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Author: Stephen J. Klemawesch, MD

EBV and MS

EBV and MS

The cause of MS (multiple sclerosis) has long been sought.  Although many factors are felt to predispose to it, genetics and environment top the lists.  For instance, the illness is much more common in Europe and North America than in the rest of the world. 

Viral infections have long been suspects.  Now there is mounting evidence that the Epstein Barr Virus (EBV) may be the culprit.  Two recently published research studies lend credence to this possibility. 

The first study was done on service members on active duty who came down with MS.  Over the study period 801 patients developed MS and all but one of them had evidence of active EBV infection.  Now, don’t over interpret this finding.  Evidence for prior EBV infection (the main cause for Mono, although CMV can also cause Mono) can be found in 90 plus percent of young adults and MS is a comparatively rare disease. 

But the other recent study done by immunologists at Stanford University found that 25% of the MS patients they studied had a blood antibody that reacted to both EBNA1 protein and GlialCAM (glial cell adhesion molecule) protein.   These two proteins are very similar in their chemical structure even though one is a viral protein and the other is a protein found in myelin sheaths.  This is a phenomenon called molecular mimicry.  Long story short what seems to be happening is the immune systems attempt to irradicate the virus via the anti-EBNA1 antibody ends up attacking the GlialCAM protein in the myelin sheath of nerves.  The myelin sheath can be thought of as the plastic or rubber insulation on an electric wire.  Damage to the sheath leads to altered nerve conduction and hence the numbness and muscle weakness found in MS. 

The Stanford scientists extended their research in a mouse model.  In one group of mice they injected EBNA-1 protein into their brains and in the control group a non-viral protein of similar size.  A handful of the EBNA-1 injected mice developed neurologic disorders whereas none of the control group did.  

Gut-Brain Axis

Gut-Brain Axis

Up until recently, scientists had minimal understanding of how our GI tract and brain are connected.  Until this new research I naively figured the only connection was my tummy telling my brain when I was hungry.  As it turns out there is a very strong bidirectional interplay between the brain and the GI tract and a major fulcrum is the gut microbiome.  The ENS (enteric (GI) nervous system) interacts with the intestinal membrane and its immune cells.  Changes in the membrane and immune cells are mediated by local hormones and neuroactive molecules.  These, in turn, affect the local nerves which send messages to the brain.  And the brain sends messages back. 

The importance of these connections has led to better understanding of both GI problems and neurologic disorders.   For instance, these is mounting evidence that altered GI microbiome plays a role in anxiety, depression, OCD behavior, autism, Parkinson’s disease, Alzheimer’s disease, and others.  On the other side of the equation is greater understanding of how the brain contributes to irritable bowel syndrome and inflammatory bowel disease. 

The ENS is often referred to as the second brain because of its size (100 million neurons and 400 million glial cells), its complexity and the similarity of neurotransmitters with the central nervous system (CNS).

One mechanism whereby the gut microbiome can contribute to neurologic disorders is via these neurotransmitters.  For instance, some “bad” gut flora lead to low levels of amino valeric acid and taurine, both of which are essential to making to making the neurotransmitter called GABA.  Patients with OCD and autism have low levels of GABA. 

On the other side of the equation, proper brain signaling to the ENS is important for producing a protein essential to a healthy intact epithelial barrier in the intestines: GDNF (glial derived neurotrophic factor).  Reduced barrier function is one of the main flaws that causes inflammatory bowel disease.  So, if the patient is suffering from stress, the brain in turn sends “distress” signals to the gut with the resultant worsening symptoms. 

Germ free mice have been the surrogate for humans in researching modifications in gut flora.  Since these specialized mice are germ sterile, researchers can establish any gut flora desired and measure its outcome.  These experiments are remarkable in that by establishing a “bad” flora researchers can make young, playful and social mice become withdrawn, and “depressed” and can also create mice who exhibit Parkinsonian movements and mice who suffer memory loss.

As exciting as this research is there are as yet no proven clinical applications for humans. 

Hypnotherapy for IBS

Hypnotherapy for IBS

Scientists at Monash University in Melbourne, Australia have developed a hypnotherapy-based computer app to help people with IBS (irritable bowel syndrome). 

The program called Nerva guides users through a ten-minute hypnotherapy session every day for six weeks.  The neural therapy is designed to correct the disordered signaling from brain to gut.  Patients who complete the six-week program report a reduction in symptom severity from 67 (on a scale of 100) to 39.  Adding a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet has additional benefit. 

Alpha Fold

Alpha Fold

An AI called Alpha Fold developed by London based company Deep Mind is a computer-based program trained to predict protein shapes by recognizing patterns in structures already solved by years of tedious experimental work using electron microscopes and other methods.  So far, it has predicted 400,000 protein structures including most of known human proteins. 

Now you might ask: “OK, what is the big deal and why is this in your newsletter?”  Well as it turns out many biologic processes work based on the shape of molecules.  For instance, as the Corona virus has mutated over the past three years its 3-dimensional structure has changed dramatically.  This is one reason that the original vaccines and the original nasal swab tests have become less efficient as doing their jobs; prevention and recognition. 

Another example is insulin allergy.  Years ago, the only available insulin for diabetics was from beef or swine.  Insulin allergy was fairly common back then.  But once the “human insulin” was developed (which uses a human gene transferred into test tube bacteria) it was mistakenly thought that there would no longer be insulin allergy.  Beef insulin has a four amino acid difference from human insulin.  Pig insulin has a three amino acid difference.  But “human insulin” from tissue culture has an identical amino acid sequence; however, the 3-D structure produced by the bacteria is different than that produced by the human pancreas. 

In some cases, this 3-D difference can lead to the development of allergy. The other foible that can occur is the development of anti-insulin antibodies which lead to insulin resistance.  Again, the antibodies are in response to the 3-D structural difference from nascent insulin. 

The efficiency and therefore the benefit of many medications is related to how well they fit into cellular receptors in the body.  This too comes down to 3-D structure.  Long story short, this new research has the potential to revolutionize medicine.  

House Plant Police

House Plant Police

Researchers at the University of Washington have developed a “souped-up” house plant to “police” indoor pollutants. 

Indoor air pollution is a reality.  A myriad of chemicals from cooking to cleaning materials to increasing outdoor pollutants can adversely affect human health. 

Benzene and Formaldehyde are known carcinogens and certain states have strict rules limiting their use (notably California and Minnesota). 

It has been known that indoor plants can remove these pollutants but their impact is very minor.  The scientists in Seattle modified the common house plant pothos by adding a rabbit gene for an enzyme that breaks down pollutants.  These “souped-up” golden pothos have a remarkable ability to remove and detoxify pollutants. 

In Canada, Oirgen Air is selling the new pothos plants and in the US Neoplants will begin sales this month. NASA scientists are conducting experiments with these plants to help reduce pollutants in the re-circulated air in the orbiting space station. 

Dear Dr. K- 

Dear Dr. K- 

I recently read that monkey pox vaccine can be given ID.  Is that true?

Yes, it is true.  In fact, early research indicates that it is the preferred route of administration in terms of getting the best immunologic protection. 

At this point the only other vaccines approved for ID (intradermal) dosing are the flu vaccines and the polio vaccine.  The advantages of ID vaccination are several.  It can generate an immune response as good or better than an intramuscular vaccine but with as little as one fifth the dose.  Owing to its superficial administration it avoids the rare risk of nerve, blood vessel or muscle injury that can occur with IM dosing.  The Gates Foundation has spent 5 billion dollars to help eradicate global polio and have used the dosing efficiency to great advantage.

A Shift in Asthma Strategy

A Shift in Asthma Strategy

They say “nothing stays the same” and as I keep aging, I couldn’t agree more! Change is always occurring in medical guidelines as well.  What I’d like to address here is how this applies to asthma therapy. 

For quite some time now, the standard of care for asthmatics has been to have both a rescue inhaler and a maintenance inhaler.  The majority of rescue inhalers use albuterol, a bronchodilator, which relaxes airway smooth muscles that are constricted.  The benefit is brief, lasting 3 to 6 hours, and the medication does not address the underlying inflammation which is the cause of the muscle constriction, that’s where a maintenance inhaler comes in.  Most maintenance inhalers are either single entity topical steroid or a combination steroid and long-acting bronchodilator. 

Overuse of albuterol is associated with excess risk for severe asthma exacerbations and even death.  Globally the majority of asthma related deaths are due to this scenario.  And a contributing cause is the cost of different inhalers: albuterol being relatively inexpensive while maintenance inhalers being expensive. 

This has led the Global Initiative for Asthma (GINA) to a new guideline that adds a topical steroid to all albuterol inhalers.  So far, the United States has not adopted this strategy.  Multiple international studies have documented a major improvement in patient outcomes with this approach:  marked reduction in the need for systemic steroids (oral or injected), reduced visits to emergency departments, reduced hospitalizations and reduced death. 

Tardigrade Research

Tardigrade Research

Tardigrades are microscopic organisms about the size of a dust mite but are really cute as they look like a baby manatee.  For being so tiny they have some really special properties that scientists hope to adapt to human health. 

Tardigrades are incredibly tough.  They can survive being frozen down to minus 272° Celsius, being exposed to a vacuum in outer space, being completely dried out and being exposed to 500 times the dose of x-rays that would kill a human. 

Tardigrade indestructibility stems from its ability to adapt.  Cold, dryness, vacuum, and x-radiation all cause damage to cell walls and to DNA within cells.  A tardigrade can abrogate these damages by synthesizing special “repair proteins”.  These special proteins support the cell’s membranes, essential proteins, and DNA.  One of these “repair proteins” Dsup has only been found in tardigrades and no other living organism.  Dsup binds to DNA and physically shields it from oxidative damage. 

In human cells our DNA has built in spare repair parts called telomeres.  As we live and are exposed to oxidative/inflammatory stresses our cells use the telomeres to repair damage.  But once the telomere resource is used up the cell will misfunction and even potentially become cancerous. 

And so, there is very active research into finding a way to protect human cells with Dsup.  Already scientists have inserted the gene to produce Dsup in experimental animals and it is working beautifully.  As a side-bar NASA scientists are looking at the possibilities of using Dsup to help long term space flight (with its attendant exposure to ionizing radiation for astronauts). 

Bronchiectasis

Bronchiectasis

Bronchiectasis is a lung condition characterized by cough and sputum production in the presence of abnormal thickening and pocket formation of bronchial walls which is visible on special lung imaging.  The little pockets are similar in their mischief to the pockets that can occur in the wall of the colon:  diverticula.  In both scenarios the pockets can sometimes accrete enough bacteria that it leads to acute bronchitis in the lung and diverticulitis in the colon.   

In the bronchial tubes the pockets can sometimes provide a haven for a smoldering presence of what are referred to as atypical bacteria.  Most common in this regard is MAC, mycobacterium avium intracellular (a cousin of the TB germ).  Also seen are Nocardia, Aspergillus and Pseudomonas.  The presence of these “smolderers” leads to chronic inflammation which in turn leads to bronchial wall thickening.  The condition is best diagnosed by high resolution CT scanning.  The “high resolution” format allows sufficient magnification of the bronchi to see the changes. 

There are a variety of treatment options.  However, key to all of these is what is referred to as “good pulmonary toilet”, that is, taking measures to keep the bronchi open and pockets empty.  Using a nebulizer daily with either saline or a bronchodilator is very helpful.  Some patients benefit from an external device called the VEST which through vibrations to the chest wall helps clearance of sputum. Antibodies can be used either for acute exacerbations or on a regular on/off schedule each month. Identifying “atypicals” either through expectorated sputum cultures or via bronchoscopy is also of value. 

In the US 1.5% of women and 1.1% of men have bronchiectasis.  So, if an individual is experiencing a chronic cough, it is a diagnosis to consider. 

Hydrogels

Hydrogels

Hydrogels are cross linked networks of biocompatible polymers that can swell or shrink in a controlled and reversible manner that can be tuned to specific physiologic conditions.  Wow!  That was a mouthful.  But if you re-read that sentence carefully you will find the description of an almost perfect delivery system (think UPS/Fedex) for intact proteins via the GI tract. 

Since the development of recombinant human insulin in the 1970’s a new class of medications called protein therapeutics has changed the practice of medicine.  Protein therapeutics are used to treat a broad array of illnesses including allergic conditions, rheumatologic disease, inflammatory bowel diseases, cancer, and endocrine disorders.  But these medicines can only work if the intact protein enters the blood stream.  Therefore, to date, the only delivery that works is to inject or infuse the protein.  Unprotected, the protein medication if taken by mouth, would be broken down into inactive digested molecules by the intestinal tract. 

Hydrogels are proving to be the perfect delivery system especially when engineered as nanogels.  This technology has already been applied to the administration of clotting factor IX (whose absence causes hemophilia B).  The potential exists for oral administration of a multitude of drugs such as; Humira, Rituxin, Xolair, Herceptin, Enbrel and many more.  The benefits would include home administration, removing the pain of being poked and cost reduction.