SLA Biomedical & Life Sciences Division Blog

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

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

What is a hemorrhagic fever?

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

How lethal are these two diseases?

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

From where did these diseases come?

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

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

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

Avoidance strategies

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

Where does the disease lurk, then, between outbreaks?

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

What currently can be done for patients?

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

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

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

What are the current strategies for fighting Ebola and Marburg?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Valmas, Charalampos, Melanie N. Grosch, Michael Schümann, Judith Olejnik, Osvaldo Martinez, Sonja M. Best, Verena Krähling, Christopher F. Basler, and Elke Mühlberger. 2010. Marburg virus evades interferon responses by a mechanism distinct from Ebola virus. Plos Pathogens 6, (1): e1000721-.

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

Large Scale, Multifactorial Studies of Risk Factors

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

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

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

Specific Risk Factors: Metabolic Syndrome & Diabetes

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

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

Other Risk Factors:

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

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

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

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

Preventive Measures: Exercise and Omega-3 Fatty Acids

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

The Drive for Evidence-Based Medicine Affects Cardiology Advice

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

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

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

A Molecular Level Understanding of

Botched Attempts By the Heart to Repair Itself

& Handle Its Electrochemical Circuits

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

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

Comparing Medications to Reduce Blood Pressure

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

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

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

“Statin Island”

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

Blood Thinners

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

Avoiding Gastrointestinal Bleeding When on Blood Thinners

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

 

Interventional Cardiology Using Catheterization

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

Cardiac Vessel Stents

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

Autologous Transplantation of Heart Cells To Stimulate Cardiac Repair

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

The Cabbage  (CABG) Patch

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

Pacemakers

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

Looking Into the Beating Heart

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

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

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

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

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

Stroke

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

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

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

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

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

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

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

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

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

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

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

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

Had this Ever Been Done Before?

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

Why Hadn’t This Been Done Before?

Two reasons come to mind.

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

The other reason is more practical.

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

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

Why Then,  Do It the Hard Way?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

University of Arkansas Libraries MULN 233E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

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.

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

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

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

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

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

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

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

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

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

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

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

What Is The Genome’s Most Striking Finding?

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

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

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

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

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

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

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

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

Had Anyone Predicted This?

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

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

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

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

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

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

Is Widespread Acceptance of this Finding A Sure Thing?

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

What Else Do We Know About Neandertals?

Superior Tool Makers

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

But Not Good Clothing Designers

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

They  Nonetheless Accessorized

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

 

Great hunters

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

And Maybe Fishermen

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

And Even Bronco-Riders  (& Maybe Cannibals)

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

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

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

They Lived in Heated Apartments

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

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

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

But They May Not Have Been Great Musical Instrumentalists

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

What Did Neandertals Look Like?

Short & Stocky

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

Pale Skinned  & Red Headed

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

With Modern (not Broad Flat) Noses Sticking Out

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

 

With Really Big Teeth In Front & Back

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

 

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

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

Why Did Neanderthals Die Out?

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

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

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

 

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

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

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Burbano, Hernan A.,  Emily Hodges, Richard E. Green, Adrin W. Briggs, Johannes Krause wet al. 2010. Targeted investigation of the Neandertal genome by array-based sequence capture. Science, 328 (& MAY 2010): 723-725.

Conard, Nicholas J., Maria Malina, and Susanne C. Muenzel. 2009. New flutes document the earliest musical tradition in southwestern Germany. Nature (London) 460, (7256) (AUG 6 2009): 737-40.

Coop, Graham, Kevin Bullaughey, Francesca Luca, and Molly Przeworski. 2008. The timing of selection at the human FOXP2 gene. Molecular Biology and Evolution 25, (7) (JUL 2008): 1257-9.

Daniau, Anne-Laure, Francesco d'Errico, and Maria Fernanda Sanchez Goni. 2010. Testing the hypothesis of fire use for ecosystem management by Neanderthal and Upper Palaeolithic modern human populations. PLoS One 5, (2) (FEB 11 2010).

de Leon, Marcia S. Ponce, Lubov Golovanova, Vladimir Doronichev, Galina Romanova, Takeru Akazawa, Osamu Kondo, Hajime Ishida, and Christoph P. E. Zollikofer. 2008. Neanderthal brain size at birth provides insights into the evolution of human life history. Proceedings of the National Academy of Sciences of the United States of America 105, (37) (SEP 16 2008): 13764-8.

de Vos, John. 2009. Receiving an ancestor in the phylogenetic tree. Journal of the History of Biology 42, (2, Sp. Iss. SI) (MAY 2009): 361-79.

Dibble, Harold L., Shannon P. McPherron, Dennis Sandgathe, Paul Goldberg, Alain Turq, and Michel Lenoir. 2009. Context, curation, and bias: An evaluation of the Middle Paleolithic collections of Combe-Grenal (France). Journal of Archaeological Science 36, (11) (NOV 2009): 2540-50.

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Green, Richard E., Johannes Krause, Adrian W. Briggs, Tomislav Maricic, Udo Stenzel et al. A draft sequence of the Neandertal genome. Science, 328 (7 MAY 2010): 710-722.

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Krause, J., C. Lalueza-Fox, L. Orlando, W. Enard, R.E. Green, H.A. Burbano, J.-J. Hublin, J. Bertranpetit, C. Hänni, J. Fortea, M. de la Rasilla, A. Rosas and S. Pääbo. 2007.  The derived FOXP2 variant of modern humans was shared with Neandertals. Current Biology 17: 1908-12 .

Krause, Johannes, Qiaomei Fu, Jeffrey M. Good, Bence Viola, Michael V. Shunkov, Anatoli P. Derevianko, and Svante Paeaebo. 2010. The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature (London) 464, (7290) (APR 8 2010): 894-7.

Lopez-Garcia, Juan Manuel, Hugues-Alexandre Blain, Gloria Cuenca-Bescos, and Juan Luis Arsuaga. 2008. Chronological, environmental, and climatic precisions on the neanderthal site of the Cova del Gegant (Sitges, Barcelona, Spain). Journal of Human Evolution 55, (6) (DEC 2008): 1151-5.

Maricic, Tomislav, and Svante Paeaebo. 2009. Optimization of 454 sequencing library preparation from small amounts of DNA permits sequence determination of both DNA strands. BioTechniques 46, (1) (JAN 2009): 51-7.

Martinez-Moreno, Jorge, Rafael Mora, and Ignacio de la Torre. 2010. The Middle-to-Upper Palaeolithic transition in Cova Gran (Catalunya, Spain) and the extinction of Neanderthals in the Iberian peninsula. Journal of Human Evolution 58, (3) (MAR 2010): 211-26.

Maureille, Bruno, Francois Djindjian, Maria Dolores Garralda, Alan Mann, and Bernard Vandermeersch. 2008. The Mousterian teeth from the Boccard Cave, Bas-de-Morant (Municipality of Creancey, Cote-D'or, Bourgogne). Bulletins Et Memoires De La Societe d'Anthropologie De Paris 20, (1-2) (2008): 59-78.

Mladina, Ranko, Neven Skitarelic, and Katarina Vukovic. 2009. Why do humans have such a prominent nose? The final result of phylogenesis: A significant reduction of the splanchocranium on account of the neurocranium. Medical Hypotheses 73, (3) (SEP 2009): 280-3.

Moncel, Marie-Helene, Maria Gema Chacon, Aude Coudenneau, and Paul Fernandes. 2009. Points and convergent tools in the European Early Middle Palaeolithic site of Payre (SE, France). Journal of Archaeological Science 36, (9) (SEP 2009): 1892-909.

Munch, Kasper, Wouter Boomsma, John P. Huelsenbeck, Eske Willerslev, and Rasmus Nielsen. 2008. Statistical assignment of DNA sequences using Bayesian phylogenetics. Systematic Biology 57, (5) (2008): 750-7.

Nielsen-Marsh, Christina M., Christin Stegemann, Ralf Hoffmann, Tanya Smith, Robin Feeney, Michel Toussaint, Katerina Harvati, Eleni Panagopoulou, Jean-Jacques Hublin, and Michael P. Richards. 2009. Extraction and sequencing of human and Neanderthal mature enamel proteins using MALDI-TOF/TOF MS. Journal of Archaeological Science 36, (8) (AUG 2009): 1758-63.

Nowaczewska, W., and L. Kuzminski. 2009. The homo sapiens 'Hemibun': Its developmental pattern and the problem of homology. Homo 60, (6) (2009): 489-516.

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Olejniczak, Anthony J., Tanya M. Smith, Robin N. M. Feeney, Roberto Macchiarelli, Arnaud Mazurier, Luca Bondioli, Antonio Rosas, et al. 2008. Dental tissue proportions and enamel thickness in Neandertal and modern human molars. Journal of Human Evolution 55, (1) (JUL 2008): 12-23.

Pennisi, Elizabeth. 2010. Cloned Neandertals still in the realm of Sci-Fi.” Science 328, (7 MAY 2010): 682-683.

Pennisi, Elizabeth. 2010. Close encounters of the prehistoric kind. Science 328, (7 MAY 2010): 680-683.

Pennisi, Elizabeth. 2010. Computer kid makes good. Science 328, (7 MAY 2010): 683.

Prossinger, Hermann. 2008. Mathematical analysis techniques of frontal sinus morphology, with emphasis on homo. Anatomical Record 291, (11, Sp. Iss. SI) (NOV 2008): 1455-78.

Richards, M. P., G. Taylor, T. Steele, S. P. McPherron, M. Soressi, J. Jaubert, J. Orschiedt, J. B. Mallye, W. Rendu, and J. J. Hublin. 2008. Isotopic dietary analysis of a Neanderthal and associated fauna from the site of Ionzac (Charente-Maritime), France. Journal of Human Evolution 55, (1) (JUL 2008): 179-85.

Richards, Michael P., and Erik Trinkaus. 2009. Isotopic evidence for the diets of European Neanderthals and early modern humans. Proceedings of the National Academy of Sciences of the United States of America 106, (38) (SEP 22 2009): 16034-9.

Riel-Salvatore, Julien. 2008. Mad Neanderthal disease? Some comments on "A potential role for transmissible spongiform encephalopathies in Neanderthal extinction". Medical Hypotheses 71, (3) (SEP 2008): 473-4.

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Smith, T. M., K. Harvati, A. J. Olejniczak, D. J. Reid, J. -J Hublin, and E. Panagopoulou. 2009. Brief communication: Dental development and enamel thickness in the lakonis Neanderthal molar. American Journal of Physical Anthropology 138, (1) (JAN 2009): 112-8.

Sorensen, Bent. 2009. Energy use by Eem Neanderthals. Journal of Archaeological Science 36, (10) (OCT 2009): 2201-5.

Stringer, C. B., J. C. Finlayson, R. N. E. Barton, Y. Fernandez-Jalvo, I. Caceres, R. C. Sabin, E. J. Rhodes, et al. 2008. Neanderthal exploitation of marine mammals in Gibraltar. Proceedings of the National Academy of Sciences of the United States of America 105, (38) (SEP 23 2008): 14319-24.

Subramanian, Sankar. 2009. Temporal trails of natural selection in human mitogenomes. Molecular Biology and Evolution 26, (4) (APR 2009): 715-7.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

University of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

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Fax: 479-575-4592

 

Ambardekar, A.A. & R.C. Reigh. (2007). Sources and utilization of amino acids in channel catfish diets: A review. North American Journal of Aquaculture 69 (2): 174-179.

Broder, J.M. & T. Zeller, Jr. (2010). Bad, but how bad? New York Times CLIX (55030): A1, A17.

Chesler, S. N., B. H. Gump, H. S. Hertz, W. E. May, and S. A. Wise. (1978). Determination of trace level hydrocarbons in marine biota. Analytical Chemistry 50, (6) (01/01): 805-10.

Claiborne, R.C. (2010). Farming fish. New York Times CLIX (55009): p.2

Greenberg, P. A catfish by any other name. . New York Times Magazine (October 12, 2008) Section MM, p. 72 http://www.nytimes.com/2008/10/12/magazine/12catfish-t.html

Hargreaves, J.A. & C.S. Tucker. (2004). Biology and culture of channel catfish. Amsterdam: Elsevier.

Hyo-Bang Moon, Hye-Seon Kim, Minkyu Choi, and Hee-Gu Choi. 2010. Intake and potential health risk of polycyclic aromatic hydrocarbons associated with seafood consumption in Korea from 2005 to 2007. Archives of Environmental Contamination and Toxicology 58, (1) (01/01): 214-21.

Isigigur, A., H. Heras, and R. G. Ackman. 1996. An improved method for the recovery of petroleum hydrocarbons from fish muscle tissue. Food Chemistry 57, (3) (01/01): 457-62.

Kannappan, S., G. I. Jasmine, P. Jeyachandran, and A. Tamilselvi. 1999. Polyaromatic hydrocarbons in fresh marine fin and shell fishes. Journal of Food Science and Technology, India 36, (5) (01/01): 472-4.

Khan, M. A. Q., S. Al-Ghais, and S. Al-Marri. 1995. Petroleum hydrocarbons in fish from the Arabian Gulf. Archives of Environmental Contamination and Toxicology 29, (4) (01/01): 517-22.

Krahn, M. M., G. M. Ylitalo, J. Buzitis, J. L. Bolton, C. A. Wigren, Sin-Lam Chan, and U. Varanasi. 1993. Analyses for petroleum-related contaminants in marine fish and sediments following the Gulf oil spill. Marine Pollution Bulletin 27, (01/01): 285-92.

Naylor, R.L., R.J. Goldburg, J.Primavera, N. Kautsky, M.C.. Beveridge et al. (2001). Effects of aquaculture on world fish supplies. Issues in Ecology , no. 8.

Nemoto, S., S. Takatsuki, R. Matsuda, K. Sasaki, and M. Toyoda. 1998. Analyses for petroleum-related contaminants in seafoods by GC/MS (SIM). Journal of the Food Hygienic Society of Japan 39, (1) (01/01): 31-8.

Norena-Barroso, E., G. Gold-Bouchot, O. Zapata-Perez, and J. L. Sericano. 1999. Polynuclear aromatic hydrocarbons in American oysters Crassostrea virginica from the Terminos Lagoon, Campeche, Mexico. Marine Pollution Bulletin 38, (8) (01/01): 637-45.

Peeler, E.J. & A.G. Murray. (2004). Disease interactions between farmed and wild fish populations. Journal of Fish Biology 65 (supplement 1): 321-322.

Perugini, M., P. Visciano, M. Manera, G. Turno, A. Lucisano, and M. Amorena. 2007. Polycyclic aromatic hydrocarbons in marine organisms from the Gulf of Naples, Tyrrhenian Sea. Journal of Agricultural and Food Chemistry 55, (5) (01/01): 2049-54.

Robertson, C. (2010). Safety fears halt fishing in Gulf areas affected by spill. New York Times CLIX (55029):  A15.

Sammut, M., and G. Nickless. 1978. Petroleum hydrocarbons in marine sediments and animals from the island of Malta. Environmental Pollution 16, (1) (01/01): 17-30.

Sobrado, C., M. C. Quintela, J. C. Gonzalez, and J. M. Vieites. 2004. Determination of heavy polycyclic aromatic hydrocarbons (PAH) in fishery products. Journal of Aquatic Food Product Technology 13, (3) (01/01): 93-102.

Doctors & The Librarians Who Serve Them Agree on the Medical Journals That Matter the Most

In 2009, two   polls asked their respondents essentially the same question:  Which are the medical journals most important to your life’s work?

The two groups  separately reporting back were first, MDs with  specific medical specialties or  special responsibilities within medical administration. These doctors  typically  read  a  mix of journals  consisting of few of the most important general medical journals and several  others more   narrowly focused on  their particular specialty.

The second group polled were biomedical librarians.  Spending several billions of dollars annually within the US alone, they subscribe both to many general medical titles as well as to many other journals across a wide variety of  clinical specialties. Despite the magnitude of their collective expenditures, individual biomedical librarians generally have to live within fairly tight budgets for those libraries they administer on behalf of medical schools and of the teaching hospitals with which they have an affiliation,  and of necessity,  have become experts at buying  the best journals first.

The New England Journal of Medicine’s  “Essential Journals Study”

 The firm polling the doctors was the Matalia Group, Inc., an independent research firm, hired by the Massachusetts Medical Society, publishers of the New England Journal of Medicine. They had successfully done this work before for the  association.  While its  sponsorship was not known to the medical poll takers,  the poll’s underlying purpose was to find out where the New England Journal of Medicine placed in the poll respondent’s  opinions  in  several medical specialty areas. They asked  questions seeking to determine whether it was among those journals read first, read the longest and most closely, and/or  re-read most often, compared to its competition. The data was reported to the advertising sales group within  the journal, and then to potential advertisers, in a publication entitled “2009 Essential Journals Study.”  

The NEJM poll is available at http://nejmadsales.org/html/marketresearch.html

The SLA DBIO 100 Poll

The group  which polled the biomedical librarians is the sponsor of this blog, the BioMedical and Life Sciences Division (DBIO) of the Special Libraries Association. The poll sought to identify the 100 most influential journals  over the last 100 years in three broad areas of biology and medicine,.

They also determined which journals were voted in the top 10, which was the publisher of the Centennial, and which was the Journal of the Centennial.  

Since the DBIO 100 poll sought to cover many areas of biology in addition to clinical sciences  within  its self-limited roster of 100 winners, by design, only 33 of the journal finalists  in the poll  could come from medicine.

Furthermore, only 3 could be selected from among those 33 for the top 10.

And of course, only one  journal of any type of biology or medicine  could be named the journal of the Centennial.  

(In the interests of full disclosure, I conceived the poll, recruited the expert panels who drew it up, edited the final version, and was the reporter of the results.)

For an electronic listing of the DBIO 100 winners: click on  http://units.sla.org/division/dbio/publications/resources/dbio100.html

For a more detailed analysis see:  Tony Stankus & 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.

Are the Polls Directly Comparable?

There  are several areas in which the polls differ.

First the NEJM poll focused on fourteen different medical specialties or user groups, not all of which were covered within the DBIO 100 poll.

Most notably, the NEJM poll included the fields of Hospitalists (doctors employed full-time  on the wards , taking over the care of patients from their personal physicians) and Formulary Committee members (doctors who decide which drugs are recommended and kept in stock for dispensing for patients while they are in the hospital). The latter two groups are particularly important to the NEJM’s advertising team, because the bulk of advertising in the NEJM (and in most other medical journals) is for drugs, including those that are regarded as best for use on patients within hospital settings.

The DBIO 100 poll allowed for  30  areas of clinical  interest, including many not covered as separate entities  in the NEJM poll. Examples included Dentistry,  Dermatology, Emergency  Medicine, General Surgery, Geriatrics, Intensive Care,  Neuropsychology, Nursing,  Nutrition, Obstetrics & Gynecology, Pathology, Pediatrics,  Physical Therapy, Psychiatry, Public Health and Radiology.

In some areas, the DBIO 100 poll combined fields within a single voting category. Examples include Urology  +  Nephrology, and  Bone & Joint Diseases  (Orthopedics  + Rheumatology), or in somewhat different groupings:  the DBIO 100 used two sections consisting of Hematology & Leukemia and General Oncology while the NEJM featured three separate categories for Hematology, Hematology/Oncology & (General)  Oncology.  The NEJM subsumed Emergency Medicine within Pulmonology  while the DBIO100 kept those two fields distinct.

By contrast with the NEJM poll,  in the DBIO 100 poll, journals of general clinical investigation, constituting the most crowded field of the entire poll in terms of  the number of entries  nominated by the expert panel that designed the ballot,  were allowed four winners, not just one.

Finally, while the NEJM poll fixed the fields of medical practice that would be surveyed, it did not rely on having respondents choose from a list of nominated titles. It asked the voters to think on their own of the titles that came to mind fist or most often, and then rate them in certain ways. It is a remarkable tribute to the NEJM that it was constantly on the mind of so many practitioners in so many fields.

Despite these differences, there is enough overlap to test whether or not, doctors and the medical librarians who serve them in teaching and research, are on the same page in terms of journals they regard as essential and influential.  

General Internal Medicine & Clinical Investigation

While the vote in this category was close in the DBIO 100 poll, The New England Journal of Medicine ranked first  in this category, just as it did in its own  poll.

 Not only did the NEJM make the overall  top 10 in the DBIO 100 poll, it ranked number two in the overall Journal of the Centennial race among all journals of biology and medicine, losing only to the journal, Nature.

Other journals that placed well in the NEJM  poll in this category included JAMA: the Journal of the American Medical Association (which almost tied with the NEJM in the DBIO 100 poll), the Annals of Internal Medicine, American Family Physician, the American Journal of Medicine, the Archives of Internal Medicine and four others. Not too surprisingly,  the expert panel that composed this category for the DBIO 100 poll included all of these titles on the ballot.

The DBIO 100 poll  also voted in as winners two other journals not even mentioned in the NEJM  top 10 in  this General Internal Medicine and Clinical Investigation category:  The BMJ: British Medical Journal and The Lancet.  

In the DBIO 100 poll the BMJ joined with the NEJM  and JAMA in  filling in the three slots of  the clinical sciences contribution to the overall top 10.

It should be noted that in addition to its strong showin in the DBIO 100, The Lancet made numerous appearances throughout the NEJM poll, placing well in among members of  Formulary committees, as well as among gastroenterologists, hematologists, neurologists,  and oncologists.

Cardiology

The NEJM’s poll respondents voted the Journal of the American College of Cardiology their first choice as an essential journal. (Not surprisingly, they voted the NEJM their second place choice, even though it is not primarily a journal of cardiology.)  Remaining journals more specifically focused on cardiology followed in this order: Circulation and  the American Journal of Cardiology.

The DBIO 100 results flipped the top of the sequence somewhat: In this exclusively cardiovascular   section, Circulation was first, followed by the Journal of the American College of Cardiology, followed by the American Journal of Cardiology.  Experts constructing the DBIO 100 poll also included titles not mentioned in the NEJM poll: Circulation Research, the European Heart Journal and Cardiovascular Research which finished in that sequence.

Endocrinology

While in the NEJM poll, the NEJM itself was voted as the most essential title by endocrinologists, the title specifically devoted to Endocrinology  that they ranked as most essential was the Journal of Clinical Endocrinology & Metabolism.  This was followed by other endocrinology titles in this descending order: Diabetes Care, Endocrine Practice, Diabetes, Thyroid, Endocrinology, and Endocrine Review.

In the DBIO 100 poll, in this section which limited itself strictly to Endocrinology, the Journal of Clinical Endocrinology & Metabolism easily finished first.  Following this were Diabetes Care, Diabetes, Endocrinology and Cell Metabolism, this last not a title mentioned in the NEJM poll.

Gastroenterology

The journal Gastroenterology won big in both the NEJM and DBIO 100 polls.  The American Journal of Gastroenterology  followed suit in second. The most notable difference between the two polls was the third place finish of Gut, the British leader, in the DBIO 100.

Hematology, Hematology/Oncology, and General Oncology

The  NEJM poll featured separate categories for Hematology, Hematology/Oncology, and General Oncology, but there was a great deal of overlap in responses.  The Journal of Clinical Oncology  topped all three groups and the journal Blood followed as the next specialty journal. These were  trailed by Oncology,  Cancer or Clinical Cancer Research in slightly different orders depending on which NEJM poll group was being checked.

The  DBIO 100 poll also chose as a leader Blood (in its own Hematology & Leukemia category) but then flipped, choosing  Cancer over  the Journal of Clinical Oncology  in deciding its first and second place winners.  DBIO 100 voters also cast ballots for more research-oriented titles not mentioned in the NEJM poll, such as Cancer Cell,  the Journal  of the National Cancer Institute,  Cancer Research, and British-based Lancet Oncology.

Infectious Diseases

The NEJM and DBIO 100 polls mirrored each other in their top three finishers among journals devoted specifically to Infectious Diseases. Clinical Infectious Diseases, the Journal of Infectious Diseases, and AIDS were one, two and three in the hierarchy. 

Both polls also showed votes for Antimicrobial Agents & Chemotherapy, although not in fourth place.

NEJM respondents showed a stronger “local responsibility” flavor in including more practical titles like Infection Control & Hospital Epidemiology. DBIO 100 voters were more research-oriented and cosmopolitan, favoring Emerging Infectious Diseases and British-based  Lancet Infectious Diseases.

Nephrology

Because the DBIO 100 poll put Nephrology in with Urology,  the best comparison to be made with the NEJM poll, is based on the answer to the following question: Which of the fewer Nephrology journals in the DBIO 100 poll also appeared in the NEJM poll,  and in what order?  Three journals were in both polls, albeit with the top two positions reversed. The DBIO 100 ranking put Kidney International  ahead of the Journal of the American Society of Nephrology, with the American Journal of Kidney Disease coming in third in both polls.

Neurology

Respondents in the NEJM poll favored Neurology, the Archives of Neurology, Muscle & Nerve, the Annals of Neurology, and Headache as their top five specialty neurology titles.

DBIO100 voters were  partially in agreement with some changes in sequencing. Neurology was indeed number one, but the Annals of Neurology moved up into second place and then  the British leader, Brain. The Journal of Neuropathology & Experimental Neurology, and British-based Lancet Neurology filled out the remainder.

Pulmonology

Despite the somewhat separate ways in which the NEJM poll handled Critical Care as a subset of Pulmonology, a reasonable comparison  with the DBIO 100 discloses the same top four in essentially  the same rank order: Chest, American Journal of Respiratory & Critical Care Medicine, Critical Care Medicine, and Critical Care.

Rheumatology

The NEJM poll put Arthritis & Rheumatism  and the Journal of Rheumatology  in first and second place, and when the journals of orthopedic surgery were factored out, so did the DBIO 100 voters.  

Conclusions

·     There is every reason to believe both polls when they suggest that that the NEJM is in fact, the most  influential, most frequently consulted, and memorable, single medical journal in the US (and likely in the world), and that the attention garnered  by its  singular content  exceeds or is on a par within  many medical specialties with  many of the more narrowly focused journals  dedicated to those specialties. While this conclusion was not explicitly  stated in the DBIO 100  poll, because the question was not posed directly that way, the NEJM’s placement by the DBIO 100’s voters as the second most influential journal in all Biology & Medicine over the last 100 years, implicitly gives great credence to this notion.)

·     DBIO 100 voters agreed with NEJM poll respondents in placing JAMA in second place, but were more cosmopolitan in their third and fourth choices. The BMJ made its presence singularly felt in the DBIO 100 poll but did not appear at all  in the NEJM poll. The Lancet did quite well in both polls, even though it led in no category.

·     The DBIO 100 poll tends to confirm the NEJM poll to a remarkable degree in ranking the more specialized journals in virtually all shared specialties, with the occasional exception of some one-(or-rare) two place reversals . The same is true of the NEJM largely confirming the DBIO 100 poll.

·     The principal difference between the polls tends to be one of the day-to-day awareness of journals of the two groups doing the voting. In the NEJM poll, physicians more quickly recalled and tended to vote more strongly for the journals to which they are most likely personally to subscribe, giving  some preference to US based, practice-oriented titles. In the DBIO 100 poll, the biomedical librarian voters went with journals which were frequently requested or cited by those physicians who themselves published frequently, with a higher percentage of these being research journals of international high standing that are not likely to be among the personal subscriptions of the doctors.

·     These are two groups of well informed professionals who are in strong general consensus agreement on the medical journals that really count.

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

University of Arkansas Libraries MULN 233 East

365 North McIlroy Avenue

Fayetteville AR 72701-6123

Voice: 479-409-0021

Fax: 479-575-4592

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

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

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

Do the bulk of studies confirm that they work?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Which makes you feel fuller longer? Liquids or Bars?

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

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

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

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

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

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

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

Won’t you somehow feel weak using meal replacements?

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

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

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

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

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

University of Arkansas Libraries MULN 233 E

365 North McIroy Avenue

Fayetteville AR 72701-4002

Voice 479-575-4031

Fax: 479-575-5592

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Crerand, Canice E., Thomas A. Wadden, Gary D. Foster, David B. Sarwer, Lauren M. Paster, and Robert I. Berkowitz. 2007. Changes in obesity-related attitudes in women seeking weight reduction. Obesity 15, (3) (MAR): 740-7.

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Gugliucci, A., K. Kotani, J. Taing, Y. Matsuoka, Y. Sano, M. Yoshimura, K. Egawa, et al. 2009. Short-term low calorie diet intervention reduces serum advanced glycation end products in healthy overweight or obese adults. Annals of Nutrition & Metabolism 54, (3): 197-201.

Haddock, C. K., W. S. Poston, J. P. Foreyt, J. J. DiBartolomeo, and P. O. Warner. 2008. Effectiveness of medifast supplements combined with obesity pharmacotherapy: A clinical program evaluation. Eating and Weight Disorders : EWD 13, (2) (Jun): 95-101.

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Kim, J. Y., J. H. Kim, H. Lee da, S. H. Kim, and S. S. Lee. 2008. Meal replacement with mixed rice is more effective than white rice in weight control, while improving antioxidant enzyme activity in obese women. Nutrition Research (New York, N.Y.) 28, (2) (Feb): 66-71.

Konig, D., P. Deibert, I. Frey, U. Landmann, and A. Berg. 2008. Effect of meal replacement on metabolic risk factors in overweight and obese subjects. Annals of Nutrition & Metabolism 52, (1): 74-8.

Lee, K., J. Lee, W. K. Bae, J. K. Choi, H. J. Kim, and B. Cho. 2009. Efficacy of low-calorie, partial meal replacement diet plans on weight and abdominal fat in obese subjects with metabolic syndrome: A double-blind, randomised controlled trial of two diet plans - one high in protein and one nutritionally balanced. International Journal of Clinical Practice 63, (2) (Feb): 195-201.

Li, Z., K. Hong, P. Saltsman, S. DeShields, M. Bellman, G. Thames, Y. Liu, H. J. Wang, R. Elashoff, and D. Heber. 2005. Long-term efficacy of soy-based meal replacements vs an individualized diet plan in obese type II DM patients: Relative effects on weight loss, metabolic parameters, and C-reactive protein. European Journal of Clinical Nutrition 59, (3) (MAR): 411-8.

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Peters, H. P., H. M. Boers, E. Haddeman, S. M. Melnikov, and F. Qvyjt. 2009. No effect of added beta-glucan or of fructooligosaccharide on appetite or energy intake. The American Journal of Clinical Nutrition 89, (1) (Jan): 58-63.

Poston, W. S. C., C. K. Haddock, M. M. Pinkston, P. Pace, N. D. Karakoc, R. S. Reeves, and J. P. Foreyt. 2005. Weight loss with meal replacement and meal replacement plus snacks: A randomized trial. International Journal of Obesity 29, (9) (SEP): 1107-14.

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

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

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

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

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

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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

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Fayetteville AR 72701-4002

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Did Communal Defense Against Historic Epidemics in East Asia Lead to Conformist Cultures Where Genes That Predispose Toward Depression & Anxiety in Western Individuals Actually Became Advantageous for East Asians?

One of the most intriguing recent papers seeking to document the notion that genes and cultures co-evolve comes from Chiao & Blizinsky (2010) of  Northwestern University.

Tracking A Gene that Predictably Leads to Increased Depression & Anxiety In Western Societies

One of their starting points is arguably the most studied mental health gene, the serotonin transporter functional polymorphism , 5-HTTLPR,  (Canli & Lesch, 2007; Caspi et al, 2003; Lesch et al, 1996; Pezawas et al., 2005; Risch et al, 2009; Sen, Burmeister & Ghosh, 2004;  Taylor et al, 2006; Uher & McGuffin, 2008).

Conventional wisdom derived from the abundant scientific and clinical literature  has long held that persons have the short form of 5-HTTLPR, have a distinctly higher chance of developing mood disorders, particularly major depression and anxiety, particularly if triggered by stressful life events. Those with the long form of 5-HTTLPR seem to enjoy a measure of protection, despite adversities in their life histories (Fox, Ridgewell & Ashwin, 2009).

The World Wide Reported Frequency of Depression & Anxiety Disorders

Chiao & Blizinsky note however, that the statistical prevalence of diagnoses for depression and anxiety disorders varies across nations and cultures. For example, certain Asian nations, most notably Taiwan, South Korea, and especially the People’s Republic of China,  report markedly lower rates, while the US , UK, and Australia report among the highest rates.(Weissman et al, 1996)

Does this mean that people are deliriously happy in the Peoples Republic and consistently sad in the US? The answer to this is clearly No, but there must be something to account for this   consistently reported  difference.

Does this mean that there are many more psychiatrists in the US, UK and Australia  who will diagnose mood disorders and write SSRI prescriptions? The answer to this is yes, although Chiao & Blizinsky factor this out. (They do report that there may be more cultural stigma in seeking treatment for depression and anxiety in East Asian countries, but also note that countries like Mexico and Brazil also have a lower rate of diagnosis and treatment of mood disorders,  despite the fact Brazilians and Mexicans are not notably ethnically or politically  related to these East Asian groups, have greater access to psychiatrists, and not any particularly well documented social disapproval of seeking some form of help for situationally induced emotional distress.)  

Chiao & Blizinsky also account for  variations in Gross Domestic Product, per-capita earnings, and a number of other factors that would be expected to sway incidence  of depression and anxiety. In terms of wealth measurements, the US, UK and Australia do quite well (even in this economic recession we would still do relatively well against most other nations), and certainly would not be predisposed to a higher frequency of mood disorders in need of  SSRIs if this was driven primarily by chronic economic want.

Furthermore, there  is quite a disparity in per-capita wealth between the Asian people of the Peoples Republic of China on one hand and Asians in South Korea and Taiwan on the other, with the latter two significantly wealthier by most measures. Yet, the low rate reported for diagnosis and treatment of mood disorders is essentially the same across all three counties.

The World Wide Distribution of the Short Form of 5-HTTLPR Favoring  Depression/Anxiety

Chiao & Blizinsky then hypothesized that  this disparity in depression and anxiety must be a case where  more Americans, Brits, and Aussies, must have the short form of the 5-HTTLPR.

But almost exactly the opposite is the case. East Asian nations with very low reported  rates of depression and anxiety have among the very highest frequencies of the short form of 5-HTTLPR within their population.

Ordinarily, this would cause the overthrow of the well established linkage of the short form of 5-HTTLPR with increased propensity for adverse mood disorders, but not even Chiao and Blizinsky   believe that to be necessary.

Why Then Don’t  East Asians with  Short Form 5-HTTLPR Develop Depression & Anxiety As Often?

Chiao & Blizinsky argue that at least historically, if not currently, cultures evolved in Asia with the  kind of structure that buffered  the genetic propensity for mental reactions in people who would ordinarily become notably   depressed and anxious over adverse “triggering”   life events and circumstances.

They note that what   bound these Asian cultures together in the past was a strong emphasis on economic order and social harmony. At least historically, if not currently,  deprivation was a common experience, and losses were shared  across the population. 

The idea of casting out depressed or anxious people with the notion that it would greatly improve communal circumstances, seemed  alien concepts for such a long period of time in historic East Asia  that people with the short form of 5-HTTLPR were able to reproduce and perpetuate this gene to an extraordinary degree, because it did not come with social or economic consequences that caused them to die out in East Asia (Gintis, 2004).

But critically, “blaming behaviors”  for failure in these cultures tended not to fall on individuals who had become depressed or anxious, but rather on a lack of well-coordinated collective effort or on the mandate of Heaven.  Indeed, individuals in East Asian cultures in the past have historically “construed” their sense of self-worth largely in relation to what they could help their village or extended clan accomplish rather than what they could accomplish on their own. And, if nothing was accomplished, then it was a matter beyond the control of the village or the clan, and particularly, not their fault as an individual .

In East Asia, a culture of communal fatalism, in these regards seemed the most sensible, because the range of an individual’s choice of occupations,  and the degree to which one’s economic or social lot could be improved, were much more narrowly circumscribed than in western cultures.

Any individuals in historic East Asian cultures  who consistently expressed outspoken optimism  and tried to persuade the community to hope for substantially better returns by creatively making fundamental changes in the social or economic order  were likely taken as being mental ill in these societies in historic times.

In fact, people lacking in optimism and personal initiative -----people who would be regarded as depressed and anxious people in western societies -----might very well have fit right in with a fatalistic culture.

If Historic Asian Cultures Did  Not Evolutionarily Discriminate Against Those with the Short Form of 5-HTTLPR, Did  This Form Offer Evolutionary Advantages Within Those Cultures?

It has been proposed that one way that the brains of individuals with the short form of 5-HTTLPR malfunction is with heightened sensitivity of their amygdalas (Hariri et al, 2002; Munafo, Brown & Hariri, 2008; Pezawas et al, 2005 ).

The amygdala is that portion of the brain that adds emotional emphasis that not only concentrates one’s thoughts on important tasks and memories in an effort to prioritize them,  but is absolutely essential for danger avoidance.

One measure in which depressed and anxious persons, particularly those with the short form of 5-HTTLPR excel in an adverse sort of way, is their ability to operate in a self-protective fashion via a state of hypervigilance  in terms of their amygdala function. (Osinsinsky et al, 2008). Their amygdalas  seems to “fire” sooner, “fire” more often, and  “fire”  to a greater degree. Their amygdalas seem to signal danger everywhere (Beevers et al, 2007).

In western cultures, this hypervigilance is  seen as making the affected person appear  afraid of everything, and would be expected to contribute to his or her  sense of hopelessness. In particular, it would  make the person disinclined to try out things that would help them break out of their adverse mood.

In western cultures, such individuals might be seen by others, and eventually see themselves,  as self-defeating  pessimists or even cowards. The social or economic disadvantages they have, or the failures they experience,  might well be attributed to flaws in  their character, such as lack of initiative or courage.

In evolutionary terms in western cultures, such individuals are not likely to thrive and reproduce in large enough numbers to pass on their genes to a large proportion of subsequent generations, because hypervigilant behaviors that stifle  self-improvement and economic advancement are socially unattractive, and  put them at a disadvantage against optimistic, creative individuals who are valued more highly in western societies.

In other words, in western societies, these would be the very people who would be strongly advised “to get help” including consulting psychiatrists who would diagnose and treat their depression and anxiety so as to improve their function in society. This  “be treated or be ashamed of oneself, ” culture , of course, might well explain the higher reported rates of diagnosis in western cultures for those syndromes, despite the reduced rate of the short form of the 5-HTTLPR gene.

But Chiao & Blizinsky note that a highly active amygdala, spurred by inheritance of  the short form of 5-HTTLPR,   confers advantages in historically highly conformist groups. It served as an early warning system to register signs of disapproval, particularly in the facial expressions of members of their in-group.

This might well explain that while people across cultures recognize the general emotional nature of facial expressions (anger, happiness, disgust, sadness, etc. ), they differ greatly in their sensitivity to the depth of the emotions,   and nuances within expressions, when dealing with people from outside their culture.

This may be particularly true of westerners encountering Asian cultures.

In other words, a westerner who is completely fluent in Mandarin might well address an audience in Beijing, and even understand that the  tersely  worded polite  verbal feedback is insincere. That foreign speaker could  even sense that the listeners were in fact angry, but  cannot gauge as well as  Chinese members of the same audience, just how angry the members of the audience are, or whether or not the faces in the audience were expressing a mix of emotions.  

Gauging when  a person is right to be afraid is particularly important to reproductive success in authoritarian regimes that historically held sway in East Asia. An inability in those cultures in those times,  to determine that one was in trouble was  likely to get a person incarcerated or worse, definitely limiting their chances to pass on any genes.

Where Does the Notion of Protection Against Infectious Diseases Come Into This Story of the Variance in Effect of a Gene Between Differing Cultures & Nations?

Randy Thornhill at the University of New Mexico has assembled a team of evolutionary biologists and evolutionary psychologists who have developed a model for the evolution of cultures based on how epidemics of microbes and parasites adversely influenced them, and on the measures those cultures took to defend themselves. In their analysis (See  Fincher et al, 2008) those societies that were repeatedly hit by infestations responded by collectivist, protectionist measures, where the free will and “out-of-line” behavior of nonconformist members was seen as a danger to the entire group.  Xenophobia that encouraged quarantine and authoritarianism to enforce hygiene (as much as was understood in those era, at any rate) worked to limit the impact of these infectious disease disasters, and by extension according to Chiao  & Blizinsky,  individuals whose genetic makeup inclined them to conform and closely identify with groupthink, were vastly more likely to live long enough to be able to pass on those genes, than we freethinking western-types, it would appear.  

It is not hard to see  now that the same short form of 5- HTTLPR genes  can make for a differing way of viewing one’s success and sense of worth. The short form can actually promote the construal of oneself  as an obedient  contributor to the health and wealth of the commune  in Eastern cultures, while in Western ones  it leads people to see themselves as, at best, failed   initiators of actions that determine one’s individual achievement and status, and thereby determine their self-worth.

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

University of Arkansas Libraries MULN 233 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

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:

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

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

CFS Symptoms

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

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

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

Competing Non-Viral Theories of Causation

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

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

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

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

The Viral Infection Theory

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

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

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

XMRV

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

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

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

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

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

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

University of Arkansas Libraries MULN 223 E

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