Zoology

One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and Thelper 2 (Th2) activity. The Th1/Th2 hypothesis arose from 1986 research suggesting mouse T-helper cells expressed differing cytokine patterns. This hypothesis was adapted to human immunity, with Th1-and Th2-helper cells directing different immune response pathways. Th1 cells drive the type-1 pathway ("cellular immunity") to fight viruses and other intracellular pathogens, eliminate cancerous cells, and stimulate delayed-type hypersensitivity (DTH) skin reactions. Th2 cells drive the type-2 pathway ("humoral immunity") and up-regulate antibody production to fight extracellular organisms; type 2 dominance is credited with tolerance of xenografts and of the fetus during pregnancy. Overactivation of either pattern can cause disease, and either pathway can down-regulate the other. But the hypothesis has major inconsistencies; human cytokine activities rarely fall into exclusive pro-

The sarcoplasmic reticulum (SR) of the remarkably fast remoter muscle of lobster second antenna was investigated with regard to ultrastructure, calcium uptake and protein composition. The SR of this unique muscle dominates the volume of the cell. We were able to preserve the configuration of the SR in its native state simply by processing the muscle for electron microscopy at 0-4"C. For the first time the SR is seen as large (0.1 pm diam.) tubules that crowd the space between myofibrils. Previous observations of this organelle have been reported that showed a rather unsatisfying discontinuous vesicular configuration of the SR. This report indicates that these structures were fixation artifacts. The uptake of calcium measured in a microsomal subfraction in the presence of ATP and oxalate does not differ significantly from similar experiments with vertebrate SR. However, gel electrophoresis of lobster SR demonstrates a single intrinsic Ca-ATPase protein of 100,000 mol. wt. with neither of the typical lower molecular weight proteins found in vertebrate SR.

Autism and allied autistic spectrum disorders (ASD) present myriad behavioral, clinical, and biochemical abnormalities. Parental participation, advanced testing protocols, and eclectic treatment strategies have driven progress toward cure. Behavioral modification and structured education are beneficial but insufficient. Dietary restrictions, including removal of milk and other casein dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food coloring are beneficial and prerequisite to benefit from other interventions. Individualized IgG or IgE testing can identify other troublesome foods but not non-immune mediated food sensitivities. Gastrointestinal improvement rests on controlling Candida and other parasites, and using probiotic bacteria and nutrients to correct dysbiosis and decrease gut permeability. Detoxification of mercury and other heavy metals by DMSA/ DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl repletion and other liver p450 support. Many nutrient supplements are beneficial and well tolerated, including dimethylglycine (DMG) and a combination of pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod liver oil; and digestive enzymes, all offer benefit. Secretin, a triggering factor for digestion, is presently under investigation. Immune therapies (pentoxifyllin, intravenous immunoglobulin, transfer factor, and colostrum) benefit selected cases. Long-chain omega-3 fatty acids offer great promise. Current pharmaceuticals fail to benefit the primary symptoms and can have marked adverse effects. Individualized, in-depth clinical and laboratory assessments and integrative parent-physician-scientist cooperation are the keys to successful ASD management. (Altern Med Rev 2002;7(6):472-499)

Autism, archetype of the autistic spectrum disorders (ASD), is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. Its prevalence has surged in recent years. Advanced functional brain imaging has confirmed pervasive neurologic involvement. Parent involvement in autism management has accelerated understanding and treatment. Often accompanied by epilepsy, cognitive deficits, or other neurologic impairment, autism manifests in the first three years of life and persists into adulthood. Its etiopathology is poorly defined but likely multifactorial with heritability playing a major role. Prenatal toxic exposures (teratogens) are consistent with autism spectrum symptomatology. Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor. Autistic children frequently have abnormalities of sulfoxidation and sulfation that compromise liver detoxification, which may contribute to the high body burden of xenobiotics frequently found. Frequent copper-zinc imbalance implies metallothionein impairment that could compound the negative impact of sulfur metabolism impairments on detoxification and on intestinal lining integrity. Intestinal hyperpermeability manifests in autistic children as dysbiosis, food intolerances, and exorphin (opioid) intoxication, most frequently from casein and gluten. Immune system abnormalities encompass derangement of antibody production, skewing of T cell subsets, aberrant cytokine profiles, and other impairments consistent with chronic inflammation and autoimmunity. Coagulation abnormalities have been reported. Part 2 of this review will attempt to consolidate progress in integrative management of autism, aimed at improving independence and lifespan for people with the disorder. (Altern Med Rev 2002;7(4):292-316)

Atherosclerosis begins at the fragile blood vessel endothelia, which may be the Achilles' Heel of the circulation. The endothelia are thin cell sheets vulnerable to injury, yet from their cell membranes come fatty acid metabolites (prostanoids, other eicosanoids) that coordinate vessel wall homeostasis and help protect against athero-sclerosis.

Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefit-to-risk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through double-blind trials for improving memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. PS has an excellent benefit-to-risk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middle-aged and elderly, but with a slightly less favorable benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascular-based cognitive dysfunction. Two meta-analyses of GbE demonstrate the best preparations offer limited benefits for vas-cular insufficiencies and even more limited benefits for Alzheimer's, while " commodity " GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is an Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and memory-strengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function , perhaps eventually in conjunction with the judicious application of growth factors. (Altern Med Rev 1999;4(3):144-161)

This review is dedicated to my grandfather Richard Kidd. The first words I remember from him were " Prevention better than cure. " I can think of no other maxim more applicable to the maintenance of cardiovascular health. Abstract Coronary artery disease (CAD) is still the main cause of premature death in the industrialized world. The revascularization modalities, bypass surgery and angioplasty, when successful provide restored blood flow to the myocardium. Bypass remains the most proven means for managing more severe cases of CAD, namely triple vessel disease with or without complications, while angioplasty works best for cases of single or double vessel disease with minimal complications. Both types of intervention partially relieve angina as they clear arterial blockage. Both save lives to an extent greater than medication alone. However, both are limited to being palliative since they fail to treat the underlying atherosclerotic occlusive process. EDTA chelation therapy appears to achieve revitalization of the myocardium, and is a viable alternative or adjunct to revascularization. Fish oils are now proven to help revitalize vessel wall endothelia and to partially reverse atherosclerotic damage. Being safe and having proven benefits, chelation therapy and fish oils can be integrated together with nutrients, lifestyle-dietary revision, exercise, and medications as necessary, into a cardiovascular revitalization strategy. Cardiovascular revitalization would be highly cost-effective and procedurally compatible with the revascularization modalities, while extending beyond revascularization to halt atherosclerotic progression, restore cardiac functionality, extend survival, and improve quality of life. (Alt Med Rev 1997;3(1):4-17)

The tripeptide thiol glutathione (GSH) has facile electron-donating capacity, linked to its sulfhydryl (—SH) group. Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes; it provides protection also for the mitochondria against endogenous oxygen radicals. Its high electron-donating capacity combined with its high intracellular concentration endows GSH with great reducing power, which is used to regulate a complex thiol-exchange system (—SH —S-S—). This functions at all levels of cell activity, from the relatively simple (circulating cysteine/— SH thiols, ascorbate, other small molecules) to the most complex (cellular —SH proteins). Glutathione is homeostatically controlled, both inside the cell and outside. Enzyme systems synthesize it, utilize it, and regenerate it as per the gamma-glutamyl cycle. Glutathione is most concentrated in the liver (10 mM), where the " P450 Phase II " enzymes require it to convert fat-soluble substances into water-soluble GSH conjugates, in order to facilitate their excretion. While providing GSH for their specific needs, the liver parenchymal cells export GSH to the outside, where it serves as systemic source of —SH/reducing power. GSH depletion leads to cell death, and has been documented in many degenerative conditions. Mitochondrial GSH depletion may be the ultimate factor determining vulnerability to oxidant attack. Oral ascorbate helps conserve GSH; cysteine is not a safe oral supplement, and of all the oral GSH precursors probably the least flawed and most cost-effective is NAC (N-acetylcysteine). (Alt Med Rev 1997; 2(3):155-176) Glutathione (γ-glutamylcysteinylglycine, GSH) is a sulfhydryl (—SH) antioxidant, an-titoxin, and enzyme cofactor. Glutathione is ubiquitous in animals, plants, and microorganisms, and being water soluble is found mainly in the cell cytosol and other aqueous phases of the living system. 1-4 Glutathione often attains millimolar levels inside cells, which makes it one of the most highly concentrated intracellular antioxidants. Glutathione exists in two forms (Fig. 1): The antioxidant " reduced glutathione " tripep-tide is conventionally called glutathione and abbreviated GSH; the oxidized form is a sulfur-sulfur linked compound, known as glutathione disulfide or GSSG. The GSSG/GSH ratio may be a sensitive indicator of oxidative stress.

Certain of the water-soluble flavonoid molecules can be converted into lipid-compatible molecular complexes, aptly called phytosomes. Phytosomes are better able to transition from a hydrophilic environment into the lipid-friendly environment of the outer cell membrane, and from there into the cell, finally reaching the blood. The fruit of the milk thistle plant (Silybum marianum, Family Asteraceae) contains flavonoids that are proven liver protectants. The standardized extract known as silymarin contains three flavonoids of the flavonol subclass. Silybin predominates, followed by silydianin and silychristin. Although silybin is the most potent of the flavonoids in milk thistle, similar to other flavonoids it is not well-absorbed. Silybin-phosphatidylcholine complexed as a phytosome provides significant liver protection and enhanced bioavailability over conventional silymarin. (Altern Med Rev 2005;10(3):193-203)

Your old friend calls and gives you real news: she has cancer. Her low tone of voice doesn't hide her desperation. The cancer is spreading fast. The HMO doctors did one round of chemotherapy—it didn't stop the cancer and she had a lot of trouble with it. Now they won't do any more. You're in the " alternative healthcare " field. What can you do to help her? The first thing I advised my friend was that she would need a very good integrative medicine practitioner, one with experience in treating cancer patients beyond the simplistic " slash and burn " of chemo-and radiation therapy. She agreed. But it was also obvious that my friend needed new tools for fighting her cancer, and fast. Good cancer fighting doctors are few and far between, so we had to be prepared to help them to help her. I dove into my boxes and boxes of files on cancer and anticancer treatments. I called up PhD colleagues who were experts on cancer (one never called me back). I called up the best integrative medical practitioners, and a pharmacist colleague who sells to them firsthand. With chemotherapy already having run its course, I had to look for ways to help my friend mobilize her own, built-in immune capacities to successfully fight this fast-spreading cancer. Her immune system would have to move from defensive mode into offensive mode, go after the cancer cells and kill them. For this she needed the best immunoceuticals I could find. In a recent issue of this magazine (July-August) I introduced nutraceuticals, nutritional substances potent enough to treat disease. Nutraceuticals can be just as effective as pharmaceuticals, and sometimes more effective. Nutraceuticals are always better tolerated than pharmaceuticals and have far fewer adverse side effects. I have introduced the term " immunoceutical " to best characterize nutraceuticals able to potentiate the immune system. I had to assess for my friend the virtues of the better anticancer immunoceuticals. I realized two limitations on this project: (a) there is no lack of promotional literature on therapies for cancer, and (b) among the touted cancer therapies there are many pretenders and few real players. Many remedies are touted against cancer yet few have had sufficient clinical assessment. Most of the nutritional preparations being promoted against cancer do not have one good double-blind trial behind them. A few have indeed been subjected to one or more double-blind clinical trials, and these are the ones I suggested my friend try first. But first, some background. The immune system is the body's major defense against any and all agents that threaten its survival. The healthy immune system is a highly integrated network of single cells, cells grouped within tissues, and whole organs, working together in tight coordination. Acting as sentries for the system are the macrophages, single cells which are distributed throughout the tissues. The macrophages are trained to detect mutated or otherwise-abnormal body cells as they pop up on the radar, then to immediately alert the other immune system warrior cells to go on the attack against these cells and eliminate them. The immune system if damaged, weak, or misdirected is likely to be poorly self-regulating and hampered in its efforts to eliminate cancer foci, whereas if potentiated by immunoceuticals it could attack more aggressively and buy time for the body to further mobilize against the cancer. By potentiating the immune system, that is, raising its functioning to a higher level, immunoceuticals can help the body mobilize a lifesaving response against cancer. The driving force of immunoceuticals is helping the body's immune system to help itself; what the Chinese traditional healers called Fu-Zheng Therapy. The best immunoceuticals help the immune system to attack cancers, as well as to rebuild and re-mobilize following chemotherapy or radiation therapy, interventions which are immuno-toxic and damage immunity. Foremost among the proven immunoceuticals are the mushroom glucans. Mushrooms have been used as medicinal foods for literally thousands of years, especially in Japan and China, and for three decades the beta-glucan substances from mushrooms have been under serious clinical investigation as anticancer immunopotentiators. Already in Japan various mushroom glucan preparations are officially approved for use against cancers. One of them (PSK) commands more than one-quarter of all the spending on anticancer drugs, even though it is not a drug but a natural constituent of an edible mushroom (Coriolus versicolor, or turkey tail).

Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor – PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide) – have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens. (Altern Med Rev 2000;5(1):4-27)

The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are orthomolecular, conditionally essential nutrients that enhance quality of life and lower the risk of premature death. They function exclusively via cell membranes, in which they are anchored by phospholipid molecules. DHA is proven essential to pre-and postnatal brain development, whereas EPA seems more influential on behavior and mood. Both DHA and EPA generate neuroprotective metabolites. In double-blind, randomized, controlled trials, DHA and EPA combinations have been shown to benefit attention deficit/hyperactivity disorder (AD/HD), autism, dyspraxia, dyslexia, and aggression. For the affective disorders, meta-analyses confirm benefits in major depressive disorder (MDD) and bipolar disorder, with promising results in schizophrenia and initial benefit for borderline personality disorder. Accelerated cognitive decline and mild cognitive impairment (MCI) correlate with lowered tissue levels of DHA/EPA, and supplementation has improved cognitive function. Huntington disease has responded to EPA. Omega-3 phospholipid supplements that combine DHA/EPA and phospholipids into the same molecule have shown marked promise in early clinical trials. Phosphatidylserine with DHA/ EPA attached (Omega-3 PS) has been shown to alleviate AD/ HD symptoms. Krill omega-3 phospholipids, containing mostly phosphatidylcholine (PC) with DHA/EPA attached, markedly outperformed conventional fish oil DHA/EPA triglycerides in double-blind trials for premenstrual syndrome/dysmenorrhea and for normalizing blood lipid profiles. Krill omega-3 phospholipids demonstrated anti-inflammatory activity, lowering C-reactive protein (CRP) levels in a double-blind trial. Utilizing DHA and EPA together with phospholipids and membrane antioxidants to achieve a " triple cell membrane synergy " may further diversify their currently wide range of clinical applications. (Altern Med Rev 2007;12(3):207-227)

Parkinson's disease (PD) is the most common disease of motor system degeneration and, after Alzheimer's disease, the second most common neurodegenerative disease. 1 Parkinson's disease takes a heavy toll in mental anguish, lost productivity, and health care expenditures. PD prominently features dopamine transmitter insufficiency, and current management is almost exclusively reliant on dopamine replacement drugs. But, while these drugs are initially effective in most patients, they do not slow the underlying degeneration in the area of the brain most affected, the substantia nigra (SN). Their effectiveness declines over time and their adverse effects become increasingly more troublesome. Broader options for long-term management are urgently needed.