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Old notes I found from 4.5 years ago on chronic fatigue

Discussion in 'General Treatment' started by Sam7777, Nov 19, 2015.

  1. Sam7777

    Sam7777 Senior Member

    I recently learned about my mast cell histamine issues, basically because I was just reacting to food in a very obvious fashion. It didn't take too long to realize.

    Then I saw this thread. . .
    I'll post the notes below.
    It made me remember that 4.5 years ago I was actually really involved in researching mast cell issues.

    A bit of a backstory:

    I....use to be a much more intelligent person. In approximately July-September 2011 I started taking alpha lipoic acid incorrectly, and that was pretty much it. That caused anterograde amnesia, and chronic fatigue, made me to this day basically lack clear memories of the first 19 years of my life.

    But leading up to that, I was desperate to understand my chronic fatigue and so I spent probably, literally, numerically, 1000's of hours in a period of five months researching my own medical issues. Luckily then, I was a lot smarter and could focus and read. Now I can't really read more than a few pages at a time or write coherently.

    But I realize that I was pretty damn on the mark back then. Sadly, I forgot about all this because I had my lights knocked out so hard. These notes I'm going to post.. .make a lot of sense out of chronic environmental illness.

    What I didn't know at the time, was what it could be precisely that would constantly aggravate the immune system in such a way. These papers kept talking about the psychological stress response or the immune response to some sort of stress response. But what could do that constantly. . .well it's food, constant reactions to chemicals in food or just food. . .but beneath that there has to be something else driving food allergies. . .and while it isn't true for everyone...for me it was clearly a massive load of mercury.

    But the underlying mechanism really, really, strongly pins the blame on basically all pollution. Generally what we're looking at here is of course the problems with modern life and nutrition/sun/artificial lights, sure, but overwhelmingly, its the combination of a liver that can't keep up and some sort of derangement brought on by persistent pollutants, that arguably are responsible for the methylation issues as well.

    The problem is, understanding the mechanisms like mast cells makes a gigantic difference. I have continuously failed to restart and maintain chelation, because frankly I have been getting stomped by food issues for 4 years. The first time I got better, it was because of a radically reduced diet. I was on a pesco-vegetarian Weston Price style diet with some bodybuilder techniques thrown in. At the time I didn't know but. . I had cut out virtually all histamine producing, high thiol, typical auto-immune triggering foods. I didn't chelate, and I didn't treat methylation, but I removed the reactions driving the entire mast cell and stress response process. This basically gave my body a break finally, to auto-repair.

    These mechanisms are critical to understanding environmental illness.
  2. Sam7777

    Sam7777 Senior Member

    This was a pattern I noticed 4.5 years ago. BEFORE I understood Cutler's book. Before I knew it was mercury. That's why its a 'big deal' I didn't know about mercury but I was on to it. I was making a list of common traits I observed in all chronically ill and fatigued people at the time.

    • Chronically Depleted and Reduced glutathione redox cycle

    • Chronic inflammatory cytokines

    • Weakened TH1 to TH2 immune balance

    • Increased Mast Cell activation

    • Endothelial Gastrointestinal mucosa villus atrophy

    • Chronic microglial and dendritic activation

    • Over-stimulation of NMDA receptors

    • Reduced adrenaline

    • Reduced nitric oxide

    • Reduced glutamate function in brain

    • Abherrent GABA and Choline function in brain

    • Abherrent Dopamine and Serotonin function in brain

    • Primarily occurring in peripheral nerves, muscle, veins

    • Potentially positive for neurotoxic substances

    • Potentially chronically impaired ATPase in neurons

    • Increased advanced glycation endproducts

    • Similarities or co-association with Diabetes 2

    • Inhibited mitochondrial metabolism

    • Increased bilirubin

    • Inhibited glycation

    • Folic acid deficiency

    • Methylation deficiency

    • Proliferated Beta Cells, low inteferon-gamma, low white blood cell levels

    • Associated with thyroid deficiency

    • Responds to increased Pregnenolone

    • Reduced endogenous synthesized vitamin D

    • Reduced time spent outdoors

    • Lack of Methylfolate

    • Lack of injectable active B12

    • All cause symptomatic increase with B12 deficiency

    • Demylenation involved

    • All cause similarity to Autism

    • Abherrent copper and biounavailable copper

    • Elevated metals

    • Deficient minerals

    • Abherrent histamine

    • Abherrent ceruloplasm

    • Increased Reverse T3

    • Flattened Diurnal Cortisol Graph
  3. Sam7777

    Sam7777 Senior Member

    [Note what you're seeing here is a mixture of quotes from a peer paper mixed in with my own notes, and I am sorry but since it's so old I can't remember what is what, but its from this paper I read about IBS. IBS is a good example of how this persistent idiopathic pain works, and its something that use to debilitate me.]

    A series of succeeding questions for the informed reader –

    1. Why do some people who have “bad nerves” seem to manifest as epidemiological and neuropsychological case studies as people with both a) initially poorly functioning HPA axis b) genetic susceptibility to disruption in their HPA axis? How much of a part do damaged detoxification organs, electrolyte imbalance caused by malabsorbtion and toxaemia, chronic stress events, and immune related issues such as CFS play a part in precipitating HPA-axis dysfunction? How much of a role does HPA-axis function play in the prognosis of environmental illness? How much of an impact do life experiences and early trauma have in the development of these conditions? Is our food really making us sick or are we so sick and depressed we cannot tolerate a normal diet to begin with? Can meditation, CBT, and EFT attenuate central sensitization and sympathetic dominance? Can controlling the mind prevent the cascade of worsening health conditions in a modern age of toxemia?

    2. What are the underlying pathologies of a poorly functioning endorphin system, neuroendocrine response, HPA axis, hippocampal, hypothalamic, and amygdyla in mediating psychic awareness, learning, and empathy as governed by the mesocortical limbic reward system? What kind of physical brain abnormalities could cause cognitive dysfunction and emotional dysfunction, and would they be the result of a poorly functioning HPA axis or the cause, and would they physically (without psychological affect) attenuate/potentiate environmental diseases? Is it the change in the HPA axis that 'releases' the higher functions and healthier cognitive behavior (meaning we are much more controlled by our environmental stimuli), or is it a peripheral brain action (meaning we have built in pre -determined behavior) that antagonises abnormal stress responses or excessive desensitization to stimuli? How might the HPA axis and CNS be further related? Is their poor inter-hemispheric communication of the brain or excitotoxicity? Immune and rheumatological pathologies that could alter limbic function, musculoskelatal, and neuroendocrine function? How might dysautonomia and evolutionary adaptations to chronic infection be involved in this neuralgia?

    3. What underlying metabolic disorder is present? Its causes? What are the roles of TSH, T3, T4, and ACTH, CRH, AVP, ADR, FH, LSH, IGF-1, HGH, GnRH, Testosterone, Androgen, Pregnenolone, Progesterone in synthesizing or stimulating the release of catecholamine, especially dopamine, adrenaline, dynorphin, enkephalin; the role of immunoglobulin, t-lymphocytes, beta cells, natural killer cells, Th1 and Th2 immune responses, and leukocytes in neurotransmitter synthesis; What is the relation of general metabolism of neurotransmitters and the pathology of defective inhibitory systems in the limbic areas; How might these same neurotransmitters and hormones play a role in causing dysautonomia, neuralgia, and peripheral neurological conditions? Why do adrenergic alpha and beta receptor function play a role as the most critical physiological subject, outside of mitochondrial physiology, when studied in neuropsychological, rheumatological, immunological, and endocrino-metabolic disorders? Does dysfunctional gluconeogenesis, cellular metabolism, and glycolysis involved in metabolic diseases such as obesity, insulin resistance, autoimmunity triggered insulin deficiency, autoimmune triggered adrenal and/or thyroid deficiency, and other autoimmune conditions point to genotoxin, neurotoxin, teratogen, and endocrine disruptor exposure;

    4. Could the kidney, liver, gaul bladder, or pancreas involved along with the lymphatic system be acting sluggishly, resulting in poor detoxification caused by toxic metabolites, malabsorption, stones, acidity, parasites, infection, and sequestered heavy metals? How would this effect cell levels of anti-oxidants, ATP synthesize, mitochondrial function, co-factors and enzymes, Krebs cycle, and cellular metabolism? How might nutrition elucidate an imbalance in aerobic vs. anaerobic metabolism at the cellular level? Could the metabolic acidosis incurred by sluggish detoxification organs and chronic malnutrition negatively affect neurotransmitter metabolism, synaptic meta-plasticity, and energy supply to the brain? Does targeted nutrition and allergy elimination only treat the symptom? What is more important to curing root pathology- targeted anti-pathogenic therapy or diet and immune balancing? Can endocrine disruptors, metals, teratogens, carcinogens, neurotoxins, and genotoxic compounds truly be removed from the body? Could dysautonomia, autoimmunity, chronic infection, pollution exposure, and genetic mutation be combining to create the perfect storm of debilitating conditions?

    But essentially, these conditions are a neuroendocrinological, metabolic(circulatory disease), psychological, and gastrointestinal disorder, possibly mediated by immune responses consisting of chronic infection and autoimmunity, co-morbidly diagnosed with pathological GI tract, displaying IBS like symptoms characterized by central sensitization, inflammatory, and immunological responses BUT perpetuated by neuroendocrine dysfunction. It is also further thought that the CAUSE of the systemic disorders could be a combination of opportunistic infections, xenotoxins and endocrine disruptors, e.g. mercury, pesticides, fertilizers.

    • 1) It starts off as a stress response mediated by the locus ceruleus-norepinephrine and CRH mechanisms of the endocrine system.

    • 2) Next, three steps of inflammatory modes are identifiable:

    • a) Endogenous reactions of the body characterized by central sensitization and hormone, neurotransmitter, and CNS mediated dysfunction. Nociceptive pain is not controlled due to sympathetic dominance.

    • b) Enterochromaffin, immunocytes, cytokine, lymphocyte, and mast cell proliferation occur throughout the submucosa and mucosa, and potentially other organs. This contributes to the above, but is caused by xenotoxics, endocrine disruptors, and allergy causing peptides from food. These do physical and chemical damage to the nerve cells.

    • c) Another gut-brain imbalance, characterized by improper pain mediation and serotonin balance, possibly mediated by raphe nuclei, the paraventricular nucleus of the hypothalamus, suprachiasmatic nucleus, and locus ceruleus, resulting in cholinergic dysfunction of the ascending and descending neuron fibers of the circular muscles of gut.

    • 3) Finally, it is thought that four five modes participate in this GI-neuroendocrinological-metabolic disorder, CRH/CRF+LC-NE & T3/T4 negative cascade/imbalance, Adrenergic dysfunction, Cholinergic dysfunction, Glycolysis disorder, and pineal gland and diurnal rhythm dysfunction.

    How dangerous are these sources of disease?

    How do they interact with the human body in a way which is detrimental to long term health?

    How is the ligation and policy within the current establishment structured to indemnify the pharmaceutical companies, seed companies, fertilizer companies, bio-tech companies, commodity distributors such as Archer Daniel midland/Walmart/Cargill, and centralized meat processing companies such as Tyson/Pilgrim pride?

    What are the epidemiological correlations between autism, diabetes, pulmonary obstruction, arteriosclerosis, heart disease, high blood pressure, high triglycerides, high cholesterol, cancers, chrons disease, inflammatory bowel disease, irritable bowl syndrome, attention deficit disorder, depression, psychosis, pathological behavior, and other chronic diseases- in relation to the current establishment of cooperating industries and their policy decisions and the resulting organizational culture and disease management approach which is created in the medical community because of those policies?

    What type of business deals have been engineered between this spectrum of related industries?

    How do these agreements influence legislation, the broader economy, and patient care?

    Can diabetic damage cause nerve damage to the intestines and result in sugar sensitivity IBS?

    Why are the crashes so closely associated with IBS and electrolyte balancing pituitary hormones, and why does taking jiaogulan and 5-HTP allow a rebounding of electrolyte balancing hormone synthesis (ACTH and ADR), cognitive function, and mood?

    The issue here is, why does your BG drop so often? Is it because glucocorticoids are not being produced, or is it because they are, but the gluconeogenesis process is resistant to the hormone?

    Hormone and Neurotransmitter Sensitivity, Metabolic Efficiency, Mineral Balancing, Toxin Removal, Key Enzyme Function, and Proper Biochemical Life Cycles and Processes;

    Aerobic metabolism and glycolysis, and thus ATP production, are at the heart of a healthy working body. Mineral imbalances, impaired biochemical cycles and processes which misuse critical nutrients, and other exogenous factors that damage mitochondrial integritycontribute to how the body relies on enzyme, neurotransmitter, and hormone function. The body cannot use vitamins and minerals properly, if the inherent metabolic processes are dysfunctional. Much mainstream medical reviews consider copper, manganese, and magnesium, along with b-vitamins, predominantly b6, as essential to the direct metabolism of catacholamines. Furthermore, an interdependence is associated with the metabolism and synthesis of glucocorticoids. If FSH, LH, IGF-1, and HGH are stimulated by the gateway limbic dopamine pathway of the brain, and the HPA axis stimulates release of TSH and ACTH, and consequently dopamine induces low levels of prolactin, than there could result a net physiological increase in hedonic tone.

    Balanced glucocorticoids achieved by balanced diet, treatment, and exercise could balance blood glucose and insulin sensitivity further leading to sustained hedonic tone. The first important bodily process necessary for this relationship, is the proper secretion and sensitivity of peripheral cells to sex hormones LSH, FH, GH, IGF-1, and GnRH. These hormones help create optimal energy and ATP synthesis throughout the body, supporting thyroid, reproduction, and growth. This also pertains to optimal immune function and cancer cell suppression. Secondly, this pathophysiological cycle is associated with feedback mechanisms responsible for increased transcription, translation, and synthesis of catacholamines.

    If desensitization occurs because of high inter-synaptic levels of catacholamines and increased release of catacholamines due to a.) re-uptake inhibitors b.) agonists via competitive transport molecule binding (cocain binding to DAT, etc) c.) lowered receptor-containing neuron density d.) decreased receptor density e.) neuron destruction, than there exists a need to balance and sustain a prolonged metabolic life of these catacholamines with enzyme inhibitors, NDMA antagonists, and CB1, mu opioid, 5HT2A, ALPHAB1 up-regulation and up-regulation of some muscarinic receptors. Down-regulation of kappa delta opioid receptors is also important. Regenerating the catacholamine pathways and balancing the metabolism of the catacholamines is essential to preventing tolerance, ADD, cognitive disorders, depression, and mood and emotion abnormalities- which are associated with IBS attacks, endocrine and CNS mediated cascading degradation of the inflammatory and immunological responses of the body, and ultimately cancer and death.

    Thus, it stands that balancing the levels of stress hormones would play a part in balancing the metabolism and ultimately regeneration of brain pathways of catacholamines. But above all else, brain chemistry cannot be prodded, goaded, and manipulated with psychotropic agents. The entire body's neurological system must be fed at a mitochondrial, metabolic, energetic, biochemical, and nutritional level with the correct substances to repair inefficient neuron cell metabolism, cell nutrient deficiencies, and standing neuron toxicity.

    IBS, GAD, Depression, Fibromyalgia, Addison's Disease, CFS, and other broad spectrum chronic disorders originate from a condition known as Sympathetic Dominance;

    The enteric nervous system (ENS), which is located in submucosa (Meisner plexus) and betweensmooth muscle fibers (Auerbach plexus) regulates the neuromuscular function of gastrointestinal (GI) tract. Sympathetic and parasympathetic autonomic nervous system (SANS and PANS) control the function of ENS, which is related to a variety of mediators and receptors, like serotonin and its receptors [21]. Serotonin is implicated in a variety of reflexes, which regulate the gut motility and secretory efficiency. Overly base or overly acid food can also instigate inflammatory reactions in the jejunum and duodenal because of under-production of HCl and bile. Decreased serotonin transcription and uptake are closely associated with IBS. Hypercortisol secretion, dysfunctional hypothalamic pituitary adrenal axis, as well as Adrenal cortitropic hormone irregularity is seen with IBS. Oddly antispasmodics such as anise and mint curb IBS, opioids such as codeine, kratom, and heroin curb IBS, and SSRI antidepressants curb IBS.Inflammation leading to prostaglandin and vagal nerve stimulation seem to also be at the root of IBS.

    Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. Granted, often the CNS and endocrine system have weakened the patient's body to the extent that CRH agonists are counter productive, therefore it serves better to focus on strengthening the body's ability to handle sustained levels of stress hormones. This approach, is perhaps, medically, the most phenomenally complex task to take on.

    An Introduction to Common Symptoms and General Endocrinology;The anterior pituitary gland is responsible for both thyroid and adrenal cascading function. The anterior pituitary gland releases Thyroid stimulating hormone to stimulate the breakdown of tyrosine into iodinated diphenyls, the raw ingredient for Trioodothyronin (T3) and Thyroxine (T4). T3 also requires monoiodotyrosine and diodotyrosine. T3 is indicated in 5HT synthesis. T4 stimulates the B- adrenergic receptors, and it is also converted to T3 as part of a critical body homeostatic function meant to monitor blood level balance of T3 and T4, via deiodinase. The B-adrenergic receptors induce gluconeogenesis or glycogen breakdown by using glucocorticoids. Glucocorticoids raise blood sugar via the CNS, while insulin lowers BG but reinitiates the cascading ACTH and TSH secretion cycle. T4 and T3 are also responsible for increased thermogenic profile and Na+/K+/ATPase levels and cell turnover associated with increased metabolism. It should be noted that the ACTH, DA, and NA secretion stimulate via CRF the CNS and thalamus to increase glucocorticoid/BG level. T3 may increase serotonin in the brain, particularly in the cerebral cortex, and down-regulate 5HT-2 receptors, based on studies in which T3 reversed learned helplessness in rats and physiological studies of the rat brain.

    Well the anxiety can be from an adrenaline flight/fight from too little cortisol. ie your body panics into a sudden burst of ACTH that produces mega amounts of cortisol along with adrenaline. This is CNS controlled rather than hypothalamus/pituitary loop regulated. Quite a few of us on the group experience this if we don’t dose enough replacement steroid. Yes it seems counter-intuitive! Essentially bob is saying that if you have low cortisol you are more prone to ACTH+CRH induced cortisol “attacks”. This is closely regulated by the CNS, which explains the reason why the symptoms are most closely associated with high levels of adrenaline via caffeine, high release ACTH and NA via panax ginsing, high release of T3 and T4 via L-Tyrosine, and high levels of DA and 5-HT. The endocrine system is mediated by a HPA axis and CNS feedback loop that ultimately produces glucocorticoids.”

    Furthermore, that suggests that if the body is not properly buffered by the “unknown prostaglandin inhibiting effect and cortisol/stress hormone induced panic attack preventing properties” of the fish pills, than IBS attacks, anxiety, tremors, and mood crashes; ergo cortisol crash are much more recurrent. Conversely, but further supporting the idea, the prevention of cortisol with large doses of eulethero and over-consumption of fish pills inhibits the entire ACTH loop that causes the release of catecholamines and the rise of BG. The evidence suggests that if you can prevent a crash but not over inhibit ACTH release, catecholamine and BG levels will be more stable. Beef by producing insulin to lower BG and stimulate ACTH, seems to do this, and somehow produces DA, if BG is not too low initially, it prevents fatigue, and seems to stimulate pituitary hormone responsible for electrolyte imbalances.

    This suggests that if massive increases or sudden crashes in cortisol production occur, the entire HPA axis and CNS will go into a negative feed back loop and deplete the glucose substrate or food source in the body, causing a rapid decline in cortisol and BG. As long as the BG drops occur, glucocorticoids will struggle to keep up, and risk spiking. The spiking does not occur in healthy people, which is why they do not get the symptoms of a spike. The increased attempt to regulate this by releasing NA and cortisol will further deplete BG below baseline and create the crashes associated with Addisonian crises.

    High levels of stress hormones and prolactin seem to come along with the decreasing blood sugar and hormone sensitivity, dopamine uptake and sensitivity decreases, ADD and brain fog increase. Either stupor or mania will come at this point depending on how underutilized the various dopamine/serotonin systems are, how low BG is, and how over or under sensitized the cholinergic system is. Potentially a very overstimulated cholinergic system and low DA with selectively overly stimulated serotonin 5-HT receptors could explain the ADD, paranoia, and intense anxiety.

    Keep in mind that under stimulated aspects of the 5-HT system present the baseline GAD and depression symptoms initially, and often were for many years- cortisol, stress, anxiety, GI tract, OCD, racing thoughts, over excitation oriented. So it is VERY unclear as to whether 5-HT is over or under stimulated, but a severe nuero-chemical imbalance is clear. And that imbalance along with low BG and glucocorticoid spikes create anxiety, brain fog, ADD, IBS, OCD, depression, dehydration, and fatigue.

    Hormone sensitivity seems to decrease strongly during the day, serotonin and blood sugar start to decline after 5 am, creativity, inspiration, drive, affection, and sociability, all wain, the decrease of catecholamine begins. When cortisol crashes, there is no cortisol catabolism to sustain BG.

    On the other hand, controlled mania with the help of rhodiola and caffeine, with high blood sugar, was often perceived well; associated with over-stimulation of receptors leading to exhibited behavior of dopaminergic interest and serotonergic pathos/creativity., but clearly creates problems. There seems to be risk of unwanted symptoms and dependence on healthy glucose metabolism and moderate levels of exercise, which are absent. Imbalance of glucocorticoid dependent catecholamine causes fatigue and is consistently associated withpoor cognition, poor empathy, poor mathematical analysis, terrible memory recall, terrible creativity, and incredibly bad concentration. Because the circadian rhythm is so indicated in the symptomatology of the overall disorder, there is a strong probability that the dorsomedial lateral nuclei of the hypothalamus is signaling release factor hormones at inappropriate times of the day, indicating a broad spectrum homeostatic maladaptive approach by the suprachiasmal nuclei. One hypothesis is that adrenaline deficiencies could be causing the psychological and endocrinological symptoms. These adrenaline deficiencies strongly suggest issues with anaerobic lactate induced myalgic muscle fatigue, commonly associated with CFS, and also general adrenal insufficiency. Side effects of the adrenaline hormone deficiency would result in blood pressure and peripheral circulatory related issues, which would further intensify adenine nucleotide loss and poor ATP synthesis. Because of both sympathetic and parasympathetic autonomic nervous system dysfunction, the paradoxical side effects of various treatments would at least be partly explained. Stimulating treatments leading to fatigue would partly be explained by the extremely poorly understood connection between multi-organ axis and their effects on one another. Thus, between adverse effects on other physiological axis and the metabolic toxins associated with impaired mitochondrial function, both mediated by adrenaline, adrenergic side effects such as axiety and blood pressure fluctuation would be common. Ultimately, most peripheral experienced side effects would fluctuate wildly correspondingly with the level of adrenaline as determined by diurnal rhythm environmental cues. The net effect of adrenaline deficiency and muscle hypoxia and ATP decrease would be decreased glycolytic function. Because of a delayed hypothalamic-pituitary-adrenal diurnal response however, a second hypothesis suggests that melatonin and nocturnal homeostatic triggers form binding reactions which lead to an ultimate inappropriate burst of various hormones during nocturnal hours. These hormones are often not secreted adequately during the day, and therefore have a propensity towards high bursts when finally released. This could explain the phenomena of night owl behavior and insomnia. The underlying patho-etiology behind adrenal fatigue and metabolic disorders seem to commonly contain the never ceasing changes in system-wide receptor sensitivity, transport mechanisms, and imbalances caused by other multi-organ axis. Treatment of symptoms will surely result in failure because of those constant changes, so a better approach would be to manipulate the suprachiasmal nuclei in order to govern the entire body and to also take optimal doses of nutrients required by important systems like the HPA-axis.

    Genetic Influences, Hypothalamus-mediated Metabolic Responses, the Pineal Gland, and, Circadian Rhythm, and Glycolysis;

    Adipocyte Hormone Influence on Insulin Sensitivity, Mitochondrial Oxidative Capacity, and Anti-oxidants; Hormones produced by adipose tissue play a critical role in the regulation of energy intake, energy expenditure, and lipid and carbohydrate metabolism. This review will address the biology, actions, and regulation of three adipocyte hormones—leptin, acylation stimulating protein (ASP), and adiponectin—with an emphasis on the most recent literature. The main biological role of leptin appears to be adaptation to reduced energy availability rather than prevention of obesity. Hence, leptin prevents insulin resistance and reduced energy expenditure. In addition to the well-known consequences of absolute leptin deficiency, subjects with heterozygous leptin gene mutations have low circulating leptin levels and increased body adiposity. Leptin treatment dramatically improves metabolic abnormalities (insulin resistance and hyperlipidemia) in patients with relative leptin deficiency due to lipoatrophy. Leptin production is primarily regulated by insulin-induced changes of adipocyte metabolism. Dietary fat and fructose, which do not increase insulin secretion, lead to reduced leptin production, suggesting a mechanism for high-fat/high-sugar diets to increase energy intake and weight gain. ASP increases the efficiency of triacylglycerol synthesis in adipocytes leading to enhanced postprandial lipid clearance. In mice, ASP deficiency results in reduced body fat, obesity resistance, and improved insulin sensitivity.Adiponectin production is stimulated by thiazolidinedione agonists of peroxisome proliferator-activated receptor-and may contribute to increased insulin sensitivity. Adiponectin and leptin co-treatment normalizes insulin action in lipoatrophic insulin-resistant animals. These effects may be mediated by AMP kinase–induced fat oxidation, leading to reduced intramyocellular and liver triglyceride content. The production of all three hormones is influenced by nutritional status.These hormones, the pathways controlling their production, and their receptors are promising targets for managing obesity, hyperlipidemia, and insulin resistance.Leptin can increase insulin sensitivity, and this action appears to be mediated by direct and indirect (CNS) effects to activate AMP kinase (AMP-K) and increase muscle fatty acid oxidation (FAOx), leading to decreased intramyocellular lipid (IMCL) content. Adiponectin increases insulin sensitivity, decreases hepatic glucose production (HGP), and lowers glucose plasma levels. The insulin-sensitizing effects of adiponectin appear to be mediated by activation of AMP-K, resulting in increased FAOx, and a lowering of hepatic triglyceride and IMCL content. Adiponectin expression and secretion are inhibited by catecholamines, glucocorticoids, TNF-, interleukin-6 (IL-6), increased adipocyte size, and possibly decreased adipocyte insulin sensitivity. FFA, free fatty acid. These relationships indicate that AMP-K and FAOx would directly be stimulated by intense exercise capable of raising AMP-K and metabolizing lipids. It also suggests that prolonged stress responses, through LC-NE and CRH systemic responses, lead to insulin resistance and reduced adiponectin and leptin. Adiponectin seems to take precedence in importance over leptin. Decreased adiponectin and leptin along with increased adipocyte size seem to work with increased ASP to create raised insulin levels. ASP production is stimulated by insulin and by the presence of chylomicrons/VLDL after meals. All the above suggests that hyperinsulinemia, increased hepatic triglyceride and glucose production, and stress creates a negative feedback loop leading to further ASP production, decreased leptin and adiponectin, and insulin resistance. A balancing effect on the metabolism to limit large spikes in blood lipid and glucose levels, which result in insulin spikes and reactive hypoglycemic incidents, is essential.With ATP catabolism, adenosine diphosphate (ADP) levels accumulate, forcing the cell to try to balance ATP/ADP ratios in order to maintain energy stasis. However, these reactions ultimately lead to an increased intracellular concentration of adenosine monophosphate (AMP). In an effort to try to control energy balance, the cell catabolizes AMP, ultimately forming inosine, hypoxanthine, and adenine. These catabolic end products are washed out of the cell, resulting in a net loss of purines and an ultimate reduction in the total pool of adenine nucleotides. Recovery and recycling of these is essential. The availability of 5-phosphoribosyl-l-pyrophosphate (PRPP) is rate limiting in adenine nucleotide de novo synthesis and salvage pathways, which is essential to recovery. PRPP is formed through pyrophosphorylation of ribose-5-phosphate that is, itself, synthesized from glucose via the pentose phosphate pathway (PPP; or hexose monophosphate shunt).The rate-limiting enzymes in the PPP, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, are poorly expressed in muscle cells. As such, in skeletal muscle the PPP is suppressed, limiting ribose availability as a substrate to drive the purine nucleotide pathway and retarding nucleotide synthesis during or following metabolism decrease.Impairment in mitochondrial oxidative phosphorylation and potentially diminished glucose metabolism impact ATP turnover, suggesting that the muscles of fibromyalgia patients are energy starved. Hence, with the cascading loss of ATP and resulting adenine nucleotide catabolism, a lack of regenerative PRPP, the ability to salvage ribose-5-phosphate for pyrophosphorylation to PRPP is decreased. Gluconeogenesis and glycolysis are hence directly tied to the synthesis of glucose-6-phosphate which is needed to produce PRPP in aerobic metabolism. Further, evidence indicates that decreased capillaries within fibromyalgia muscle fibers, which reduce the oxidative capacity, leading to the limited energy turnover, purine pool depletion, and increased pain.

    Free radical proliferation occurs more within mitochondria than any other part of the cell. Furthermore, the brain uses as much as 20% of the body's glucose and ATP supply in, meaning the greatest potential for stress induced cell death occurs within the brain. Some key anti-oxidants are catalase, superoxidase dimutase, and secondary metabolite phytochemicals such as rutin, quercetin, flavanoids, and caratenoids. One of the most powerful natural anti-oxidants in the body is glutathione, but like reduced ATP and adenine nucleotide loss, net loss of overall glutathione free radical neutralization can occur. The key thing to remember is that two enzymes play important roles in these processes: Glutathione peroxidase triggers the reaction of GSH to GSSG, which is when glutathione “takes the hit” to spare the cell from the generated free radicals. Glutathione reductase triggers the conversion of GSSG back to useable GSH. These enzymes come into consideration when looking at how to support the glutathione system nutritionally.

    Circulation-Metabolic NO Mediated Disorders and Relations to HPA Axis and Hypothalamus;There is evidence for a deficit in neuroendocrine regulatory mechanisms, via the vasoregulatory CNS functions, which may limit organ and tissue function directly, or indirectly through decreased blood pressure and impaired tissue level perfusion. This is closely associated with fibromyalgia and chronic fatigue syndrome. Thus, hypothalamic, pineal gland, and pituitary-adrenal dysfunction could be implicated closely with microvascular and metabolic disorder. Obesity causes the Metabolic Syndrome which is driven by microvascular inflammation, endothelial cell dysfunction, oxidative stress, activation of the angiotensin-II (ANG-II), reduced bioavailable nitric oxide (NO) and sympathetic activation. This raises inquiry into whether early obesity is associated with microvascular abnormalities in endothelial nitric oxide (eNO), neuronalNO (nNO) and Angiotensin-II that precede increased central sympathetic outflow, and metabolic syndrome in teenagers and young adults. Further, these precipitous reductions in energy and glucose pointed out above, regarding mitochondria, could effect the brain as they do the skeletal muscles, and such cognitive and affective related symptoms are well known among sufferers.Hypo-thalamic related disorders are known to lead to excess levels of glucocorticoids, loss of hippocampal learning and memory, and deleterious changes in the structure of hippocampal nerve cells and sometimes neuronal death. As is seen in IBS, cascading inflammation of brain cells is also possible via cytokine synthesizing cycles.
    First, neuropeptides must be explained. Neuropeptides often act back on their cells of origin, for example to facilitate the development of patterned electrical activity. They can also act on their neighbors to bind the collective activity of a neural population into a coherent signaling entity. Finally, the coordinated population output can transmit waves of peptide secretion that act as a patterned hormonal analogue signal within the brain. At their distant targets, peptides can re-program neural networks, by effects on gene expression, synaptogenesis, and through functionally rewiring connections by priming activity-dependent release. Thus neuropeptides fit the rapid synchronized action consistent with systemic inflammation such as IBS and brain cell stress. These neuropeptides also signal and influence the cholinergic and adrenergic function of the body leading to microvascular changes capable of antagonizing optimal mitochondrial oxidative phosphorylation, glucose supply, anti-inflammatory effects, immunomodulating effect, and free radical neutralization. Key microvascular mediating hormones are vasopressin and oxytocin. Vasopressin and oxytocin have been linked to human neurological disorders such as social anxiety disorder, depression, schizophrenia and autism spectrum disorder.Precipitous falls in blood pressure are partially countered by vasopressin-induced vasoconstriction. Oxytocin secretion also occurs during inflammation and it is thought to promote insulin and glucagon secretion and thus regulate peripheral metabolism during an infection. Thus, oxytocin, vasopressin, and glucocorticoids act together to repress inflammation during a stress induced state in conjunction with stress induced release of cytokines and prostaglandins which stimulate the locus ceruleus-norepinephrine and CRH mechanisms of the endocrine system.This is more so in line with down regulated responses of the endogenous analgesic endorphin system. Inflammation causes suppression of the hypothalamic pituitary gonadal axis. However, in cases of where there is severe or prolonged chronic inflammation, there may be changes in brain and hormonal function that are deleterious. For example, many chronic inflammatory illnesses appear to be associated with fatigue, depression, sleep disorders and pain that can be attributed, in part, to cytokine- induced changes in glucocorticoid actions within the brain. Important note, chronic low grade inflammation could influence vasopressin and oxytocin.Activated immune cells synthesize pro-inflammatory peptide molecules called cytokines, among which are interleukin (IL)- 1β, IL-6 and tumour necrosis factor α (TNFα); these cytokinesbind to receptors on endothelial and perivascular cells of brain blood vessels and induce synthesis within the brain of a variety of other inflammatory molecules, including prostaglandins and additional cytokines. These substances can directly stimulate the afferent neuron terminals but also can induce the release of algogenic substances (histamine, serotonin (5HT), nerve growth factor (NGF) and prostaglandins).The release of substance P from the neuron terminals induces the production and release of histamine and NGF from mast cells. Glucocorticoids provide an important regulatory role by suppressing the generation of pro-inflammatory cytokines by cells of the immune system.Glucocorticoid release is controlled by the hypothalamic pituitary adrenal (HPA) axis and immune molecules acting at multiple sites throughout this axis. Neurones in the paraventricular nucleus of the hypothalamus that synthesize corticotropin releasing hormone (CRH) are activated initially by prostaglandins and subsequently by circulating cytokines to prolong the HPA response. Additionally, chronic immunological responses to inflammation would result in increased CRH and CRF responses to stimulate the LC-NE and CRH anti-inflammatory stress responses. In a state of reduced hormone function and glucocorticoid receptor resistance the body's ability to reduce inflammation would be impaired, but circulating CRH would be high because of prostaglandin triggers.

    The Duality of the Endocrine System;

    The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The thyroid controls the metabolic rate and the adrenals have to handle the stress of the extra metabolic function.The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.

    Neurology and opioid receptor function in regard to the mid-brain, cerebral cortex and subcortical areas, the spinal cord, and peripheral areas;The nociceptive stimulation originating from peripheral areas throughout the body ultimately travels via C and A delta fibers along the spinal cord to the hypothalamus. The hypothalamus delivers the pain messages to the periaquaductal gray where enkephalin is released into the nucleus magnus raphe, and ultimately the raphe nuclei. The raphe nuclei secrete serotonin, which induces excitation of the inhibitory interneurons of the dorsal horns within the substantia gelatinosa of the spinal cord. Here the neurons will release either dynorphin or enkephalin to intercept nociceptive pain from the primary spinal C and A delta fibers, preventing secondary messaging. The endogenous analgesic opioid neurotransmitters will activate mu opioid receptors that block substance p from being released throughout the body, thus preventing inflammation.

    Genetic Predisposing of IBS;

    Although the family clustering of IBS has been noticed in medical practice for several years, Whorwell et al. [56] found that 33% of patients with IBS reported a family history of IBS compared with only 2% of the control group. Polymorphic allotypes s/s and l/l are associated with hereditary serotonergic dysfunction. Gene polymorphisms involve the serotonergic and adrenergic systems and genes encoding proteins with immunomodulatory and/or neuromodulatory features [62]. One candidate gene is the serotonin transporter gene (SERT). The serotonin transporter protein is responsible for re-uptake of serotonin from the synaptic cleft. Within this gene, there is a 44 bp insertion/deletion of repeat elements in the promoter region. This polymorphism results in a long (l), and a sort (s) allele. The s/s allotypes are associated with diarrhea-predominant IBS, while the l/l allotypes are associated with constipation-predominant IBS. The s allele is associated with lower transcriptional efficiency and therefore lower serotonin transporter expression, and decreased cellular uptake of serotonin. Therefore, it is possible to have post-injury overly-reactive immunological and inflammatory responses mediated along the ENS due to post-recovery increased immunocytes level (which receive over-stimulation of 5HT3 and 5HT4 receptors), while simultaneously having poor serotonin re-uptake within the cerebral cortex and limbic system; translating to IBS attacks and clinical depression reoccurring cyclically. Most traditional chemical dependency treatment programs are not holistic, and make no attempts to tailor therapy based on individual differences in adrenal function, thyroid function, hormone imbalances, tissue levels of heavy metals like mercury, or genetic polymorphisms affecting the dopaminergic system. All of these influence addiction behavior, and must be considered carefully. People addicted to drugs typically carry at least one of the following risk alleles: DRD2=A1; SLC6A3 (DAT) =10R; DRD4=3R or 7R; 5HTTlRP = L or LA; MAO= 3R; and COMT=G.

    Etiologic Factors of IBS

    The etiology of IBS is most likely multifactorial. Several environmental factors, psychosocial stressors, gut flora alterations contribute to the pathophysiology of IBS, along with abnormal gastrointestinal motility and secretion and altered visceral perception. On the other hand, for the integration of visceral reflexes, the afferent stimuli throughout the hypothalamus stimulate efferent neural fibers which through PNS stimulate or inhibit the contraction of smooth muscle fibers and the secretion of enterocytes in the gastrointestinal tract modifying the gut motility and secretion. The parasympathetic autonomic nervous system is relaying nociceptive pain caused by the inflammation induced release of chemical mediators to the thalamus and than back again to neural fibers in the enteric lining, which results in the IBS attack.

    Failure of intestinal clearance may come as a result of impaired intestinal persistalsis, in case of myopathic, neuropathic, autoimmune, infectious, metabolic, endocrine or neoplastic diseases. PI IBS has been reported after Campylobacter, Salmonella and Shigella infections [50]. Those patients, who later on develop IBS, show increased numbers of enterochromaffin (EC) cells and lymphocyte cell counts at 3 months compared to those who do not develop IBS. Recent studies suggest an increase in peripheral blood mononuclear cell cytokine production in unselected patients, an abnormality that may be ameliorated by probiotic treatment. Preexisting damage can lead to over expressed immunological responses. It seems that older subjects have fewer immunocytes in their rectal mucosa and may be less reactive to infection. Depression and the presence of adverse life events double the relative risk of persistent symptoms [51]. Immune responses and perceived pain over stimulate mucosa neurons.

    Lactose intolerance, as well as intolerance to sorbitol or fructose, has been implicated in IBS. It is likely that the specific enzyme deficiency is not the cause of IBS, but that the hypersensitive guts of patients with IBS show exaggerated responses to the gaseous and fluid distention caused by incomplete absorption of carbohydrate.

    Visceral sensitivity at the level of enteric mucosa and submucosa;

    A four step process ensues; inflammation and afferent terminal neuron stimulation, efferent neural fibers and chemical mediator release, PANS to thalamus, neuron stimulation and distention plus cramping. The presence of an injury in enteric mucosa leads to the release of chemical mediators like K+, ATP and bradykinin but also inflammatory mediators like prostaglandin E2 (PGE2) [6]. These substances can directly stimulate the afferent neuron terminals but also can induce the release of algogenic substances (histamine, serotonin (5HT), nerve growth factor (NGF) and prostaglandins).The release of substance P from the neuron terminals induces the production and release of histamine and NGF from mast cells. Recent data attribute the enhancement of neural sensitivity for algogenic stimuli to increased expression of sodium channels on primary afferent endings. Recent studies on pseudoaffective (cardiovascular) reflex responses to gut distension have suggested an action through a 5HT3 receptor subtype coupled to a sodium channel present on primary afferent endings. At the level of mucosa and submucosa, a variety of mediators like adenosine, tachykinin, calcitonin generelated peptide (CGRP) and neurokinins participate in a cascade of events. Mast cells and small nerve fibers are proliferated in regeneration after bacteriologic, physical, or environmentally induced damage. Both BK and 5HT3 subtype receptor antagonists attenuate symptoms of an IBS attack.

    Visceral sensitivity at the level of spinal cord;

    Synaptic transmission between afferent neurons and dorsal horn neurons must be increased, so they release neurotransmitters through a process called central sensitization. While omega 3 acid can act as an antagonist of the PGE2 receptors, and BK and 5HT3 receptors can have antagonists administered, this focuses on direct afferent neuron stimulatory release. These blockades do not focus on mast cell release of histamine and NGF mediated by SP receptor stimulation. Recent studies support the idea that NMDA receptors are implicated both at the level of spinal cord and peripherally- related to the sensitization of primary afferents. SP receptors lead to phosphorlaytion of NMDA receptors and ultimately to increased electronegative voltage, thus reversing the effects of antagonists such as magnesium. Thus, since SP receptor stimulation releases NGF and histamine, while simultaneously up-regulating NMDA receptors and increasing neurotransmitter release, it is closely associated with the central sensitization which triggers the PANS and thalamus. Interestingly, peripherally released CGRP may modify sensory inputs, causing changes in blood flow, smooth muscle contractions, immune reaction and mast cell degranulation, but causes hyperalgesia when released from central endings of primary afferents. The intravenous administration of the CGRP1 antagonist (h)-CGRP-(8-37) suppresses the abdominal cramps caused by intraperitoneal administration of acetic acid in awake rats [14].

    Furthermore, dopaminergic system kappa-opioid receptors are indicated. It seems also that κ agonists may act peripherally to prevent visceral pain and are more active in inflammatory conditions. It must be quoted that opioid receptors have been identified on both smooth muscle fibers and primary afferents localized in the gut [15]. Lastly, somatostatin and its receptors (SST1 and SST2) have also been identified on spinal cord and are probably related to the regulation of visceral pain, like GABAA and a2 adrenergic receptors.

    Visceral sensitivity at the level of cerebral cortex and subcortical areas & Abnormal Gut Motility and Secretory Disorders;

    It is believed that serotoninergic pathways, inhibit neural impulses at the level of dorsal horn neurons. This would inhibit the afferent neuron synaptic transmission to the dorsal horn neurons via GABA, conversely to the acetylcholine stimulation of the NDMA receptors which create central sensitization. It seems also that the interactions between serotoninergic pathways and limbic system are very important for the sensation of visceral pain. Evidence clearly suggests disruption in the serotonergic pathways could create pain induced psychological problems, and that psychological problems could create visceral pain. Within the submucosa lies the interconnection of cholinergic afferent neurons. Ascending interneurons activate excitatory motor neurons by releasing substance P and acetylcholine (Ach) onto myocytes resulting in circular muscle contraction. Descending cholinergic neurons stimulate inhibitory motor neurons releasing nitric oxide (NO), vasoactive intestinal peptide (VIP) and adenosine triphosphate (ATP) leading to circular muscle relaxation. Other studies evaluated the role of 5HT receptors in the peristaltic reflex and demonstrated the intricate involvement of CGRP. Environmental stress factors stimulate cortitropic release factor hormone which in turn stimulates histamine release from mast cells, leading to efferent neuron terminal stimulation, hypothalamus stimulation, and thus act along with CRF to create IBS attacks. The regulation of intestinal secretions is comparable to the regulation of gut motility, and directly stimulates 5HT4 peripherally and indirectly stimulates 5HT3 throughout the ENS, PANS, CNS, and SNS.

    Autonomic Nervous System Dysfunction;

    IBS is associated with dysfunction of the ANS, but predominately characterized by increased function in SANS and decreased function in PANS. IBS is fundamentally a immunological and inflammatory reaction within the submucosa and mucosa, mediated by the ENS, PANS, CNS, and SANS, but is a de facto neurological disorder. It is believed that vagal dysfunction is associated with constipation as a predominant symptom whereas adrenergic sympathetic dysfunction is associated with diarrhea as a predominant symptom [35]. Other studies reported that IBS diarrhea-predominant patients were shown to have cortisol hyper-responsiveness unlike that of constipation-predominant IBS patients and controls [36]. Furthermore, large differences in male and female responses to administered pharmacological agents are documented, with high sympathovagal balance in males.
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  4. Martial

    Martial Senior Member

    Ventura, CA
    for someone who feels off their a game in terms of memory, thought process, critical thinking, and analysis, you are pretty fricken sharp.
    xrayspex, helen1 and sillysocks84 like this.

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