Additive aluminum as a cause of induced immunoexcitoxicity resulting in neurodevelopmental and neurodegenerative disorders: A biochemical, pathophysiological, and pharmacological analysis.

Much has been learned about the neurotoxicity of aluminum over the past several decades in terms of its ability to disrupt cellular function, result in slow accumulation, and the difficulty of its removal from cells. Newer evidence suggests a central pathophysiological mechanism may be responsible for much of the toxicity of aluminum and aluminofluoride compounds on the brain and spinal cord. This mechanism involves activation of the brain's innate immune system, primarily the microglia, astrocytes, and macrophages, with a release of neurotoxic concentrations of excitotoxins and proinflammatory cytokines, chemokines, and immune mediators. Many studies suggest that excitotoxicity plays a significant role in the neurotoxic action of several metals, including aluminum. Recently, researchers have found that while most of the chronic pathology involved in the observed neurodegenerative effects of these metals are secondary to prolonged inflammation, it is the enhancement of excitotoxicity by the immune mediators that are responsible for most of the metal's toxicity. This enhancement occurs through a crosstalk between cytokines and glutamate-related mechanisms. The author coined the name immunoexcitotoxicity to describe this process. This paper reviews the evidence linking immunoexcitotoxicity to aluminum's neurotoxic effects and that a slow accumulation of aluminum may be the cause of neurodevelopmental defects as well as neurodegeneration in the adult.

The biochemical basis of neurodegenerative disease: The role of immunoexcitoxicity and ways to possibly attenuate it.

There is growing evidence that inflammation secondary to immune activation is intimately connected to excitotoxicity. We now know that most peripheral tissues contain fully operational glutamate receptors. While most of the available research deals with excitotoxicity in central nervous system (CNS) tissues, this is no longer true. Even plant has been found to contain glutamate receptors. Most of the immune cells, including mask cells, contain glutamate receptors. The receptors are altered by inflammation, both chemokine and cytokines. A host of new diseases have been found that are caused by immunity to certain glutamate receptors, as we see with Rasmussen's encephalitis. In this paper, I try to explain this connection and possible ways to reduce or even stop the reaction.

Postconcussion syndrome: a review of pathophysiology and potential nonpharmacological approaches to treatment.

The incidence of all-cause concussions in the United States is estimated to range from 1.6 to 3.8 million annually, with the reported number of sport- or recreation-related concussions increasing dramatically, especially in youth sports.(1,2) Additionally, the use of roadside bombs in Iraq and Afghanistan has propelled the incidence of concussion and other traumatic brain injuries to the highest levels ever encountered by the US military. As a result, there has also been a marked increase in postconcussion syndrome (PCS) and the associated cognitive, emotional, and memory disabilities associated with the condition. Unfortunately, however, there have been no significant advancements in the understanding or treatment of PCS for decades. The current management of PCS mainly consists of rest, reduction of sensory inputs, and treating symptoms as needed. Recently, researchers investigating the underlying mechanisms of PCS have proposed that activation of the immune inflammatory response may be an underlying pathophysiology that occurs in those who experience prolonged symptoms after a concussion. This article reviews the literature and summarizes the immune inflammatory response known as immunoexcitotoxicity. This article also discusses the use of nonpharmacological agents for the management of PCS that directly address this underlying mechanism.

Covid-19 pandemic: What is the truth?

The ongoing "pandemic" involving the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2) has several characteristics that make it unique in the history of pandemics. This entails not only the draconian measures that some countries and individual states within the United States and initiated and made policy, most of which are without precedent or scientific support, but also the completely unscientific way the infection has been handled. For the 1st time in medical history, major experts in virology, epidemiology, infectious diseases, and vaccinology have not only been ignored, but are also demonized, marginalized and in some instances, become the victim of legal measures that can only be characterized as totalitarian. Discussions involving various scientific opinions have been eliminated, top scientists have been frightened into silence by threats to their careers, physicians have lost their licenses, and the concept of early treatment has been virtually eliminated. Hundreds of thousands of people have died needlessly as a result of, in my opinion and the opinion of others, poorly designed treatment protocols, mostly stemming from the Center for Disease Control and Prevention, which have been rigidly enforced among all hospitals. The economic, psychological, and institutional damage caused by these unscientific policies is virtually unmeasurable. Whole generations of young people will suffer irreparable damage, both physical and psychological, possibly forever. The truth must be told.

New concepts in the development of schizophrenia, autism spectrum disorders, and degenerative brain diseases based on chronic inflammation: A working hypothesis from continued advances in neuroscience research.

This paper was written prompted by a poignant film about adolescent girl with schizophrenia who babysits for a younger girl in an isolated cabin. Schizophrenia is an illness that both authors are fascinated with and that they continue to study and investigate. There is now compelling evidence that schizophrenia is a very complex syndrome that involves numerous neural pathways in the brain, far more than just dopaminergic and serotonergic systems. One of the more popular theories in recent literature is that it represents a hypo glutaminergic deficiency of certain pathways, including thalamic ones. After much review of research and study in this area, we have concluded that most such theories contain a number of shortcomings. Most are based on clinical responses to certain drugs, particularly antipsychotic drugs affecting the dopaminergic neurotransmitters; thus, assuming dopamine release was the central cause of the psychotic symptoms of schizophrenia. The theory was limited in that dopamine excess could only explain the positive symptoms of the disorder. Antipsychotic medications have minimal effectiveness for the negative and cognitive symptoms associated with schizophrenia. It has been estimated that 20-30% of patients show either a partial or no response to antipsychotic medications. In addition, the dopamine hypothesis does not explain the neuroanatomic findings in schizophrenia.

A possible central mechanism in autism spectrum disorders, part 3: the role of excitotoxin food additives and the synergistic effects of other environmental toxins.

There is compelling evidence from a multitude of studies of various design indicating that foodborne excitotoxin additives can elevate blood and brain glutamate to levels known to cause neurodegeneration and in the developing brain, abnormal connectivity. Excitotoxins are also secreted by microglial activation when they are in an activated state. Recent studies, discussed in part 1 of this article, indicate that chronic microglial activation is common in the autistic brain. The interaction between excitotoxins, free radicals, lipid peroxidation products, inflammatory cytokines, and disruption of neuronal calcium homeostasis can result in brain changes suggestive of the pathological findings in cases of autism spectrum disorders. In addition, a number of environmental neurotoxins, such as fluoride, lead, cadmium, and aluminum, can result in these pathological and biochemical changes.

A possible central mechanism in autism spectrum disorders, part 2: immunoexcitotoxicity.

In this section, I explore the effects of mercury and inflammation on transsulfuration reactions, which can lead to elevations in androgens, and how this might relate to the male preponderance of autism spectrum disorders (ASD). It is known that mercury interferes with these biochemical reactions and that chronically elevated androgen levels also enhance the neurodevelopmental effects of excitotoxins. Both androgens and glutamate alter neuronal and glial calcium oscillations, which are known to regulate cell migration, maturation, and final brain cytoarchitectural structure. Studies have also shown high levels of DHEA and low levels of DHEA-S in ASD, which can result from both mercury toxicity and chronic inflammation. Chronic microglial activation appears to be a hallmark of ASD. Peripheral immune stimulation, mercury, and elevated levels of androgens can all stimulate microglial activation. Linked to both transsulfuration problems and chronic mercury toxicity are elevations in homocysteine levels in ASD patients. Homocysteine and especially its metabolic products are powerful excitotoxins. Intimately linked to elevations in DHEA, excitotoxicity and mercury toxicity are abnormalities in mitochondrial function. A number of studies have shown that reduced energy production by mitochondria greatly enhances excitotoxicity. Finally, I discuss the effects of chronic inflammation and elevated mercury levels on glutathione and metallothionein.

Accelerated cancer aggressiveness by viral oncomodulation: New targets and newer natural treatments for cancer control and treatment.

An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world's populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses has been used to describe this phenomenon. A number of recent studies have shown a growing number of ways these oncomodulatory viruses can alter the pathology of these tumors by affecting cell-signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegalovirus. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.

Viruses and tumor cell microenvironment: A brief summary.

An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world's populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses have been used to describe this phenomenon. A number of recent studies have shown a growing number of ways; these oncomodulatory viruses can alter the pathology of these tumors by affecting cell signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegaloviruses. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into the cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.

A possible central mechanism in autism spectrum disorders, part 1.

The autism spectrum disorders (ASD) are a group of related neurodevelopmental disorders that have been increasing in incidence since the 1980s. Despite a considerable amount of data being collected from cases, a central mechanism has not been offered. A careful review of ASD cases discloses a number of events that adhere to an immunoexcitotoxic mechanism. This mechanism explains the link between excessive vaccination, use of aluminum and ethylmercury as vaccine adjuvants, food allergies, gut dysbiosis, and abnormal formation of the developing brain. It has now been shown that chronic microglial activation is present in autistic brains from age 5 years to age 44 years. A considerable amount of evidence, both experimental and clinical, indicates that repeated microglial activation can initiate priming of the microglia and that subsequent stimulation can produce an exaggerated microglial response that can be prolonged. It is also known that one phenotypic form of microglia activation can result in an outpouring of neurotoxic levels of the excitotoxins, glutamate and quinolinic acid. Studies have shown that careful control of brain glutamate levels is essential to brain pathway development and that excesses can result in arrest of neural migration, as well as dendritic and synaptic loss. It has also been shown that certain cytokines, such as TNF-alpha, can, via its receptor, interact with glutamate receptors to enhance the neurotoxic reaction. To describe this interaction I have coined the term immunoexcitotoxicity, which is described in this article.

Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum.

Our review suggests that most autism spectrum disorder (ASD) risk factors are connected, either directly or indirectly, to immunoexcitotoxicity. Chronic brain inflammation is known to enhance the sensitivity of glutamate receptors and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity over a prolonged period. Neuroscience studies have clearly shown that sequential systemic immune stimulation can activate the brain's immune system, microglia, and astrocytes, and that with initial immune stimulation, there occurs CNS microglial priming. Children are exposed to such sequential immune stimulation via a growing number of environmental excitotoxins, vaccines, and persistent viral infections. We demonstrate that fluoride and aluminum (Al3+) can exacerbate the pathological problems by worsening excitotoxicity and inflammation. While Al3+ appears among the key suspicious factors of ASD, fluoride is rarely recognized as a causative culprit. A long-term burden of these ubiquitous toxins has several health effects with a striking resemblance to the symptoms of ASD. In addition, their synergistic action in molecules of aluminofluoride complexes can affect cell signaling, neurodevelopment, and CNS functions at several times lower concentrations than either Al3+ or fluoride acting alone. Our review opens the door to a number of new treatment modes that naturally reduce excitotoxicity and microglial priming.

Parkinson's disease: Microglial/macrophage-induced immunoexcitotoxicity as a central mechanism of neurodegeneration.

Parkinson's disease is one of the several neurodegenerative disorders that affects aging individuals, with approximately 1% of those over the age of 60 years developing the disorder in their lifetime. The disease has the characteristics of a progressive disorder in most people, with a common pattern of pathological change occurring in the nervous system that extends beyond the classical striatal degeneration of dopaminergic neurons. Earlier studies concluded that the disease was a disorder of alpha-synuclein, with the formation of aggregates of abnormal alpha-synuclein being characteristic. More recent studies have concluded that inflammation plays a central role in the disorder and that the characteristic findings can be accounted for by either mutation or oxidative damage to alpha-synuclein, with resulting immune reactions from surrounding microglia, astrocytes, and macrophages. What has been all but ignored in most of these studies is the role played by excitotoxicity and that the two processes are intimately linked, with inflammation triggered cell signaling enhancing the excitotoxic cascade. Further, there is growing evidence that it is the excitotoxic reactions that actually cause the neurodegeneration. I have coined the name immunoexcitotoxicity to describe this link between inflammation and excitotoxicity. It appears that the two processes are rarely, if ever, separated in neurodegenerative diseases.

Methodological problems with population cancer studies: The forgotten confounding factors.

Among clinical physicians it is the population study that is considered to be the "gold standard" of medical evidence concerning acceptable treatments. As new information comes to light concerning the many variables and confounding factors that can affect such studies, many older studies lose much of their original impact. While newer population studies take into consideration a far greater number of confounding factors many are still omitted and a number of these omitted factors can have profound effects on interpretation and validity of the study. In this editorial, I will discuss some of the omitted confounding factors and demonstrate how they can alter the interpretation of these papers and their clinical application.

Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control.

Since President Nixon officially declared a war on cancer with the National Cancer Act, billions of dollars have been spent on research in hopes of finding a cure for cancer. Recent reviews have pointed out that over the ensuing 42 years, cancer death rates have barely changed for the major cancers. Recently, several researchers have questioned the prevailing cancer paradigm based on recent discoveries concerning the mechanism of carcinogenesis and the origins of cancer. Over the past decade we have learned a great deal concerning both of these central issues. Cell signaling has taken center stage, particularly as regards the links between chronic inflammation and cancer development. It is now evident that the common factor among a great number of carcinogenic agents is activation of genes controlling inflammation cell-signaling pathways and that these signals control all aspects of the cancer process. Of these pathways, the most important and common to all cancers is the NFκB and STAT3 pathways. The second discovery of critical importance is that mutated stem cells appear to be in charge of the cancer process. Most chemotherapy agents and radiotherapy kill daughter cells of the cancer stem cell, many of which are not tumorigenic themselves. Most cancer stem cells are completely resistant to conventional treatments, which explain dormancy and the poor cure rate with metastatic tumors. A growing number of studies are finding that several polyphenol extracts can kill cancer stem cells as well as daughter cells and can enhance the effectiveness and safety of conventional treatments. These new discoveries provide the clinician with a whole new set of targets for cancer control and cure.

Immunology primer for neurosurgeons and neurologists part I: Basic principles of immunology.

Our knowledge concerning the workings of the immune system has evolved considerably over the past 20 years, with great strides being made as regard to complex interactions and repertoire of effector reactions under a host of conditions. Many of our previous understandings have been challenged, especially concerning tumor immunology and autoimmunity. Also of critical importance is our understanding of how the immune system terminates its attacks and the mechanisms used to regulate the balance between proinflammatory and antiinflammatory mechanisms, so as to prevent excessive immune bystander damage. I will discuss in part I the basic physiology of innate immune function and the immune systems reactions to invasion by microorganisms.

Immunoexcitatory mechanisms in glioma proliferation, invasion and occasional metastasis.

There is increasing evidence of an interaction between inflammatory cytokines and glutamate receptors among a number of neurological diseases including traumatic brain injuries, neurodegenerative diseases and central nervous system (CNS) infections. A number of recent studies have now suggested a strong relation between inflammatory mechanisms and excitatory cascades and these may play a role in glioma invasiveness and proliferation. Chronic inflammation appears to be a major initiating mechanism in most human cancers, involving cell-signaling pathways, which are responsible for cell cycling, cancer cell migration, invasion, tumor aggressiveness, and angiogenesis. It is less well appreciated that glutamate receptors also play a significant role in both proliferation and especially glioma invasion. There is some evidence that sustained elevations in glutamate may play a role in initiating certain cancers and new studies demonstrate an interaction between inflammation and glutamate receptors that may enhance tumor invasion and metastasis by affecting a number of cell-signaling mechanisms. These mechanisms are discussed in this paper as well as novel treatment options for reducing immune-glutamate promotion of cancer growth and invasion.