Is Medicine ready for Genome Sequencing?

Genetics news has been popular for many years, complete with premature promises of revolutionary new medical treatments. These inflated expectations are certain to disappoint the uninitiated. The unfolding science reveals more complexity and uncertainty with each discovery. New methods emerge quickly that empower scientists to discover more, faster and at lower cost, but there is no assurance that new discoveries will take us closer to practical applications, rather than farther away from affordable medical miracles.

The mastermind behind the whole festival of life is DNA, a self-seeking molecular code. DNA expresses genes that direct the assembly of amino acids into proteins. Some of the proteins are enzymes that assemble molecules that are used to construct living cells. The human genome is a living text that continually edits and rewrites itself. Over half of the human genome is occupied by repeating sequences and a historical record of evolution. Some gene sequences suggest two lines of evolution. One is a set of genes from aerobic bacteria. The second set comes from the single-celled organisms that incorporated bacteria as mitochondria. Animal cells depend on mitochondria to combine oxygen with fatty acids and amino acids to produce energy.

Human DNA is contained in chromosomes is 3 about billion letters long. When a cell divides, DNA splits down the center of the rungs leaving two long strands with only one nucleotide per rung. An enzyme, DNA polymerase, copies each strand. The nucleotides always form complementary pairs; adenosine pairs with thymine and cytosine with guanine. As the new strand is made, each nucleotide pairs with its partner. Copying errors are common. Slippages occur if the new strand gets out of sync with the parent strand. They have to be aligned so that the copies are linked in the same order as the original. A shift of just one base pair in the sequence alters the meaning of the code. Copying errors are a form of genetic mutation. Human populations accumulate mutations that contribute to the diversity of human abilities, diseases and destinies.

In their description of the National Human Genome Research Institute’s Encyclopedia of DNA Elements (ENCODE) project, Guigó and Reese stated: “Finding human genes is a complex task because of the peculiar anatomy of the eukaryotic genome. Eukaryotic genes lie within long stretches of intergenic DNA, and within the genes only a few short fragments—the exons—are spliced together, often in alternative configurations, to form the mRNAs. Sequence signals in the genome are degenerate, and computational programs using them are able to identify the exons and link them into genes with relative success. But only through the sequencing of the corresponding mRNA molecule can a gene be unequivocally identified. It is unclear, however, what fraction of genes can be ascertained through mRNA sequencing. In addition, genes are only one type of functional elements. It is likely that most of the functionality of the human genome sequence remains largely unexplored.”The modest aim of the first phase of ENCODE was to identify all functional elements in about 1% of the genome sequence through the collaborative effort of computational and laboratory-based scientists.

In time, the complete genomes of many species and many individuals within a species will be determined. Sophisticated comparative analyses of genomes will reveal more about the evolution of species. Computers with increasingly sophisticated software are essential to using genomic information in meaningful ways. DNA sequencing, brilliant programming and digital computing are perfect matches.

Personal Genome

The idea that each person will have their entire genome sequenced and that someone, somehow can read the genome and predict the future is both intriguing and misleading. Sequencing technology is advancing rapidly toward cheaper, faster, somewhat reliable genome analysis. However the brutal truth is that having access to a complete genome of 3 million base pairs in a sequence is having a surplus of mostly useless information. The intriguing aspect of having abundant genome information is that the doors open to a century of new research, new methods of computing large data sets and work for armies of researchers who can run studies of populations of humans to find out what the genomic information really means. In other words, genomes are just a beginning of a journey of discovery, not an endpoint.

A nature editorial reviewing the 10 years since the fist human genome was reported stated:" The first post-genome decade saw spectacular advances in science. The success of the original genome project inspired many other 'big biology' efforts — notably the International HapMap Project, which charted the points at which human genomes commonly differ, and the Encyclopedia of DNA Elements (ENCODE), which aims to identify every functional element in the human genome. Dramatic leaps in sequencing technology and a precipitous drop in costs have helped generate torrents of genetic data, including more than two dozen published human genomes and close to 200 unpublished ones. Along the way, geneticists have discovered that such basic concepts as 'gene' and 'gene regulation' are far more complex than they ever imagined. But for all the intellectual ferment of the past decade, has human health truly benefited from the sequencing of the human genome? Francis Collins and Craig Venter both say 'not much'. Granted, there has been some progress, in the form of drugs targeted against specific genetic defects identified in a few types of cancer, for example, and in some rare inherited disorders. But the complexity of post-genome biology has dashed early hopes that this trickle of therapies would rapidly become a flood. Witness the multitude of association studies that aimed to find connections between common genetic variants and common diseases, with only limited success, or the discovery that most cancers have their own unique genetic characteristics, making widely applicable therapies hard to find. (Editorial. The human genome. Nature 464, 649-650 (1 April 2010) | doi:10.1038/464649a; Published online 31 March 2010)

George Church, a professor of genetics at Harvard Medical School, founded the Personal Genome Project with the intention of sequencing selected individuals who were willing to share their genomes and medical histories in a public database. Personal Genomes.org held a conference in Boston April, 2010, inviting prominent individuals who have already been sequenced to share their experiences. Personal Genomics stated that there are fewer than 25 individuals to-date with public genome sequences, we expect that in this decade, there may be 1 million or more individuals with complete genome sequences worldwide.

Rehm et al reviewed the history of gene-disease correlations: "During the past 25 years, major advances in deciphering the genetic bases of human disease have been achieved, and more than 5000 disorders are now recognized at the genetic level. Although this is an extraordinarily important achievement in our understanding of the biologic features of human disease, the integration of these findings into clinical care is severely challenged by a lack of publicly available and accurate interpretations of the vast amount of human genetic variation known to exist. More than 80 million genetic variants have been uncovered in the human genome and for the majority, we have no clear understanding of their role in human health and disease. Thus, we are very far from a world in which we can sequence patients’ genomes and easily interpret their risk of disease, even if patients carry a variant in a gene that is associated with a highly penetrant genetic disorder. The rarity of most variants that are identified in genes has made it difficult to decipher the effect of such variants on gene function; most rare variants are labeled a “variant of uncertain significance.” A final factor contributing to our lack of consistent, clear, and clinically relevant annotation of human genetic variation is the so-called silo effect, in which various commercial and academic entities maintain isolated, sometimes proprietary, databases of variant interpretations, thus preventing the sharing of critical knowledge that could benefit patients, families, health care providers, diagnostic laboratories, and payers." (Heidi L. Rehm et al.ClinGen — The Clinical Genome Resource. N Engl J Med June 4, 2015.)

In 2017 the U.S. Food and Drug Administration today allowed marketing of 23andMe Personal Genome Service Genetic Health Risk (GHR) tests for 10 diseases or conditions. These are the first direct-to-consumer (DTC) tests authorized by the FDA that provide information on an individual’s genetic predisposition to certain medical diseases or conditions, which may help to make decisions about lifestyle choices or to inform discussions with a health care professional. The tests are based on identifying SNPs associated with 10 diseases. Seven of these diseases are rare. The FDA cautioned: "Risks associated with use of the 23andMe GHR tests include false positive findings, which can occur when a person receives a result indicating incorrectly that he or she has a certain genetic variant, and false negative findings that can occur when a user receives a result indicating incorrectly that he or she does not have a certain genetic variant. Results obtained from the tests should not be used for diagnosis or to inform treatment decisions. Users should consult a health care professional with questions or concerns about results. (USA FDA. FDA allows marketing of first direct-to-consumer tests that provide genetic risk information for certain conditions. News Release April 6 2017).

Medical Genetics Old Fashioned

In medical papers, old ideas of genes often prevail. Phrases such as genetic tendency, genetic component, and genes play a role in are typical of obsolete generalities that confuse rather than inform. The new appreciation that genes are not solid, real entities is difficult for physicians to understand. Part of the problem is that medical education pretends that humans are static entities and that diseases are discrete phenomena.

A dynamic, interactive systems model better accounts for what actually happens. Rather than solid, reliable genes, you can imagine segments of DNA as codes that are read differently depending on circumstances. Much of the coding deals with getting food, digesting it, distributing and using nutrients, and excreting waste products. Food intake to the body is a major player in determining gene expression.

Beyond the genome lies epigenetics - the study of how the expression of the DNA code is altered as dynamic processes that can change in minutes. The expression of DNA is balanced between stability mechanisms that preserve the long-term species memory in the genome and adaptive mechanisms that change the expression, depending on circumstances. It is the adaptive mechanisms and changing DNA expressions that make individual predictions based on genome analysis alone an act of faith rather than a reliable expression of science.

Epigenetics began with the discovery that DNA nucleotides can be silenced by adding methyl groups. Somehow, somebody in cells or cell to cell communications adds or subtracts methyl code to change the expression of DNA. Methylation was just the beginning of discoveries that revealed more and more mechanism that alter the expression of the genome. The DNA code is translated into many different kinds of RNA. The emphasis has been on messenger RNA that is transferred to ribosomes where it acts as a template for protein synthesis. The meaning of gene has be limited to protein encoding sequences of DNA, but already this understanding is seen as a partial truth at best. Short RNA pieces, for example, can interfere with messenger RNA encoding.

Single-nucleotide polymorphisms (SNPs)

A screening technology that identifiers single-nucleotide polymorphisms (SNPs) has developed rapidly and is less expensive and more accessible than complete genome sequencing. As a tool of basic science SNP scanning is interesting and promising. Databases have developed that associated SNPs with diseases in thousands of cases and provide a preliminary view of complex traits and diseases caused by many genetic and environmental factors working together. SNP screens have been offered commercially as tests for disease risk. Their value is doubtful. In a 2010 review of SNP research Monolo stated:" What is becoming clear from these early attempts at genetically based risk assessment is that currently known variants explain too little about the risk of disease occurrence to be of clinically useful predictive value. One can anticipate that as sample sizes increase and more risk variants are identified, the predictive value of cumulative genotypic scores will increase. It has also been argued that the use of dense genotyping information, from tens of thousands of SNPs with only nominal associations with disease, may improve the accuracy of phenotypic prediction. Care is needed in evaluating genetic predictive models, since they are often specific to the population in which they were developed, and their value can vary with genotypic frequencies, effect sizes, and disease incidence. Possible clinical uses of predictive scores — for example, in deciding which patients should be screened more intensively for breast cancer with the use of mammography or for statin-induced myopathy with the use of muscle enzyme assays — will require rigorous, preferably prospective, evaluation before being accepted into clinical practice. Genome wide scans permit screening for many conditions at once. If probabilities were applied to 40 independent diseases, for example, roughly 90% of the population would be placed in the top 5% of those at genetic risk for at least one of the diseases, 33% would be in the top 1%, and 4% would be in the top 0.1%. Expanding such screening to 120 diseases would nearly triple the proportion in the top 0.001% at risk and identify 1.2% at the top 0.01%, levels that could justify population-based screening if appropriate interventions were available. The ability to assess risk for 120 conditions at the same time also raises the concern that predictive models will yield conflicting recommendations; if implemented, they could reduce a person's risk for development of one condition and exacerbate the risk for development of another. Such considerations are timely and important, since several commercial ventures are marketing genome wide association–based screening directly to consumers. Patients inquiring about genome wide association testing should be advised that at present the results of such testing have no value in predicting risk and are not clinically directive. Clinicians would do well to use the discussion as an opportunity to point out other identifiable, modifiable risk factors that motivated patients can control. Whether to heed such advice or instead undergo testing and present the physician with the test results as a fait accompli is the choice of the individual patient. A decision to undergo genome wide association testing may result in the diversion of scarce time and resources to counseling or follow-up investigation of findings." Teri A. Manolio. Genomewide Association Studies and Assessment of the Risk of Disease. NEJM Volume 363:166-176 July 8, 2010 Number 2

While there is great interest in developing rapid, inexpensive genome sequencing, we lack even the most basic understanding of how to read the genomic data. The predication of disease risk is the least likely result of genomic data. Since the code is interactive, the expression of any sequence associated with a disease may be altered by changing food intake or other variables in the environment. Author: Stephen Gislason MD   Self Care for the 21st Century is available as a PDF file for free download. Click to download the PDF file http://www.nutramed.com/download/SelfCare.pdf

Fibromyalgia, the Misunderstood Disease

Fibromyalgia

People with chronic pain describe a variety of patterns -generalized aching associated with tender "pressure points" are common complaints. Fibromyalgia sufferers often say:" I feel like I am 90 years old." Stiffness after sitting or lying down is common. The stiffness and pain will often improve with mild activities, but overly vigorous exertion makes it worse. There are many ideas about Fibromyalgia. Patients are often frustrated and confused. Physicians are not always helpful and insurance companies are reluctant to pay disability claims. Some people have strong opinions and beliefs about Fibromyalgia and some support groups champion one idea over all others.

The Problem

• Generalized pain and stiffness
• Associated fatigue, digestive disturbances, cognitive dysfunction and many other symptoms

The Solution

•  Complete, comprehensive diet revision, using the Alpha Nutrition Program
• Physical therapy, exercise

We believe that Fibromyalgia is one expression of non-specific hypersensitivity disease and should be treated with diet revision as the first and most essential form of therapy. Not everyone agrees with us. The recent marketing a drug directed at fibromyalgia pain has legitimized the diagnosis. If the drug has any benefit, it comes with a high price to purchase and then a cost to you as you endure the side effects. We have prepared an intelligent guide for people with FM who are motivated to experiment, modify their lifestyle and make a sustained effort to improve. Drugs should not be the preferred remedy.

The Alpha Nutrition Program can help to resolve Fibromyalgia and related disorders. The program is both a a diagnostic and a treatment procedure. The first Phase of the program is an attempt to clear symptoms. This is home science. You start with the hypothesis that your food intake is causing or contributing to your illness and you do an experiment to find out if it is true.

You want to accomplish four important goals at the same time:

• Remove all the problems in your existing food supply
• Add all the nutrients your body needs
• Reintroduce the best, nourishing foods available and establish a new healthier diet
• learn how to take better care of yourself
• Begin gentle exercise and slowly regain physical fitness.

Background

Musculoskeletal and rheumatic complaints account for approximately 15% of the patients seen by primary care physicians. These complaints include muscle pain and weakness, regional pain syndromes such as back or neck pain, rheumatoid arthritis, and gout. More aggressive pain associated with joint and muscle inflammation is less common and occurs in patients with the autoimmune disorders, ankylosing spondylitis, lupus erythematosus, polymyalgia rheumatica and polymyositis.

Marcus stated: "We need to recognize that pain is an epidemic of sorts and that we are not adequately handling patients with pain." He estimated that headaches disrupt productivity in 40-million Americans each year, while back pain interferes with work in 36-million people, muscle pain affects 24-million people and neck pain affects 20-million people. For persistent pain in general, the cost estimates are around $100 billion per year. For back pain in particular, estimates are $16-20 billion per year. He stated: "Back pain is often a problem of fitness…if we made weight loss and exercise a national priority, the result would be tremendous savings for our beleaguered health care system…Even something as simple as walking the equivalent of two miles per day could reduce utilization and cost of medical services.

Obscurity to Big Pharma

Fibromyalgia and chronic fatigue have evolved from relative obscurity to become a brand name for a bizarre assortment of products and services. Drugs are prescribed by physicians in a haphazard manner as if they were browsing through the pharmacy shelf picking out drugs at random. A variety of pain relief clinics offer another random assortment of services. A variety of imaginative explanations is offered with little evidence. Sick lifestyles and environment problems are generally ignored. Drug prescriptions include pain relievers, muscle relaxants, antidepressants, anti-anxiety drugs, sleeping pills and anticonvulsants.

WebMD in 2016 offered this orthodox medical perspective:” Your fibromyalgia specialist may prescribe pain medication or antidepressants to help treat the pain, fatigue, depression, and anxiety that comes with the disease. In addition, your doctor may recommend physical therapy, moist heat, regular aerobic exercise, relaxation, and stress reduction to help you self-manage your symptoms. There is no one "pill" that treats or cures fibromyalgia. A multidisciplinary approach that uses both medication and alternative or lifestyle strategies seems to work best to treat fibromyalgia symptoms.”

Lyrica and Other Useless Drugs

Big Pharma has moved the marketing of Fibromyalgia into big-money TV advertising. The US FDA approved the drug, Lyrica (Pregabalin), for fibromyalgia and TV ads show happy patients enjoying a pain-free life.  This is  a serious anticonvulsant drug with alarming negative effects including suicide. Lyrica can cause life-threatening, allergic reactions.  Symptoms of an allergic reaction include swelling of the face, mouth, lips, gums, tongue, throat or neck. Lyrica may cause depression, anxiety, restlessness, trouble sleeping, panic attacks, anger, irritability, agitation, aggression, dangerous impulses or violence, or extreme increases in activity or talking.  Our questions are why would any physician prescribe and why would any patient take this potentially dangerous drug?

Go to Alpha Online to learn more about fibromyalgia and its solution.

Bad Chemicals= Social Chaos

Common effects of erratic brain function are conflict and chaos. Two people living together with erratic brain function increase chaos by more than a factor of two. More people interacting erratically increase chaos exponentially until family structures, community structures, and national structures become dysfunctional.

Bad chemicals entering human brains from polluted air and water, wrong foods, alcoholic beverages, legal and illegal drugs is a recipe for a society's dysphoric disintegration. We might better appreciate the folly of "fighting a drug war" when we realize that most chemical demons live at home. Unfortunately, in terms of substances that can impair brain function, drug sellers include every corner store, fast food outlet, pop vendor, pharmacy and supermarket. Local bars and liquor outlets generate a continuous stream of social and health problems at an enormous cost to society.

We must be smart enough to see the connections among food materials which influence brain function: alcoholic beverages, nicotine in tobacco, teas, coffee, chocolate, spices, food additives, sugar excess, wheat, milk, eggs, prescription drugs and street drugs. We should be very concerned about the prescription drug problem with drug addiction and dependency that is supported by all our institutions. Unfortunately, the practice of medicine has become a drug-pushing affair. An addicted society will better tolerate the social pathology and diseases caused by tobacco smoke, alcoholic beverages, air pollution, bad food, sedatives, antidepressants, tranquilizers, and sleeping pills but displaces its dysphoric energy in a "drug war" against cocaine, heroin and a few other "drugs of abuse".

Humans are seldom consistent in setting goals and priorities so that societal confusion about the use and abuse of food chemicals and drugs is more or less predictable. Smart policy makers will, however, understand that most citizens are under the influence of one mid-altering drug or another. The daily use and abuse of several brain chemicals produces mentally disabled people who are neither reasonable nor correct in their thinking and conduct. When physicians intervene and prescribe more chemicals, they add to the chaotic mix, not realizing there is there is little hope of benefit. To my way of thinking, this drug psychotherapy has become a perverse enterprise with no happy endings in sight.

From the Human Brain by Stephen Gislason MD

Immune Cells

The role of immune networks is to defend the body against foreign invasion. Microbes such as bacteria invade the body and activate innate antibacterial systems, such as the complement cascade. Polymorphonuclear leukocytes are attracted to this activity and attempt to ingest the bacteria.

The surfaces of the body are protected by cells on duty much like a military organization defends a country. The interior body surfaces are lined with a moist mucous-secreting surface that senses and reacts to the ambient environment. Antigens are protein molecules that are recognized by immune cells. Any chemical can link to a protein and become an antigen. Immune sensors or lymphoid tissues are present in the surface linings or mucosa of the intestine and respiratory tract (MALT).

These sensors are mast cells, macrophages and mobile lymphocytes of both T and B varieties. B and T-helper lymphocytes can only see antigen presented by macrophages and other antigen-presenting cells (APC).

The purpose of the surveillance is to detect and respond to foreign antigens. In the gut, lymphocytes are also contained in follicles, the solitary lymphoid nodules (SLN), found along the length of the intestine and in much of the upper and lower respiratory tracts. SLNs sample the soluble and particulate matter from the environment. The gut-associated lymphoid tissues (GALT) and the lung or bronchus-associated lymphoid tissues (BALT) are sensing agents for the whole body, identifying antigens for later detection by internal immune defenses. Both GALT and BALT and SLNs, contain predominantly B cells in which the major immunoglobulin classes synthesized are IgM and IgA.

Antigen Presenting Cells

Immune responses often begin with macrophages, dendritic cells and other antigen-presenting cells (APC) that ingest process and then present antigens on their surface. The antigen signal attracts other immune cells who recognize it and are activated by it. Antigen is presented adjacent to the major histocompatability complex (MHC) proteins on the surface of APCs. The details of how APCs ingest, digest and then express foreign antigens are being worked out. The antigen moves through the cell membrane and is incorporated into a phagosome which interacts with acts endoplasmic reticulum, a protein transfer system that moves the antigen via a transporter to a location in the cell where the antigen binds to MHC class I molecules. The antigen-MCH complex is then moved thorough the cell membrane to appear on the outside as a receptor.

Molecules on bacterial membranes activate toll-like receptors (TLRs) on macrophages and dendritic cells. These cells respond by secreting proinflammatory cytokines as well as proteins such as CD86 and CD40 that activate other cells amplifying the original signals and exciting an inflammatory cascade. Dendritic cells (DCs) discover antigens in peripheral tissues and then migrate to the local lymph nodes, where they encounter CD4+ or CD8+ T cells, which are activated by the presentation of antigen-derived peptides in association with major histocompatibility complex (MHC).

DCs take up antigen through different receptor families, such as Fc receptors for antigen-antibody complexes, C-type lectin receptors (CLRs) for glycoproteins, and pattern recognition receptors, such as Toll-like receptors (TLRs), for microbial antigens. Geijtenbeek et al suggested that:” DCs are continuously sampling and presenting self- and harmless environmental proteins to silence immune activation. Uptake of self-components in the intestine and airways are good examples of sites where continuous presentation of self- and foreign antigens occurs without immune activation. In contrast, efficient antigen-specific immune activation occurs upon encounter of DCs with nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors such as TLRs that result in DC maturation and subsequently immune activation. Here we discuss the concept that cross talk between TLRs and CLRs, differentially expressed by subsets of DCs, accounts for the different pathways to peripheral tolerance, such as deletion and suppression, and immune activation.”
Monocytes are circulating macrophages that can enter tissue spaces and promote inflammation. Macrophages are found within the endothelium generally and are concentrated in the lung, liver and spleen where they remove antigen and immune complexes from the blood.

Some tissues have resident macrophages such as the Langerhan's cells in the skin. Killer T-cells recognize antigen presented on MHC class I on all types of somatic cells. The purpose of the surveillance is to detect, and respond to foreign antigens. Since most antigens are proteins and foreign proteins arrive daily in the food ingested, I am interested in the mechanisms by which food proteins activate immune cells and cause disease.

APCs can ingest foreign protein and process them into peptides in proteasomes. Peptides are then transported into the endoplasmic reticulum to MHC class I molecules for presentation. Houde et al, for example, showed that latex beads labelled with fluorescent ovalbumin (egg white protein) were ingested and fluorescence could be detected in the cytoplasm, indicating that proteins are moved from outside into the cyoplasm for degradation by proteasomes. They showed that phagosomes are a site of loading onto MHC class I molecules on the cell surface, leading to T-cell stimulation.

Lymphocytes

Two major groups of lymphocytes are recognized as Thymus dependent or T-lymphocytes; and Bursa dependent or B-lymphocytes. Adaptive immune responses require B cells to provide antibody and T cells to provide cell-mediated immunity. Cell surface receptors recognize antigens. B-lymphocytes learn make antibodies to specific antigens. Although T and B cells share a common progenitor, their development occurs in different locations in the body. B cells develop in the bone marrow and mature in lymphoid tissue. T lymphocyte progenitors leave the bone narrow and travel to the thymus where they mature.
The identity of a foreign molecule, microorganism or cell, is recognized by an antigenic determinant, an amino acid sequence, usually contained in an intact protein. Once an antigenic determinant is recognized, its sequence is remembered by clones of antigen-specific B and T-memory cells which can activate other B lymphocytes that make antibodies against the antigen. T memory cells are also referred to a as helper T cells which are activated by the binding of a specific antigen encountered in the past, a signal that initiates defense against familiar pathogens.

One of the growing complexities in immunology is the description of cell surface receptors for a growing list of cytokines. Research reports are dense with acronyms, abbreviations and codes that may deter even an experienced reader. Some of these markers are described as CD followed by a number; CD122, for example is a receptor for interleukin 2- . In addition some descriptions emphasize the presence or absence of a well-studied receptor; CD122 + or -. CD receptors may be associated with other surface molecules in complexes. For example, natural killer T lymphocytes (NKT) have CD94-NKG2 complexes that bind to major histocompatibility complex (MHC) class Ib, aka Qa-1, on the surface of antigen presenting cells. CD8+ suppressor T cells regulate peripheral immune responses.
The frequencies of blood lymphocyte subsets are monitored by flow cytometry using monoclonal antibodies to identify subtypes: for example, OKT4 identifies CD4+, T-helper cells and OKT8 identifies CD8+, T-suppressor cells.

Virus-specific CD8 and CD4 T lymphocytes play an important role in controlling HIV replication; however CD4 and CD8 lymphocytes are infected by HIV virus. Identifying and counting CD4 cells is a major tool in following patients with AIDs taking antiretroviral medications.

See Immunology Notes at Alpha Online

Food Allergy

The problem is not that 25% of people recognize symptoms from food ingestion, but that many more people do not recognize that food is making them ill. We hope the reader will take the time to find out why we think food allergy is such an important mechanism of disease and how to resolve common food-related health problems by diet revision. Food allergy, as a topic in medicine, has been suppressed for many years and is not taught in medical schools. Too many vested interests have much to lose if more people discovered that popular foods were making them ill. Commonly quoted "expert" opinions tend to minimize the incidence and importance of food allergy. While the dogma is misleading, it represents vested interests and is remarkably persistent.


The conviction that food allergy is a ubiquitous cause of disease comes from knowing the benefits of careful diet revision in medical practice. In response to allergy lobby groups in the USA, the US Congress passed a bill that requires notice on the labels of foodstuffs that contain eight of the most common food allergens. The Food Allergen Labeling and Consumer Protection Act, will require plain English labeling beginning in 2006 of products containing wheat, milk, soy, peanuts, tree nuts, fish, shellfish, or eggs. The bill also requires the Food and Drug Administration to develop a definition of the term "gluten-free" to help those with celiac disease and who require a gluten free diet for other reasons.


The concept of immune responses to food antigens is useful in understanding many diseases. Many of the major unsolved disease of our civilization are either degenerative and/or inflammatory and many are recognized to be inflammatory, immune-mediated, hypersensitivity diseases. In this book, a general theory of hypersensitivity disease as a continuum of disease-causing mechanisms is presented. The term "hypersensitivity" refers to immune-mediated processes that lead to disease. As we consider the possible role of food antigens in causing or contributing to immune-mediated diseases, we look for opportunities to help patients with simple and safe therapeutic strategies such as diet revision. The basic phenomena that concern us are:

• Food antigens activate immune networks.
• Activated immune networks produce symptoms
• Long-term activation of immune networks causes chronic disease, with inflammation in target organs.
• The food supply is the most abundant and continuous source of antigenic material.

Different types of food allergy

1. The immediate or type 1 food allergy pattern is easily recognized because it involves quick and dramatic symptoms. Hay fever is the most common type 1 allergy and can be diagnosed by allergy skin tests. Some food allergy is also type 1 and shows up on skin tests.


2. Delayed patterns of food allergy are not so obvious and generally go unrecognized. Allergy skin tests do not show this problem nor do IgE antibody tests. Symptom onset is delayed many hours after eating foods and chronic disease is often the result. Rheumatic diseases, autoimmune diseases, multiple sclerosis, insulin-dependent diabetes, thyroiditis, psoriasis are examples of hypersensitivity diseases that involve humoral and cell-mediated immunity. The common specific problems that are related to food allergy include asthma, rhinitis, atopic dermatitis, urticaria, anaphylaxis, angioedema, allergic gastroenteropathy, and allergic arthritis.


Many patients will express several of these hypersensitivity phenomena over a lifetime and demonstrate an underlying tendency to be hypersensitive. An important concern is the possibility that the chemical soup created by our civilization drives increasing numbers of individuals into hypersensitivity illness. The advocates of a broad definition of food allergy run the risk of being evangelical.


At Alpha Nutrition, a major commitment is to educate people about delayed patterns of food allergy and to point to opportunities people have to resolve serious illness on their own. Our strategies of self-management are simple and straight forward, but require knowledge, perspective and self control. We are the first to acknowledge that some people lack these prerequisites and our information will not help them.


Dr. Gislason stated: "I began to learn about food allergy in 1981 when I first developed inflammatory arthritis. I discovered a simple truth that eating a few safe foods resolved my illness and returning to my previously normal diet recreated the illness that was so severe, I could not work or enjoy life. I thought that my medical colleagues would be as excited as I was to discover that such a serious illness could be cured with diet revision. I did encounter the occasional MD who shared my enthusiasm for further research but most MDs were hostile to the science of food allergy, even when the therapies they offered patients were ineffective and even harmful. I have learned a lot about the politics of medicine and the strategies used by corporations to control the market place. Corporate control has advanced remarkably since I began my quest to understand the mechanisms of food allergy and to teach self-management solutions. Drug companies own medical practice and compete for their market share with skill, determination and huge promotional budgets. They do not want people to solve health problems on their own. They want people to depend on MDs and buy dru
gs "


Learn More About Food Allergy at Alpha Online

Inflammation in Vascular Disease

The mechanisms of arterial disease appear to be multiple. Hollander of Boston University suggested that atherosclerosis was an autoimmune disorder with immune complexes injuring blood vessel walls. We think that circulating immune complexes often contain food proteins as antigens and this mechanism is important in causing a wide spectrum of food allergic disease. Since proteins derived from meat, milk, eggs and wheat have the highest risk of appearing in the blood as immune complexes, these foods are reduced or eliminated in the Alpha Nutrition Program.
We ask a simple question - If there is any possibility that chronic symptoms such as attacks of migraine, heart rhythm abnormalities, digestive disturbances, breathing difficulties or brain dysfunction are linked to food ingestion, would it not be prudent to investigate and remove food -causes using diet revision as an inexpensive, safe, effective strategy?

Keaney et al reported that:” background Inflammation within vulnerable coronary plaques may cause unstable angina by promoting rupture and erosion. In unstable angina, activated leukocytes may be found in peripheral and coronary-sinus blood. “



A non-specific indicator of inflammation is the C-reactive protein levels in the blood. Elevated levels are associated with increased risk of heart attacks and strokes. For example, Ridker et al studied 27,939 apparently healthy American women, who were followed for eight years for the occurrence of myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Elevated C-reactive protein levels were a better predictor of vascular events than low LDL cholesterol levels. The researchers reported that: ” 77 percent of all events occurred among women with LDL cholesterol levels below 160 mg per deciliter (4.14 mmol per liter), and 46 percent occurred among those with LDL cholesterol levels below 130 mg per deciliter (3.36 mmol per liter)… C-reactive protein and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biologic markers provided better prognostic information than screening for either alone.”



Myeloperoxidase is another serum marker of inflammation that may be informative.  Myeloperoxidase is an enzyme that generates reactive oxygen species, is released from white blood cells. In one study, plasma myeloperoxidase levels were predictive of subsequent coronary events in patients with chest pain. Myeloperoxidase levels, in contrast to troponin T, creatine kinase MB isoform, and C-reactive protein levels, identified patients at risk for cardiac events in the absence of myocardial necrosis.“



Inflammation can be treated by removing the causes of inflammation, treating infection and using anti-inflammatory medication such as ASA and  Statins. The role of food proteins and immune complexes as agents of inflammation is rarely investigated and may turn out to be the hidden agent behind many heart attacks and strokes. Several studies are investigating a variety of immune-modulating therapies to prevent heart attacks and strokes.



See Arterial Disease at Alpha Online

Fibromyalgia

Obscurity to Big Pharma

Fibromyalgia and the chronic fatigue syndrome have evolved from relative obscurity to become a brand name for a bizarre assortment of products and services. Drugs are prescribed by physicians in a haphazard manner as if they were browsing through the pharmacy shelf picking out drugs at random. A variety of pain relief clinics offer another random assortment of services. A variety of imaginative explanations is offered with little evidence. Sick lifestyles and environment problems are generally ignored. Drug prescriptions include pain relievers, muscle relaxants, antidepressants, anti-anxiety drugs, sleeping pills and anticonvulsants.

WebMD in 2016 offered this  perspective:” Your fibromyalgia specialist may prescribe pain medication or antidepressants to help treat the pain, fatigue, depression, and anxiety that comes with the disease. In addition, your doctor may recommend physical therapy, moist heat, regular aerobic exercise, relaxation, and stress reduction to help you self-manage your symptoms. There is no one "pill" that treats or cures fibromyalgia. A multidisciplinary approach that uses both medication and alternative or lifestyle strategies seems to work best to treat fibromyalgia symptoms.”

Lyrica and Other Useless Drugs

Big Pharma has moved the marketing of Fibromyalgia into big-money TV advertising. The US FDA approved the drug, Lyrica (Pregabalin), for fibromyalgia and TV ads show happy patients enjoying a pain-free life.  This is  a serious anticonvulsant drug with alarming negative effects including suicide. Lyrica can cause life-threatening, allergic reactions.  Symptoms of an allergic reaction include swelling of the face, mouth, lips, gums, tongue, throat or neck. Lyrica may cause depression, anxiety, restlessness, trouble sleeping, panic attacks, anger, irritability, agitation, aggression, dangerous impulses or violence, or extreme increases in activity or talking.  

Our questions are why would any physician prescribe and why would any patient take this potentially dangerous drug?? 

Our view is that the Chronic Fatigue Syndrome (CFS) , Fibromyalgia and related disorders are not discrete diseases in the usual sense, but patterns of maladaptive responses to food and the environment. We believe that chronic fatigue syndrome is an expression of non-specific hypersensitivity disease and should be treated with diet revision as the first and most essential form of therapy. 

The Alpha Nutrition Program is designed to improve fibromyalgia, chronic fatigue and related disorders. The most definitive clearing program is a food holiday, using an elemental nutrient formula (Alpha ENF), composed of nutrients in their pure form with no other food intake. Alpha ENF allows a sick person to return to a baseline of normal functioning, without the intake of numerous adverse substances that may have been present in their food supply.

See www.nutramed.com/fibromyalgia/

Diesel Exhaust Causes Disease

The Combustion Process

Gasoline and diesel fuels are mixtures of hydrocarbons (made of hydrogen, oxygen and carbon atoms.) Hydrocarbons are burned by combining with oxygen. Nitrogen and sulphur atoms are also present and combine with oxygen when burned to produce gases. Attempts to reduce exhaust emissions from gasoline and diesel engines have been compromised by limitations of testing, inherent flaws in the design and inadequate maintenance of emission control devices.

Diesel engines a pose different emission control problems than gasoline engines. Diesels require more sophisticated and expensive components than the catalytic converters fitted to gasoline engines. Diesel emissions contain nitrogen oxide gases and carbon particles, the smallest of which contribute to lung and heart disease. Increases in airborne fine particulate matter increases the risk for myocardial infarctions, strokes and heart failure. Particle deposition in the lungs activates the sympathetic nervous system and triggers the release of systemic pro-inflammatory responses.

Brook and Rajagopalanb stated: "Higher circulating levels of inflammatory cytokines cause vascular endothelial dysfunction and activation of vasoconstrictive pathways while blunting vasodilator capacity. At the molecular level, the generation of oxidative stress with the consequent up-regulation of redox sensitive pathways appears to be a common mechanism of these pro-hypertensive responses. Due to the ubiquitous, continuous and often involuntary nature of exposure, airborne fine particles may be an important and under-appreciated worldwide environmental risk factor for increased arterial BP.

In Sept. 2015 a scandal erupted when Volkswagen, the world's largest car manufacturer, was caught cheating on emission tests of their diesel engines. In testing lab conditions, VW could show conformity with emission standards fro nitrogen oxides. Subsequent independent testing of VW diesel vehicles in road tests revealed high levels of nitrogen oxides emitted in real operating conditions. Errors in media reports proliferated with talk of defeat devices and software that would fool emission tests.

Relevant engineering data was not readily available but likely the cause of the problem was the Nitrogen Oxide converter (aka NOx storage catalytic converter ) that required injections of unburned fuel to keep the converter clean and functional. The exhaust output was supposed be free of nitrogen oxides. The computer that controlled fuel injection was programmed to inject more fuel than was needed for combustion for about 2 seconds per minute. The fuel reaching the converter would burn increasing the temperature in the converter. Burning the diesel fuel in the converter would likely increase the emission of other air pollutants. The software functioned optimally for emissions testing and was turned off when the engine was in service. The NO converter was a poor design that would increase fuel consumption and decrease engine performance if the converter was operated for full emissions control.

Jack Baruth advocated the end of diesel cars and pickup trucks. He stated: "Western democracies encouraged diesel even though they were perfectly aware of the health hazards posed by diesel particulate exhaust. Those risks are far better documented than even the most "settled" climate science, and they are very real. Eurocrats chose diesel in order to be seen to be doing something about global warming, and the manufacturers had to abide by their choice. The result? Paris has had to ban cars for hours or even days at a time because of smog. According to The Guardian, "diesel-related health problems cost (the British National Health Service) more than 10 times as much as comparable problems caused by petrol fumes. Last year the UN's World Health Organization declared that diesel exhaust caused cancer and was comparable in its effects to secondary cigarette smoking. And that was when people thought that these diesels were meeting pollution standards! Now, of course, we know that many of them were not, and that even the diesel cars that weren't designed to cheat the tests are not performing in the real world the way they do in the test labs. In other words, diesel-powered automobiles are killing people, and in not inconsiderable numbers. The jury is in and the evidence is clear." (Jack Baruth. Road & Track. Oct 2015)

A review in the Science journal, Nature, questioned the relationships between auto manufacturers and regulatory bodies: "Among the questions raised by the scandal that allowed the German car maker Volkswagen to sell 11 million vehicles containing software that cheats emissions tests, many will ask why the regulators failed to notice and halt the practice. The answer is not complicated. Regulated industries exert massive, discreet pressure on regulators such as the US Environmental Protection Agency (EPA), to stop them doing their jobs properly."

To put the VW scam in perspective,  the big problems were corporate cheating and deliberate violation of public trust. It appears that this deception will cost VW several billion euros and is an embarrassment for all of Germany. Regulatory agencies have been alerted to their limitations and will be changing testing procedures for all new engines that include monitoring emissions during real driving tests in real driving conditions.

See Air and Breathing by Stephen Gislason MD

Blood Circulation to the Brain

The brain is a unique organ in the body. The blood circulation in the brain is more complex, more regulated, and less understood than the circulation in any other tissue. The large arteries carrying blood to the brain are the internal carotids and the vertebral arteries. The condition of these arteries determines how much blood flow is available to the brain. The smaller cerebral (pial) arteries respond to changing demands from blood supply from cerebral tissues. This auto regulation tries to maintain stable cerebral blood flow even with unstable cerebral perfusion pressure. Brain circulation responds in complex ways to a large number of stimuli. Failure of autoregulation may be one of the most common sources of brain dysfunction especially in people with high blood pressure on medications.

Brain activity regulates brain circulation by controlling cardiac output and blood pressure. Emotions, especially anger, are strong events that act on the cardiovascular system; heart rate increases and blood pressure rises, often dramatically. Cognitive tasks increase blood flow and metabolic rate in the regions of the brain that process the task. Changes in localized blood flow are the basis of functional imaging studies that reveal the modules in the brain that are active during task processing.

Blood-brain barrier

Cerebral microvessels have a unique feature, the blood-brain barrier, which protects sensitive brain cells from disturbing elements circulating in the blood. Endothelial cells line blood vessel. Their behavior regulates permeability. In the brain, tight intercellular junctions limit endothelial permeability. A variety of chemical signals to and from endothelia cells control blood vessel transactions with glial cells and neurons. Cerebral vessels have nerves supplies -sympathetic, parasympathetic, and sensory nerve fibers. Gaseous transmitters such as nitric oxide (NO) dilate small blood vessels and participate in the regulation of blood flow.

Syncope (fainting) is an expression of reduced cerebral blood flow. Prolonged standing, emotional arousal, blood pressure drugs, cardiac arrhythmias, and autonomic nervous system failure are common causes of syncope. Blood tends to pool in the legs with prolonged standing. Muscle activity is required to pump venous blood uphill back to the heart. With reduced venous return, cardiac output drops and humans faint. A common symptom, the feeling of lightheadedness is an expression of reduced blood flow to the brain. Since cerebral arterial disease increases with age, decreasing symptoms of limited blood flow become more common such as lightheadedness, fainting, personality changes and deteriorating cognitive ability.

Some of the disturbances will be regional with selectively compromised functions. Other disturbances will be global. The use of medications to reduce blood pressure may have adverse effects because lowering blood pressure can decrease cerebral perfusion in patients with chronic vascular brain pathology; they may develop focal hypoxia and even ischemia in poorly perfused regions of their brain.

Stroke is the leading cause of disability in the U.S. and Canada

Stroke is the leading cause of permanent disability in the U.S. and Canada, second leading cause of dementia and the third leading cause of adult death. Stroke is the third leading cause of death and a major source of disability in the US where 700,000 people have a stroke and 158,000 die from stroke. From 1993 to 2003, the stroke death rate fell 18.5%, but the actual number of stroke deaths declined only 0.7%, according to 2006 statistics.

The main event of a heart attack is the occlusion by a sudden blood clot of one or more blood vessels supplying the heart muscle. A similar occlusion of blood vessels supplying the brain will result in the death of brain tissue or cerebral infarction. Another cause of stroke is hemorrhage from a ruptured blood vessel. Yet another stroke mechanism is the occlusion of a brain artery by a clot that traveled to the brain from another body location, usually the heart; embolism is most likely to occur in people with atrial fibrillation and mechanical heart valves.

Neurologists say doctors and the public should give stroke victims the same urgent treatment given to heart attack victims. The clot-dissolving drug TPA (tissue plasminogen activator), when used in the first three hours after a stroke, can restore blood flow in the brains of some patients. Some hospitals have better tools for dealing with strokes, but require the stroke patient to seek treatment quickly. The message in the media is to act fast on the warning signs of a stroke - stokes are now described as "brain attacks" to encourage the same sense of urgency attributed to heart attacks. Symptoms include weakness or numbness, especially on one side of the body; blurred vision, usually in one eye; slurred speech; dizziness; and explosive headache.

The hope for dramatic rescue of stroke victims with TPA is somewhat tarnished by the impractical requirement of getting the right treatment right away. One major problem is that some strokes are caused by bleeding into the brain and TPA would make this worse. Before getting TPA, patients must be checked to ensure they are not bleeding in the brain. If you were planning to have a stroke, you have to set up an ideal circumstance in order to be rescued. You would have to recognize that you were having a stroke almost immediately; you would have to get to a well-equipped hospital promptly; the emergency room would have to be set up to make the diagnosis promptly, get a high quality CAT scan done and interpreted by an expert and then you would have to satisfy several criteria for treatment - the first is that the CAT scan shows that there is no bleeding associated with the stroke symptoms.

Preventing Strokes

We share the conviction with a growing number of experts in the field that simple, safe home remedies especially diet revision and exercise can substantially reduce this destructive disease and save untold suffering and billions of health-care dollars. Smoking must stop. Diabetes, high blood pressure, and high blood cholesterol must be controlled to prevent stroke and, again, diet revision with weight loss and increased daily exercise can work wonders. Drugs are only required if risk factors are not controlled by changes in diet and lifestyle.

Well-known risk factors are

• high blood pressure
• smoking
• high alcohol intake
• diabetes
• excess body fat
• physical inactivity.

Stroke Prevention

• Diet Revision -- Alpha Nutrition Program
• Exercise and Weight Loss
• Reduce blood pressure

See The Human Brain is Health and Disease by Stephen Gislason MD

Self-Care

Dr Gislason wrote: "Selfcare only works if you have adequate knowledge and effective problem solving strategies. In the best case, you would know enough about your body functions to interpret symptoms as they arise and you would take corrective action. You would develop a good sense of what problems you can manage yourself and you would know when to seek help. You would use all the preventive strategies available to you and would use screening tests to detect early stages of disease. I have written several books on specific diseases with the idea of presenting adequate knowledge and suggesting problem solving strategies."

The Alpha Nutrition Program is a rational plan that requires new learning, discipline and self-control.  A basic intention is to do a better job of self-regulating. Self-regulation implies control over behavior. I learned by watching a few thousand people attempt to do this program that people with some measure of self-control were uncommon. I learned that self-discipline was in short supply and that rational plans tended to fail without a lot of support. Since eating is a social activity, changes in eating habits require a social method. 

Some exceptional people live well-organized lives with traditional lifestyle eating habits and operate from an internal locus of control that gives them an enviable ability to self-manage. If you have a well-developed center, you have an easier time developing new patterns, once you accept that it is necessary and desirable to change. You can plan an orderly transition from old to new. People with a strong internal locus of control are more skilled at collecting and evaluating information. They accept professional advice as information, not as parental authority. They tend to feel more confident making their own decisions."

Interface with MDs

For many years, we have proposed a collaborative relationship between patient and physician. The growth of medical information in the internet gives every intelligent person access to current information and to a variety of options. Often a patient with a specific disease is better informed than the physician. Carolyn Clancy, director of the US Agency for Healthcare Research and Quality stated: Patients are becoming more involved in decisions about their care. Even though this is a major change to how we (MDs) practice medicine, it will, over time, create a genuine partnership between doctors and patients. We recognize the importance of clear, ongoing communication, including questioning why a particular treatment decision was made. We need to engage our patients in the same way. My agency has developed a new public awareness campaign with the Ad Council to encourage patients to take a more active role in their healthcare.

A Free Copy of the book Self Care for the 21st Century is available as a PDF file for download.

Narcotic Drugs Addiction and Death

Narcotic drugs have always been associated with addiction; however, narcotic drugs remain the best agents to relieve pain. Pain management is the reason people are most likely to seek medical attention. Physicians try to balance their desire to elevate suffering against concerns that the patient in pain just wants a drug prescription. Physicians remain constrained by problems of drug dependence and addiction and are reluctant to prescribe narcotics or prescribe weak, inferior narcotics such as codeine and demerol. 

Weintstein et al polled 386 physicians in Texas and found that a significant number of physicians had prejudice against the use of opioid analgesics, displayed lack of knowledge about pain and its treatment, and had negative views about patients with chronic pain. They suggested that new educational strategies are needed to improve pain treatment in medical practice.  

 The narcotics that are considered to have the greatest addiction potential include codeine 60 mg, oxycodone, methadone, hydromorphone, demerol (meperidine), fentanyl, and morphine. The World Health Organization (WHO) suggested a progressive treatment of pain. For mild pain: aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs and adjuvants. For moderate pain: mild opioids. For severe pain: traditional opioids. Physician concerns are justified. Narcotic-dependent people routinely solicit prescriptions from a number of physicians and become good at feigning painful conditions. Every primary care physician will have patients who tend to demand prescriptions for pain relievers and other psychotropic drugs and will become chronic users, unless the physician steadfastly resists their demands and limits prescriptions to short term use. 

Prescribed narcotics are always available for sale on the street. Most originate with doctors who are lenient prescribers. Drug traffickers have lists of lenient Doctors who write narcotic prescriptions on demand for a fee.  Prescribed narcotics are always available for sale on the street. For example, about two million Americans have admitted taking OxyContin (oxycodone) illegitimately. The US Drug Enforcement Administration reported that it is one of the most abused prescription drugs. Another narcotic, hydrocodone also has a high potential for abuse. Hydrocodone, as a narcotic cough medicine, is one of the favorite drugs sought by recreational users when they visit emergency departments. Both drugs act on the opioid mu receptor which blocks the transmission of pain in the spinal cord.

In the USA OxyContin is a $1.5 billion per year product. A report in the New York times from rural Kentucky ( July 2004) provides a perspective on narcotic drug use: “Ever since prescription painkillers like OxyContin became the drugs of choice among dealers and addicts in Appalachia, the days of small-town pharmacists' dispensing medicines from behind an ordinary counter have become a quaint memory. Now many pharmacies have turned into virtual fortresses. Some have bars over the windows. The most sought-after drugs are stored in vaults. The pharmacists often work behind safety glass, and some have even armed themselves. Surveillance cameras and alarm systems monitor every spot. Dan Smoot, chief detective for Operation Unite, an anti-drug task force said that prescription drugs remained the top problem for police agencies in the mountains. Mr. Smoot recently led the largest drug raid in Kentucky history, arresting over 200 people on charges of buying or selling prescription drugs on the black market.” 

The muscle relaxer, carisoprodol (Soma) is another favorite street drug which contains a metabolite of meprobamate, an old tranquilizer. Taken with alcohol, Soma produces stupor or "Soma coma." Tramadol (Ultram) is a pain medication that can produce a mild euphoric state. Dextromethorphan is a cough suppressant found in many cough syrups, which produces a euphoric state when taken in large quantities and can produce visual hallucinations.    People who take opioid analgesics for many days will develop physical dependence and will suffer withdrawal effects if the drug is discontinued suddenly. Symptoms of withdrawal include drug cravings, muscle cramps, joint pains, anxiety, nausea and vomiting. Withdrawal is most intense following IV heroin use and is relatively milder after taking oral medications.

Fentanyl has become the most potent narcotic with the greatest danger in the form of sudden death. Gatehouse and Nancy reported on the tragic rise in Fentanyl deaths in Canada. They described:" Over the past few months, fentanyl has been making headlines across North America, as police discover more and more of it on the streets, and overdose deaths surge. Authorities in Alberta linked the drug to 120 fatalities in 2014, and 50 more in just the first two months of this year. In British Columbia, it killed almost 80 people in 2014, and was responsible for a quarter of all drug deaths, up from just five per cent in 2012. In Ontario, where 625 people died of opioid overdoses in 2013, fentanyl was involved in 133 of those cases and, each year, it now kills twice as many people as heroin. First developed by pharmaceutical trailblazer Paul Janssen in 1959, it was originally used as an anaesthetic under the brand name Sublimaze. The slow-release transdermal patches for chronic pain relief were introduced in the mid-1990s. Its dangers have also long been recognized. There have been a number of scholarly studies about all the doctors and nurses, especially anaesthesiologists, who have become addicted to it, and notable victims such as Jay Bennett, the late guitarist for Wilco, who died of an accidental fentanyl overdose in 2009 after being prescribed the patch for an old hip injury. And the drug’s illicit analogues—there are at least a dozen variations—have been killing people on the streets since the late 1970s, most infamously under the name “China White.”

The deeper story of the drug and its abuse is even more worrying. Police and health workers now face an unprecedented situation, with a burgeoning street trade in both the legitimate prescription patches and illicitly manufactured fentanyl—often sold in pill form and made to look like OxyContin, a far less powerful narcotic. The drug, also available in liquid and powder form, is increasingly being used to cut cocaine and heroin, dramatically boosting their potency, often with fatal consequences. Indeed, fentanyl seems to turning up almost everywhere you look. And it’s killing both inexperienced newbies and hardened addicts. The illicit fentanyl that’s currently flooding Canadian markets in pill form has more benign nicknames: greenies, green beans and green monsters (all references to its emerald hue). But that doesn’t make it any less deadly. Stamped as OxyContin, the fentanyl has been retailing for as little as $10 a pill—an indication of how cheap it is to manufacture, and how easy it is to obtain the raw material.

The big B.C. investigation in March turned up two industrial pill presses that were used to make the 29,000 tablets. Two of the 14 people arrested in associated raids in Alberta and Saskatchewan are “full-patch” members of the Hells Angels. A third man is the president of an affiliated motorcycle gang, the Fallen Saints.

Then there’s the other problem: the growing abuse of the legitimate pharmaceutical version of the drug. Prescriptions for high-dose painkillers have skyrocketed over the last 15 years. A study by a group of Ontario researchers, published last fall in Canadian Family Physician,  determined that Canadians are now the world’s biggest per capita consumers of legal opioids, with more than 30 million high-dose tablets and patches distributed every year. Such widespread availability of opioids inevitably leads to widespread abuse. A recent meta-analysis by an American Scientist, published in the journal Pain, found that the average rate of misuse of prescribed painkillers is around 25 per cent  and that one in 10 medical users ends up addicted. In recent years, it was OxyContin that was driving that trend, because it could easily be crushed and snorted. But, once governments forced the manufacturer to introduce a tamper-resistant formulation, called OxyNeo, to the Canadian market in early 2012, the preferred high quickly became fentanyl.

Dr. Karen Woodall, a toxicologist with the Ontario Centre of Forensic Sciences in Toronto, regularly testifies as an expert in fentanyl cases. She first noticed the drug in 2005 in the autopsy files that cross her desk. She later traced deaths as far back as 2002, mostly via people overdosing after chewing cut-up bits of patches—a particularly dangerous practice, since there’s no way to predict the quantity of the drug in each piece. “The big problem with fentanyl is that a lot of people who aren’t tolerant to the drug are taking it. And if you’re not tolerant, it’s a lot more likely to cause serious toxicity and even death,” she says. “It severely depresses breathing and the heart rate. Combined with alcohol or other drugs that slow the central nervous system, it becomes even more dangerous. It’s a serious issue, we’re seeing more and more deaths.”  


From The Human Brain by Stephen Gislason MD

 

Cytokines

The study of immunology has revealed a complexity of immune cell types and prolific interactions that overwhelm even the experts. The emerging description of chemical signaling that occurs among immune cells and between immune cells and all other tissues of the body has become especially complicated. As the collected data become denser, even highly specialized researchers have difficulty visualizing what is actually occurring in a diseased body.

The MD examining a patient, using conventional medical tools, is hopelessly inadequate and does not understand what is really going on. Classifications and names have changed with advancing discoveries. There more than 30 members of the interleukin family, for example, subdivided into families. To make a complex matter simple, they can be sorted into pro-inflammatory and anti-inflammatory groups.

Cell Signals

Cytokines are soluble proteins that regulate immune responses. One idea is that cytokines are short range signals. For example, it was though that production in lymphoid tissues is tightly localized and signaling occurs between conjugate cells. Perona-Wright et al assessed cytokine signaling during infection by measuring in vivo phosphorylation of intracellular signal transducer and activator of transcription (STAT) proteins. They stated: We show that interferon-γ (IFN-γ) and interleukin 4 (IL-4) signaled to the majority of lymphocytes throughout the reactive lymph node and that IL-4 conditioning of naive, bystander cells was sufficient to override opposing T helper type 1 (TH1) polarization. Our results demonstrate that despite localized production, cytokines can permeate a lymph node and modify the majority of cells therein. Cytokine conditioning of bystander cells could provide a mechanism by which chronic worm infections subvert the host response to subsequent infections or vaccination attempts.

 Another idea is that cytokines provide long-range signalling and help to organize systemic responses to infection and injury. The nature series of scientific journals sponsors a data base that by 2006 listed over 3700 signaling proteins that carry messages among cells of the body. Dove described the state of signalling science: “Ask a cell biologist to explain signal transduction, and you are in for a long story. The science of understanding how individual cells sense their environments and respond to stimuli fills library shelves, occupies whole departments of colleges and inspires the careers of thousands of researchers around the world. Even so, the field sometimes seems woefully understaffed.

The advent of whole-genome sequencing and gene-expression profiling revealed what most biologists already suspected: we are just beginning to understand cell signaling. For example, cells rely heavily on surface receptor proteins to communicate with the outside world. Often, signals flows through receptors that are coupled to effector molecules called G proteins. Inside the cell, information flow often entails an enzyme finding a specific target protein and attaching or removing phosphates, lipid groups, or other chemical structures. The modified target commonly goes on to modify other targets and so on through baroque cascades of interactions.”

Scientists have described a bewildering complexity of cytokines and variable cytokine production in different humans. We know that humans are not created equal. One significant inequality lies in the ability to produce cytokines of different types. An individual’s cytokine profile will help to determine the response to antigen challenges, susceptibility to different diseases and the severity of the disease, once contracted. Advances in techniques of identifying ever larger numbers of signaling molecules have produced research papers dense with measurement data, often in a curious limbo, where the ephemeral dynamics of cell interactions are scarcely mentioned and not at all understood.

From Immunology Notes by Stephen Gislason MD