SLA Biomedical & Life Sciences Division Blog

Robert G. Edwards : 2010 Nobel Prize Winner in Physiology or Medicine

This year’s Nobel Prize in Physiology or Medicine went to a man whose name is synonymous with “test tube babies” although in point of fact, the equipment that is used for the actual fertilization is more like a petri dish.

Prof. Robert G. Edwards of Cambridge University in England  began his career by systematizing the previous scientific literature on the conditions conducive to the successful fertilization of mammals within laboratory conditions. Then he significantly advanced it experimentally all the way to the human experience.  His research partner, Dr. Patrick Steptoe, (who died in 1988 and therefore could not share in this Nobel Prize with him)  was a well-respected  gynecologist who had experience in gynecological laparoscopic surgery (minor surgery involving the insertion of tubes with lighting and micro-instruments into the gut). He  adapted  existing techniques to the retrieval of human eggs, from ovaries that had been hormonally stimulated to release them in multiples.

Through the combined efforts of Edwards and Steptoe, it finally became possible to combine sperm, which is readily available fresh or frozen (but  which can be thawed on demand), with the ovum, after which the subsequently developing embryo could be frozen for later use,  or be  re-implanted fresh  in the mother, whose uterus would, once again, be hormonally adjusted to be receptive.

Today in Western countries as many as one in 100 live healthy births are the happy result of their pioneering work.

Education and Professional Training

Professor Edwards was in many ways a  clear cut, and almost predictable  British scientific success story. He attended a prominent public high school in Manchester, England (“public” in the American sense, meaning not a private boarding school) that would be very much the equivalent of Boston Latin or Bronx Science in the US. He served honorably in the British Army, and then took a degree in Agriculture at the Bangor campus of the University of Wales (one of the three oldest  and most prestigious of the “red brick” universities in that part of the UK ). He then took his Ph.D. in Animal Science with an emphasis on Reproduction and Genetics at the University of Edinburgh (one of the world’s oldest and most distinguished universities, and the strongest in Scotland in the sciences). He then spent the bulk of his career at Cambridge, arguably the UK’s greatest school in the sciences, and the university home of  88 previous Nobel Prizewinners, more than any other institution on earth.

Succeeding Despite A Lack Of Consistent Scientific & Medical Support In The Early Years

It is perhaps serendipitous that the September 2010 issue of Human Reproduction contains an extensive article documenting the early difficulties of Edwards & Steptoe in gaining reliable financial support for their research (Johnson et al 2010). The stumbling blocks to funding  were not as straightforward  and simple as might be imagined: namely,  opposition from the Roman Catholic Church or religious fundamentalists  to Edwards & Steptoe “playing God”, but rather based on a more complex mix of factors including some practical assessments as to how their research could successfully be carried out without running into snafus based on lack of oversight by the agencies in charge of administering grant monies.  

The Medical Research Council, the UK’s version of the US National Institutes of Health extramural research funding program, basically had four worries, and each had some merit based on what was known at the time.

First, there was an ongoing debate within the MRC leaning towards the idea  that any allocation for  obstetric & gynecological research should focus on the problem of world overpopulation and contraception, rather than on infertility

Second, Edwards and Steptoe felt that they had already gathered enough information from work with other mammals, to proceed  more quickly to humans, while the MRC’s referees felt that they should have extensive trials with chimps first.

Third, Edwards and Steptoe declined an offer to move into a research hospital already being funded and closely supervised by the MRC, since they preferred the greater investigative freedom, the  more genial atmosphere, and apparently, the reduced level of bureaucracy and administrative report-writing  of the University of Cambridge  campus and facilities, even though these were not yet set up for patient care.   The MRC also worried that year-to-year fluctuations in the research  funding of the University might cause disruptions of the university’s portion of the budget for Edwards and Steptoe’s research, since all grants there were competitive and an annual renewal of funds might not be forthcoming if another researcher at the university had come up with a more attractive program.

Fourth,  some MRC administrators apparently felt that Edwards and Steptoe had already gone out of their way to become celebrity scientists through a great deal of media exposure, and should any of the resulting babies be born with birth defects, these researchers  and the MRC as a whole, would not only be easy targets for adverse publicity but possibly also legal action.

However, it proved to be exactly  through the media-savvy  of Edwards and Steptoe that they were eventually able to raise enough private financial support to get their program underway, and after two completely normal births, the MRC reversed itself and funded them generously.

Where Has Edwards Published Most Often? And Would Your Library Have Been Able To Accommodate Him?

Librarians like this blogger often ask themselves if they could have readily fulfilled  the information needs of this Nobel Laureate, using the journals they have selected for their own library’s collections. We keep score of the adequacy of our judgment and budget partly by determining whether the assortment of journals within which this prizewinner published, would be in our holdings, since this test  is one pretty clear surrogate representing a research scientist’s reading needs.

Edwards, it turns out, is typical for most biomedical scientists who attain the Nobel Prize. He has published consistently (over 30 years straight with multiple articles in journals of international importance) and prolifically (over 400 articles) and widely (over 30 different journals, many by invitation), but he also had clear favorites that reported the bulk of his research.

Leading the pack was Human Reproduction, a British-based Oxford University Press journal, which is not only one of the field’s leaders, but which was founded by Edwards in 1986. Along with its companion publication Human Reproduction Update,  it accounted for 81 of his articles.

Edwards was also the founder in the year 2000 of an Elsevier electronic journal that accounted for 42 papers, Reproductive Biomedicine Online.

Three American journals along similar lines also published multiple  Edwards papers. The journal currently called Reproduction (but which until year 2000 was known as the Journal of Reproduction & Fertility, and still published by the Society for Reproduction & Fertility featured 16 papers. Nine Edwards papers appeared in the American Journal of Obstetrics & Gynecology, a collaboration between Elsevier and a coalition of  research and professional groups headed by the American Gynecological & Obstetrics Society. Fertility & Sterility, a journal jointly published by Elsevier and the American Society for Reproductive Medicine,  had eight Edwards papers.

Edwards also had an excellent track record publishing in collateral disciplines. It is no surprise that given the prominent role of hormones in reproduction that he appeared 12 times in the British-based Journal of Endocrinology from the Society for Endocrinology, and given that many of his techniques were based on observing and advancing animal embryology, it is natural that one of the oldest journals with strengths in that field, the Wiley title, the Journal of Experimental Zoology, would be the home for 7 of his articles.

Where Edwards was every bit the Nobel Prizewinner was in his choice of multiscience journals, Nature from Nature Publications Group(25 papers) and  the  Proceedings of the Royal Society of London B – Biological Sciences (7 papers)  and as well as  The Lancet (13 papers),  a leading journal of clinical investigation, from Elsevier. While all three are British-based,  these are among the most influential journals of their type worldwide, and have readerships that are actually greater numerically internationally than in their home country.

How Often Was Edwards Cited And Where Was He Cited?

While counting citations would seem a straightforward exercise in this age of online databases, authors with very common surnames and initials, such as R.G. Edwards,  share that same surname and initials with other scientists. In Edwards’ case there are at least one physicist and another biologist who are also R.G. Edwards, and figures for citations to their papers tend to be commingled and require sorting out. It is nonetheless safe to say that our particular Robert G. Edwards was cited almost 13,000 times in the scientific and clinical literature.

Which journals cited him most often? We ask this because it’s another good proxy measure librarians use in modeling whether or not they could service the needs of a potential patron.

The answers here are not too surprising. According to a sample taken of citations to his most famous papers, we find three journals that consistently account for double digit percentages: Fertility & Sterility, Human Reproduction (both of which were favorite outlets for Edwards) and the Biology of Reproduction ( a US-based journal published by the Society for the Study of Reproduction which tends not to cover human reproduction and as such was not as frequent an outlet for Prof. Edwards).

The next tier is occupied by the journal now known as Reproduction (another Edwards favorite) and by three journals of endocrinology,  the first of which,  the Journal of Endocrinology,  was a preferred venue of Edwards, while  the latter two,   Endocrinology and the Journal of Endocrinology & Clinical Metabolism are  US-based publications of the Endocrine Society.

Rounding out the top ten citers of Edwards are three journals strong in what is now called Developmental Biology, but which was historically termed Embryology.  Edwards had a good track record as both an author and cited authority in the Journal of Experimental Zoology, published a few papers in the journal now known as Molecular Reproduction and Development (originally Gamete Research) a NYC Wiley title that still cites him often, and he is cited frequently by Developmental Biology, a US-based  journal sponsored by the Society for Developmental Biology, and managed by Elsevier.

All in all, the vast majority of works of Robert G. Edwards and citations to those works are concentrated in relatively few scientific and clinical journals (compared to a universe with thousands of titles), and every one of them makes sense to experienced developers of library collections and budgeters for electronic access to journals in the basic life and clinical sciences.

The professional librarians of the BioMedical and Life Sciences Division of the Special Libraries Association had voted no fewer than seven of the journals discussed in this blog posting  to its list of the 100 most influential journals of biology and medicine of the twentieth century (perhaps now better known as the DBIO 100). These include the American Journal of Obstetrics & Gynecology, Developmental Biology, the Journal of Clinical Endocrinology & Metabolism, the Journal of Experimental Zoology,  The Lancet, Nature and the Proceedings of the Royal Society of London B: Biological Sciences. Indeed Nature was voted the Journal of the Centennial of SLA, and the three publishers most often mentioned in this blog posting, Elsevier, Wiley and Nature Publications Group, were ranked first, second and third respectively, in terms of  publishing the most journals within the top 100.

http://units.sla.org/division/dbio/publications/resources/topten.html

Furthermore, a quick check of WorldCat for libraries still having Edwards’ 1,000+ page,  1980 treatise, Conception in the human female, a title described in a review in Nature (Short 1981) as “a treasured possession,” on their shelves shows that it is still likely to be valued in virtually all the major research institutions in not only the US but many in the rest of the world: China, Germany, Israel, Saudi Arabia, and South Africa among them.

 The world has been well served by Professor Edwards and a great many biomedical and life sciences librarians around the could conceivably (pun intended) have returned the favor!

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

University of Arkansas Libraries 233E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

Edwards, Robert G. 1980. Conception in the human female. NY: Academic Press.

Johnson, M.H., S.B. Franklin, M. Cottingham,  &  N. Hopwood. 2010. Why the Medical Research Council refused Robert Edwards and Patrick Steptoe support for research on human conception in 1971. Human Reproduction 25 (9): 2157-2174.

Short, R.V. 2001. Beyond mechanics in human reproduction. [Review of Conception in the human female by Robert G. Edwards]. Nature 294: 784.

Stankus, Tony & Sarah E. Spiegel. 2009. The SLA DBIO 100 Poll: 100 Journals Voted by SLA’s BioMedical and Life Sciences Division as the Most Influential over the Last 100 Years. Serials Review  35 (4): 202-212.

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

Axelrod, Nelson, Yuan Lin, Pauline C. Ng, Timothy B. Stockwell, Jonathan Crabtree, Jiaqi Huang, Ewen Kirkness, et al. 2009. The HuRef browser: A web resource for individual human genomics. Nucleic Acids Research 37, (01): D1018-24.

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-.

Gibson, Daniel G., Gwynedd A. Benders, Cynthia Andrews-Pfannkoch, Evgeniya A. Denisova, Holly Baden-Tillson, Jayshree Zaveri, Timothy B. Stockwell, et al. 2008. Complete chemical synthesis, assembly, and cloning of a mycoplasma genitalium genome. Science (New York, N.Y.) 319, (5867) (02/29): 1215-20.

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.

Glass, John I., Hutchison,Clyde A.,,3rd, Hamilton O. Smith, and J. C. Venter. 2009. A systems biology tour de force for a near-minimal bacterium. Molecular Systems Biology 5, : 330-.

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.

Levy, Samuel, Granger Sutton, Pauline C. Ng, Lars Feuk, Aaron L. Halpern, Brian P. Walenz, Nelson Axelrod, et al. 2007. The diploid genome sequence of an individual human. Plos Biology 5, (10) (09/04): e254-.

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.

Venter, J. C. 2010. Multiple personal genomes await. Nature 464, (7289) (04/01): 676-7.

Venter, J. Craig, Mark D. Adams, Eugene W. Myers et al. 2001. The sequence of the human genome. Science 291 (5507): 1304-1351.

Wang, Guangjun, Jie Zhang, Fuping Song, Jun Wu, Shuliang Feng, and Dafang Huang. 2006. Engineered Bacillus thuringiensis GO33A with broad insecticidal activity against lepidopteran and coleopteran pests. Applied Microbiology and Biotechnology 72, (5) (10): 924-30.

Williamson, Shannon J., Douglas B. Rusch, Shibu Yooseph, Aaron L. Halpern, Karla B. Heidelberg, John I. Glass, Cynthia Andrews-Pfannkoch, et al. 2008. The sorcerer II global ocean sampling expedition: Metagenomic characterization of viruses within aquatic microbial samples. Plos One 3, (1): e1456-.

Yan, Ginxin, Fuping Song, Changlong Shu, Jingjing Liu, Chunqin Liu, Dafang Huang, Shuliang Feng, and Jie Zhang. 2009. An engineered Bacillus thuringiensis strain with insecticidal activity against Scarabaeidae (Anomala corpulenta) and Chrysomelidae (Leptinotarsa decemlineata and Colaphellus bowringi). Biotechnology Letters 31, (5) (05): 697-703.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

OTHER ORGANS, OTHER POSSIBILITES

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

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

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

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

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

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

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

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

 

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

 

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

 

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

 

Dr. Ira Casson and the NFL team of experts

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

The Criticisms & the Sad, Adverse Case Histories

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

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

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

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

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

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

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

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

Congress Throws the Red Flag

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

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

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

University of Arkansas Libraries MULN 223E

365 North McIlroy Avenue

Fayetteville AR  72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Schwarz, A. (October 29, 2009). NFL scolded over injuries to its players. New York Times, CLIX, (54843), A1, continued on A18.

Solomon, G. S., & Haase, R. F. (2008). Biopsychosocial characteristics and neurocognitive test performance in national football league players: An initial assessment. Archives of Clinical Neuropsychology: The Official Journal of the National Academy of Neuropsychologists, 23(5), 563-577.

Takhounts, E. G., Ridella, S. A., Hasija, V., Tannous, R. E., Campbell, J. Q., Malone, D., et al. (2008). Investigation of traumatic brain injuries using the next generation of simulated injury monitor (SIMon) finite element head model. Stapp Car Crash Journal, 52, 1-31.

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

Viano, D. C., Casson, I. R., & Pellman, E. J. (2007). Concussion in professional football: Biomechanics of the struck player--part 14. Neurosurgery, 61(2), 313.

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

Viano, D. C., Casson, I. R., Pellman, E. J., Zhang, L., King, A. I., & Yang, K. H. (2005). Concussion in professional football: Brain responses by finite element analysis: Part 9. Neurosurgery, 57(5), 891.

The Amygdala’s Role In Learning, Memory, Social Intelligence, Criminal Behavior, Mood Disorders And Especially The Retention of Traumatic Memories In Adult PTSD

The amygdala comprises two almond-sized-and-shaped portions of the mid-brain, that are becoming more and more common targets for study. The numbers of  research reports involving the amygdala  has been skyrocketing with each passing year. As of the date of this blog, September 9, 2009, PubMed reports 21,633 papers in which the amygdala is mentioned, 1933 of them being major review articles. 

And while there are two units (left and right sides of the brain) to the amygdala, it is more often discussed as if it were one organ, so the singular term “amygdala”, and the common usage plural “amygdalas,”  not the Latin plural “amygdalae” is used here and throughout most of the medical literature.

The amygdala is connected with the prefrontal cortex, an area involved with our highest intellectual properties,  and receives sensory inputs from it all the time. But the amygdale is not a part of the conscious brain.  It does not think through images or situations in a sophisticated way. Instead it is part of the limbic system, an evolutionarily highly conserved area that was well developed in animals before man, and is part of an active  vigilance-for-survival  mechanism.

The amygdale  is like  a guard dog that never sleeps.  It instantly senses danger and calculates magnitude of risk in microseconds. It then passes the message on to the hippocampus, which then routes the message to memory and action centers which help initiate responses and activate coping mechanisms. 

 Simultaneously ,  the amygdale causes cause a flood of cortisol, a notable stress hormone, throughout the body. Indeed the “gut sense” that one is in danger is quite literally through the action of the amygdale in prompting “fight-or-flight” hormone surges.

Descartes’ Rational Mind vs. Body Dualism Exploded by Damasio and LeDoux’ s Emotional Brain and Amygdala

Nonetheless, it has become increasingly clear that the amygdale is not just a fear machine.

The study of the function of the amygdale has helped resolve one of the great debates in neuroscience over the last 250 years: Whether the Body (in this case, the amygdala and the brain)  governed the Mind (in this case, the sense of consciousness, self-awareness, thought processing, learning and memory), or whether these were two truly distinct operations.

This debate has largely been framed through a challenge to the thinking of Rene Descartes, 1596-1650,  a French philosopher and scientist, who posited that   man had a rational mind, intellect or soul whose functioning was largely independent of the body and its body parts and which did not have to obey the laws of physics. He gave the mind  and thought processes a higher place, saying “I think, therefore, I am.”

In other words, explanations of the operation of the mind, soul or intellect ----including problems of consciousness, thought, learning and memory----cannot, according to Descartes,  be reduced to the laws governing biology, chemistry & physic, which clearly have dominion over the body and its parts. 

Therefore,  according to Descartes, the study of thought processes   and learning were  properly outside the field of medicine, and  suitable only for philosophy courses.

Descartes did allow for the pineal gland to be the possible location of the soul or intellect, but basically saw clear jurisdictional lines  separating the body and most of its organs from all things that are the product of the “rational” mind: thoughts, memories, and especially the acquisition of new knowledge.

However, it  is now increasingly well-argued in works by two of  the last century’s greatest neuroscientists,  Antonio Damasio (University of Iowa),  author of Descartes’  Error: Emotion, Reason and the Human Brain (1995), and of The Feeling of What Happens: Body and Emotion in the Making of Consciousness (2000)and Joseph LeDoux (NYU), author of The Emotional Brain: The Mysterious Underpinnings of Emotional Life (1996) and of The Synaptic Self: How Our   Brains Become Who We Are,  that  an actively functioning emotional-alarm-circuit  amygdala (clearly a body part) allows for new information  to be better incorporated into memory (clearly a intellectual process that Descartes saw as “rational” and not Body-Part-Independent) and subsequently into action.

Indeed our sense of reality and what we pay attention to (in a sense our own construction of the  conscious world in which we see ourselves living ) are in many ways amygdala-dependent .

Or in the view  of Damsio and LeDoux, “ We feel, as well as think, therefore, we are who we are in the world as we perceive it”

The amygdala may very well do this by helping the brain identify salient points of new inputs (whether they have red or green flags indicating either danger or reward) and to prioritize them by the use of the “magnitude dial” of the amygdale (important enough to pay close attention, or not so important or threatening and therefore, something to ignore).

Ultimately, as Damasio and LeDoux would argue, we tend better to learn and remember those things that have particular, added  emotional emphases in our lives, and we have to work harder at recall to retrieve information that has no special meaning.

In other words, we remember that on July 3^rd, our mother died, but we cannot recall what we had for breakfast on November 15^th,  because that was not an unusually emotionally charged occurrence.

Incoming information about a death in the family is processed by the amygdale as a fearful new fact, which gives it additional weight in its routing, storage, and availability for retrieval within the brain.  Whether you had oatmeal or eggs is likely not.

A well-functioning amygdale also appears to help us interpret the emotional state of others through accurately processing the emotions they display through their facial expressions.  This conveys an evolutionarily important advantage, because seeing the signs of either collective panic (danger) or group jubilation (opportunity)  in the demeanor of others enables you better to  take action sooner.

You need not personally see the coming tidal wave to realize that you must run to higher ground. Likewise, you can determine if your parent or teacher is happy with you, or angry, before they ever say a word.

  Shrunken or Damaged Amygdala

It is perhaps no surprise that persons with ADHD  who have trouble focusing have been revealed in some studies to have a diminished amygdalas, reducing their ability to see what is important and to pay attention to it.

Likewise, persons with Aspberger’s Syndrome and more severe Autistic Spectrum Disorders, have diminished amygdalas,  suggesting that their inability to zero in on people’s faces or activities, keeps them unaware of the emotional states of others. They have a reduced ability to formulate a Theory of Mind that is important to learning  throughout the lifespan.

In other words, they cannot pay attention to what is being demonstrated by others and imitate it as part of learning or social integration, because they view all incoming information as having equal threat or reward potential, and therefore being of no particular worth of paying attention to one thing or person over another thing or person.

At the worst,  some autistics  see all incoming information as being consistently threatening, and will disengage from the outside world, because such a constant threat level is unsustainable owing to the inner turmoil it generates.

A similar pattern of behavior, where suspiciousness and a sense of being attacked, is found in some patients with Alzheimers, when the beta-amyloid plaques that are characteristic of the disease, interfere with the operation of the amygdala.

A legal hot-button issue is that some brain imaging studies have found that criminal sociopaths have diminished amygdalas. (see the work by Yaling Yang, an expert on the brain abnormalities of psychopaths and pathological liars, and her co-workers, at UCLA, below). Shrunken or malfunctioning amygdales  are associated with a lesser ability to determine the emotional states of other persons, so that presumably, the criminal had little or no ability to realize the depth of pain and suffering he or she was inflicting. This is argued by some criminal defense attorneys as allowing for a medical or psychiatric disability that eliminates or reduces culpability for their crimes.

 However, usage of such defenses also opens up the possibility that if the diminished amygdalas are the cause of the criminal behavior, then perhaps the criminal should be confined to an asylum for the criminally insane until the amygdalas “get back to normal,” an anatomical  recovery that may take longer than the usual prison sentence, assuming it ever happens.

Persistent, Dysfunctional Fearful Memories and PTSD

Obviously one of the major clinical concerns where the amygdala may play a role is in patients with persistent anxiety and depression. A wide variety of brain function and imaging studies do in fact, implicate amygdala dysfunction or hyperactivity activity  in  the linkages of the amygdale to the hippocampus or the prefrontal cortex. 

Therapies that have achieved the most success seem to have help to break, at least temporarily, the association of some reasonably neutral stimuli (for example,  a loud noise) with a particularly traumatic memory (for example, a bomb going off).  In other words, they disrupt, at least temporarily, the negative  Pavlovian cycle of  stimulus and automatic response.

But a developmental brain study breakthrough in the journal Science by Gogolla et al. cited in detail below, shows why this may actually be easier in children than in adults.

It turns out that at about four weeks of age (which translates into some years within early human childhood)  in lab rats  that had been exposed to Pavlovian fearful conditioned stimuli, the memory of that fearful stimuli, and the associations that came with it, seemed permanent, and could be brought again and again  to the surface with only modest levels of adverse stimuli, even after several months (many years in human aging). They couldn’t forget.

However, before that age , these painful associations and the memory of the fear became extinct.

The difference appears to be a protective protein coat that encapsulates certain areas of the amygdala beginning at four weeks. 

The coat appears to eliminate, or at least greatly reduce the loss of fearful memories, generated by training with negative Pavlovian stimulus and responses, perhaps as an adult survival aid. In other words, adults who remembered what was dangerous had an evolutionary advantage over those who kept forgetting.

However, the same team of scientists that discovered this memory-entrapping protein coat for the amygdala, also came up with a line of  rats  that were genetically deficient in producing that protein and developing that amygdale coat.

 These rats lost their fearful memories and anxiety routinely past the four weeks critical point, despite having been exposed to a similar negative Pavlovian stimulus and response training.  In other words, no coat means  no recall of fearful memories or triggering of “Pavlovian panic” in the rats.

Whether or not this could somehow be adapted to humans with PTSD is uncertain, and the wisdom of effectively erasing a large portion of,  if not all,  adverse memories and fear responses would surely be a matter of great ongoing medical and psychiatric debate.

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

Univesity of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

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What is Regenerative Medicine? And What Will an Easing Of Restrictions on Embryonic Stem Cell Research Mean for this Field?

On March 9, 2009, President Obama lifted some sanctions initially imposed during the George W. Bush presidency on the study and use of human embryonic stem cells, a development of great importance for the new field of regenerative medicine.

 

 

 Regenerative   medicine today largely focuses on using cultured stem cells to replace adult specialized cells that are no longer operating well,  or operating at all.

 

 

The causes for the cellular malfunction or absence may be damage from  infectious diseases or trauma, collateral damage from tumor removal,  x-ray or chemotherapy treatments, as well as inherited diseases.

 

But most often   the need for cell replacement appears to be age-related.

 

Why do Cells Need to Be Replaced?

 

There is overwhelming evidence that specialized cells in adults lose much of   their ability to divide into health functioning cells with time.

 

Yet transplanting wholly mature and specialized cells that perform the same function as the adult cells that are failing in an organ or body part has been only marginally successful to date.

 

 

Immunological rejection and the fact that the transplanted older cellular  materials may themselves senesce, has often lead to rather short-terms restorative gains, if there are any gains at all.

 

The transplanted cells undergo only so many cell cycles of mitosis and then shut down.

 

 

Why are Stem Cells Good Candidates as Replacement Cells?

 

 

Stem cells share a property with many cancer cells. They can multiply forever, given the right environment and nutrients. In a sense, they are a self-perpetuating source of raw material for eventual cell replacement therapies.

Just as importantly,  stem cells have the ability, with the right prompting,  to transform themselves into specialized cells that can be transplanted.

 

 

 

 

The theory is that they will remain vital longer than do the usually  transplanted adult cells and tissues, and sometimes they do not provoke immunological rejection as soon or as extensively. 

 

The union of these two abilities basically means that, if all things go well, the regenerative physician-scientist has a kind of cellular clay deposit that replenishes itself and that clay can be spun and fired into a wide variety of specialized pots and vases, that subsequently hold up well.

 

 

Are All Stem Cells The Same?

 

 

There are two basic types of stem cells.

 

 

 

 

By far, the most promising to date have been human embryonic stem cells. These show the greatest flexibility in what kinds of cells and tissue they can be made to become in the lab.

 

 

These cells are obtained, as their name suggests,  from donated fertilized human embryos (usually “surplus” embryos that the mother-to-be now feels no need for keeping around because  she has already had a successful pregnancy or pregnancies).

 

 

 

 

These intact embryos  are sacrificed, by being torn apart,  at an early stage of their development, when the cellular components retain  the essential quality of being unspecialized or more technically “undifferentiated.” 

 

 

 

 

The now separated embryonic cells are plated onto petri dishes, where,  with the right growth medium, they thrive, until they are directed to develop into the more specialized cells that are required.

 

 

 

 

However, there are also adult stem cells. These have been derived from bone marrow, liver lobes, fat deposits, skin, umbilcal cords, and other tissues.

 

 

 

 

A key difference in their processing is that   in many instances they have to have their  “inflexible” adult specialization knocked out of them through switching off some of their regulatory genes.

 

 

 

 

In  other words, they have to lose the ability to do certain highly specialized tasks that are “used to doing”  in order to be retrained.

 

 

 

 

In return for this, they assume a child-like plasticity to grow in petri dishes with much the same vigor as do the embryonic stem cells, and after a time, they can be re-programmed into the cells that are needed for a particular patient’s replacement needs.

 

 

 

 

Reprogrammed adult stem cells actually have the possibility of being derived from the very patient who needs the cell replacement, meaning that they have the potential to have almost zero chance of being rejected.

 

 

 

 

What Obstacles Need to Be Overcome in Order for Stem Cell Research to Fulfill its Clinical Promise?

 

 

 

 

There is no getting around the fact that many people, even those who are scientifically very well-informed, feel that destroying human embryos is destroying human life, and are therefore opposed to this line of research on moral grounds.

 

 

 

 

Those who disagree with that argument say that the embryos would  likely be destroyed anyway, so that there is no point in letting them go to waste.

The counterpoint to that argument is that a market will develop for producing human embryos directly for embryonic stem cell research, and support for the idea and underlying cell culture technology of cloning humans embryos will be accelerated.

 

 

 

 

Apart from the moral arguments, there  is   an unfortunate, and  occasionally observed tendency of some introduced embryonic stem cells to form tumors rather than healthy functioning replacement tissues, and as yet this cannot be predicted or controlled.

 

 

Some of the most intensive work today is focused on characterizing markers (usually cell surface proteins)  for healthy versus suspect stem cells, and for identifying subpopulations of stem cells that seem more promising than others.

 

 

 

 

Because, without  marker screening,  the embryonic stem cell cure could be as bad or worse than the disease.

 

 

 

Finally, two essential stem cell and tissue engineering  technologies need to be greatly expanded.

 

 

 

 

The first is the enhanced tailoring of the chemical,  physical and even dynamical  environments (petri dishes  shaken or not shaken, rotated or not rotated, inverted or right-side-up, with structural scaffolds or without them) of the undifferentiated cell cultures, so they can be induced to be exactly the right kinds of specialized cells.

 

 

 

 

There are conceivably hundreds of different specialized cells   that  are needed, but not yet hundreds of surefire ways of making them, to the exclusion of other cell types.

 

 

 

Second, even once the right types of cell are arrived at in pure culture, how are they to be stored before being administered, and in what medium are they to be administered?

 

 

 

Right now, many stem cells are apparently being frozen for storage, but it is not clear that this does not sometimes destroy or alter the functionality of some of the stem cells after thawing.

 

 

 

Means of administration of stem cells include the development of solutions that will not kill either the stem cells or the tissues surround the site of injection.

 

 

 

This is a serious consideration because different sites in the body have subtly different biochemical pH balances,  ionic concentrations, and mechanical pressures involved. 

 

 

 

Likewise, time-release gels or sponge-like matrices are being developed so that the cells are released more gradually, or so that they will not be attacked by adverse conditions on site before they can become established.

 

 

 

What Are The Types Of Condition Or Body Parts That Are Under The Most Study?

 

 

 

The list of target diseases is growing. By far the greatest level of research has been in areas of neuroregeneration, for conditions like Parkinson’s disease and spinal cord injury.

 

 

 

Coming in at something like second place is diabetes research, followed by bone and joint work, especially cartilage repair.

 

 

 

Work on eye diseases and the kidney have been less common, but are increasing.

 

 

 

But the greatest surge in recent months has been in revascularization of damaged heart tissue and cardiac vessels.

 

 

 

More diseases and organ systems are likely to be targeted for a stem cell program, given that some restrictions that have limited the embryonic stem cell side have been swept aside.

 

 

 

Progress in basic understanding and prototypical storage and delivery systems will accelerate.

 

 

 

When will actual “cures” be had?

 

 

 

The best guess is somewhere in the 10-15 year range.

 

 

 

Tony Stankus [email protected] Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

 

 

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Yamahara, K., & Itoh, H. (2009). Potential use of endothelial progenitor cells for regeneration of the vasculature. Therapeutic Advances in Cardiovascular Disease, 3(1), 17-27.

Yamahara, K., & Nagaya, N. (2008). Stem cell implantation for myocardial disorders. Current Drug Delivery, 5(3), 224-229.

Yokoo, T., Kawamura, T., & Kobayashi, E. (2008). Stem cells for kidney repair: Useful tool for acute renal failure? Kidney International, 74(7), 847-849.

Zhou, Q., & Melton, D. A. (2008). Extreme makeover: Converting one cell into another. Cell Stem Cell, 3(4), 382-388.

The Courage of ICU Nurses Who Must Save Patients From Themselves: The Controversy Over The Use of Physical and Chemical Restraints on Ordinarily Cognitively Competent & Nonterminal Adult Hospital Patients at Risk Of Pulling Out Their Respirator Tubes.

One of the most significant differences in hospital practice between the European Union and the US and its Australian counterparts is that the European tend to regard the use by nurses in intensive care of physical restraints, and doctor’s orders for the use of IV injections to sedate them, as excessive.

To be fair, on both sides of the Atlantic (and the Pacific & Indian Oceans as well) the use of restraints on the demented or otherwise aged mentally ill in chronic care has been reduced to a bare minimum, at least partly as a result of successful political agitation against its apparent cruelty, particularly in the understaffed and underfunded nursing homes and mental hospitals in which it was most commonly practiced.

The fact that these patients often died sooner of   unrelated causes may be due to some peculiar unintended effects.  Care that involved less use of restraints, sometimes led to fewer assessments of both the integrity of the restraints and the state of the patient,  so that downturns were more slowly perceived by the healthcare team. 

This is particularly the case with matters like aspiration pneumonia caused by the patient obtaining food or drink and then mis-swallowing them when unsupervised.

The American defense of their greater use of physical restraints in ICU settings is that the forceful extubation (yanking out the breathing tube) by the patient or by family members who are distraught at the sight of a loved relative on a respirator,  is not uncommon, and is very dangerous for the patient.

It might be argued that adult patients who are trying to extubate themselves are expressing a wish that ought to be legally honored. (There appears to be little argument that children ought not be allowed to decide this for themselves.)

This argument against restraints tends to ignore the fact that most patients who are intubated and in an American ICU at this time of managed care in hospitals , are those who have suffered a severe illness or injury from which, in the judgment of the physicians and nurses,  they are likely to recover, a fact that the patient is in no condition to assess given the combinations of pain, prior hypoxia and prescriptions, all of which have the potential to skew clear thinking.

Most hospitals, and certainly most health insurances, will no longer pay for undoubtedly terminal patients to stay in ICUs for an extended time when the situation is futile, particularly if “comfort care” can be provided in another ward or in another setting altogether.

In addition, later this year (2008), Medicare will no longer pay for the extension of hospitalization caused by patient falls, deeming this a preventable occurrence, through, among other measures, the judicious use of restraints for persons whose balance, gait, and cognitive capacity are not up to ambulating without assistance. .

Moreover, most advanced medical directives drawn up by American attorneys or made available as forms by health providers in the US specify the discontinuance of extraordinary means (including mechanically assisted ventilation) only if there is no reasonable chance for the patient to regain   their health, sometimes qualified with clauses requiring that they be sustained only if it is likely that they will regain a high level of functioning, or have the chance of living without unmanageable pain.

Consequently,  it would appear that decisions made by patients in their more rational moments, particularly if well-elaborated (and ideally communicated to the family well in advance) ought to be honored over those that may represent what, for the lack of a better phrase, a patient made crazy by pain or panic.

In the interim, ICU nurses must often get the patient to cooperate in their own care, sometimes when the patients are agitated and delirious, and in some cases when the patients have somehow communicated to relatives that they are being “tortured” or “being held against their will.” 

Suspicious as it sounds to critics of  restraints, the use of  anxiety reducing drugs is often prescribed not only to minimize agitation but because its relaxant effect better enable breathing by machines ( ventilator- lung synchrony).

Critics of this chemical restraint should be somewhat assuaged by the fact that trends in the US are to wean patients off of both the ventilator and medication much sooner than was formerly done, partly because the chance for adverse outcomes from all causes seems to rise the longer one stays in the ICU, and the chances for better cognitive functioning go up when the patient is out of the ICU, breathing on their own, and ideally, in a lowered state of pain and anxiety.

There have been conflicting reports on whether the use of physical or chemical restraints has caused more or less emotional damage through vivid recall of the ICU and intubation experience.

It has generally been shown that the older the patient, the more likely it is that he or she has little or no recall, no matter what level of sedation was administered.

(At age 57, I cannot always remember what I had for lunch, so there may be some normal decline in recall of any events.)

But it has also been shown that the recalls are typically unreliable with adult ICU patients at any age, because they conflate imagined with real painful or frightful experiences.

Nonetheless, even some conflated memories of misadventures  seem to have a curiously protective effect for the patient against PTSD, because they help the patient comprehend the severity of their prior illness, and cause the patient to focus on going forward to recovery.

Ultimately, it is the higher and tougher duty of the ICU nurse to get patients to that stage, because when everyone else, particularly patients and families are losing their heads, nurses have to keep theirs, even if it means tying down hands, arms, (or relatives!).

This blogger recommends all of the following e articles to you, but the two-part series by Hofso and Coyer are arguably the best overviews available if you have only limited time.

Antonelli M et al. 2007. A multiple-center survey on the use in clinical practice of noninvasive ventilation as a first-time intervention for acute respiratory distress syndrome. Critical Care Medicine 35 (1): 18-25.

Birkett KM, Southerland KA & Leslie GD. 2005. Reporting unplanned extubation. Intensive & Critical Care Nursing 21 (2): 65-75.

Bova KA. 1996. Commentary on Decreasing unplanned extubations in the surgical intensive care unit [original article by Tominaga G et al appears in AM J SURG 1995;170(6):586-90]. AACN Nursing Scan In Critical Care 6 (3): 35-35.

Bray K, et al. 2004. British Association of Critical Care Nurses position statement on the use of restraint in adult critical care units. Nursing in Critical Care 9 (5): 9.

Byard RW, Wick R & Gilbert JD. 2008. Conditions and circumstances predisposing to death from positional asphyxia in adults. Journal of Forensic and Legal Medicine 15 (7): 415-419.

Capuzzo M, et al. 2001. Analgesia, sedation and memory of intensive care. Journal of Critical Care 16: 83-89.

Cornock M. 1998. Stress and the intensive care patient: perceptions of patients and nurses. Journal of Advanced Nursing 27 (3): 518-527.

Devlin JW et al. Survey of sedation practices during noninvasive positive-ressure ventilation to treat acute respiratory distress. Critical Care Medicine 35 (10): 2298-2302.

DeWit M & Epstein SK. 2003. Administration of sedatives and level of sedation: comparative evaluation via the Sedation-Agitation Scale and the Bispectral Index. American Journal of Critical Care 12: 343-348.

Dimond B. 2008. Dilemma: Do relatives have legal powers regarding continuation or withdrawal of treatment for patients in ICU? Nursing Times 104 (31): 13.

Egerod I, Christensen BV & Johansen L. 2006.Trends in sedation practices in Danish intensive care units in 2003: a national survey. Intensive Care Medicine 3: 260-266.

Elk S & Ferchau L. 2000.Physical restraints -- are they necessary? American Journal of Nursing 24.

Evans D & FitzGerald M. 2002. Reasons for physically restraining patients and residents: A systematic review and content analysis. International Journal of Nursing Studies 39 (7): 735-743.

Evans D, Wood J & Lambert L. 2003.Patient injury and physical restraint devices: A systematic review. Journal of Advanced Nursing 41: 274-282.

Guldbrand P, et al. 2004. Survey of routines for sedation of patients on controlled ventilation in Nordic intensive care units. Acta Anaesthesiologica Scandinavica 48 (8): 944-950.

Happ MB, et al. 2004. Communication ability, method, and content among nonspeaking nonsurviving patients treated with mechanical ventilation in the intensive care unit. American Journal of Critical Care 13 (3): 210-220.

Heffner JE. 2000.Editorial: a wake-up call in the intensive care unit. New England Journal of Medicine 342 (20): 1520-1523.

Hofso K & Coyer FM. 2007. Part 1. Chemical and physical restraints in the management of mechanically ventilated patients in the ICU: contributing factors. Intensive & Critical Care Nursing23 (5): 249-255.

Hofso K & Coyer FM. 2007. Part 2. Chemical and physical restraints in the management of mechanically ventilated patients in the ICU: a patient perspective. Intensive & Critical Care Nursing 23 (6): 316-322.

Jacobi J, et al. 2002.Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Critical Care Medicine 30 (1): 30.

Jones C, et al. 2001. Memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Critical Care Medicine 29: 573-580.

Kent MA. 1996. The ethical arguments concerning the artificial ventilation of patients with motor neurone disease. Nursing Ethics 3(4): 317-328.

Kollef MH, et al. 1998. The use of continuous IV sedation is associated with prolongation of mechanical ventilation.Chest 114: 541-548.

Kress JP, et al. 2000. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. New England Journal of Medicine 342: 1471-1477.

Kress PK, et al. 2003.The long-term psychological effects of daily interruption on critically ill patients. American Journal of Respiratory and Critical Care Medicine 168 (12): 1457-1462.

Lavery GG. 2004. Optimum sedation and analgesia in critical illness: we need to keep trying. Critical Care 8 (6): 433-434.

Löf L  et al. 2006. Severely ill ICU patients' recall of factual events and unreal experiences of hospital admission and ICU stay -- three and 12 months after discharge. Intensive and Critical Care Nursing 22: 154-166.

Maccioli GA, Dorman T& Brown BR. 2003. Clinical practice guidelines for the maintenance of patient physical safety in the intensive care unit: use of restraining therapies -- American College of Critical Care Medicine Task Force 2001-2002. Critical Care Medicine 31: 2665-2676.

Martin B. 2002. Restraint use in acute and critical care settings: Changing practice. AACN Clinical Issues 13 (2): 294-306.

Micek ST, et al. 2005.Delirium as detected by the CAM-ICU predicts restraint use among mechanically ventilated medical patients. Critical Care Medicine 33(6): 1260-1265.

Minnick A, Leipzig RM& Johnson ME. 2001. Elderly patients' reports of physical restraint experiences in intensive care units. American Journal of Critical Care 10: 168-171.

Minnick AD, et al. 1998.Prevalence and patterns of physical restraint use in the acute care setting. Journal of Nursing Administration 28 (11): 19-24.

Peruzzi WT&Hurt K. 2005.Approach to sedation in the ICU. Seminars in Anesthesthesia and Perioperative Medicine and Pain 2:  427-433.

Powers J. 1999. A sedation protocol for preventing patient self-extubation. Critical Care Nursing 18 (2): 30.

Prielipp RC &Young CC. 2001. Current drugs for sedation of critical ill patients. Seminars in Anesthesia and Perioperative Medicine and Pain 20 (2): 85-94.

Rose L & Bucknall T. 2004. Staff perceptions on the use of a sedation protocol in the intensive care setting. Australian Critical Care 17 (4): 151-159.

Russell S. 1999. An exploratory study of patient's perceptions, memories and experiences of an intensive care unit. Journal of Advanced Nursing 29: 783-791.

Samuelson K, Lundberg D & Fridlund B. 2006. Memory in relation to depth of sedation in adult mechanically ventilated intensive care patients. Intensive Care Medicine 32: 660-667.

Schweickert WD, et al. 2004. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Critical Care Medicine 32: 1272-1276.

Simini B. 1998. Unexpected endotracheal extubations. Lancet 352 (129): 671-672.

Soliman HM, Melot C & Vincent JL. 2001. Sedatives and analgesic practice in the intensive care unit: the results of a European survey. British Journal of Anaesthesiology 87: 186-192.

Stein-Parbury J & McKinley S. 2000.Patients' experiences of being in an intensive care unit: a select literature review. American Journal of Critical Care 9: 20-27.

Wittbrodt ET. 2005. Daily interruption of continuous sedation. Pharmacotherapy 25 (5): 25.

Woods JC, et al. 2004. Severe agitation among ventilated medical intensive care unit patients: Frequency, characteristics and outcomes. Intensive Care Medicine 30 (6): 1066-1072.

Wunderlich R, et al. 1999. Patients perceptions of uncertainty and stress during weaning from mechanical ventilation. Dimensions of Critical Care Nursing 18 (1): 2-8.

Tony Stankus [email protected] Life Sciences Librarian & Professor

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice 479-401-0021

Fax: 479-575-4592

Combat-Induced PTSD and Blaming the VA : Controversies in the Reliability & Frequency of PTSD Diagnoses, & What the Vietnam Experience Tells Us About Correlations of PTSD with Actual Exposure to Combat and Rates of Malingering

It is sadly not unusual, in connection to soldiers and marines returning from Iraq and Afghanistan who have sought psychiatric help for PTSD, to hear news reports alleging substandard VA in-patient or out-patient facilities or staffing, lack of after-discharge follow up, seemingly cruel denial of disability benefits, or when begrudgingly given, their lack of adequacy.

The effect of this is reinforced by television shows intended for entertainment, which feature a plot where a crime is committed by a combat veteran said to be suffering from PTSD, usually involving him in killing his wife, kids, or co-workers, and/or often himself. The denouement depends on whether or not the screenwriters wish to find the VA, the Department of Defense, or some other prominent and presumably greedy or crooked corporation or political figure guilty of the crime, rather than the veteran himself, who was portrayed to the viewer, at least, as truly ill with PTSD despite what the bureaucracy said about his not needing services, or their lack of adequacy or quality.

In both our news or our entertainment, then, we are likely getting saturated with depressing news about returning veterans and PTSD, and it is not surprising that many of us feel someone has to be blamed for this mess. Given that it is the VA that is charged most directly with dealing with the physical and mental health needs of veterans, it would appear to those who are outraged that they must therefore be the most responsible for denying each and every undoubtedly deserving veteran their rights to treatment and compensation for their having developed PTSD while in combat for our country.

But what if there were actual many serious questions about the validity of the official description and diagnosis of PTSD in successive editions of the DSM (the Diagnostic and Statistical Manual) , the bible, as it were, for psychiatrist, psychologists, and social workers? Could that explain a part of the problem?

What does the accumulated evidence suggest are the rates of developing PTSD among the soldiers and marines as a whole? When an exhaustive analyses of case records are done retrospectively, do the experts report that the VA has under-diagnosed or over-diagnosed PTSD?

What war-time circumstances make it seem more likely that a person has PTSD than not? Is every one who is the military at the time of war equally likely to develop PTSD?

And are there any cases of persons faking PTSD to either collect disability payments? What would make anyone think that this was even likely?

Some answers to these questions are emerging, and while they are not entirely consistent with one another, they should give one pause before automatically blaming the health care professional at the VA (and it would behoove VA hospital librarians to be aware of some of the following articles).

Is There An Even-Handed Study, Published in a Serious, Peer-Reviewed Journal, About What is Wrong with the way the VA handles PTSD patients?

Probably the best example of a thoughtful and thorough-going critique can be found in a piece by Frueh et al. in the American Journal of Public Health. They present a series of findings about the VA that are at once seemingly pro-and-anti veterans claims with respect to PTSD. On the responsive side, they report “The number of veterans receiving VA disability payments for PTSD increased 79.%%, whereas those receiving payments for other disabilities increased only 12.2%. On the slow-to-get-it-right-side: “In 2006, the VA took an average of 657 days for appeals resolution of disability claims.” Two core problems seem to be blamed more than others: There is vast inconsistency between the rates of returning veterans beings diagnosed with PTSD by hospital and by region, because of the way DSM is applied. They suggest that this is because the DSM description of the illness and guidelines for diagnosis are not based on generally agreed upon scientific evidence, and this is because an adversarial culture is almost unavoidably fostered in psychiatric treatment at the VA, because about 95% of the veterans seeking diagnosis and treatment of any mental disorder are filing a disability claim for PTSD at the same time. These veterans have zero financial interest in NOT being diagnosed with PTSD, and tend to view any diagnosis by the mental health professional that is handling their case that is not PTSD as hostile to their rights. This does not mean that all these patients are filing for PTSD benefits only for the money, or that they do not have PTSD. It does mean that some of them could be out as much as $36,000 a year in cash and many related health benefits ( an annual income that sadly, many under-educated or under-skilled veterans might have trouble making even without a qualifying PTSD diagnosis).

Is There a Consensus Based on Solid Scientific Evidence that the Current Standards for Diagnosis of PTSD Are Reliable?

The most recent review to date (June 2008) by Rosen & Lilienfield in Clinical Psychology Review suggests that “virtually all core assumptions and hypothesized mechanisms [through which PTSD is said to develop in the patient] lack compelling or consistent support.” They strongly recommend a thoroughgoing revision of the PTSD section in the next version of the DSM. This view is in part by shared by Elhai et al in the Journal of Clinical Psychiatry who feel that some of the criteria are not particularly distinctive, particularly “PTSD’s overlapping anxiety and mood disorder”. But they go on to suggest that in the current climate, any revision is unlikely to reduce the prevalence of diagnoses, nor will it likely “address questions raised about the diagnosis’ construct validity.” There is an entire issue (v.21, number 2, 2007) of the Journal of Anxiety Disorders focused on “Saving PTSD from itself in DSM-V” that is required reading for anyone who feels that the portrayal of PTSD as expressed in DSM-IV is still credible under close scientific scrutiny.

At What Rates do Veterans of Actual Combat Develop Disabling or Significantly Impairing PTSD?

There is a long-running debate between Dohrenwend et al and probably the best known PTSD practitioner and researcher in the country, RJ McNally of Harvard University’s Psychology Department, about the degree to which the largest database concerning the mental health of returning soldiers and marines, the NVVRS, or National Vietnam Veterans Readjustment Study, under-reports, reports at about the right level, or over-reports PTSD. Dohrenwend et al revised the rate of credible findings from an original estimate of 15.2% down to 9.1%, which McNally suggests would be actually down to 5.4% if it were based more strictly on having the PTSD actually render the veteran unable, or significantly impaired in his ability, to make a living and conduct his personal and family life. The story is arguably best reported in a commentary by Kilpatrick in the Journal of Traumatic Stress , which also includes a defense by the co-principal investigators of their original assessment.

Can Racial and Ethnic Differences in the Development of PTSD Among Combat Veterans Be Explained?

Dohrenwend et al. report in the Journal of Traumatic Stress that their analyses of records from the NVVRS, or National Vietnam Veterans Readjustment Study, shows that “Compared with [MW]Majority White [meaning non-Hispanic White], the Black elevation is explained by Black’s greater exposure [to actual combat] ; the [HW] Hispanic elevation, by Hispanics’ greater exposure [to actual combat], younger age, less education, and lower Armed Forces Qualification Test Scores [a test of general knowledge and aptitude for learning new skills]. The PTSD elevation in Hispanic versus Blacks is accounted for mainly by Hispanics’ younger age.” Basically, the younger the soldier or marine is, the less educated he or she is, the less advanced military training or experience he or she has, the lower the level of command and responsibility he or she has, and most importantly of all: the more actual combat they experience and close at hand casualties they witness, the likely it is that they develop PTSD. although even if all these conditions are met, only a small fraction actually do develop it.

Where Can I find a Readable & Highly Cited Overview of Controversies Surrounding PTSD to Get Started?

While it is somewhat dated (2003), this blogger can recommend, the paper by McNally in the Annual Review of Psychology 54: 229-252, entitled “Progress and Controversy in the Study of Posttraumatic Stress Disorder.” At the time of this blog this article has already been cited 96 times in other journals of behavioral medicine and clinical psychology. Among the rather sobering findings reported is the high rate at which veterans who had seen no combat whatsoever filed claims for PTSD, and indeed of the number of persons, including prominent public figures and actors, who were not even veterans at all, claiming to have suffered effects.

In Closing, A Cautionary Note on Dismissing PTSD Out of Hand

Not even the worse critics of the current means of diagnosing PTSD, or of its current treatment or of the process by which some claims of disability or compensation are granted or denied, argue that this is a factitious disorder in all cases. There is a growing body of evidence of late that there are some biological correlates in terms of brain imaging, human biochemical measurements, and a credible finding that those with mild brain trauma (conccusions mostly) seem to be at greater risk.

References & Other Suggested Readings

Axelrod BN. 2006. Interpreting symptoms in military personnel after combat. g>Lancet 367 (9524): 1709-1710.

Browne T et al. 2007. Explanations for the increase in mental health problems in UK reserve forces who served in Iraq. British Journal of Psychiatry 190 (6): 484-489.

Coyne JC & Thompson R. 2007. Posttraumatic stress syndromes: Useful or negative heuristics? Journal of Anxiety Disorders 21 (2): 223-229.

Dorhenwend BP et al. The psychological risks of Vietnam for US veterans: A revisit with new data and methods. >Science 313 (5789): 979-982.

Dohrenwend BP et al. 2007. PTSD and Vietnam veterans – A Response. >Science 315 (5809): 186-187.

Dohrenwend BP et al. 2007. Continuing controversy over the psychological risks of Vietnam for US veterans. Journal of Traumatic Stress 20 (4): 449-465.

Dohrenwend BP et al. 2008. WAX-related posttraumatic stress disorder in Black, Hispanic and majority white Vietnam veterans: The roles of exposure and vulnerability. Journal of Traumatic Stress 21 (2): 199-208.

Elhai JD et al. 2007. Varying cautionary instructions, monetary incentives, and comorbid diagnostic training in malingered psychopathology research. Journal of Personality Assessment 88 (3): 328-237.

Frueh BC et al. 2005. Documented combat exposure of US veterans seeking treatment for combat-related post-traumatic stress disorders. British Journal of Psychiatry 186: 467-472.

Frueh BC et al. 2007. US Department of Veterans Affairs disability policies for posttraumatic stress disorder: Administrative trends and implications for treatment, rehabilitation, and research. American Journal of Public Health 97 (12): 2143-2145.

Frueh BC et al. 2008. VA disability and posttraumatic morbidity: Frueh et al. respond. American Journal of Public Health 98 (5): 775-776.

Hall, Ryan C.W & Hall, Richard C.W. 2006. Malingering of PTSD: Forensic and diagnostic considerations, characteristics of malingerers and clinical presentations. General Hospital Psychiatry 28 (6): 525-535.

Hall, Ryan C. & Hall, Richard C. 2007. Detection of malingered PTSD. An overview of clinical, psychometric, and physiological assessment: Where do we stand? Journal of Forensic Sciences 52 (3): 717-725.

Hoge CW et al. 2006. Post-traumatic stress disorder in UK and US forces deployed to Iraq. g>Lancet 368 (9538): 837.

Hoge CW et al. 2008. Mild traumatic brain injury in US soldiers returning home from Iraq. New England Journal of Medicine 358 (5): 453-463.

Hoge CW et al. 2007. Association of posttraumatic stress disorder with somatic symptoms, health care visits, and absenteeism among Iraq war veterans. American Journal of Psychiatry 164 (1): 150-153.

Hotopf M et al. 2006. The health of UK military personnel who deployed to the 2003 Iraq war: A cohort study. g>Lancet 367 (9538): 1731-1741.

Hotopf M et al. 2006. Post-traumatic stress disorder in UK and US forces deployed to Iraq: Authors reply. g>Lancet 367 (9524): 837.

Howard MD. 2007. Escaping the pain: Examining the use of sexually compulsive behavior to avoid the traumatic memories of combat. Sexual Addiction and Compulsivity 14 (2): 77-94.

Jelicic M & Merckelbach H. 2004. Traumatic stress, brain changes, and memory: A critical note. Journal of Nervous and Mental Diseases 192 (2): 548-553.

Jones R. 2006. Interpreting symptoms in military personnel after combat. g>Lancet 368 (9538): 838.

Kasai K et al. 2008. Evidence for acquired pregenual anterior cingulated gray matter loss from a twin study of combat-related posttraumatic stress disorder. Biological Psychiatry 63 (6): 539-541.

Kashdan TB et al. 2007. Anhedonia, emotional numbing and symptom overreporting in male veterans with PTSD. Personality and Individual Differences 43 (4): 725-735.

Kilpatrick DG 2007. PTSD and Vietnam veterans. >Science 315 (5809): 184-185.

Kilpatrick G. 2007. Confounding the critics: The Dohrenwend and colleagues reexamination of the National Vietnam Veteran Readjustment Study. Journal of Traumatic Stress 20 (4): 487-493.

Knoll J & Resnick PJ. 2006. The detection of malingered post-traumatic stress disorder. Psychiatric Clinics of North America 29 (3): 629-end of article.

Lanius R. 2007. Complex adaptations to traumatic stress: From neurobiological to social and cultural aspects. American Journal of Psychiatry 164 (11): 1676-1683.

Linden M et al. 2007. Posttraumatic Embitterment Disorder: Definition, Evidence Diagnosis & Treatment. Hogrefe & Huber. 155pp.

Maren S & Chang CH. 2006. Recent fear is resistant to extinction. Proceedings of the National Academy of Sciences 103 (47): 18020-18025.

McNally RJ. 2003. Progress and controversy in the study of posttraumatic stress disorder. Annual Review of Psychology 54: 229-252.

McNally RJ. 2006. Cognitive abnormalities in post-traumatic sress disorder. Trends in Cognitive Sciences 10 (6): 271-277.

McNally RJ. 2007. Can we solve the mysteries of the National Vietnam Veterans Readjustment Study?. Journal of Anxiety Disorders 192-200.

McNally RJ. PTSD and Vietnam veterans – A Response. >Science 315 (5809): 185-186.

McNally RJ. 2007. Revisiting Dorhrenwend et al.’s revisit of the National Vietnam Veterans Readjustment Study. Journal of Traumatic Stress 20 (4): 481-486.

McTeague LM, McNally RJ & Litz BT. 2004. Pre-war, war zone and post-war predictors of pisttraumatic stress in female Vietnam veteran health care providers. Military Psychology 16 (2): 99-114.

Milliken CS et al. 2007. Longitudinal assessment of metnal health problems among active and reserve component soldiers from the Iraq war. JAMA: Journal of the American Medical Association 298 (18): 2141-2148.

Murdoch M et al. 2006. The association between in-service sexual harassment and post-traumatic stress disorder among department of veterans affairs disability applicants. Military Medicine 171 (2): 166-173.

Nathan PE. 2005. Bringing home the psychological immediacy of the Iraqi battlefield. Pragmatic Case Studies in Psychotherapy 1 (2): 1-3.

Norman SB et al. 2007. Profiling posttraumatic functional impairment. Journal of Nervous and Mental Disease 195 (1): 48-53.

Pitman RK et al. 2006. Clarifying the origin of biological abnormalities in PTSD through the study of identical twins discordant for combat exposure. Annals of the New York Academy of Sciences 1071: 242-254.

Rasmusson AM, Vythilinga M & Morgan CA, 2003. The neuroendocrinology of posttraumatic stress disorder: new directions. CNS Spectrum 8 (9): 665-667.

Rosen GM. 2004. Litigation and reported rates of posttraumatic stress disorder. Personality and Individual Differences 36 (6): 1291-1294.

Rosen GM. 2006. DSM’s cautionary guidelines to rule out malingering can protect the PTSD data base. Journal of Anxiety Disorders 20 (4): 530-535.

Rosen GM & Frueh BC. 2007. Challenges to the PTSD construct and its database: The importance of scientific debate. Journal of Anxiety Disorders 21 (2): 161-163.

Rosen GM & Lilienfeld SO. 2008. Posttraumatic stress disorder: An empirical evaluation of core assumptions. Clinical Psychology Review 28 (5): 837-868.

Rosen GM & Taylor S. 2007. Pseudo-PTSD. Journal of Anxiety Disorders 21 (2): 201-210.

Schlenger WE et al. The psychological risks of Vietnam: The NVVRS perspective. Journal of Traumatic Stress 20 (4): 467-479.

Spitzer, RL et al. 2007. Saving PTSD from itself in DSM-V. Journal of Anxiety Disorders 21 (2): 233-241.

Wessely S. 2005. War stories: Invited commentary. British Journal of Psychiatry 186: 473-475.

Wheeler DP & Braggin M. 2007. Bringing it all back home: Social work and the challenge of returning veterans. Health and Social Work 32 (4): 297-300.

Zohar J et al. 2008. Post-traumatic stress disorder: Facts and fiction. Current Opinion in Psychiatry 21 (2): 74-77.

Tony Stankus [email protected] Life Sciences Librarian & Professor
University of Arkansas Libraries MULN 223 E
365 North McIlroy Avenue
Fayetteville AR 72701-4002
Voice: 479-575-4031
Fax: 479-575-4592