SLA Biomedical & Life Sciences Division Blog

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

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BLAMING MOM FOR CASES OF AMBIGUOUS GENDER

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

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

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

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

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

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

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

THE INTERPLAY OF SRY, Sox 9, & FOXL2

IN SERTOLI, LEYDIG, GRANULOSA & THECA CELLS

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

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

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

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

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

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

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

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

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

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

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

WHY THIS MATTERS

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

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

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

University of Arkansas Libraries MULN-223E

Fayetteville, AR 72701

Voice 479-575-4031

Fax: 479-575-4592.

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

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

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

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

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

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

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

THE BEEF INDUSTRY HAS LEARNED FROM ITS SORRY HISTORY

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

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

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

 

KNOWING THE ENEMY, E.  COLI O157:H7

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

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

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

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

 

E. COLI O175:H7 HIDES ON THE HIDE

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

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

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

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

WASHING THE BEEF AS WELL AS THE HANDS & CUTTING TOOLS

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

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

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

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

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

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

THE SPECIAL PROBLEMS OF GROUND BEEF AND HAMBURGER

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

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

Does this mean that hamburger is inherently unsafe to eat?

 

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

University of Arkansas Libraries MULN 223E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-575-4031

Fax: 479-575-4592

 

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

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Kalchayanand, N., T. M. Arthur, J. M. Bosilevac, D. Brichta-Harhay, M. N. Guerini, S. D. Shackelford, T. L. Wheeler, and M. Koohmaraie. 2009. Effectiveness of 1,3-dibromo-5,5 dimethylhydantoin on reduction of Escherichia coli O157:H7- and Salmonella-inoculated fresh meat. Journal of Food Protection 72, (1) (01/01): 151-6.

Kim, Y. H., J. T. Keeton, S. B. Smith, J. E. Maxim, H. S. Yang, and J. W. Savell. 2009. Evaluation of antioxidant capacity and colour stability of calcium lactate enhancement on fresh beef under highly oxidising conditions. Food Chemistry 115, (1) (01/01): 272-8.

Laury, A. M., M. V. Alvarado, G. Nace, C. Z. Alvarado, J. C. Brooks, A. Echeverry, and M. M. Brashears. 2009. Validation of a lactic acid- and citric acid-based antimicrobial product for the reduction of Escherichia coli O157: H7 and salmonella on beef tips and whole chicken carcasses. Journal of Food Protection 72, (10) (10): 2208-11.

Looper, M. L., T. S. Edrington, and C. F. Rosenkrans J. 2009. Influence of body condition and forage type on prevalence of Escherichia coli O157:H7 and salmonella in grazing beef cows. Letters in Applied Microbiology 49, (3) (09/08): 361-5.

Neuman, Willliam. (December 4, 2009) . After delays, vaccine to counter bad beef is being tested. New York Times,  p.A1.

Oliver, David M., Trevor Page, A. L. Heathwaite, and Philip M. Haygarth. 2010. Re-shaping models of E. coli population dynamics in livestock faeces: Increased bacterial risk to humans? Environment International 36, (1) (01/26): 1-7.

Ou, D., and G. S. Mittal. 2007. Single-sided pan frying of frozen hamburgers with flippings for microbial safety using modeling and simulation. Journal of Food Engineering 80, (1) (01/01): 33-45.

Outbreak of Shiga toxin-producing Escherichia coli O157 infection associated with a day camp petting zoo--Pinellas county,  Florida, May-June 2007. 2009. MMWR.Morbidity and Mortality Weekly Report 58, (16) (05/01): 426-8.

Outbreaks of Escherichia coli O157:H7 associated with petting zoos--North Carolina, Florida, and Arizona, 2004 and 2005. 2005. MMWR.Morbidity and Mortality Weekly Report 54, (50) (12/23): 1277-80.

 Prendergast, D. M., K. M. Crowley, D. A. McDowell, and J. J. Sheridan. 2009. Survival of Escherichia coli O157:H7 and non-pathogenic E. coli on irradiated and non-irradiated beef surfaces. Meat Science 83, (3) (01/01): 468-73.

Presi, P., K. D. C. Stark, R. Stephan, E. Breidenbach, J. Frey, and G. Regula. 2009. Risk scoring for setting priorities in a monitoring of antimicrobial resistance in meat and meat products. International Journal of Food Microbiology 130, (2) (01/01): 94-100.

Schaffner, D. W., and K. M. Schaffner. 2007. Management of risk of microbial cross-contamination from uncooked frozen hamburgers by alcohol-based hand sanitizer. Journal of Food Protection 70, (1) (01/01): 109-13.

Trindade, R. A., J. Mancini-Filho, and A. L. C. H. Villavicencio. 2010. Natural antioxidants protecting irradiated beef burgers from lipid oxidation. LWT -- Food Science and Technology 43, (1) (01/01): 98-104.

Wu, V. C. H., Xujian Qiu, B. G. Reyes, Chih-Sheng Lin, and Yingjie Pan. 2009. Application of cranberry concentrate (Vaccinium macrocarpon) to control Escherichia coli O157:H7 in ground beef and its antimicrobial mechanism related to the downregulated slp, hdeA and cfa. Food Microbiology 26, (1) (01/01): 32-8.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What’s the catch?

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

All six are associated with increased diabetes risk.  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

University of Arkansas Libraries MULN 223 –E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

 

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

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

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

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

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

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

Comparing The Journals Favored By This Year’s Nobel Prizewinners In Medicine And Chemistry With The 100 Journals Voted As The Most Influential Over The Last 100 Years By The Biomedical & Life Sciences Division Of The Special Libraries Association

This year,  Elizabeth Blackburn (University of California at San Francisco Medical School), Carol Greider  (The Johns Hopkins University Medical School) and Jack Szostak (Massachusetts General Hospital of the Harvard University Medical School) were voted the Nobel Prize in Physiology or Medicine by a committee of medical faculty experts at the Karolinska Institute (effectively the Scandinavian equivalent of any of the three preceding institutions)   in Sweden.

Also this year, Venkataraman Ramakrishnan (Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, essentially the equivalent of the US NIH), Thomas Steitz (Yale University), and Ada Yonath (Weizmann Institute of Science in Israel, much like Caltech or MIT in  the US), were awarded the Nobel Prize in Chemistry), for work on ribosomes, a component of cells that is essential to the construction of proteins. In many respects, this prize could just as easily been awarded in the Physiology or Medicine category, given its strong molecular and cellular biology emphasis.

Where Nobel Laureates have published is important information for librarians who must buy journals, very often with very limited dollars, because they represent a kind of endorsement of the best journals in the world, as expressed  by the best scientists in the world.

Consider that, after a probationary stint as a junior scientist in someone else’s lab where they did not make  such important decisions,  each Nobel Laureate,  in their mature careers as heads of their own labs,  voted with every manuscript as to which journals they regarded as being not only the most subject-appropriate, but the most influential among the most subject-appropriate ones. 

In 2009, another panel of experts also cast votes. This time it was not about who would be this year’s Nobel Prizewinners, but rather   which were the 100 most influential journals, in this case,  of the last 100 years in biology and medicine.

 These expert voters were the members of the BioMedical & Life Sciences Division (the DBIO) of the larger (11,000 member) Special Libraries Association (SLA). This was done on the occasion of the 100^th anniversary of SLA. The editors and publishers of their journals were feted in a banquet in Washington DC, where they were applauded by the very librarians that had voted in their publications. To see this “DBIO 100”  list, click on http://units.sla.org/division/dbio/publications/resources/dbio100.html  

From this list, a Top Ten Journals category and the single Journal of the Centennial were also selected: http://units.sla.org/division/dbio/publications/resources/topten.html

 

To what degree did the choices made by the Nobel Laureates and the choices for the DBIO 100, the Top Ten, and the Journal of the Centennial, made by some of the best and brightest among biomedical librarians coincide?

This blog will provide  some answers.

Two words of warning.

First,  the DBIO 100 Poll conducted by these librarian deliberately excluded journals that were predominantly devoted to review articles (e.g. The Annual Reviews series), to paragraph-sized summaries of conference presentations (e.g. Abstracts of  Papers Presented to the American Chemical Society), or to experimental procedures and laboratory protocols (e.g. Methods in Enzymology and Related Areas of Molecular Biology).

Second, the DBIO 100 Poll was deliberately designed to include journals in all areas of biology and medicine. This means that at least 34 titles covering Natural History topics ( including  four of the Top Ten, viz.,   the American Journal of Botany, the Journal of Zoology, the American Journal of Physical Anthropology, and the Journal of Paleontology ) would be clearly out of scope for these Nobel Laureates.  Even many of the 33 winners in the Clinical Group, would seem odd venues (e.g. AJN: The American Journal of Nursing, the Journal of Bone and Joint Surgery, the Journal of the American Dental Association, etc.) given that the Nobel Prizes in Physiology and Medicine, and in Chemistry, have overwhelmingly stressed molecular and cellular biology in recent decades.

In a sense,  only  the  33 journals in the DBIO 100’s Molecular & Cellular group were reasonably likely venues for  this year’s s Nobel prizewinners, although a limited amount of crossover to some clinical journals remained  a possibility.  

The question then becomes how can we measure the performance of these 33 expert-librarian-selected journals, against a more comprehensive (and at least ten times more expensive) list that would contain virtually all the titles in which the laureates would be likely to publish?

The Thomson Reuter 2008, JCR, Journal Citation Reports, (the JCR for short)   a particularly authoritative guide to the journals of greatest consequence in the sciences and other fields,  lists several hundred journals  in areas related to the fields we will discuss. (There are 728 listed in the combined categories, although given that  there is some duplication in titles appearing on more than one category list, a more reasonable estimate would be 600).

 The JCR certainly includes every one of the 33 DBIO 100 titles in the pertinent areas, and It  would presumably  contain all the journals of this year’s laureates, making  for a good comparison set, even though there are doubtlessly even larger, but less discriminating lists, that would cost an order of magnitude even more than that of the JCR. 

Journals of General Science

Arguably the hardest journals in which to get a paper published are Science, Nature, and the Proceedings of the National Academy of Sciences (PNAS). Given that these scientists were doing Nobel Prize-worthy work, it  may not be that great a surprise that despite the hurdles any author faces in the process of gaining a manuscript acceptance there, each of these journals played a prominent role in the output of the  five of the six laureates.

Nature was the most common outlet for Szostak, but appeared in the list of publications for five of the six. The Proceedings of the National Academy of Sciences was the most common outlet for Blackburn, and second most common for Greider and Steitz, and appeared in the top 5 for Yonath. Finally in the cv’s of five of the six, Science made at least one appearance (but  usually many more).  

How did the DBIO panel of expert voters rank these titles? All three made the Top Ten, and Nature was named the Most Influential Journal of the Century.

So far, so good for the DBIO100 voters.

Journal of General Biology & General Clinical Investigation

The first of these two  categories, General Biology,   included those journals which cover a rather broad spectrum of biology, as opposed to focusing on a particular topic, such as  genetics or ecology. The DBIO voters named three winners:  The FASEB  (Federation of American Societies for Experimental Biology) Journal , Current Biology, and the Proceedings of the Royal Society of London B Biological Sciences.

The second category, General Clinical Investigation,  included four journals that made the DBIO 100, the first  three of which also made the Top Ten. These were the New England Journal of Medicine, the BMJ: British Medical Journal, JAMA: The Journal of the American Medical Association, and The Lancet.

Was  the DBIO 100 voting in one or both of these more general categories reflected in the publications lists of the laureates?

While they were by no means in the dominant position of the three titles above, The FASEB Journal  was included  by  four laureates (Blackburn, Greider, Steitz & Szostak),  while two laureates (Blackburn and Greider) had papers in Current Biology. 

The fact that the Proceedings of the Royal Society of London B Biological Sciences was not among the choices of any of the six might be best explained by the fact that it includes  proportionally more biology of the Natural History type, than do the other two.

Only one journal of general clinical investigation made the lists of any of the  laureates. Both Blackburn and Greider have  appeared in the New England Journal of Medicine, which is the title among the four in this group,  which most notably makes a point of taking a select number of basic science papers of potential clinical importance on a fairly regular basis.

Journals of Biochemistry,  Molecular Biology, Genetics

Among the titles most commonly favored by this year’s laureates are Biochemistry (particularly by Szostak, but also included by Steitz and Yonath ), the Journal of Biological Chemistry  (Blackburn , Greider, Ramakrishnan & Steitz), Biochimica et Biophysica Acta  (Steitz & Yonath), the Journal of Molecular Biology ( the favorite of both Steitz and Yonath, but included by all  the laureates), EMBO (European Molecular Biology Organization) Journal  (all  six again), Molecular & Cellular Biology (Blackburn, Greider & Szostak) ), Nucleic Acids Research (Blackburn, Greider, Steitz & Szostak) and Nature Structural and Molecular Biology  (The favorite title of Ramakrishnan in recent years, but also included by Blackburn & Szostak).  Blackburn, Greider & Szostak  published in Genetics. In addition, Greider appeared in Nature Genetics.

Each and every one of these journals had been voted in by the DBIO before the laureates themselves had been so honored.

Cell Biology

The leading journals of Cell Biology as chosen by DBIO 100 voters were Cell, by a massive margin over its nearest competitor, the Journal of Cell Biology.

Cell was the highest ranking journal of  cell biology in the output of all  six laureates; the Journal of Cell Biology figured only in the record of Blackburn.

However, conspicuously absent from the DBIO 100 was another  title clearly favored by Blackburn, the Molecular Biology of the Cell, now the official title of the American Society for Cell Biology, an organization of which she was president in 1998. This title broke away from Rockefeller University’s venerable and DBIO 100-voted  Journal of Cell Biology, which used to be published on  the Society’s behalf. But the elder title has thrived despite the establishment of the newer rival  Molecular Biology of the Cell, nonetheless. 

Other Journals in Common Between the Laureates and the DBIO 100 Voters

Steitz and Yonath both published in the Journal of Bacteriology, while Blackburn & Grieder both appeared in Blood. Steitz alone published in the Journal of Medicinal Chemistry, while only Blackburn  appeared in the journal Gastroenterology.  In none of these cases is it likely that these forays are core to their ongoing work.  

What Were The Success Rates Of The 33 DBIO 100 Titles In  Identifying The Journals That Mattered Most To The Nobel Laureates This Year?

Journal Citation Reports included almost all the journals that published papers by our laureates. (It did miss  some laureate papers that fell in the JCR’s General Chemistry and Organic Chemistry categories, but these categories were not covered at all in the DBIO 100 poll, and   therefore out of scope for a fair comparison). But overall,  the JCR performed splendidly.

 In other words,   a selective assortment of 600+  journals, proved likely to contain almost 100% of the journals within which this year’s class of Laureates  published.

But how  well did the DBIO 33 of the DBIO 100 journal set  ----an assortment that was essentially only about  5 % of that of JCR in numbers, fare?

In other words,   if 600 carefully selected journals from the JCR = 100% of Nobel Laureate output, what proportion of output was covered by a list only about %5 as long?

Statistics suggest that the DBIO 5%  should predict about 5%.

The results, however,  were quite extraordinary.  

Subject to the exclusionary rules mentioned earlier, the DBIO 100’s “33” accounted for 49% of the papers of Szostak & Yonath; 53% of the papers of Blackburn; 83% of the papers of Ramakrishnan; 90% of the papers of Greider, and 91% of those of Szostak.

Eighteen DBIO member-voted titles out of the 33  DBIO member-voted titles in the original comparison set, plus  the five more clinical  and more occasional DBIO member-voted titles ( a total of 23 titles) accounted for a group average of  69% of the Nobel Laureates output this year.

It seems that Nobel Prizewinners know where to go with their papers, and there they will find SLA’s DBIO librarians, despite having very little money with which to work in more and more cases, at the ready with a majority of the titles that matter the most to their careers.

It seems that SLA’s DBIO librarians know how to pick them too.

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

University of Arkansas Libraries MULN 233 E

365 North McIlroy Avenue

Fayetteville AR 72701-4002

Voice: 479-409-0021

Fax: 479-409-0021

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

Effective Vaccines Are on The Way

 

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

 

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

 

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

 

Will They Arrive in Time?

 

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

 

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

 

The answer is no for two reasons.

 

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

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

 

What are the Odds of Someone Getting the Flu?

 

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

 

Two Countries with Extensive H1N1 Flu Experience

 

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

 

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

 

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

 

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

 

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

 University of Arkansas Libraries MULN 223 E 

365 North McIlroy Avenue Fayetteville AR 72701-4002 

Voice 479-409-0021 

Fax: 479-575-4952

 

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

 

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

 

Centers for Disease Control and Prevention (CDC). (2009). Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis --- North Carolina, 2009.  MMWR Morbidity and Mortality Weekly Report, 58, (35), 969-972.

 

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

 

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

 

Eastwood, K., Durrheim, D.N., Massey, P.D., & Kewley, C. (2009).  Australia’s pandemic “Protect” strategy: The tension between prevention and patient management.  (2009). Rural and Remote Health, 9. (3), epub ahead of print.

 

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

 

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

 

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

 

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

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  Shrunken or Damaged Amygdala

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

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

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

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

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

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

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

Persistent, Dysfunctional Fearful Memories and PTSD

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

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

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

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

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

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

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

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

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

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

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

Univesity of Arkansas Libraries MULN 223 E

365 North McIlroy Avenue

Fayetteville, AR 72701-4002

Voice: 479-409-0021

Fax: 479-575-4592

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Belly Fat, Inflammation, Type II Diabetes, Anti-inflammatory Drugs and Anti-Oxidants: Studying Metabolic Syndrome, Possible Cures, & Discovering the Very Subtle Ways They Might Work at the Molecular & Cellular Level All at the Same Time

The pathway of medical and pharmaceutical research is often portrayed as straightforward : First, characterize a disease thoroughly,  and when that’s finished,  find a drug by some sort of trial and error process with rats and then humans. 

But in fact, at any given time, researchers are simultaneously characterizing the many manifestations of a disease and its interrelations with other diseases, trying out putative folk remedies and natural products that have  a fair amount of positive, anecdotal evidence, as well as doing research at the molecular and cellular level to determine what biochemical processes underlie or control some step of the disease process.

The doctors who treat the whole patient  continue to  do a kind of clinical epidemiology which tends to reveal new trends and apparent associations, which gives them something new to say  to the drug researchers, even as the work of molecular and cellular biologists gives them something to report  to the drug discovery people and the clinicians at any given time.

Research in understanding and hopefully curing disease  is better pictured as occurring at traffic intersections than at rest stops on a one-way highway.

A Case Study of Making Clinical Associations Between Well Known Diseases: Metabolic Syndrome

The  routine usage in diagnosis of the broadly encompassing term Metabolic Syndrome  is only about 40 years old, although the various diseases associated with it were very well known many decades before that.

Basically, a patient presents with an inordinate amount of belly fat, a sedentary lifestyle, and often, early signs of adult-onset diabetes. There is a strong association of this syndrome with heart disease, stroke, fatty liver, and various cancers, although it was probably rare for any one physician to have a patient show up with all of these diseases all at once.

For clinical internal  medicine, the first step was make the links that all these separate illnesses seemed tied together in a statistical sense. The  determination that Metabolic Syndrome was a useful diagnostic concept was far more driven as much by cumulative clinical chart reviews, than by well-worked-out “a priori”  theories of what the underlying cause was.  

What prolonged experience in the clinical realm suggested was that patients who had a lot of visceral fat tended to get adult onset diabetes. But it was also true that patients with abundant visceral fat also tended to have coronary artery disease and also get strokes. And patients with visceral fat also seemed to come down with certain cancers. Many of them also had livers as if they were alcoholics, even if they did not actually drink alcohol.

Even after this realization of a strong link was made, the treatments and clinical advice for the separate component diseases that were a part of this cluster tended to be very distinct, and not always transferrable from one disease to another. One did not give radiation treatment for diabetes. Insulin shots did not seem beneficial in cancer. The warning signs of stroke were very different from those of liver failure.

But even after the realization that these diseases were clearly linked, there was no stop in trying to find separate cures for each and every one of them. They all had their own separate research and treatment charities, advocacy groups, and even NIH institute buildings, and even if no one came up with the mythical all-in-one cure, they all regularly came up with some new information to share at that traffic jam intersection of differing researchers.

What Did Work to Ease the Very Different Manifestations of Metabolic Syndrome?

One of the first realizations of a clinical strategy that worked, at least for many, if not all patients with one of the cluster of diseases, was to encourage them to lose weight, and in particular, to exercise more, with the underlying goal of reducing that belly fat. This was bostered by the fact, that there was substantial evidence that for many patients, the fatter they got, the worse their metabolic syndrome and its consequent component diseases seemd to come into play.

But this simple  weight loss/exercise prescription was hard for patients to follow, and did not seem to have an underlying basis in science. It just seemed to be an association between two occurrences: weight loss and/or exercise and betterment of symptoms, not a unambiguous display that weight loss or exercise somehow caused improvement of symptoms by some definite mechanism.

A couple of other statistical associations also came on the scene.

First, as is the case with most seemingly promising cause-and-effect explanations, some patients did lose weight and got better, while others did not. Some patients who never lost weight, never got the syndrome, even if they  were quite fat around the stomach. And, of course, some people who were never fat got one or more of the component diseases anyway. 

What helped make sense of these seeming failures of fool-proof cause-and-effect predictions for outcomes, was yet another series of observations.

First, for  some patients (viscerally obese or not) these diseases ran in families, with perhaps the fattest family members having the worst of it, but even some slender ones were affected as well.

This suggested that there was a genetic component. This of course, put the nucleic acids and proteins  research community, the molecular biologists,  to work to sort out what genes might be involved, and then, what proteins might be encoded by specific segments of DNA. Their working theory was that if you could somehow shut off or counter those genes, you’d have a good shot at a cure.

Second, some people seemed to have in their geographic location, and on inspection, usually in their diet much more so than the particular the rhythms of their daily lives, some protection against developing the component diseases of metabolic syndrome, in many cases despite having  what should be the predisposing girth.

This put ethnopharmacologists and nutritionists on the trail. What was it about those French people who drank a lot of red wine (despite a diet high in butter, and both saturated and unsaturated fats) that made them better off? And what about those  tea drinkers (sometimes black or green tea and sometimes herbal blends)?  And eating blueberries seemed to help in some way for some people. Was the apparent reduction in having the consequences of  having a belly fat body caused by these additions to their diet, or was it just a coincidence?

 This research community then began to try to isolate just what specific chemicals might be in that wine, those teas, or in the blueberries, that seemed to confer that protection.

And it was not long before promising substances like the antioxidants called polyphenols  (which are found in tea and in a number of fruits and vegetables) and resveratrol and procyanidin(s) (found in red wine) were tested for their possible association with reductions in the incidence and severity of metabolic-complex-related diseases.

They were found in some cases to work well with rats but not so well with humans, or in some cases, to work well with humans, but more so, for some humans, but not others. 

These paradoxes did not stop pharmacological research, but they did cause pharmacologists to question  if there was a common underlying mechanism that made these compounds effective for some people or lab animals that had certain genetic markers and protein-producing patterns, but not for people with other markers or patterns. It was time for a chat with the molecular biologists.

A Clinical Reconceptualization: Belly Fat Behaves Like an Endocrine Organ

It took less than a decade after the grand idea that all these disparate diseases might well be part of a common syndrome, for a key idea to emerge: just as the pancreas that produces insulin is an endocrine organ, and when it functions poorly diabetes results, it was entirely possible that the accumulated belly fat became an endocrine organ of its own, secreting some combination of chemicals or blood factors that caused insulin resistance, which in turn caused the strongly associated adult diabetes, which in turn was strongly associated with heart disease, and strokes, if not necessarily certain cancers.

But endocrine organs can secrete more than one substance that affects the body in a single way. They can secrete more than one variant or conformer of a hormone, or secrete a hormone that  can have more than one possible effect, depending where it docks within the body. This is particularly likely when a kind of heterogeneous , almost accidental organ made up of belly fat and random tissue  is involved.

This led to a hunt for other substances that could be caused by the errant belly fat endocrine organ, and a number of them turned up. Belly fat was associated with high levels of Cardiac Reactive Protein (associated with heart attacks), Tumor Necrosis Factor (associated with cell death), and certain kinds of  white blood cells which produced elevated  levels of lab proteins associated with a number of the differing component diseases within the metabolic syndrome.

The clinicians then had to talk with the biochemical and drug communities to help figure out what some of the commonalities were among these disparate but abnormal levels of substances and numbers of cells.

Inflammation as a Working Unifying Concept

What became clear was that many of these substances were the result of inflammation in the body. In some cases, some initial presence  of these substances caused even more damage over time, which caused the production and release of even more inflammatory responses, in a kind of vicious cycle that had to broken for the patient to get better.

The clinical  approach became more focused for diagnosis and the measurement of the success of any proposed medical treatment on  how well  the medicine or the procedure was working to reduce the signs of inflammation. As a corollary clinicians asked pharmacologists (and vice-versa) would some anti-inflammatory drugs used for other causes, work in metabolic syndrome related diseases?

Pharmacologists  turned around and asked their molecular biology friends what appeared to be the connections between the genes of people who showed high levels of inflammation and those that had had one or more of the component diseases of the metabolic syndrome. Furthermore, they wanted to know what were the genetics of those people who seemed to respond to given drugs or had a protective effect from some antioxidants like the polyphenols. The ideal goal at this molecular level was to see if drugs could be made for people who did not enjoy that protective effect, but that worked as well.

Some State Of The Art Papers Today

Right now we are seeing the ongoing exchange of ideas across disciplines and levels of biological organization. No one group has all the answers, but this does not keep the clinicians from compiling data on the commonalties signs, symptoms and diseases among their  patients , nor  restrain the pharmacologists from finding out what is the  key  compound and its most active site, when sorting out  some heterogeneous natural product that has hundreds of components,  nor does  it undercut the love of molecular biologists to explain diseases at the cellular level.

Rather, they all take whatever they’ve heard lately  at that traffic intersection of  different specialties, and see if it makes sense for their working explanations of what is going on with patients with metabolic syndrome, and its related diseases like adult-onset diabetes, and see if they can get a better diagnostic test, treatment, or preventive medical practice out of it.

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

Voice: 479-401-0021

Fax: 479-575-4592

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Garcia-Lafuente, A., Guillamon, E., Villares, A., Rostagno, M. A., & Alfredo Martinez, J. (2009). Flavonoids as anti-inflammatory agents: Implications in cancer and cardiovascular disease. Inflammation Research, 58(9), 537-552.

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H1N1 2009: The Swine Flu is Not About the Pigs. It’s About Viral Recombination Possible in Many Animals Including Man, and Can Be Combated with Sensible Precautions & Good Science

The current bout of swine flu, more properly 2009 H1N1,  appears to have originated in Mexico, but neither pigs per se nor Mexicans  “caused it.”

 

Killing  all the pigs, infected and uninfected,  (much as has been mandated in Egypt) and quarantining all Mexico would not stop the further spread of the virus.

 

Uninfected pigs cannot give H1N1 to other uninfected pigs or to humans.

 

Although ironically, infected humans can give it to pigs.

 

Only infected creatures, human or otherwise, can spread it, and only they should be quarantined in all cases.

 

It does makes some sense to quarantine those persons (or pigs) who have been in very close contact with those who are sick.

 

 

And the quarantine times that seem to be working out now for animals or humans that have been in close contact with infected animals or humans appears to be limited: 10 days to two weeks are about the longest spans this author has seen mentioned.

 

Eating well-cooked pork is absolutely not a cause of this so-called swine flu.

 

 

It would seems likely that being a swine farmer, veterinarian,  or pork meat packer who may come into contact with infected pigs is at increased risk.

However, the vast majority of H1N1 cases in the US have come from people infected by other people not by contact with pigs.

 

Indeed, some people may become alarmed at  news reports that tens of thousands of pigs (mainly in Mexican feedlots)  have been found to be affected, but this should be put into the context.

 

Each year over 130,000,000 hogs are processed in the US, and this increasingly centralized industry has an incredible financial incentive to keep their hogs infection-free.

 

Under the current system of raising hogs in the US, a high percentage of hogs are owned by the pork processors or otherwise supplied to pork processors by contract growers who have swine herd veterinarians on retainer precisely to avoid or root out any illnesses that could cause injury to the health of humans or to the sale of pork.

 

The pork industry already is fighting the misconception held by some that pork may be somehow be intrinsically unhealthy when compared to other proteins sources, like chicken breast, hence the “Pork: the other White Meat” campaign. They are on top of this flu situation.

 

 

The cause of this new flu is in essence genetic recombination that happens in nature, whether or not man intervenes.

 

It is now realized that many flu viruses can be in circulation at the same time, in humans and/or  in pigs, and it appears most likely that avian, human, and swine viruses came into contact with one another, and nucleic acid fragments from one or more of these sources apparently interpolated themselves in nucelic acid sequences within individual infected pigs, within larger  pig herds during the span of 2005-2009.

 

Those recombinant viruses then successfully were spread from pig to pig and then from pig to human, and then from human to human , and yes, from human to pig.

 

This H1N1 strain may actually be older than the stated 2009 date of origin.

 

Because kits for its specific testing were not developed, or when available, were not utilized, it was not detected in sufficient numbers to make the headlines we now see, as if it were something entirely unexpected  and unstoppable.

 

How can we put the morbidity and lethality of this alleged swine flu into perspective?

 

If you want to worry about an animal that will cause you harm, don’t look with fear at pigs, look at your neighborhood dog. The CDC reports that annually there are about 4,500,000 reported cases of dog bite in the US. Over 800,000 of them result in trips to the hospital and over 30,000 result in reconstructive plastic surgery.

 

Or, let us compare the lethality of H1N1 with garden variety seasonal flu.

 

In 2009, how many people in the US have died of seasonal flu as of  today(May 13, 2009)? Over 13,000. How many have died of H1N1? 3.

 

And unless you are very old, very young, or suffer from a chronic medical condition that compromises your body’s ability to fight infections of practically any kind, you are very likely to survive an H1N1 infection, should you get it, with no long term sequelae.

 

 

Is there other good news in this story. Sure. While some strains of flu have developed resistance, two drugs appear to be working effectively: Oseltamivir and Zanamivir.

 

Are there still mysteries and dilemmas yet unresolved about H1N1?

 

While there are doubtlessly a great many, there are two being increasingly mentioned.

 

First, it appears that many H1N1 patients are having bouts of severe diarrhea, and that hand contamination  with a potential for virus spreading from repeated toileting  is a concern, that is added to the usual worry about contamination of hands through coughing and sneezing of mucus droplets that contain the virus.

 

The solution to both  newer and well-established routes of transmission is practical and literally at hand: Vigorous hand washing with soap and water and/or use of alcohol-based cleansing gels.

 

Second, there is some worry that the virus will further mutate and/or  recombinate and return with a vengeance next Fall. This must be recognized as a possibility, and scientists will doubtlessly be on the lookout.

 

But their focus will not be soley on pigs, but on any animal, including humans, within which  this might occur, and on sensible means to contain and counteract it.

 

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

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