Epigenetics

(This article was adapted from our new book Emotional Frustration-the hushed plague.)

After the Darwinian revolutionary writings[i] enshrined the concept that natural selection and evolution were the major mechanisms to modify our bodies, some alternative hypotheses were summarily discarded for the sake of clarity. Jean Baptiste Lamarck, a French naturalist, proposed that all the species have strived to attain the perfect state, for which there are multiple variations; the living organisms not only evolved but they did it slowly, little by little and successively.[ii]

In 1800 Lamarck gave his first lecture in the prestigious Musée National d’ Histoire Naturelle where he discussed the mutability of species—later developed in a book.[iii] According to Lamarck, life becomes diversified due to these factors:

  1. The Power of Life: tends to make organizations increasingly complex.
  2. Effects of the Environment: modifying influence of circumstances.

When the molecular structure of the human DNA was discovered by Watson and Crick in 1953[iv], scientists determined that its coded information could not be altered in any significant way by the environment or the person’s lifestyle choices. In 1975 Robin Holliday and John Pugh, English biologists, and Arthur Riggs, an American, found that methylation—an inherited chemical change of the DNA strand—can be modified by the environmental factors.[v] Epigenetics.[vi]

Studying laboratory animals, they discovered that severe environmental stress can have long-term effects in the information provided by the genes, i.e. epigenesis. The genetic material stays untouched but its “expression” or “reading” is greatly altered; this biological alteration can be transmitted in some instances to future generations that have not experienced the initial triggering factor in their lifetimes. Rat or mouse pups are subjected to maternal separation and then their behavior is studied for signs of depression; their genetic material is analyzed for alterations.

Rudolph and Adrian Bird published a seminal paper in 2003 where they said: “stable alterations of this kind are ‘epigenetic’ because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years have focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histones modifications.”[vii]  As part of our reaction to stress, we secrete a hormone called glucocorticoid that mediates certain immune mechanisms like inflammation; when the offending agent disappears, the glucocorticoids bind to some brain receptors and its production in the adrenal cortex stops in a feedback loop. [viii]In 2106 Gustavo Turecki and Michael Meaney published a paper where they show that the gene that codifies this glucocorticoid receptor is inactive in animals that had experienced great stress in their early days, thereby limiting their ability to shut off its production.[ix] Even after the cause for stress has disappeared, they keep producing the stress hormone.

The epigenetic mechanism consists of a physical barrier of methyl markers in the DNA, which prevents the proper reading of the stored information in genes. Can this epigenetic trait be transmitted from a mother to her children? Scientists are still debating this issue but there are indications that when the DNA replicates during the cell mitosis, the methyl markings can be introduced in the new genetic material.

Scientific studies have shown that when women are subjected to undue stress during pregnancy, they give birth to children with impaired responses to stress. After the Allied landing in Normandy in August 1944, there was a prolonged stand-off between the opposing armies in the Lower countries, Belgium and Holland.[x] In order to force the population into not helping the Resistance and the advancing armies of Montgomery and Patton, the German Army rationed food supplies.[xi] The women who were pregnant at the time of the tragic Dutch Hunger winter, eventually gave birth to children with a higher rate of obesity and schizophrenia.  Nadine Burke Harris says that the origin of many of our societal problems may arise from the exposure to undue stress in childhood that leave a genetic marking.[xii]

Did our mothers and grandmothers possess the right intuition before science confirmed it?

What do you think? Please tell us.

Don’t leave me alone.

References

[i] Charles Darwin, “On the origin of species”, Mass Market Paperback, New York, 2003.

https://www.amazon.com/Origin-Species-150th-Anniversary/dp/0451529065

[ii] Encyclopedia Britannica, “Jean-Baptiste Lamarck”, https://www.britannica.com/biography/Jean-Baptiste-Lamarck

[iii] Jean Baptiste de Monet de Lamarck, « Recherche sur l’organisation des corps vivants : précédé du discours d’ouverture du cours de zoologie donne dans le Musée d’Histoire Naturelle » Fayard, Paris, 1986.

https://www.amazon.com/Recherches-sur-lorganisation-corps-vivants/dp/2213017018

[iv] Leslie A. Pray, “Discovery of DNA structure and function: Watson and Crick” Nature Education, 1(1):100, 2008.

[v] Nelson Cabej, “Building the most complex structure on Earth: an epigenetic narrative of Development and Evolution of animals”, Elsevier, February 2013.

https://www.elsevier.com/books/building-the-most-complex-structure-on-earth/cabej/978-0-12-401667-5

[vi] Israel Rosenfield, Edward Ziff. “Epigenetics: The Evolution Revolution”, The New York Review of Books, June 7, 2018. https://www.nybooks.com/articles/2018/06/07/epigenetics-the-evolution-revolution/

[vii] Jaenisch R., Bird A., “Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals” Natural Genetics, 2003 March, Supplement 245-54.1

https://www.ncbi.nlm.nih.gov/pubmed/12610534

[viii] Robert M. Sapolsky, L. Michael Romero, Allan U. Munck, “How do Glucocorticoids Influence Stress responses? Integrating Permissive, Suppressive, Stimulatory, and Preparative Actions” Endocrine Reviews, Volume 21, Issue 1, February 2000, pages 55-89. https://doi.org/10.1210/edrv.21.1.0389

[ix] https://www.utsc.utoronto.ca/~pmcgowan/documents/McGowanBrainRes08.pdf

[x] William Shirer, “The rise and fall of the Third Reich, Fiftieth Anniversary edition”, Barnes and Noble, 2018.

https://www.barnesandnoble.com/w/rise-and-fall-of-the-third-reich-william-l-shirer/1100214065#/

[xi] Ibidem as above.

[xii] Nadine Burke Harris, “The deepest well: healing the long-term effects of childhood adversity” January 2018.

https://www.amazon.com/Deepest-Well-Long-Term-Childhood-Adversity/dp/0544828704/ref=tmm_hrd_swatch_0?_encoding=UTF8&qid=&sr=

The SPRINT-MIND study – Control of BP to reduce risk of Dementia

The randomization for the clinical trials of the SPRINT-MIND study was started on November 8, 2010, in 102 sites in the USA and Puerto Rico under the guidance of Dr. Williamson et al. Out of the 9361 randomized participants—mean age of 67.9 years and a female participation over 35%— approximately 91% of them completed one year of follow-up cognitive evaluation. The participants were randomized into two groups: in the first one, half were treated to maintain a systolic blood pressure of less than 120 mm of HG—the intensive group—and the other half was treated to maintain one of less than 140m mm HG—the standard treatment group. The median time of interventions was 3.34 years. Initially designed to end in 2018 the study was ended in August 2015 due to bioethical reasons because the researchers found benefits for the first group.

Individuals confined to a nursing home, with a diagnosis and/or treatment of dementia, diabetes or stroke were excluded form this study. The researchers did not explicitly screen participants for a diagnosis of Mild Cognitive Impairment (MCI) in their selection, which raises the possibility that a few of the participants might have already clinical signs of Dementia at the beginning. Moreover, they purposefully did not include the older patients with several co-morbid conditions, which might actually bear the higher risks of aggressive treatment of high blood pressure—orthostatic hypotension, stroke or ongoing cardiovascular failure. Another example of how trials discriminate against older patients and expose them to unknown grave risks with their cookie-cutter approach.

During a median intervention period of 3,34 years, probable dementia occurred in 149 participants of the intensive and care group and 176 in the standard treatment group; intensive BP control reduced the risk of MCI—14.6 versus 18.3 cases per 1,000 person-years—and the combined rate of MCI or probable dementia—20.2 versus 24.1 cases per 1000 person-years. The trial failed to reach statistical significance on its primary cognitive outcome of a reduction in the occurrence of dementia. Some academics claim that the study failed to reach significance because the testing was cut short and more time should be allotted for follow-up of patients; the Alzheimer’s Association has announced the provision of a U$ 800,000 grant to add two more additional years to the study.

In a Neurology Today article on this study, Dr. Emer R. McGrath said that the technique for obtaining blood pressure readings they had utilized—use the average of three automatic readings with no personnel in the room—might give mischievously low readings than the one in practices. The risk of over-treatment and adverse effects in already frail patients is worrisome indeed. Other practitioners point out that researchers do not know which BP medication might work best and at what age. However, the majority of those interviewed were hopeful that the follow-up study might bring statistical significance to the concept of controlling the BP to avoid future onset of dementia.

We already know that a methodical control of one’s blood pressure as of middle age will make a significant difference to avoid cardiovascular and renal diseases in our older years. Similarly, we believe that the same Wellness interventions will help us at least delay the mind ravages of ageing in order to have a better quality of life.

What do you think? Please tell us.

Don’t leave me alone.

Is transfusion of “young plasma” the modern Fountain of Youth?

Baby boomers, long accustomed to the ethos of youth, have a hard time accepting their inevitable ageing, especially when it involves the onset of serious neurodegenerative pathologies like Alzheimer’s Disease. Apart from trying countless, varied drug and Wellness interventions, which include a healthier diet and exercise, some worried adults are spending a lot of money in non-FDA approved therapies like transfusions of plasma. In a February 2019 warning, the Food and Drug Administration (FDA) informed consumers that they should be very wary of those providers and clinics that offer “miracle cures” with young plasma.

The FDA warning did not exclude the possibility that “plasma transfusions” might eventually become a valid therapeutic tool , after conducting carefully designed peer-reviewed clinical trials under the supervision of institutional review boards and strong regulatory oversight. The practice has risks. The use of transfusions can produce infections, allergic reactions, circulatory volume overload and the danger of botched maneuvers.

In the July 2019 issue of AMA Neurology, Dr. Sharon Sha et al, from the prestigious Stanford University, informed the results of a small study that involved 10 participants with Alzheimer’s disease; nine individuals got four weekly infusions of the plasma fraction under a protocol of the double blind crossover and nine other individuals got four weekly infusions under an open label. The researchers found that the plasma infusions were safe and tolerable for all the participants. Dr. Sha found that even though there was not a clinically significant improvement in their mood and cognitive alterations, there was some improvement in their cognitive abilities, which eased the burden of the caregivers.

This pioneering Stanford trial was funded by Alkahest, a California biotechnology company that was co-founded by Dr. Tony Wyss-Coray, a Stanford neuroscientist who invented a technique. Parabiosis is the study of the circulatory changes when a young mouse is connected to an old one; the surgical technique allowed the exchange of blood and its derivatives in both directions. Alexander Eggel and Wyss-Coray found that the old mice that received the plasma improved their ratings in the memory testing using the maze techniques and the histochemical studies of their brains showed increased plasticity, which is a hallmark for good synaptic activity in learning and memory.

Are all the components of young plasma responsible for these results or is it produced by fractions? Alkahest has designed a “selected plasma fraction” from the processing of pooled plasma and at present is testing two of those in three Phase 2- clinical trials for chronic diseases; it is also testing a small molecule-inhibitor in the treatment of macular degeneration, which produces blindness. In a scientific meeting in Barcelona about Clinical Trials in Alzheimer’s Disease, Grifols, another biotechnology company, showed encouraging results of a clinical trial using plasma products.

Obtaining the necessary safety data about these techniques will eventually pave the way for the use of plasma fractions in many neurodegenerative diseases; however, many scientists warned that, even with the benefit of efficacy and safety features, there might not be not a “magical cure” as the nefarious components in old blood might ultimately prevail in the protracted clinical process. In a January 2018 article, Bjorn Hofmann wrote: “eternal youth and endless bliss have always been vital human dreams. Although parabiosis may brings us closer to the fountain of youth than ever, it is still too early to provide full-fledged assessments of its implications or to foresee how it will change health, aging, medicine and society.”

What do you think? Please tell us.

Don’t leave me alone.

The nutritional value of Moringa

After resoundingly defeating King Darius III at the battle of  Gaugamela, near modern-day Mosul in Irak,  Alexander the Great conquered the Achaemenid Empire of Persia which stretched to the Indian sub-continent in the East. Believing that the world ended in India, he then led his impressive Macedonian Army in 326 B.C. into its Easternmost frontier, which corresponds to the present-day Punjab in Pakistan. His army faced the forces of King Porus in the battle of Hydaspes and defeated them; however, there were many casualties in the conquering army, including Bucephalus, Alexander’s dear horse. When the conqueror decided to continue his march, his army, exhausted and homesick, rebelled at Hyphasis and obliged him to give up his dream, turning southward instead.

The Macedonians were surprised by the stamina and fighting capacity of Porus’ soldiers, which they attributed to the healing and wellness faculties of an indigenous plant from a tree: Moringa. It is a native tree of many regions of Africa and Asia, the sole genus in the flowering plant family Moringaceae; the name derives from the Tamil denomination of “drumstick”. The most diffused variant is Moringa oleifera, which grows at the foothills of the Himalayas, in Northeastern India.  For centuries this plant has been used to treat anxiety, stress, asthma, anemia, chronic bronchitis, skin infections, cholera, etc.; its anti-inflammatory, anti-spasmodic, anti-hypertensive, anti-tumor, anti-pyretic, anti-epileptic, diuretic, anti- cholesterol, anti-diabetic properties were known by many cultures.

The modern interest in phytotherapy—the study of the healing power of extracts of natural origin—has rekindled the scientific initiatives to determine the real value of the components of this plant, which has been labelled as “the tree of life” in ancient cultures for its great versatility. The Moringa has vitamins, minerals, beta-carotenes, antioxidants, anti-inflammatory components and omega 3; its leaves have a high content of Vitamins C, calcium, Beta-carotene, potassium and essential proteins. The high concentration of flavonoids, ascorbic acid, carotenoids and phenolics extends the period of usage of fat containing foods, a critical factor to conserve food in the under-developed world.

Recent studies linked the presence of low-grade inflammation to Insulin resistance and Obesity through the presence of cytokines, tumor or necrosis alpha factor, interleukin-1-Beta, etc. Moringa oleifera has significant power as a blood glucose-lowering agent because some of its metabolites—N-Benzyl thiocarbamate, N-Benzyl carbamates, benzyl nitrites and benzyl—trigger the release of Insulin in pancreatic cells in experimental rats. An in-vitro study of a Philippine variant showed that several of its metabolites decreased the size of tumors; abnormal growths treated with methanolic extracts of Moringa fruits and leaves were slowed down. Aqueous extracts of pods’ husks have anti-microbial properties against Gram positive, gram negative and yeasts organisms.

The Moringa leaves can be eaten fresh, cooked or stored as dried powder for many months, without losing any of its nutritional value.  In the tropical areas, the Moringa tree remains in full leaf at the end of the dry season, a critical period for the continued sustenance of the population because most of the trees become leafless. It can be safely used a dietary supplement for children, the elderly and pregnant women as well.  For the above-mentioned reasons, it has been dubbed as the Miracle tree or Mother’s best friend.

What do you think? Please tell us.

Don’t leave me alone.

 

A rehab therapy useful for MS

When patients with Multiple Sclerosis—and other chronic debilitating diseases—start losing the motor function of the upper and/or lower extremities, they feel rightly frustrated. The inability to write steadily, grab a cup, walk without falling and similar common activities will limit their interaction with family, friends and co-workers, leading to anxiety and depression. The chronic pain can be managed more efficiently than the forced isolation due to the above.

Some clinical trials have suggested that MS patients might benefit from several rehabilitation techniques, but they were short in duration and did not answer the fundamental question; can the techniques learned in the rehabilitation clinic be transferred to the patients’ homes efficiently? A new study claims that the “Constraint-induced movement therapy” (CIMT) used in the rehab of stroke patients can be useful, even with short practice runs, in the care of MS motor limitations.

VW Mark et al. designed a Phase II randomized clinical trial with 20 participants that had hemiparetic MS and were assigned either to a 35 hours-training in CIMT or alternative medicine. The CIMT intervention, done on ten consecutive days, had the following components:

  1. Intensive training with the limited extremity for basic activities for three hours/day.
  2. Training with “behavioral shaping”: try to achieve motor goals progressively and with constant encouragement from the therapist, even for small gains.
  3. Restraint of the less compromised limb to prod the use of the affected one.
  4. Use of a “transfer package” to stimulate the practice at home, which included a contract, practice homework, keeping a diary and a 30 minute-daily interview with the therapist.

The participants were evaluated with the “Motor Activity Log” (MAL), a scripted interview to compare the gains from the use of the technique with the previous functional baseline. The participants in the control group did aquatic therapy, yoga and other relaxation techniques. For the group that underwent CIMT there was a mean change in MAL of 2.7 after one year, compared to 0.5 in the control group. A change of 1.0 was considered clinically meaningful for participants; auspiciously, all the CIMT patients and three of the control group reached that clinical goal.

In the second stage of this same study, the researchers studied whether the practice of CIMT could promote changes in the white matter of MS patients with Magnetic Resonance Imaging (MRI) techniques such as T1 weighted scans and whole brain diffusion tensor scans. They found that there were improvements in the white matter of the corticospinal tract, temporal and visual areas. These extraordinary findings were in line with previous data obtained form monkeys in labs. If the neuroplasticity of the nervous tissue can warrant significant clinical changes after just a few days of focused, personalized rehabilitation for MS patients, this technique must be transferred home with a special package. Patients and their families would certainly be more than willing to try it.

Patients with MS should be aware that physical defeat only comes when they “throw the towel into the ring.” They should never, ever give up hope.

What do you think? Please tell us.

Don’t leave me alone.

 

Drug overdose and suicide in Epilepsy

One of the most devastating piece of news physicians can get is that one of our familiar patients has died, not of natural causes or the pathological progression of a disease, but due to suicide. The correct treatment of Epilepsy requires a longstanding relationship with the patients and their families, trying to seek a seizure-free environment so they can have a fruitful, enjoyable lifestyle. Unfortunately, too much attention is being given to medication and little to depression and anxiety.

Dr. Harley C. Gorton directed a study in the United Kingdom that canvassed two large primary care-data sets, the Clinical Practice Research Datalink (CPRD) in England and the Secure Anonymized Information Linkage (SAIL) Databank in Wales, in order to detect unnatural deaths in epileptic patients. Oftentimes the certificate of death of patients do not list Epilepsy as a contributing factor, which severely limits the study of that condition’s morbidity and mortality. Those two databases are linked to hospitalization, outpatient care centers and death records. This study suggested that physicians should pay more attention to co-morbid conditions like anxiety, depression and substance abuse, plus monitor the use of opioids and psychotropic medication.

In this study the researchers matched 44,678 participants with Epilepsy in the CPRD database to 891,429 participants without it in a period spanning from 1998 to 2014; they matched 14,051 participants with the disease in the SAIL database to 279,365 people from 2001 to 2014. Epileptic patients were 2.77 times more likely to die of an unnatural cause, 2.97 times more likely to die of unintentional injury or poisoning, and 2.15 times as likely to die of suicide. People taking medication had 4.99 times higher risk of collateral effects and 3.55 times higher risk of misuse. The most widely abused medication were opioids (56.5%) and psychotropic agents (32.3%)

The researchers stated that “patients should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts and behavior.” They also said that “the suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions.” The care personnel should understand that “good seizure control” is not limited to just a proper medication schedule to obtain a good quality of life for the patients. An excessive focus on seizure control in the follow-up of epileptic patients will sideline the necessary screening for psychiatric and behavioral health issues with the timely referral to other specialists.

It is extremely uncomfortable to discuss the issue of “mental health” with our patients and their families in our medical offices, especially because an archaic stigma lingers on in our societies. However, we must start the discussion in a respectful way, without alarming them excessively; we must stress out that we want to offer them information, without suggesting any particular venue. Sometimes epileptic patients have difficulties to access the mental health care services because the payors will not cover the expenditures, or they lack the proper information due to a disconnect. Our personal attitudes towards these patients must include a greater dosage of sympathy for them.

Suicide Prevention Hotline 1-888-628-9454/ www.suicidepreventionlifeline.org

What do you think? Please tell us.

Don’t leave me alone.

A new drug for progressive Multiple Sclerosis

Multiple Sclerosis is not a single pathological entity but rather two abnormal processes that advance in parallel yet inter-connected tracks and varying degrees of severity, which results in different clinical presentations. In the beginning the infiltrative inflammation predominates in the brain and spinal cord with the clinical imprimatur of relapses and remissions. Patients, who are usually young, have the illusion that once the inflammation process subsides, they would be disease-free for a long time.

However, a more sinister and crippling process has already started: degeneration. The clinical picture consists of progression with limiting sequelae like chronic pain and spasticity of upper and lower limbs. The available drugs targeted the first process but failed to address the second one. Until a new drug was studied: siponimod. Like fingolimod, it is a modulator of sphingoside-1-phosphate (SIP) receptors but it only selectively modulates types 1 and 5 receptors of the lymphoid tissue; the first one promotes the disposal of lymphocytes while the second one is stored in the CNS.

Kapos et al. collected more than 1600 patients from almost 300 clinical centers in the USA and Europe to study the administration of 2 mg of sipominod per day to half the cohort to compare it to the other half that only received a placebo for a median period of eighteen months. The principal studied index was “time to three-month confirmed disease progression” (CPD), which was defined as a 1.0 point increase in expanded Disability Status Scale (EDSS) score for the participants with moderate disability or 0.5 point increase for those with severe disability initially.

Only 26% of participants receiving siponimod had grave, prolonged disability compared to 32% of those receiving only the placebo; the drug had a hazard ration of 0.79 and a relative reduction of 21% of the risk to develop crippling symptoms. Once the study was finished all the participants were offered the chance to take it. Imaging studies showed a reduction from baseline in T2 lesion volume and the gadolinium-enhancing lesions. Moreover, those participants taking the drug had less decline in the brain volume between the 12th and 14th months compared to placebo.

Investigators are moderately optimistic about these results, but they point out that, in order to prevent the serious disabilities this disease provokes in young people, they must strive to intervene earlier in progressive forms of MS. Much, much earlier.

What do you think? Please tell us.

Don’t leave me alone.