mycoides capricolum, provided the auto body, and the synthetic DNA loop provided the engine, transmission, and everything else mechanical and electrical.

For safety’s sake they edited out some snippets of DNA that might cause this bacterium to become virulent.

Furthermore, they put in some tell-tale markers that enabled the researchers to look into the cell culture into which these microorganisms were growing, and be able to see under a microscope which micoorganisms were really the synthetic ones, and which were contaminants or some  Mycoides capricolum that had somehow kicked out the synthetic DNA, and somehow managed to regain their own native DNA.

It is very clear from those tell-tale markers that these synthetic DNA supplied microorganism are, in fact, the ones reproducing themselves.

Had this Ever Been Done Before?

No, no one had basically replaced everything that was natural DNA within a cell with a complete functional complement of  synthetically produced DNA, and had that cell successfully reproduce itself using only  the new totally synthetic DNA.

Why Hadn’t This Been Done Before?

Two reasons come to mind.

The most obvious answer to the general public would be that it must have been incredibly hard to do this, and indeed, according to a highly readable exposition from Elizabeth Pennisi (cited below),  it took a team of 20 scientists more than a decade and tens of millions of dollars to accomplish this.

The other reason is more practical.

For decades now,  genetic engineers have been using existing viruses, bacteria, yeasts, and eukaryote cells to do their hard work, by inserting only the specific piece of DNA that would change their behavior in some favorable way.

We’ve used snippet insertion genetic engineering to get us drugs that will control excess bleeding (Li & Heide 2005, Moltzan, Anderson, Callum et al 2008), kill virulent microbes (Gillor, Nigro & Riley 2005), limits out-of-control growth hormones (Piasley, Trainer & Drake 2004), make insulin (Vajo & Duckworth 2000), and give us  natural insecticides (Wang, Zhang, Song et al 2006, Yan, Song, Shu et al 2009).

Why Then,  Do It the Hard Way?

This most recent paper is a proof-of-concept study. It basically reassures at least some investors and many scientists that it is possible to swap out everything, when genetically engineering a new microbe.

The advantages could be the avoidance of some untoward immunological/allergic response, should it be used in humans, or the better elimination of  any opportunity for the microbe changing back to some wild version. 

There are existing ways genetic engineers can do many of these things, but the take-home lesson from experience is that  even the best genetic engineers cannot predict with absolute certainty what the 99.999% of the original DNA might do or mutate into doing, after that highly desirable one-thousandth -of-one-percent snippet of desirable is in a human body or released into some vast antibiotic cell culture factory.

By holding the non-target  DNA to the absolute minimum, and knowing what the job for that minimal portion is, then the genetic engineer using the Venter approach can eliminate even the possibility for untoward further genetic mutations.

Will This Make Venter Famous, or Win Him the Nobel Prize?

Craig Venter is already world famous, and very likely Nobel-worthy,  for his work studying the webs of interacting DNA -----the metagenomics-----in complex microbial communities in the sea ( see for example Sharon, Tzahor, Shmoish et al 2007, Shaw, Halpern, Beeson et al 2008) and for essentially ending  his race with the massive and massively funded research community of the NIH  for a complete map of the human genome in a dead heat, despite working with a vastly smaller crew  with fewer and smaller private investor funds with which to work (Venter, , Adams, Myers et al. 2001)

Furthermore, he has mapped the complete genomes of nasty microbes, like  Aspergillus fumigates (Fedorova, Khaldi, Joardar et al 2008) and those of some experimental organisms that are commonly used to study basic problems in biology, like the hydra (Chapman, Kirkness, Simakov et al 2010).

He’s a huge fan of analyzing the actual genome of individuals with a view of making medical decisions that fit the patient as closely as possible, an approach which he calls personalized medicine (Ng, Murray, Levy & Center 2009, Ng, Zhao, Levy, Strausberg & Venter 2008, Venter 2010.

And believing, perhaps,  that there would be no more interesting genome than his, has had done this for  his own total genome (Levy, Sutton, Ng et al 2007), and placed it as an exemplar of how such a database might be  web-searchable (Axelrod, Lin, Ng et al 2009).

Among the genes in his genomes publicized are those leading to alcoholism (I don’t know if he drinks) tobacco use and nicotine addiction (I don’t know if he smokes or chews) and a few that match to some degree, at least in the minds of his critics and some of his business associates,  his more public persona (novelty seeking and conduct disorder).

And there are the usual banes of modern man: a propensity for coronary artery disease, high triglycerides, high blood pressure, obesity, metabolic syndrome,  and even Alzheimers…….although, in a kind of Benjamin Franklin-endored way,  it appears that he is also genetically predisposed to going to bed early each night, and arising very, very early the next day (Advancedd Sleep Phase Syndrome).

But so far, no one has identified where the genetic locus of his drive,  insight, entrepreneurial,  and self-promotional spirit, and yes, likely his flat-out genius resides.  

But judging from his incredible record, it’s in there somewhere.

Tony Stankus, FSLA [email protected] Professsor, Life Sciences Librarian & Coordinator of Science Librarians

University of Arkansas Libraries MULN 233E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

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Benders, Gwynedd A., Vladimir N. Noskov, Evgeniya A. Denisova, Carole Lartigue, Daniel G. Gibson, Nacyra Assad-Garcia, Ray-Yuan Chuang, et al. 2010. Cloning whole bacterial genomes in yeast. Nucleic Acids Research 38, (8) (05/01): 2558-69.

Chapman, Jarrod A., Ewen F. Kirkness, Oleg Simakov, Steven E. Hampson, Therese Mitros, Thomas Weinmaier, Thomas Rattei, et al. 2010. The dynamic genome of hydra. Nature 464, (7288) (03/25): 592-6.

Fedorova, Natalie D., Nora Khaldi, Vinita S. Joardar, Rama Maiti, Paolo Amedeo, Michael J. Anderson, Jonathan Crabtree, et al. 2008. Genomic islands in the pathogenic filamentous fungus aspergillus fumigatus. Plos Genetics 4, (4) (04): e1000046-.

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Gibson, Daniel G., Gwynedd A. Benders, Kevin C. Axelrod, Jayshree Zaveri, Mikkel A. Algire, Monzia Moodie, Michael G. Montague, J. C. Venter, Hamilton O. Smith, and Hutchison,Clyde A.,,3rd. 2008. One-step assembly in yeast of 25 overlapping DNA fragments to form a complete synthetic mycoplasma genitalium genome. Proceedings of the National Academy of Sciences of the United States of America 105, (51) (12/23): 20404-9.

Gibson, Daniel G., John I. Glass, Carole Lartigue, Vladimir N. Noskov, Ray-Yuan Chang et al. 2010. Creation of a bacterial cell controlled by a chemically synthesized genome. Science, 328 (May 20, 2010) epub ahead of print doi: 10.1126/science.1190719

Gibson, Daniel G., Lei Young, Ray-Yuan Chuang, J. C. Venter, Hutchison,Clyde A.,,3rd, and Hamilton O. Smith. 2009. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nature Methods 6, (5) (05): 343-5.

Gillor, Osnat, Lisa M. Nigro, and Margaret A. Riley. 2005. Genetically engineered bacteriocins and their potential as the next generation of antimicrobials. Current Pharmaceutical Design 11, (8): 1067-75.

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Lartigue, Carole, Sanjay Vashee, Mikkel A. Algire, Ray-Yuan Chuang, Gwynedd A. Benders, Li Ma, Vladimir N. Noskov, et al. 2009. Creating bacterial strains from genomes that have been cloned and engineered in yeast. Science (New York, N.Y.) 325, (5948) (09/25): 1693-6.

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Li, S-M, and L. Heide. 2005. New aminocoumarin antibiotics from genetically engineered streptomyces strains. Current Medicinal Chemistry 12, (4): 419-27.

Maróti, Gergely, Yingkai Tong, Shibu Yooseph, Holly Baden-Tillson, Hamilton O. Smith, Kornél Kovács L., Marvin Frazier, J. C. Venter, and Qing Xu. 2009. Discovery of [NiFe] hydrogenase genes in metagenomic DNA: Cloning and heterologous expression in Thiocapsa roseopersicina. Applied and Environmental Microbiology 75, (18) (09): 5821-30.

Moltzan, C. J., D. A. Anderson, J. Callum, S. Fremes, H. Hume, C. D. Mazer, M. C. Poon, G. Rivard, S. Rizoli, and S. Robinson. 2008. The evidence for the use of recombinant factor VIIa in massive bleeding: Development of a transfusion policy framework. Transfusion Medicine (Oxford, England) 18, (2) (04): 112-20.

Ng, P. C., Q. Zhao, S. Levy, R. L. Strausberg, and J. C. Venter. 2008. Individual genomes instead of race for personalized medicine. Clinical Pharmacology and Therapeutics 84, (3) (09): 306-9.

Ng, Pauline C., Sarah S. Murray, Samuel Levy, and J. C. Venter. 2009. An agenda for personalized medicine. Nature 461, (7265) (10/08): 724-6.

Paisley, Angela N., Peter J. Trainer, and William M. Drake. 2004. The place of pegvisomant in the acromegaly treatment algorithm. Growth Hormone & IGF Research: Official Journal of the Growth Hormone Research Society and the International IGF Research Society 14 Suppl A, (06): S101-6.

Pennisi, E. 2010. Synthetic genome brings new life to bacterium. Science 328: 958-959.   

Shaw, Allison K., Aaron L. Halpern, Karen Beeson, Bao Tran, J. C. Venter, and Jennifer B. H. Martiny. 2008. It's all relative: Ranking the diversity of aquatic bacterial communities. Environmental Microbiology 10, (9) (09): 2200-10.

Vajo, Z., and W. C. Duckworth. 2000. Genetically engineered insulin analogs: Diabetes in the new millenium. Pharmacological Reviews 52, (1) (03): 1-9.

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The Renaissance in Neanderthal Studies: Publication of the Neandertal Genome Sequence Is Yet Another Addition to Our Growing Scientific Knowledge

The publication of a draft sequence of the genomic sequence of Neandertal  in the May 7, 2010 issue of Science sets a new high-water mark in paleoanthropology coups  for that journal, even after their breakout last year with the publication of the details of the skeleton of Ardipithecus ramidus in its October 3, 2009, issue, pp.60-106.

What Is The Genome’s Most Striking Finding?

People of European and Asian ancestry share between 1%-4% of their DNA with Neandertals, but people of purely African ancestry apparently do not (Green, Krause, Briggs et al. 2010). It had been the predominant view prior to this that Neandertals and early modern humans did not mate. But if they did, it would have been expected that Africans as well as Eurasians would have Neandertal DNA.

Does This Mean That All Mankind Did Not Come Out Of Africa?

Not necessarily. It most likely means that that at some point, at least two groups of forerunners of modern man, who may well have come out of Africa,    traveled to and settled within points in Europe and Asia.  It appeared that at some point, for a period lasting several thousand years at the least, Africans stop migrating  to Europe and Asia often enough to have mated with these now isolated   Northern forerunners.

It may well have been that Africans were deterred by their better judgment,  since Europe and Asia were undergoing repeated Ice Ages during this period, and the living conditions in Africa were likely superior.

In any case, there is no doubt that both Africans and the Northern migrants continued to evolve separately, despite isolation from one another.

One of these two isolated Eurasian groups  consisted of the Neandertals, and the other Eurasian group was,  for lack of a better understood term,   the most widely recognized group of early modern humans, which we might call the  Cro-Magnons.  (Although Early Modern Human is the more encompassing and scientifically preferred term today).

 The cited DNA analysis from the journal Science now shows beyond a reasonable doubt that Neandertals and Early Modern Humans did mate -----at least in the Middle East between Europe and Asia -----and have some viable offspring at some point and exchanged genetic material that remains in our modern DNA today. 

The studies showing no Neandertal DNA in Africans used the DNA of the  Shan and Yoruba tribes in Africa, groups which had never left the African continent, and not the DNA of other groups , particularly  African-Americans, who have largely intermarried with Europeans and to some extent, Asians, and whose progeny therefore are the result of later intermarriages which may well  show some Neandertal DNA as well.

Had Anyone Predicted This?

Forhan, Martiel and Blum (2008) cited below were one of the more recent groups that showed how it could be so, but a minority had been in favor of the idea all along. Arguably the best known of these is Erik Trinkhaus  of Washington University in St. Louis, who has long argued from anatomical studies.  

Why Did It Take So Long to Come to This Seemingly Decisive Determination?

While there was always some suspicion that Neandertals and Early Modern Humans had mated based on anatomical blends of the two types seen in some fossil finds that were suggestive of “hybrids, ”  it was thought that a DNA analysis would provide the gold standard test. But this gold standard test was frustrated earlier by a number of confounding variables.

1. Could they find a sample or samples that were unambiguously Neandertal to everyone’s satisfaction. (They eventually did, in a cave that was by unanimous consensus,  a purely Neandertal site that had not later been occupied by Early Modern Humans.)

2. Would they be able to screen out the two major contaminating sources of non-Neandertal DNA: microbes like bacteria, viruses and molds on or in the specimen, and then modern human DNA that somehow got into or onto  the samples? (Yes, even most critics contend that extraordinary steps were taken….although even some of this team’s initial findings suggested that it was extremely problematic.)

3. Was there enough computing power and clever enough computer algorithms to do the sequence screening, sorting, and matching necessary for the task? (Yes, read the story by Pennisi cited below: Computer Kid Makes Good” for an excellent account of the group's bioinformatics leader. For technical details see Burbano, Hodges & Green et al 2010 cited below)

Is Widespread Acceptance of this Finding A Sure Thing?

In an excellent essay by John DeVose (2009) he notes, based on a study of several other paradigm shifts in the field,  that on average, it takes a generation of paleonanthropologists  (about 20 years of new Ph.D.s coming into the field and adding their weight to one side or another) to come to a new consensus, so we really have about that long before the next generation of researchers fully buy into this Neandertal genetic proposition, or not, before we can say it’s a  done deal.

What Else Do We Know About Neandertals?

Superior Tool Makers

Neandertals were far better tool makers than was previously thought (See Moncel, Chacon, Coudenneau & Fernandes 2009) , and not only made better finished blades than many Modern Early Humans, but procured better raw materials from farther distances than expected (Bar-Yosef & Van Peer 2009).  But like early modern humans, and modern humans today, it was obvious that most Neandertal tools were made for, and used by,  right-handed individuals (See Uomini 2009).

But Not Good Clothing Designers

While it seems likely that Neandertals wore hides and furs as capes, it seems unlikely that they the sewed seams necessary to make close-fitting garments, owing to the scarcity  of bone needles common among Early Modern Humans (See Sorenson 2009). (Neandertals did use awls, which would allow for fasteners of drape-like garments.)

They  Nonetheless Accessorized

Pigments and seashell fragments typical of making bodily ornaments and body paints or make up have been found in Neandertal settings in Spain (See Zilhao et al 2010).

 

Great hunters

Analysis of cave animal remnants and  isoptopic studies of Neandertal bone all concur: Neandertals were fearless and apparently socially well organized pack hunters of rather fiercesome predators: cave bears, and dire wolves  and giant wild bulls (aurochs) and  wooly mammoths and mastodons. It appears that they competed with giant hyenas for reindeer and deer. (See Richards, Taylor, Steele et al 2008, and Richards & Trinkhaus 2009 cited below).

And Maybe Fishermen

It appears that at least those Neandertals in Spain, and perhaps near Gibraltar, caught and ate fish , and harvested shellfish. They may also have hunted, killed and eaten seals if not whales (See Stringer, Finlayson, Barton et al 2008, and also Nowell & Horstwood 2009,  but see also Klein & Steele 2008 which reflects a more conservative judgments).

And Even Bronco-Riders  (& Maybe Cannibals)

Berger & Trinkhaus (1995) noted that Neandertal bobnes show an awful lot of healed fractures from which the Neandertals clearly lived to hunt another day. It has been suggested that Neandertals  literally jumped upon or wrestled with their big game thereby incurring these  fractures through violent struggle. (Today’s rodeo riders show remarkably similar patterns of broken and healed fractures on x-ray studies).  Other Neanderthal  bone remains show cut marks made by stone tools, suggestive of warfare and cannibalism, but there is also evidence that Neandertals buried their dead with herbs and flowers as well as with tools to be used in the after-life, suggesting that they had a reverential attitude towards the bodies of the dead…..although this does not necessarily preclude eating your in-laws or enemies for revenge.

They Used Fire for Cooking But Not for Forest Clearing for Agriculture

Comparison of Neanderthal and Early Modern Human sites shows that they seemed equal in their use of fire, and at least European populations of both hominids did not appear to use fire to clear out woodland for farming, as had been seen in some of the oldest Asian populations. Neandertals did, however, dry  and/or smoke their meat ------ think of Neandertals as the founders of beef jerky. (Sorenson 2009).  

They Lived in Heated Apartments

Some excavations showed that Neandertals lived in caves or constructed rock shelters with a compartmentalized pattern of sleeping spaces and heat sources so that there was a sequence of a fireplace every nine feet or so near each sleeping spot (Vallverdu, Vaquero, Caceres et al 2010).

There is a Good Deal of Debate on If & How Well Neandertals Spoke

There are two diametrically opposed views here: Krause, Laluenza-Fox, Orlando et al 9 2007) say that a key gene connected to the ability to speak distinctly  FOXP2 was present in both Neandertal and Early Modern Humans  while Coop, Bullaughey Luca & Przeworski ( 2008)  say that such a result seemed more likely owing to contamination of the fossil DNA with modern human traces.

But They May Not Have Been Great Musical Instrumentalists

Despite good tool-making skills and with some support for the fact that they could speak (and presumably sing) well enough, only Early Modern Man seems to have a record of making musical instruments (Conrad, Malina & Muenzel 2009).  

What Did Neandertals Look Like?

Short & Stocky

In terms of modern humans: They were shorter, squatter, stored more fat around their bellies, and had  shorter, thicker  arms and legs, had thick short necks and rather big heads (See DeLeon, Ponce, Golovanova et al 2008, and Weaver 2009).

Pale Skinned  & Red Headed

In other words, they looked exactly like me, except that while I have the fair skin genetic analysis has determined was common among Neandertals, I do not have the red hair most often predicted (See Healy 2008). 

With Modern (not Broad Flat) Noses Sticking Out

Both Neandertals and early modern humans began to have more prominent noses over time, largely because our brains needed more space within the skulls (Mladina, Skitarelic & Vukovic 2009).  Nonethless, there were enough differences so that a trained paleonantropologist  can pretty much quickly tell a Neandertal from an early modern human by their nasal cavity within the skull ( Schwartz, Tattersall & Teschler-Nicola 2008).

 

With Really Big Teeth In Front & Back

Neandertals had bigger, and faster growing teeth (Smith, Harvati, Olejniczak et al 2009) ,  but thinner enamel (Olejniczak, Smith, Feeney et al 2008). This may not have been a disadvantage given that thicker enamel is more necessary if one has a diet higher in grains and nuts which need more through grinding does meat (See Rivals, Moncel & Patou-Mathis 2009).

 

Not All Neandertals Lived in the Same Regions: They had Distinct Ethnicities

Neandertals had three well-established populations which which can be differentiated based on remains: the Western European, the Southern European and the Middle Eastern (see Fabre, Condemi & DeGioanni 2009). There is evidence  over travels and intermarriage among them however. Given that they migrated at least partly with interregional marriage as an outcome, it should not be so unlikely that they mated with nearby Early Modern Humans.

Why Did Neanderthals Die Out?

The consensus opinion is that they simply were outnumbered by Early Modern Humans who were better at marshalling resources that added to one’s chances of surviving, particularly plant-source foods and possibly early agriculture. This reduced dependence on a hunting-only diet may have meant that Early Modern Humans could survive periodic scarcities of wild game better, and in doing so increase their numbers relative to Neandertal populations within the same regions within which both groups competed for resources (See Banks, D’Errico, Francesco et al 2008). There is a more recent, but not widely supported  hypotheses that they may have died of the equivalent of “Mad Cow Disease” through their overdependence on animal diets, which may well have included inadvertently eating animals with transmissible encephalopathogies (See Riel-Salvatore 2008 & Underdown 2008).

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

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

 

Banks, William E., Francesco d'Errico, A. Townsend Peterson, Masa Kageyama, Adriana Sima, and Maria-Fernanda Sanchez-Goni. 2008. Neanderthal extinction by competitive exclusion. PLoS One 3, (12) (DEC 24 2008).

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———. 2009. Dental developmental pattern of the Neanderthal child from Roc de Marsal: A high-resolution 3D analysis. Journal of Human Evolution 56, (1) (JAN 2009): 66-75.

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US Farm-Raised Catfish: An Environmentally Sustainable, Aquacultured, Affordable, Safe, & Tasty High Quality Protein Dinner that Supports the Economies of the States Most Adversely Affected by the BP Oil Spill in the Gulf Coast

In recent days there has been a great deal of speculation as to whether or not the seafood fisheries of the Gulf Coast will have been so damaged by the British Petroleum oil split  as to limit,  or entirely cutoff the supply of fish from this area,  for the American dinner table.

On Monday, the New York Times (Robertson 2010) reported that the National Oceanic and Atmospheric Administration were restricting fishing in waters from the mouth of the Mississippi River in New Orleans to Pensacola Bay in Florida and taking samples of seafood to ensure food safety.

While there is some very recent analysis that suggests that the situation is being exaggerated (Broder & Zeller 2010), there have certainly been many cases in the past when seafood of various types has been quarantined or subjected to special testing following contamination with petroleum from off-shore platforms, oil tankers, or even simply  residue discharges  from inefficient diesel engines that drove naval  or merchant marine traffic (Chesler, Gump, Hert, May & Wise 1987, Moon, Kim, Choi & Choi 2010,  Isigigur, Hera & Ackman 1996, Kannpan, Jasmine, Jeyachandran & Tamilselvi 1996, Khan Al-Ghais & Al-Marri 1995,  and many other listed below), including some from previous Gulf oil spills (Krahn, Ylitalo,  Buzitis et al, 1993).

In addition to the health concerns of consumers, there is understandable empathy for the people in the Southern US who will be losing much of their income at a time when there is a generalized recession. Particularly likely to be disrupted are the economies of Louisiana, Mississippi, and Alabama, those states  closest to the spill.

But, there may be a biology-based answer that helps the situation of both those concerned for safe seafood and for the economies of the affected states of the South: US farm-raised channel catfish.

US farm-raised channel catfish is overwhelmingly aquacultured in four states: Mississippi, Alabama, Arkansas, and Louisiana.

This industry provides the consumer with rather reasonably priced finfish that is grown with extraordinary attention to producing  “unfishy”, “non-muddy” tasting, exceptionally  high-quality-protein-containing, virtually zero contaminant, food for the table,  all the while supporting a domestic industry that has been hammered by the dumping of typically underpriced,  often uninspected, misleadingly labeled as “Cajun, ” and not in a few cases seriously contaminated,  imported aquacultured fish on the US market (Greenberg 2008).

Part of the excellent record of US farm-raised channel catfish for food safety and fresh taste doubtless has to do with the fact that it is about the freshest seafood one can have. It is only about 30 minutes between when the catfish is shipped live in an aerated tanker truck to when it is a fillet resting on ice or individually flash frozen in a processing plant operating under USDA Food Safety and Inspection Services Hazard Analysis and Critical Control Points (HACCP) guidelines (Hargeaves & Tucker 2004), something the aquaculture of very few other countries is likely to be able to match at this time.

Unlike what is often the case with foreign raised catfish relatives like “tra” from Vietnam, or  genuine channel catfish from the Peoples Republic of China, US farm-raised channel catfish are generally raised in specially constructed artificial pods, typically filled with clean well water that largely stays that way owing to the extremely low amounts of nitrate, phosphates, and ammonia emanating from the catfish. Environmental dumping of strongly odorous and polluting water, or the growing of the fish in murky or polluted water in the first place,  is simply not the standard procedure for  US farm-raised channel catfish farming today, the way it is many other countries and with other varieties of fish.

Likewise captive breeding and growing out within the confines of  these man-made ponds eliminates the problems of spreading infestations of parasites, like sea lice,  to bystander populations of other wild fish, caused by the heavy concentrations of captive fish being raised in underwater cages or pens in open waters (Peeler & Murray 2004).

Furthermore,  in US farm-raised channel catfish operations there is no large-sale savaging of the world-wide population of smaller wild caught fish which are caught to be ground up into meal for farm-raised salmon or shrimp (Naylor, Goldburg, Primavera et al 2001). US farm-raised catfish feed is 98% plant product based.  US farmed-raised  channel catfish are incredibly efficient at turning this largely corn and soy ration into protein: With three times the efficiency of chickens and five times that of beef cattle (Ambardekar & Reigh 2007).

It is rare when an American agribusiness sector receives kudos for its environmentally friendly  and humane animal handling from both academia and non-governmental advocacy agencies, but such is the case for this industry when compared to its foreign competitors (Claiborne 2010) . The Audubon Society, the Environmental Defense Fund, and Food & Water Watch have joined together with the leading trade association for US farm-raised channel catfish, the Catfish institute, www.uscatfish.com , in pointing out aquaculture abuses and calling for action.

For more detail, consult the upcoming issue of the Journal of Food & Agricultural Information where I will be profiling this commodity.

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

University of Arkansas Libraries MULN 223 E

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