Inflammation, Cancer, Targets of Ginseng

A word of warning about using Ginseng:

If you are diabetic it is ill advised. Ginseng has a remarkable affect on the adrenal glands and this may impact on sugar regulation. Always consult your doctor before using Ginseng.

Ginseng is known to interfere with the actions of various pharmaceutical drugs.

Ginseng should not be used on a continual basis, it can induce adrenal exhaustion.


Article: Inflammation, Cancer, and Targets of Ginseng
Image:
Authors: Lorne J. Hofseth and Michael J. Wargovich
Journal: J. Nutr. 137: 183S–185S, 2007.
Location: Life\Nutrition\Title
Date obtained: 18/10/2008
Date Read: 21/10/2008
Date to Review:
Web Page:
Keywords:
Printed:
Notes:
Abstract
Chronic inflammation is associated with a high cancer risk. At the molecular level, free radicals and aldehydes, produced during chronic inflammation, can induce deleterious gene mutation and posttranslational modifications of key cancerrelated proteins. Other products of inflammation, including cytokines, growth factors, and transcription factors such as nuclear factor kB, control the expression of cancer genes (e.g., suppressor genes and oncogenes) and key inflammatory enzymes such as inducible nitric oxide synthase and cyclooxygenase-2. These enzymes in turn directly influence reactive oxygen species and eicosanoid levels. The procancerous outcome of chronic inflammation is increased DNA damage, increased DNA synthesis, cellular proliferation, disruption of DNA repair pathways and cellular milieu, inhibition of apoptosis, and promotion of angiogenesis and invasion. Chronic inflammation is also associated with immunosuppression, which is a risk factor for cancer. Current treatment strategies for reactive species overload diseases are frequently aimed at treating or preventing the cause of inflammation. Although these strategies have led to some progress in combating reactive species overload diseases and associated cancers, exposure often occurs again after eradication, treatment to eradicate the cause fails, or the treatment has long-term side effects. Therefore, the identification of molecules and pathways involved in chronic inflammation and cancer is critical to the design of agents that may help in preventing the progression of reactive species overload disease and cancer associated with disease progression. Here, we use ginseng as an example of an antiinflammatory molecule that targets many of the key players in the inflammation-to-cancer sequence. J. Nutr. 137: 183S–185S, 2007.

TABLE 1 Key players in the inflammation-to-cancer sequence1
The inflammatory player: Examples of mechanisms toward carcinogenesis
RONS, COX, and NOS Damage DNA, modify cancer protein, alter proliferation and
apoptosis (depending on concentration, microenvironment, and genetic background
of target cells), inactivate tumor suppressor pathways (e.g., pRb and p53).
NF-kB Activate proliferation and inhibit apoptosis by activating modulators of these
event: cytokines (e.g., TNF-a), growth factors, survival genes (e.g., Bcl-XL),
angiogenic factors (e.g., VEGF), inflammatory genes (e.g., COX and NOS). Recent
high profile studies indicate this molecule is a key molecular node in the
inflammation-to-cancer sequence (2).
TLRs Activate MAP kinase and NF-kB pathways.
Cytokines Activate or deactive many inflammation and cancer pathways (1). Example:
The proinflammatory cytokine, IL-6 can antagonize p53, inactivate pRb, and activate
survival genes (Bcl-2 and Bcl-XL); The antiinflammatory cytokine, IL-10, can inhibit
proliferation and ras signaling.
Growth factors Transforming growth factor-b, at high concentrations, activates
p21/p27-mediated growth arrest and smad- and p53-mediated apoptosis.
MMPs MMP-2 promotes proliferation by activation of the discoidin domain tyrosine
kinase receptor 2. MMPs also are immunomodulators and stimulate angiogenesis,
inhibit cell adhesion, and inhibit apoptosis.
PPARs PPAR-g ligands are mostly protective to the inflammation- to-cancer sequence.
They inhibit iNOS, COX-2, NF-kB, MMPs, and E2Fs; they activate p53, p27, and p21.
Kinase pathways p38 stimulates proliferation and inhibits apoptosis. An inhibitor of
MAP kinase signaling (CNI-1493) has shown promise in ameliorating Crohn disease
in humans (3).
p53 and pRb pathways Both pathways are inactivated in reactive species overload
diseases (4,5).

Studies indicate that ginseng has potential as a chemopreventive agent or adjuvant treatment. Some of the cancers shown to decrease significantly with ginseng use include cancersof the pharynx, stomach, liver, pancreas, and colon (22,23). Mechanisms include inhibition of DNA damage (24), induction of apoptosis (25), and inhibition of cell proliferation (26). It is also becoming increasingly clear that ginseng has potent effects on the inflammatory cascade and may inhibit the inflammationto- cancer sequence.
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Ginseng targets the inflammatory players There is evidence that ginseng has potent effects on key players in the inflammatory cascade (Fig. 1). For example, ginsan, a polysaccharide extracted from P. ginseng, showed inhibition of s, the p38 MAP kinase pathway, and NF-kB in vitro and inhibition of proinflammatory cytokines in vivo (27). The ginsenoside Rg3 was shown to inhibit phorbol ester–induced COX-2 and NF-kB induction (28). BST204, a fermented ginseng extract, can inhibit inducible NOS (iNOS) expression and subsequent nitric oxide production from lipopolysaccharidestimulated RAW264.7 murine macrophages.

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Ginseng can also inhibit other mediators of the inflammation- to-cancer sequence, such as matrix metalloproteases and kinase pathways (31).
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Project:

Aussies and Iodine

Some may recall the time when table salt was fortified with iodine. Today that product seems rather hard to find and perhaps it is academic because so many people shy away from salt.

In this study they found a worryingly high percentage of Aussies had low iodine. A huge 43% were found to be iodine deficient. In relation to children and pregnant women this is potentially a very serious problem. Lack of iodine in children can lead to cognitive impairments and a range of other issues, in adults it can induce goiter. Iodine is essential for proper functioning of the thyroid, a gland that plays a regulatory role in the general rate of metabolism.

Food Standards Australia has released this report.

Sources of iodine:

Iodised Salt.
Seafood products.
In Australia, iodine fortified bread should be available in September 2009.

For an overview of iodine, recommended intakes and sources of iodine read this report from Nutrition Australia.

Bottled Water is Bollocks

Why the trend in bottled water became so prevalent was beyond me until I heard reports about the quality of drinking water in some parts of the world. Nonetheless, in most First World Countries tap water is of sufficient quality that we should not be wasting our money on bottled water. Unless of course we want to impress our friends ...

Numerous studies on bottled water have raised serious questions about the value of the product and this latest study adds further weight to the claim that bottled water is largely a waste of money. It can be summarised as follows:

• Bottled water is no guarantee that the water is contaminant free. Indeed many companies will not release their own testing results of the water you buy.
• The promotional images of bottled water are very misleading, bottled water is often municipal tap water that has been purified but still contains contaminants.
• Some bottled water even contained contaminants in excess of the safe recommended levels.
• Some bottled water was indistinguishable from tap water.

You can read the full report here.

There are another important considerations in relation to bottled water. It requires plastic bottles and you may recall all the fuss recently concerning bisphenol A, a very common component in plastic bottles, is now being found to have a wide range of potentially very unpleasant health consequences. For more information this link to an earlier post of mine might help.

If only that were all. The other issue in relation to bottled water is that the manufacturing and distribution of the this product is a coal burning exercise. Even if one is doubtful concerning Global Warming, the delivery of bottled water in plastics and by transport is terribly inefficient compared to water from the tap, especially given that there is on likely benefit drinking bottled water over tap water.

Antioxidants, Neurodegeneration, and Cancer

Research article. Interesting but lacking depth. Good balance on the issue of antioxidant supplementation.

The study can be downloaded here.

Article:
The role of antioxidant supplement in immune system, neoplastic, and
neurodegenerative disorders: a point of view for an assessment of the
risk/benefit profile
Authors:
Daria Brambilla, Cesare Mancuso,Mariagrazia Rita Scuderi,Paolo Bosco,Giuseppina Cantarella, Laurence Lempereur, Giulia Di Benedetto, Salvatore Pezzino, Renato Bernardini,
Journal: Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location: Life\Nutrition\title
Date obtained: 3/10/2008
Date Read: 19/10/2008
Date to Review:
Web Page:
Printed:
Notes:
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
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However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alphatocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury [8,9]. Thus, it is of relevance that prior to considering introducing antioxidant therapy into mainstream medicine, significant advances in basic cell biology, pharmacology and clinical bioanalysis will be required.
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Heme oxygenase is a microsomal enzyme which metabolizes heme into ferrous iron, carbon monoxide and biliverdin (BV); the latter is then reduced by BVR into bilirubin (BR), a molecule endowed with strong antioxidant and antinitrosative activities [11-14]. Interestingly, all these protective factors act in a concerted way, enhancing the antioxidant defense system of the cell. When the balance between ROS/RNS and antioxidants turns in favor of the former, oxidative/nitrosative stress occurs.
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Extracellularly generated ROS can diffuse through anion channels into the cytoplasm; the resulting variation in the cell redox state leads to modulation of an array of transcription factors (eg. NF-kB, AP-1), protein kinases (e.g. AKT, JNK, p38), and receptor activated MAP kinases involved in apoptosis [17, 24,25,26]
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However, not only immune cell produce ROS necessary for the microbicidal activity, but they are also sensitive to external ROS, due to their high polyunsaturated fatty acids (PUFA) content. Immune cells are atypical, as compared with other somatic cells, in that they contain high levels of antioxidant vitamins, presumably providing protection against lipid peroxidation and immunosuppression, both of which are well known risks posed by high PUFA content [38].
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Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61].
61. Hidvégi M, Ráso E, Tömösközi-Farkas R, Paku S, Lapis K, Szende B: Effect of Avemar
and Avemar + vitamin C on tumor growth and metastasis in experimental animals.
Anticancer Res 1998, 18(4A): 2353-2358.
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Heme oxygenase-1, the inducible isoform of HO, is a key protein in the cell stress response and its up-regulation is a common event during pro-inflammatory conditions [11,69-72]. Recent work clearly demonstrated that regulatory T cells overexpress HO-1 and release CO under pro-oxidant conditions. Carbon monoxide may inhibit the proliferation of effector T cells, thus reducing the immune response and prevent autoimmunity and/or graft reaction [73,74]. Dietary antioxidants, in particular polyphenols, has been shown to increase HO-1 expression in different in vitro systems [3,75,76] and the potential use of this natural substances to regulate immune response should be carefully addressed.
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Other studies report that combination of vitamin A and other antioxidants, significantly increases mortality related to neoplastic diseases. [91]. According to these studies, selenium would be the only element displaying beneficial effects, as it has been shown that it reduces total cancer incidence, an apparently sex-related effect, as it is predominant among males, rather than in females [89].
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Due to their scarce bioavailability, only a negligible amount of polyphenols reaches brain tissue and the concentrations achieved are much lower than those efficacious in vitro [3]. As far as NSAIDs, ad hoc designed clinical trials with a large number of patients, clearly demonstrated that these drugs do not have any significant effect in slowing cognitive decline in patients suffering from mild-to-moderate AD [120,121].
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It is noteworthy to underlie that as for all drugs, antioxidants may give important side effects if not correctly used or in combination with other drugs. Vitamin A, E and â-carotene for instance, have been shown to have pro-oxidant effects at higher doses or under certain conditions [39].
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Exercise and Brain Aging

There is now abundant research pointing to the beneficial effects of aerobic exercise on cerebral health. This recent study finds that taking up exercise can improve cognition and cerebral health. There is a striking relationship between cardiovascular and cerebral health. The reason for this is obvious: the brain consumes approximately 20% of our oxygen intake, so maintaining maximal blood supply to the brain is critical. One of the reasons Ginkgo Biloba works is because it reduces platelet activating factor, thereby improving cerebral circulation.

Exercise and do it often. You don't have to run marathons, in fact intense exercise can do more harm than good. Light exercise is okay but it is important to push yourself, just going for a casual walk is good but going for a brisk walk is much better.

Exercise effects on cognitive and neural plasticity in older adults
Kirk Erickson and Arthur F Kramer
British Journal of Sports Medicine (2008).
The abstract:

Older adults frequently experience cognitive deficits accompanied by deterioration of brain tissue and function in a number of cortical and subcortical regions. Because of this common finding and the increasing aging population in many countries throughout the world, there is an increasing interest in assessing the possibility that partaking in or changing certain lifestyles could prevent or reverse cognitive and neural decay in older adults. In this review we critically evaluate and summarize the cross-sectional and longitudinal studies that assess the impact of aerobic exercise and fitness on cognitive performance, brain volume, and brain function in older adults with and without dementia. We argue that six-months of moderate levels of aerobic activity are sufficient to produce significant improvements in cognitive function with the most dramatic effects occurring on measures of executive control. These improvements are accompanied by altered brain activity measures and increases in prefrontal and temporal grey matter volume that translate into a more efficient and effective neural system.

Low antioxidant status and high sunlight exposure = Retinal Degeneration

I don't know if the below is a true statement because I have never heard it before but it does highlight why even blue light is damaging to vision. Lesson: obtain sunnies with blue light filtering capacity. Take it as high risk that by the time you reach 70 there is a distinct possibility you have some degree of cataract formation and retinal degeneration. The key is to contain the progress of these conditions as much as possible. That can be done but even with the best of care some of us are going to need cataract surgery and may develop AMD. Genes! In particular, a diet specifically addressing the oxidative balance in your blood is very important.

Most importantly control cholesterol, I have seen enough research to indicate that high cholesterol, particularly the small LDL variant (vLDL), readily penetrates the Retinal Pigment Epithelium and thus sets off unwanted cascades of nasties.

http://www.sciencedaily.com/releases/2008/10/081013171431.htm

... The eye is particularly vulnerable to the damaging effects of sunlight. Ultraviolet radiation is absorbed by the lens, but visible or “blue” light penetrates to the retina so allowing us to see. Protection against the harmful effects of blue light is provided by the antioxidant vitamins C and E, the carotenoids (lutein and zeaxanthin) which filter blue light, and zinc. --------

The Aging Brain

This study from the Neurobiology of Aging highlights the significance of white matter in the aging process of the brain. The news item can be read here. White matter is the extensive sheath that surrounds the long and not so long axons of nerve cells. The presence of white matter markedly improves the speed at which signals can traverse through long axons. The process of myelination is long and we can in our late 20's or even early 30's before this process is completed.



Myelin creation is not a one off event, it is subject to continual degradation and renewal. The cells that produce myeline are called oligodendrocytes, a type of glial cell. Unfortunately oligodendrocyte cells demonstrate some particular vulnerabilities to insult. In those with Multiple Sclerosis, a common autoimmune condition, the immune processes responds to various "danger signals" emitted by oligodendrocytes and this can establish an ongoing destruction of these cells and myelin production. The initial triggers for this condition remain unknown but there are a number of strategies that Multiple Sclerosis sufferers can undertake which may alleviate the progress of the condition.

As we age the balance between myelin degradation and renewal falls out of kilter, the result being that we start losing the myelin covering. Of interest is the association between dementias and changes in white matter, it may even be the case that in some individuals the destruction of myelin is so extensive as to initiate a series of inflammatory processes that in turn induce dementias.

There is an important lesson here. The brain controls the body, maximising cerebral health is critical to maintaining good health as we age.

Lipofuscin And Aging

Lipofuscin is the deposition of waste products in the cell that are not degraded. The critical factor seems to be rate at which proteins and lipids are degraded by the various "house keeping" functions in the cell. In these days the emphasis on the dynamics of aging is typically excessive oxidation events and lipofuscin receives little attention. Lipofuscin is something that needs to be addressed because as lipofuscin deposits increase the cell becomes increasingly unable to do its job.

In the graphic below I have extracted a table from a very old study. It highlights the huge increase in lipofuscin aggregation with age. They used acetyl l carnitine has a therapeutic intervention and the results were quite good but only at very high dosages. Other and much more recent research has found that acetyl l carnitine can also play an important role in preventing Age Related Macular Degeneration (AMD). In those studies they created a compound called Phototrop, a combination of acetyl L carnitine, omega 3 fatty acids, and co-enzyme Q10.

Word of warning: you should always use alpha lipoic acid with ALC because ALC increases mitochondrial function and mitochondria are the key region where oxidants are formed.

The table below is from

Japan J Pharmacol, 38, 365-71(1988)

Another worrying study concerning mobile phones

There are now a number of studies pointing to the dangers of mobile phones. Of particular concern is the widespread and frequent use of mobile phones amongst teenagers. This study reveals a disturbing quality about the microwave radiation emitted from mobile phones: the markers of oxidative stress, MDA(malondialdehyde) and XO(xanthine oxidase) remain up to 40 days after exposure to the microwave radiation in a rat model. One factor causing this sustained expression of inflammatory markers was the persistent reduction in catalase, a key antioxidant pathway in our cells.

Previous research has found increased risk of brain tumours in the young. While the telecommunications industry strenously denies any danger from using mobile phones increasing research is painting a very different picture. Some authorities have even claimed that the widespread use of mobile phones is paving the way for an epidemic of brain tumours.

Thanks to Dr. Lefever for forwarding this study to me.

The full study can be downloaded here.

Electric Eels and Electronic Implants

This study from Nature Nanotechnology is fascinating. They claim to have found a way to model the cells in electric eels that create electricity so that artificial cells can be used to power medical implant devices.

The news item can be read here.

Financial Risk Taking and Testosterone

Previous studies have found that the higher one's position in the social ladder, the higher the Testosterone levels tend to be. In light of this study then it is not surprising that we find ourselves in this current financial predicament because financiers, for reasons which escape this humble mind, earn extraordinarily high incomes. Think about it, there are any other number of professions that should be paid more because the people in these professions have much greater responsibility and experience much greater stress than those in the finance industry. Those poor souls can't go running home to mama(the Central Banks) when they stuff up, they go broke. Financiers go running to mama and expect a handout for being naughty boys. This has to stop and I hope this crisis makes everyone take a long hard look at the financial industry.

Here is a news release on the study.

The Future of Global Warming

It has always been my belief that we will never sufficiently reduce carbon dioxide output to address global warming. The simple fact is that we must find ways to capture existing CO2 AND reduce carbon dioxide output. This technology is amongst many currently under investigation.

Supplements for Osteoarthitis - Conflicting Results Again

I've seen this a number of times with various over the counter supplements. Some studies paint a good picture, others show equivocal results, and other studies claim the supplement is a dud. There is far too much hype concerning the purported value of all those supplements out there but the research is indicating that some supplements can be of great value not only in addressing specific pathologies but also general health. For example, Juvenon (see picture on the right) is a supplement compound backed up by credible research. While I haven't tried juvenon itself I have tried to the two components of it. It took a while for the effects to kick in but it definitely worked.

Osteoarthritis is a very common condition and many alternative therapists advocate the use of the supplements glucosamine and chondroitin sulfate. Studies have been mixed but mostly negative. This latest study suggests a mild favourable effect for glucosamine.

How does the consumer know what to do in these circumstances? Here are some guidelines:

1. Look for reliable well conducted clinical trials on the supplement. If these don't exist then be very careful. Typically I will never advocate the use of a compound that has not been subject to clinical trials.
2. NEVER trust the sellers of a product to provide reliable information. NEVER NEVER NEVER.
3. Ask others who have used the supplement for their impression of it. This may help but remember individual responses to various drugs and supplements vary so widely that there is no guarantee what works for one person will work for you. This, incidentally, is also true of clinical trials. That something has worked in a clinical trial is no guarantee it will work for you. Remember, clinical trials are statistically based and hence the results apply to the treatment group, the results may not even be applicable to individuals within the treatment group.
4. As long as you are convinced the supplement is safe and even in the absence of clinical trials there is no harm in giving it a go. It may just work for you even work clinical trials make low claims to efficacy or even state no efficacy. I appreciate this sounds contradictory but we are individuals and sometimes, even if by placebo effect, people do find benefits in supplements that have no scientific support for their use.

Vitamin C May Inhibit Chemotherapy

For some time there has been a controversy regarding the use of antioxidants during chemotherapy. Concerns have been raised because antioxidants protects cells against stress and so taking large doses during chemo may impede the effectiveness of chemotherapy.

This study appears to bear that out. What they found is that vitamin C, both in vitro and in a mouse model, allowed the tumour cells to survive by protecting the mitochondria. That makes a great deal of sense because mitochondria are a "gateway" for death signals and anything that preserves mitochondrial function typically helps keep the cell alive.

Sounds simple but isn't, there is also the possibility that in some cancers activating certain functions of mitochondria, in particular the release of pro-apoptotic factors, can activate cell death pathways. Additionally some studies have found that high doses of intravenous vitamin C can be effective in killing cancer cells. What a dilemma, take antioxidants to try and prevent healthy cells from chemotherapy damage and run the risk of helping the cancer cells to survive.

Ironically part of the problem here lies in the singular tense word "cancer". Even cancer originating in the same body tissue of the same person may be a different type of cancer. Because of this, strategies to target cancer are never going to constitute a single magic bullet, we will always have to tailor the strategy to the specific type of cell present in the tumour. So in some instances antioxidants may not present a problem because in some cancers the mitochondria are disabled or poorly functioning. In other cancers improving mitochondrial function may induce death signals like APAF1, BAX, BAD. Even then it can become complicated because some cancers have high expression of the small heat shock protein, hsp27. This protein can bind these death signals so preventing cell death.

Just to confuse the picture there is clinical evidence that the intravenous administration of vitamin C can kill cancer cells. The reasons behind this are unclear but it is known that high doses of vitamin C, particularly in the presence of free iron, can drive oxidative processes via Haber-Weiss and Fenton reactions, thereby inducing cell death. To achieve such high doses though intravenous injection is required because the body will not absorb large amounts of vitamin C orally. Hence all those people taking large doses of oral vitamin C are wasting their money. For a look at the use of intravenous vitamin C read of this article. A short comment in the Canadian Medical Journal puts forward the case for using intravenous vitamin C in cancer therapy.

It is never going to be easy! So when you see all those internet advertisements proclaiming a universal cure for cancer don't go there. It simply isn't true, each type of cancer requires a different strategy. That is why the success in cancer treatments is not uniform. Great strides have been made in treating some cancers while other types, for example brain tumours, virtually no progress has been made in 20 years. In all this remember what Mencken once wrote:

"For every human problem, there is a neat, simple solution; and it is
always wrong"

The Creative Mind: Myths and Mechanisms - Margaret Boden

Professor Margaret Boden is a cutting edge thinker in the fields of Artificial Intelligence and creativity. Recently I stumbled upon her recent publications which prompted me to re-examine some ideas about creativity. I was fascinated to find that even to this day she sets as required reading the above text. For a preview of The Creative Mind: Myths and Mechanisms click here.

This is a legendary text that should be read by all who are interested in the nature of creativity. Be warned though, this book will not provide prescriptions or rules for being creative; the author is far too intelligent and wise to lead her readers into nonsense. I read this text in 1998, it is one of the few books I have kept in my once extensive library. In these days I prefer everything to be computer based because with Google Desktop search and the brilliant Infoselect program I never loose information on my computer. The ability to track down and quickly access information is an important component of creativity.

One of the most striking concepts to emerge out of this text is that of "conceptual space". While doing some research for this post I noted that Boden is still invoking this concept in her recent books and lectures. It is a wonderful little concept that is part and parcel of my arsenal of cognitive tools. That is somewhat paradoxical because in my areas of interest there are so many conceptual spaces that I can and will keep wandering across for the rest of my days. Over recent years I have come to appreciate that creative thinking in this Big Land is 99.999999% blood, sweat, and tears and the rest is luck. That is quite common, in fact creative thinking in many realms is incredibly difficult and time consuming.

One of the fascinating aspects of the concept of "conceptual space" is that it provides insight into how discoveries can quickly proceed and then come to a standstill. As new spaces are opened up discoveries can happen quickly because there are so many good opportunities to be had. It is like a gold rush, the first in pick up the nuggets lying here there and everywhere, those following behind have to search much more harder to find the nuggets. This also explains why "mavericks" can, early on, make such huge gains. If you look at the history of science mavericks tend to succeed early in the development of the science, as the field matures mavericks, lacking the training, knowledge and expertise that comes with years of education, tend to fade into the past.

Conceptual spaces are bounded. This is a very important point. The boundaries specify the search radius and also determine the types of solutions that can be found. Einstein touched on this when he stated:

You can't solve a problem on the same level that it was created. You have to rise above it to the next level.

Note his use of the word "level". In physics that is important because they are seeking a Theory of Everything. In most domains however the idea of "levels" is misleading, Boden's concept of space is much more appropriate. Interestingly, as the physicists Lee Smolin and Paul Davies have stated, the idea of a "Theory of Everything"is eerily reminiscent of God.

There is a tendency for people to speak about creativity as "pushing the envelope". This is also misleading. In many intellectual domains we don't have to push anything except our perseverance, there is plenty of unexplored territory. Phrases like "pushing the envelope" encourage a view that creativity is about breaking the rules and being extreme. Genuine creativity is something entirely different. As Boden states:

But far from being the antithesis of creativity, constraints on thinking are what make it possible. In short, to drop all current constraints and refrain from providing new ones is to invite not creativity, but confusion.

It is the partial continuity of constraints which enables a new idea to be recognized, by author and audience alike, as a creative contribution.

Her comments here touch on what I was referring to earlier. As a conceptual space is explored it soon emerges that there are constraints on one's thinking. One cannot abandon previous concepts simply to be creative, one must have very good reasons for abandoning long held concepts. It is not enough to abandon an idea simply because it gets in the way of creative thinking.

Boden also strongly emphasises the need for persistent effort and patience:

Even Mozart needed twelve years of concentrated practice before he could compose a major work, and much the same seems to be true of other composers.

This commitment involves not only passionate interest, but self-confidence too. A person needs a healthy self-respect to pursue novel ideas, and to make mistakes, despite criticism from others. Self-doubt there may be, but it cannot always win the day. Breaking generally accepted rules, or even stretching them, takes confidence. Continuing to do so, in the face of scepticism and scorn, takes even more.

However she does not exclude the need for the right attitude towards creativity:

Like much play, creativity is often open-ended, with no particular goal or aim.
... Likewise, the artist or scientist may explore a certain style of thinking so as to uncover its potential and identify its limits.

This reminds of a wonderful quote from that wise old Greek Heraclitus:

Man is most nearly himself when he achieves the seriousness of a child at play.

The above is not intended to suggest that creativity is solely about hard work and learning. It is obvious that Eureka! moments are important and most of us have experienced the same at various times during our lives. At least I hope most of us have. When seeking creative ideas it is important to maintain a balance. There are times when no amount of further study and conscious thinking will lead us to a solution. The mathematician Hadamard claimed that were 4 stages in his problem solving: preparation, incubation, illumination and verification. Surely all of us have experienced those occasions when the solution to a problem arises in the most unexpected circumstances. I remember an interview with the Nobel Laureate physicist Roger Penrose. He had been struggling with a particularly difficult problem for a long time. Walking with a friend on the street, the solution came to him just as he stepped off the curb to cross the street.

Such anecdotal stories are too common to dismiss as mere co-incidence, there are too many stories of people finding solutions to problems in such a manner. A word of caution though: Revelation comes only to the prepared mind. Forget that "muse" nonsense, people who experience Eureka moments have almost invariably been working long and hard on the problem. Often they have completely explored the available conceptual space, the breakthrough comes when they stumble upon undiscovered country. So it is not surprising that Einstein once quipped:

How do I work? I grope.

The important thing is not to stop questioning. Curiosity has its own reason for existing. One cannot help but be in awe when he contemplates the mysteries of eternity, of life, of the marvelous structure of reality. It is enough if one tries merely to comprehend a little of this mystery every day. Never lose a holy curiosity.

The below statement is from: Cracking Creativity: The Secrets of Creative Genius, Michael Michalko

When someone asked Einstein what was the difference between him and other people he replied that if other people were asked to find a needles in haystack they would find one then give up, but he would keep looking."

Creative people tend to be like that. Show them something new under the sun and you can almost see the cogs start turning. They are quizzical, fascinated by new things, want to understand these, what these things can be used for, sometimes just to understand why something works. Not all of us can be like that. In my opinion too many of us are often forced to be too practical and too concerned with outcomes rather than play. It is tragic to see so many people have lost their sense of childish fun and enthusiasm. We are taught to "grow up", "behave", and "be sensible". All that reminds me of Eric Olthwaite in Ripping Yarns when his neighbour said to him, "You're a boring little tit."

As to why some people have have retained that sense of fun and exploration I do not really know, though the work of Frank Sulloway may provide some insight into this matter, the truth is education can damage our curiousity. Too much of modern education is conducted in a highly competitive environment where wrong answers are punished. Yet creativity invariably involves making lots of mistakes, sometimes disastrous ones. Fear of being wrong kills creativity.

So if you are interested in improving your creative potential this book is certainly a good starting point. The text is still available and you should also consider her recent texts on the subject. I would love to add those to my reading list but I have already downloaded research articles with circa one hundred unread. Hmmm, now what was that about perseverance?

A Bright Side to Statins

In my earlier post, The Dark Side of Statins, I mentioned research indicating that statins may impede muscle repair. This latest finding claims that statins promote DNA repair enzymes and in so doing help protect the endothelium(inner lining of the blood vessels). The enzyme here is one involved in repairing what are referred to as "double strand breaks". These types of breaks are very damaging to the chromosomes because with the breaks bases fall away from the ends of the chromosome, so the more quickly this and other enzymes are brought into play the better the outcome. The news release can be read here.

It is important to remember that this study addressed the health and aging rate of cells in unhealthy arteries, which tend to age much faster than healthy arteries. Whether or not this statin will confer any substantial benefit to those with healthy arteries is a different question. Given the evidence that statins can induce side effects such as impaired muscle repair and there is also some evidence of cognitive issues arising with their use, there is little sense in advocating wide scale statin use for the general public. Remember the wonderful aspirin? Or how about the wonderful NSAID drugs, which turned out to be killing people and causing all manner of problems? These are great drugs but these are drugs to address specific pathologies and even then the long term use of the same may create more problems than those apparently solved.

We need to exercise some caution here. There is an emerging view that vast numbers of the public should be placed on statin drugs yet the real reason for this is because vast numbers of the public are leading lives destined to induce atherosclerosis and a host of other ailments. Claims that simply popping a statin will stave off the consequences of a poor lifestyle, even if these do have some validity, must be set against the enormous costs of drugs, the known side effects of drugs, and the unknown long term consequences of drugs.

All developed countries are faced with a number of huge health related issues. Health costs are out of control, hospitals are over crowded, and with an aging population the health burden is going to increase. We would all like to have our cake and eat it too. Eventually we will be forced to eat an apple, go for a run, and hopefully the medicine cabinet will remain empty for a very long time.

If you wish to maintain a healthy heart and cardiovascular system there is no great secret. It is as simple as regular light exercise, even just brisk walking, avoiding all drugs, legal or otherwise(excepting a couple of glasses of red wine with the evening meal), good stress management skills, and a healthy diet. Yeah, that's simple, but why can't I do it?

The Mysteries of Vision

One of the most misleading analogies in neuroscience is "eye is like a camera". It is nothing of the sort. The anatomy of the eye makes that plainly obvious. For example, look at the graphic above. The top most part is the Retinal Pigment Epithelium. It plays a vital role in re processing vitamin A, absorbing excessive light, providing nutrients for the photoreceptors, and eliminating waste from the retina. Some studies suggest that the failure of the RPE to process and remove waste products is a cardinal feature in Age Related Macular Degeneration. The photo-sensitive portion of the photoreceptors is directly underneath the RPE.

Here's the rub: light does not travel from the top but from the bottom of this graphic. For light to stimulate the photooreceptors it must travel through the ganglion cell layer right up to the tip of the photoreceptors near the RPE. Quite amazing that we see it at all and it explains why some bods refer to the retinal structure as being "back the front". Now find me a camera that works like that ... .

Over and above that consideration the brain also goes to tremendous lengths to process visual information. It has been estimated that up to 30% of all CNS tissue can be involved in visual processing. The signals from the retina first must travel to the lateral geniculate nucleus(LGN) a set of small nuclei in the thalamus, from there the journey continues to the back of the brain to the VI or striate cortex, which appears to involve rudimentary visual processing, and then must travel forwards again to the temporal lobe(for object identification) and the parietal cortex(for position in space determination). This is the simple explanation!

What is becoming intriguing in our the research into vision is the research indicating that when we see the world the image we have in our minds is the result of this visual processing that is combined with our visual memory storage. That is, to a certain extent at least, the world we see is contingent on what we have been seeing our whole lives. With this little introduction in mind, have a look at these interesting visual hallucinations.

Go to this link and then download the relevant files. Have fun!

The Dark Side of Statins(cholesterol lowering drugs)

Cholesterol-lowering drugs and the effect on muscle repair and regeneration

Statin drugs are life savers and a principal component in allowing many people with high cholesterol to avoid heart attacks and strokes. Many statins exhibit anti-inflammatory properties and there have been trials for statins in dementia treatment. The results have not been that promising.

Many patients have reported problems with statin drugs and the research is now starting to bear this out. While statin drugs are life savers as with nearly all drugs there can be untoward effects. If you are taking statins and experience any of the symptoms mentioned in this article speak to your doctor. Take the article with you so they know you are not just dreaming up the symptoms.

If you are taking a statin drug it is strongly advisable to also take a co-q10 supplement with the statins because statin drugs typically inhibit HMG-CoA, a rate limiting enzyme for co-q10 production in the body. It is very important to maintain co-q10 levels because it is a strong antioxidant that plays a pivotal role in the electron transport chain, the "powerhouse" in our cells.

Caloric Restriction is a NoGo for Humans

Differences between People and Animals on Caloric Restriction

Most people interested in health related issues have heard of caloric restriction, the only known laboratory method for extending life. In this study they recruited members of the CR Society who had been practicing caloric restriction for 7 or more years. The results are disappointing and back claims by other scientists that human beings may not benefit from caloric restriction. My personal view is that caloric restriction is too severe and cannot be applied in our busy and work oriented society. Additionally other studies have indicated that constant caloric restriction can cause the following problems

• reduces immunity(some studies indicate it can lead to death of helper B cells, thereby restricting our adaptive immune capacity),
• loss of fertility for both males and females,
• cognitive issues, in fact a recent study claimed that chronic CR can actually cause brain damage.

In this study the researchers did find a way to alter the key physiological marker for the beneficial effects of CR: reducing IGF1 expression. IGF is Insulin Growth Factor. Under stimulation from human growth hormone, IGF is released by the liver and travels throughout the body. The researchers asked one set of the participants to lower their protein intake and within 3 weeks this caused a dramatic reduction in IGF levels. Again however I must stress: that reducing protein intake induced a favourable IGF response, one has to be consider that such a radical reduction in protein intake may have serious long term implications that easily outweigh the benefits of reduced IGF levels.

A point of clarification. Many people think that the more growth hormone the healthier they are. This is misleading and false. Reducing growth hormone levels in age is consistently associated with less pathology and a longer life.

References:

Fontana L, Klein S, Holloszy JO. Long-term low-protein, low-calorie diet and endurance exercise modulate metabolic factors associated with cancer risk. American Journal of Clinical Nutrition, vol. 84; pp. 1456-1462, Dec. 2006



Fontana et al. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell, 2008; 7 (5): 681 DOI:

The Horror, The Horror!

Political Conservatives Fear Chaos; Liberals Fear Emptiness

Mistah Kurtz died long ago so get over it. (With apologies to the wonderful Joseph Conrad)

Keep in mind that with these studies the results are statistical so don't go around thinking that because someone has liberal or conservative political beliefs ipso facto that particular person experiences what the study results suggest.

According to this study conservatives fear of social chaos and absence of order while liberals fear emptiness. The potential for social chaos and absence of order is always a problem for societies so these things need to be guarded against. As for feelings of emptiness just get over it. The universe is a cold heartless place and the sooner you realise that and go on living the better off you will be. Stuff the rubbish touted by Deepak Chopra, Gary Zukav, and even Anthony Robbins for that matter. These people are fools who delude others into thinking that life truly is meaningful. It isn't. This has long been known but few are willing to embrace it wholeheartedly. When people do truly accept the meaninglessness of existence they realise it was a stupid thing to worry about. Alas I fear that humanity will continue to generate all manner of Imaginary Friends to keep The Horror away. As that wonderful French writer Albert Camus noted, "Seeking the truth is not seeking what is desirable." More importantly, remember his words:

But it is bad to stop, hard to be satisfied with a single way of seeing, to go without contradiction, perhaps the most subtle of all spiritual forces. The preceding merely defines a way of thinking. But the point is to live.

The Myth of Sisyphus.

So if you are a conservative and fear emptiness the problem is that you fear nothingness. When you think about it, that's kinda stupid. At least conservatives aren't that silly.

Parkinson's Disease and Pesticides

There are now many reports concerning the relationship between some pesticides and Parkinson's Disease. The disturbing aspect of this recent study(abstract below) is that they found high levels of two commmon pesticides in the nigra region of Parkinson's patients. This region of the brain is typically referred to as the substantia nigra. It is a rather small round nuclei that contains a great many dopamine producing neurons. These neurons play a critical role in modulating motor function, hence the classic gait of Parkinson's patients and the slow loss of control over motor function. It is important to note though that loss of movement control is not the only problem in Parkinson's patients, cognitive and emotional problems also arise. There is also evidence of neural destruction beyond the nigra region and this can extend into the temporal lobes. As always, when we look at the actual results of neuroscience studies we find that the living brain is not as neat and tidy as our lovely diagrams of it.

Parkinson's Disease is one the strangest neuropathologies. We have very little idea concerning the etiology of Parkinson's Disease but the linkage with some pesticides is very strong. Rotenone, a "natural" pesticide favoured by organic farmers, is great at killing neurons in this region. Epidemiological studies have established very strong linkages with occupational exposure to some pesticides and the incidence of Parkinson's Disease. If you enjoy playing golf make damn sure that in the very least you wash your hands after each game, preferably have a shower. Make sure you don't wear your golf shoes in the house, the residues could spill onto the floor surface where your kiddies love to play. Golf courses are toxin sinks, so much so that a few studies have found a direct correlation with living near a golf course and in the incidence of cancer in children and pets. If you are an active gardener who uses pesticides be very careful. Follow the safety instructions and be very careful about spillages. You have been warned.





Neuroreport. 2008 Aug 27;19(13):1317-20.
Synergistic microglial reactive oxygen species generation induced by pesticides lindane and dieldrin.
Mao H, Liu B

Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Elevated environmental exposure to pesticides is a known risk factor to the development of sporadic Parkinson's disease resulting from the degeneration of nigral dopamine neurons. Among the suspected agents are the highly persistent and bioaccumulative organochlorinated pesticides (OCPs). We report here that lindane and dieldrin, two widely present OCPs that are found enriched in the nigra of postmortem Parkinson's disease brains synergistically induced the production of reactive oxygen species (ROS) in microglia. Inhibitor studies indicated that the lindane and dieldrin-induced ROS generation was mediated by NADPH oxidase. As microglial ROS is a key contributor to the degeneration of the oxidative damage-vulnerable dopamine neurons, our findings shed significant light on the role of OCPs in the development of Parkinson's disease.

Dying to See the Light

It was Dr. Fenwick who first proposed this study into near death experiences. Many argue that near death experiences are proof of an after life but I remain cynical of the same. One possible reason why some can still have perceptions when the heart has stopped is that the brain has a unique supply of glucose and oxygen. Brain cells(neurons) can only use sugar as a fuel source. Remarkably, there is a type of buffer built into this energy source. Astrocytes, glia that are in direct contact with the blood vessels, absorb glucose from the blood, process it, then release pyruvate into the intra-cellular spaces. Neurons will take up the pyruvate as their energy source. A couple of years ago there was also a study indicating that the CNS may have a "reserve oxygen supply". So there remains the possibility that the brain can continue functioning, albeit for a very short time, after the heart has stopped.

This research should settle the matter once and for all.

For information on Dr. Peter Fenwick's research, just google the name.

Cannabinoids and Multiple Sclerosis

Previous studies have indicated that cannabinoids can act as potent neuroprotectants in a variety of contexts. Hampson et al found that the two major cannabinoids in cannabis sativa, THC and cannabidiol, demonstrated antioxidant capacity greater than vitamins C and E and comparable to the most powerful laboratory antioxidant available to them. This finding may explain why, independent of cannabinoid receptor CB1 or CB2 activation, these cannabinoids demonstrate neuroprotective and anti-inflammatory properties.

This recent study highlights how CB2 receptor activation demonstrates powerful neuroprotective capacity in the animal model(EAE) of Multiple Sclerosis. (Click here for the news release.) In this study the administration of a CB2 agonist reduced neuron cell death by 50%, a remarkable result but one that is consistent with many other studies. They focused on activation of the CB2 receptor. This receptor plays an important regulatory role in the immune response and is also found in the broad equivalent of immune cells in the CNS: microglia.

The great promise of CB2 agonists is that these are non-psychoactive, thereby allowing a potent therapeutic effect without the patient having to deal with the psychoactive effects of THC, which activates the CB1 receptor. Some may retort that this is not a good thing and there may even be some merit in that because CB1 activation has been found to induce neurogenesis and also demonstrates some neuroprotective properties. However in relation to MS, because CB1 tends to inhibit neuronal activation(retrograde inhibitory transmitter), excessive activation of this receptor may make their symptoms worse. There have now been a number of studies where Multiple Sclerosis patients have been allowed to smoke cannabis. The results have been equivocal but there has been enough evidence that some governments have allowed the smoking of cannabis for those suffering MS. There are now so many studies pointing to the therapeutic of cannabinoids that even a study group in conservative Australia has called for the introduction of medicinal cannabis. Unfortunately there is also strong evidence that smoking marijuana can damage the lungs though there is no evidence of it increasing the risk of lung cancer.

A very important word of warning: women who are pregnant or planning to become pregnant must not smoke marijuana. While the evidence is slight it is sufficient to raise very serious concerns about smoking marijuana during pregnancy.

An important finding in this study is that CB2 agonists inhibited the recruitment of immune cells into the CNS. It may even be the case that this is a critical pre-condition for MS attacks to occur. Further research is required to clarify this issue.

With many studies now demonstrating considerable therapeutic potential for cannabinoids it is time for governments and the medical community to adopt a scientific attitude towards the use of cannabinoids in the treatment of a variety of inflammation related conditions. By way of example, consider this study of THC and cannabidiol in relation to Alzheimers. The results indicated that these cannabinoids not only inhibited production of ACHe, an enzyme targeted by many Alzheimers related drugs, but also played an important role in inhibiting the production of amyloid protein, considered by many to be very important in preventing Alzheimers Disease. In fact this study found that both THC and cannabidiol demonstrated greater efficacy than all the current Alzheimer drug interventions they tested.

Apart from their neuroprotective qualities, various studies have indicated that cannabinoid based therapies may be useful in the following pathologies:

Preventing the complications of diabetes
Allergies
Autoimmune conditions
Cancer treatment, particularly brain tumours.
Neuropathic pain.
Atherosclerosis

Conquering Depression

Over at SkepticLawyer Legal Eagle has commented on the prevalence of depression in the legal profession. As noted in her post there are many obvious reasons for those in the legal profession experiencing such high rates of depression. Her post prompted me to go over some old data I had read long ago.

Understanding the physiology of depression very much remains a work in progress. In this post I provide a cursory introduction to the these problems.

There are many types of depression.

Dysthymia: a mild form of depression that is very common
Major Depression: less common but much more disabling, major depression is now being perceived as a risk factor for the following conditions:

• heart disease
• dementia in latter life
• cancer
• Gut problems like Irritable Bowel Syndrome
• mild cognitive impairment

Bipolar Disorder: a condition where the individual swings from manic states to intense depression
Cyclothymia: a milder form of bipolar disorder that is frequently misdiagnosed as depression.
SAD: Seasonal Affective Disorder: strangely enough while SAD is usually associated with depression onset with winter, it can also occur with the onset of summer; though the latter is much rarer.
Post partum Depression: a condition experienced by mothers shortly after giving birth.
psychotic depression: depression so severe the individual becomes psychotic
Atypical Depression: where the individual is not necessarily melancholic but demonstrates lack of motivation and anhedonia(lack of pleasure in activities that formerly provided pleasure). People with atypical depression often over eat, tend to be tired all the time, and are often overly sensitive about rejection from others.

Note: The definitions of depression types can vary over time and from place to place.

As the foregoing demonstrates "depression" is a highly variable condition that can manifest itself in a wide variety of ways. It is hardly surprising that trying to understand the physiology of depression remains a work in progress. One obvious problem is that how depression is diagnosed can vary widely from country to country and from clinician to clinician. At the clinical level the issues are very difficult to address. One patient may actually be in a state of major depression but their self reports might be more indicative of dysthymia. More commonly, patients reporting symptoms of depression are cyclothymes. So have mercy on the clinicians, they face a daunting task.

Fortunately recent research may have stumbled upon a "final common pathway" that proffers the potential for better clinical interventions in the years to come. If you have taken anti-depressants you may have experienced what a great many people experience: it can take quite some experimenting to find the anti-depressant that works for you. This can be very frustrating but with ongoing research there is increasing hope for better treatments.

The recent breakthrough I am referring too is the claim that the final common pathway for the successful treatment of depression may well be the re-invigoration of both neurogenesis(new neurons being produced) and gliogenesis. The latter term refers to the "support" cells of the brain, glia. Neurons are amongst the busiest cells in the body and have a specialised network of supporting cells to both nourish and protect them. This is especially crucial for neurons because while new neurons can be produced these can only be produced in relatively small numbers.

It has long been recognised that depression is strongly associated with changes in the endocrine and immunological axes. In 1960's it was hoped that glucocorticoid resistance would prove to be a reliable biological marker of major depression. No such luck, at best 40% of individuals with major depression will exhibit glucocorticoid resistance. Sadly though this was an important clue that was overlooked. Most turned their attention to the amines and for many years the predominant focus was on serotonin and norepinephrine. Fortunately though some researchers maintained a different focus.

Horrobin and Bennett wrote a fascinating paper in 1999 that highlighted some intriguing relationships between psychiatric disorders and immune regulation. When I first read this paper I told my collaborator that "their theory is for s*&t". I have come to rue that arrogant criticism. Their paper was prescient in that it paved the way for a biologically based understanding of how fatty acids, in particular the omega 3 - omega 6 balance in our diets, can have significant implications for our cerebral health and propensity towards depression. It is now well established that omega 3 supplements or boosting fish intake can serve as a valuable adjunct treatment in depression.

Other researchers kept up the good work. In particular, this striking study from Capuron & Dantzer, made no apologies for demanding a new approach towards understanding depression. Recent genetic research indicating that polymorphisms for inflammation related genes are very strong indicators for the propensity towards depression have vindicated this approach.

This post is already too long so I'll cut to the chase.

• Glucocorticoids, induced by psychological stress and other stressors, inhibit growth factors.
• A key growth factor that regulates neurogenesis is Brain Derived Neurotrophic Factor(BDNF). This is particularly important in the hippocampus.
• Ongoing stress initiates inflammatory mediators which in turn induce the expression of nitric oxide.
• While nitric oxide is an important component of neural activity excess nitric oxide inhibits BDNF production.
• Because the hippocampus can modulate the stress response, ongoing loss of neurogenesis in the hippocampus can cause a vicious positive feedback loop; thereby increasing the stress response and the expression of inflammatory mediators.
• If, as is common today, there is an excess of omega 6 fatty acid relative to omega 3 intake, this will exacerbate the inflammatory response.
• Most antidepressant drugs are agonists(increasing the levels of) serotonin and norepinephrine. Activation of some serotonin receptors increases BDNF production and increased norepinephrine appears to lower the expression of inflammatory mediators in the brain.
• Increasing BDNF re-commences neurogenesis and helps pave the way for recovery.

What are the Important Lessons Here?

• Manage Stress! An uncontrolled stress response is the most common cause of depression. In our fast paced world all of us are exposed to real and potential stressors. This is one reason why meditation has been found to be useful in helping those with depression. Also, learn the relaxation response.
• Kill the ANTs: Automatic Negative Thoughts. We all have these little creatures in our skulls and they can be very irritating. Cognitive Behavioral Therapy can be very useful in exterminating the little blighters. Initially though try and develop the habit of suppressing these thoughts. That can take time but the benefits will last you a lifetime. It may even save your life.
• Maintain good sleep habits. One of the first warning signs of looming depression is insomnia. This can constitute a vicious cycle because loss of sleep increases the expression of inflammatory mediators. In fact loss of sleep and chronic circadian disruption can often by the final insult that casts us into a deep depression.
• Boost your intake of fish and consider taking fish oil supplements. Additionally, have a careful look at your diet and if necessary improve it.
• Where possible enjoy the sunshine for short periods each day. Sunshine is essential for vitamin D production and there is now a strong body of evidence indicating that maintaining a strong vitamin D status is not only important for the bones but also confers protection against many cancers, excessive systemic inflammation, and reducing the risk of dementias. Sunshine also gives a slight boost to serotonin production hence its association with being happy and the converse, "gloomy days". Early morning sunlight exposure is also important in maintaining circadian stability which aids sleep and promotes general well being.
  
• Be realistic. Some evidence indicates that those who consistently experience depression expect too much of themselves. You are only here once so enjoy it. Being happy is much more important than being productive or being special. Look at how many celebrities end up in rehab or with serious drug problems. Remember this: Work has its place and its place is not to replace living.
• Don't surround yourself with negative people. Most people are kind and generous of spirit so why bother with those who want to put you down or always criticize you?
• Remember this: Life is not a problem to be solved but a reality to experienced. (Van der Leuww)
• If at first you don't succeed so bloody what!? Have a rest and remember: If you reach for the stars at least you won't end up with a handful of mud. (Og Mandino, University of Success) Success is great, happiness is greater.
• Remember: All sunshine makes a desert(Arab proverb). We all go through trying times and many of us will experience depression. Tackle depression before it tackles you.
• Antidepressant drugs are one of the great breakthroughs in medicine. Don't be afraid to use these to help you recover but try not to become reliant upon these drugs. When you feel yourself becoming depressed don't dig yourself so deep that you can't see the sun.
• Remember: Man is most nearly himself when he achieves the seriousness of a child at play. (Heraclitus) Granted it is not always possible to like a child at play but aiming for that is much better than taking life so seriously that we completely lose our playful nature.

Homocysteine, Alzheimers, and Cerebrovascular Disease

Elevated homocysteine is generally regarded as an indicator that all is not well with our health. The vitamins B6, B12, and folate are crucial regulators of homocysteine levels. Anyone interested in maintaining optimal health must ensure that they have adequate intake of these nutrients. It is important to remember that some individuals experience very poor absorption of B12 and injections of B12 may be required. Symptoms of B12 deficiency are pernicious anaemia and fatigue. In particular, elderly people have may B12 absorption problems. A study reported in the eMJA found that many older Australians have B12 deficiency. Vegetarians can also experience B group deficiencies which goes some way to explaining why vegetarians, in spite of a low fat diet, are susceptible to cardiovascular disease.

Those experiencing chronic fatigue syndrome may benefit from injections of B12. Anyone with cardiovascular disease or a history of anaemia needs to carefully monitor their intake of B6, B12, and folate. It is a good idea to periodically have your homocysteine levels checked. If elevated, a B group supplement is advisable but it is far preferable that a good diet rich in these nutrients is followed all the time.

If you are experiencing ongoing fatigue that cannot be explained then consider the possibility that you are experiencing a deficiency in these nutrients. Because such a deficiency is so damaging to our health it is advisable to start taking a B group supplement immediately but much more importantly you should simultaneously change your diet to make sure you are receiving an adequate supply of these nutrients.

This recent study highlights why it is important to immediately address any suspected deficiency in these nutrients. The importance of immediate intervention is further highlighted in this mice study published in the PNAS. A vitamin B deficient diet for as little as ten weeks induced elevated homocysteine, neurodegeneration, and loss of capillaries.




Sources of B6:

Beef liver(warning: be careful of consuming too much beef liver because of the very high vitamin A levels)
wheatgerm
Bananas
Chicken Breast
Tuna
chickpeas
kidney beans
dairy products

Sources of B12:

chicken breast
Tuna, canned in water
Corn kernels
mango
Eggs
Dairy products
red meat, poultry, and fish

Sources of folate:

Asparagus, Bran flakes, Broccoli, Spinach
Oranges, peas, wheatgerm
Bee liver
Collard greens
spinach, raw
oranges
peanuts, dry roasted
wholewheat bread
broccoli



Note: pregnant women need to be particularly careful to maintain good folate levels.

Plastics And Poison

Numerous studies are now finding that worrying implications regarding bisphenol A, a chemical found in many plastics. Previously animal studies had raised concerns, this study from JAMA highlights the risk to humans. We need to do something about all the chemicals that we are now exposed too. All of us are exposed to these chemicals and research is increasingly pointing towards dangerous implications of this exposure.

The news item can be read here.

ScienceDaily (Sep. 16, 2008) — Higher levels of urinary Bisphenol A (BPA), a chemical compound commonly used in plastic packaging for food and beverages, is associated with cardiovascular disease, type 2 diabetes and liver-enzyme abnormalities, according to a study in the September 17 issue of JAMA. This study is being released early to coincide with a Food and Drug Administration (FDA) hearing on BPA.
...

The research article can be read here.

Association of Urinary Bisphenol A Concentration With Medical Disorders and Laboratory Abnormalities in Adults

Exercise is not Enough to Ward off Type 2 Diabetes:

Numerous studies now indicate that just going to the gym a few times a week is not enough to prevent type 2 diabetes. Long hours sitting, as work so often demands, is a significant risk factor even if we engage in regular exercise. This study highlights the risk of long hours of sitting and provides some insight into the underlying physiological processes that can occur from such inactivity.

As a general rule it is a good idea to stand up every 30 minutes. No, not for another cup of coffee, but to go for a quick walk. Plan your work day to allow this type of break.

The news item can be read here.



Below is the abstract details.

Diabetes Care 31:661-666, 2008
Breaks in Sedentary Time. Beneficial associations with metabolic risk



OBJECTIVE—Total sedentary (absence of whole-body movement) time is associated with obesity, abnormal glucose metabolism, and the metabolic syndrome. In addition to the effects of total sedentary time, the manner in which it is accumulated may also be important. We examined the association of breaks in objectively measured sedentary time with biological markers of metabolic risk.

RESEARCH DESIGN AND METHODS—Participants (n = 168, mean age 53.4 years) for this cross-sectional study were recruited from the 2004–2005 Australian Diabetes, Obesity and Lifestyle study. Sedentary time was measured by an accelerometer (counts/minute–1 < 100) worn during waking hours for seven consecutive days. Each interruption in sedentary time (counts/min 100) was considered a break. Fasting plasma glucose, 2-h plasma glucose, serum triglycerides, HDL cholesterol, weight, height, waist circumference, and resting blood pressure were measured. MatLab was used to derive the breaks variable; SPSS was used for the statistical analysis.

RESULTS—Independent of total sedentary time and moderate-to-vigorous intensity activity time, increased breaks in sedentary time were beneficially associated with waist circumference (standardized β = –0.16, 95% CI –0.31 to –0.02, P = 0.026), BMI (β = –0.19, –0.35 to –0.02, P = 0.026), triglycerides (β = –0.18, –0.34 to –0.02, P = 0.029), and 2-h plasma glucose (β = –0.18, –0.34 to –0.02, P = 0.025).

CONCLUSIONS—This study provides evidence of the importance of avoiding prolonged uninterrupted periods of sedentary (primarily sitting) time. These findings suggest new public health recommendations regarding breaking up sedentary time that are complementary to those for physical activity.

Abbreviations: AusDiab, Australian Diabetes, Obesity and Lifestyle

Evolving Thoughts: Cleesing the God Gene

A hilarious comedic piece from a giant of comedy: John Cleese. Thanks to John Wilkins for finding this.

Enjoy!

Evolving Thoughts: Cleesing the God Gene

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Sarah Palin on Saturday Night Live

A Healthy Diet with No Gimmicks

Modern Western diets are great at making us sick. Too much red meat, too much saturated fat, nowhere near enough monounsaturated and polyunsaturated fats. The ever growing burden of health costs on governments can be greatly reduced if the population en masse radically changes dietary practices.

The news release:

ScienceDaily (Sep. 12, 2008) — Sticking to a full Mediterranean diet provides substantial protection against major chronic diseases including heart disease, cancer and Parkinson's and Alzheimer's disease, according to a study published on the British Medical Journal website.

....

The BMJ paper can be downloaded here.

The PDF version can be downloaded here.

The Causes and Prevention of AMD

With an aging population vision deterioration is rapidly becoming a major health concern. Fortunately there are a number of measures we can undertake to markedly reduce the risk of vision loss with age. There are two principle visual pathologies that occur with aging. “Dry” Age related Macular Degeneration and “wet” AMD. Dry AMD predominates and involves the gradual build up of drusen. Wet AMD is probably also initiated by drusen accumulation but what happens is the sprouting of new blood vessels, probably as an attempt to restore circulation. Unfortunately these blood vessels tend to be “leaky”, spilling their contents into the retina and direct exposure to blood is often toxic to neurons. Wet AMD(also called, “exudative AMD”) only constitutes about 10% of all AMD cases and is very difficult to treat. We will focus on the more common Dry AMD because there are a number measures the individual can take to both prevent is occurrence and moderate its progression once diagnosis has been made.

The Current Understanding of the causes of Dry AMD

In dry AMD former the presence of drusen, a fatty deposit in the the main visual area of the retina(macula), can be seen by an optometrist. While not in itself indicative of AMD, the gradual accumulation of drusen is a warning sign that all is not well with your vision. Whether or not drusen is a serious indicator of emerging pathology depends on the types and density of drusen. Many people over 50 will have some levels of drusen. With increasing longevity it is essential that there is more public awareness of how to protect the retina so that good vision is maintained throughout the greater part of life. Until recently it was presumed that once drusen was present it could not be eliminated. In a follow up post on vision I will provide some background to this new supplement which will provide insights as to its efficacy.

Why is vision loss so common with age?

The retina is amongst the most vulnerable regions of the Central Nervous System. Technically the retina is part of the Central Nervous System. The layer of cells that play a critical role in protecting retinal neurons is called the Retinal Pigment Epithelium(RPE). Some researchers have claimed that the RPE cells are the most active in the body, constantly providing nutrition to the retina whilst simultaneously eliminating waste products from the eye. Presently the evidence indicates that it is the gradual diminution of waste product degradation and elimination that gives rise to drusen accumulation.

The elimination of waste products from the retina is a very complex process involving a number of steps. Dysfunction at any of these steps can give rise to the gradual accumulation of lipofuscin(proteins, fat combinations mostly, but with many other elements present) and subsequent pathology. For example, a number of juvenile macular degeneration pathologies involve a change in one gene that inhibits the waste removal process. The ongoing accumulation of waste products, which may have commenced at birth, gradually gives rise to a visual pathology and can result in total blindness. Recent trials of gene vector therapy hold out considerable hope that these conditions will soon be treatable.

The Nutshell Description of Waste Removal from the Retina

A key and initial component of light signaling in the retina is a part of the receptor cells called Photoreceptor Outer Segments(POS). These long segments are being constantly created and utilised in vision. These segments are periodically shed from the POS and it is vital these are rapidly transported to the RPE where degradation can commence. The problem with these segments is that these are very easily oxidised and can then become attached to proteins, thus the emergence of lipofuscin deposits and subsequent drusen formation in the retina. Once these oxidation processes occur it can be much more difficult, and in some cases perhaps impossible, for the RPE to absorb(phagocytosis), degrade, and pass on the waste products to the circulation. In Dry AMD the accumulation appears to mainly at the waste product elimination level, thus drusen is frequently present between Bruch’s Membrane- a membrane that separates the RPE from the choroid, where blood vessels are present. I suspect this failure to eliminate drusen is also arising because of insufficient degradation in the RPE. Undoubtedly, as we learn more, the picture will become more complex.

Why does this Problem Increase with Age?

As we age there is a general reduction in reparative processes. Healthy living can ameliorate this somewhat but in relation to the retina this loss of function plays a critical role in degenerative processes. Lifestyle and dietary changes are very important in preventing this ongoing loss of function reaching a critical level where secondary, possibly inflammatory immune mediated processes, come into play and accelerate the rate of tissue destruction.

The accumulation of waste products has been demonstrated to impair these reparative processes. As these products accumulate in the retina a vicious cycle ensues: the more waste products present, the less efficiently the waste product removal processes function. These waste products induce oxidative processes, thereby adding another dimension to the problem. This is a lifelong process so the lesson here is: maintaining good vision with age begins in our teenage years.

What are the Risk Factors for AMD?

• Smoking, particularly in relation to the much more severe wet AMD.
• Poor oxidation status. That is, insufficient dietary intake of antioxidants, particularly lutein and zeaxanthin, both of which are found in very high levels in the retina.
• There is evidence to suggest that lifelong exposure to strong sunlight can accelerate the accumulation of lipofuscin. Wear high quality sunglasses with “wrap around” features.
• Deprivation of oxygen supply to the retina. Regular aerobic exercise is very important for retinal health.
• Poor sugar regulation, as occurs in Diabetes, is probably a risk factor. Diabetes is a leading cause of blindness.
• Fatty acid intake. DHA, an omega 3 fat, is a precursor to NPD1, an neuroprotective agent very important for retinal health. Numerous authorities now assert that a chronic deficiency in omega 3’s, especially if there is an excess of omega 6 fats in the diet, can be a causative factor in many age related conditions.
• Cardiovascular Disease. Loss of blood supply and clogged blood vessels can have serious implications for retinal health.
• Obesity, possibly because of its association with cardiovascular disease and high triglyceride\cholesterol levels, but also chronic obesity tends to increase systemic inflammation.

Strategies to reduce the risk of AMD

• Stop smoking.
• Include generous portions of leafy greens in your diet. While the epidemiological data on antioxidant intake and the risk of AMD is conflicting, at this point in time it is prudent to make sure your diet contains good levels of lutein and zeaxanthin in the diet. Apart from these important antioxidants, a well balanced diet, particularly in relation to fats, is vital for overall health. Strange as it may sound, an egg a day is worth considering because eggs are highly nutritious and rich in lutein and zeaxanthin. Contrary to popular opinion, eggs are not a significant risk factor for cardiovascular disease, some authorities even assert the opposite.
• Vitamin A\beta carotene levels need to be maintained. However there is some data to suggest that high levels of these may very slightly increase the risk of AMD. If you are a smoker, there is now a general consensus that high beta carotene intake will increase the risk of lung cancer. Unfortunately there is also data suggesting that beta carotene may help prevent emphysema. A further complicating factor here is a recent study the results of which suggested that beta carotene supplements had no effect on AMD prevalence. Supplements of vitamin A and beta-carotene should not be required. If a person is deficient in Vitamin A then there is something seriously wrong with their diet.
• If you have high cholesterol and\or blood pressure, do something about it. High blood pressure is a risk factor for Wet AMD and a host of other pathologies.
• Wear sunglasses. A key driver of oxidative processes in the retina is light, especially UV light and there evidence to suggest that blue light might also be a risk factor. Make sure you buy high quality sunglasses that wrap around your eyes and have strong UV inhibiting properties.
• Eat fish regularly to maintain your omega 3 levels. Not too often though and be careful, there are now many studies indicating that the oceans are so polluted that heavy fish consumption can result in the accumulation of dangerous chemicals and metals in our body. The general recommendation is 3 times a week. I think the time is rapidly approaching when even that level of consumption will become problematic. We must stop poisoning the oceans.
• Over 40 years of age, have regular eye checkups, including retinal examinations. Ask your doctor about any the presence of drusen\lipofuscin. If your doctor suggests it could be a problem in your case, ask if a retinal image is a good idea so that on latter examinations a comparison can be made.
• Exercise. Regular aerobic exercise is vital to our overall health.

Zen Rules!

This study from Plos One found that Zen meditation practice improved concentration and the ability to ignore distracting stimuli. There are now a number of studies on various types of meditation practice and the results are intriguing. Some of the benefits appear to be:

• adjunct treatment for ADD
• adjunct treatment for depression
• may improve the immune response.
• may improve the stress response regulation
• Reduces anxiety.
• it makes you seem spiritual to others.

“Thinking about Not-Thinking”: Neural Correlates of Conceptual Processing during Zen Meditation

Abstract

Recent neuroimaging studies have identified a set of brain regions that are metabolically active during wakeful rest and consistently deactivate in a variety the performance of demanding tasks. This “default network” has been functionally linked to the stream of thoughts occurring automatically in the absence of goal-directed activity and which constitutes an aspect of mental behavior specifically addressed by many meditative practices. Zen meditation, in particular, is traditionally associated with a mental state of full awareness but reduced conceptual content, to be attained via a disciplined regulation of attention and bodily posture. Using fMRI and a simplified meditative condition interspersed with a lexical decision task, we investigated the neural correlates of conceptual processing during meditation in regular Zen practitioners and matched control subjects. While behavioral performance did not differ between groups, Zen practitioners displayed a reduced duration of the neural response linked to conceptual processing in regions of the default network, suggesting that meditative training may foster the ability to control the automatic cascade of semantic associations triggered by a stimulus and, by extension, to voluntarily regulate the flow of spontaneous mentation.

Curry Power

Curcumin is a compound found in curries. Of late it has attracted a great deal of interest because it demonstrates a range protective properties. Other studies have indicated that it can inhibit protein aggregation in the brain, commonly thought to be a key driver of dementias.

In this study, using a mouse model for diabetes, the researchers found a considerable protective effect on the retina that was independent of hyperglycemia. Given that diabetes is the leading cause of blindness in developed countries and the incidence of diabetes seems to growing month by month, curry consumption could play an important role in helping protect the retina.

Curry consumption is probably advisable for everyone, not just diabetics.

Effects of curcumin on retinal oxidative stress and inflammation in diabetes
Renu A Kowluru and Mamta Kanwar
Kresge Eye Institute, Wayne State University, Detroit, MI, USA
author email corresponding author email
Nutrition & Metabolism 2007, 4:8doi:10.1186/1743-7075-4-8
Published: 16 April 2007

Abstract
Background
Oxidative stress and inflammation are implicated in the pathogenesis of retinopathy in diabetes. The aim of this study is to examine the effect of curcumin, a polyphenol with antioxidant and anti-inflammatory properties, on diabetes-induced oxidative stress and inflammation in the retina of rats.
Methods
A group of streptozotocin-induced diabetic rats received powdered diet supplemented with 0.05% curcumin (w/w), and another group received diet without curcumin. The diets were initiated soon after induction of diabetes, and the rats were sacrificed 6 weeks after induction of diabetes. The retina was used to quantify oxidative stress and pro-inflammatory markers.
Results
Antioxidant capacity and the levels of intracellular antioxidant, GSH (reduced form of glutathione) levels were decreased by about 30–35%, and oxidatively modified DNA (8-OHdG) and nitrotyrosine were increased by 60–70% in the retina of diabetic rats. The levels of interleukin-1ß (IL-1ß) and vascular endothelial growth factor (VEGF) were elevated by 30% and 110% respectively, and the nuclear transcription factor (NF-kB) was activated by 2 fold. Curcumin administration prevented diabetes-induced decrease in the antioxidant capacity, and increase in 8-OHdG and nitrotyrosine; however, it had only partial beneficial effect on retinal GSH. Curcumin also inhibited diabetes-induced elevation in the levels of IL-1ß, VEGF and NF-kB. The effects of curcumin were achieved without amelioration of the severity of hyperglycemia.
Conclusion
Thus, the beneficial effects of curcumin on the metabolic abnormalities postulated to be important in the development of diabetic retinopathy suggest that curcumin could have potential benefits in inhibiting the development of retinopathy in diabetic patients.