CONTENTS

In order of relevance

Introduction

My Study
My Regimen
My Story
My Theory
My Advice
My Diagnosis
My Opinions

Mental Attitude
Self Healing

Frequently Asked Questions
Useful Links

Antioxidants
Antiox Articles

OPCs
Vitamins
Minerals & Aminos
Medications 

Diet
Liver Function
Healthy Foods 

Stress
Inspiration
Therapies
Treatments
Theories

Articles
Mycoplasma
Lyme Disease
Organophosphates

Talking to Doctors
Diagnosing ALS
Self Assessment

Acknowledgements

Steven Shackel

Home Page

Excellence Award








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ARTICLES
This page contains edited journal extracts and newspaper/magazine articles with references (where available) to enable you to follow ongoing research at a glance or follow up and locate the original unedited articles. See my Useful Links page on this website for ways to find other scientific articles on the Internet.

(ALS) Amyotrophic Lateral Sclerosis or (MND) Motor Neurone Disease
are referred to as ALS/MND.

PALS is short for People (or a person) with ALS.


Back to Home Page



RECOMMENDED

The ALS Therapy Development Institute (ALS TDI) offers updated research plus forums. There are now many ALS/MND websites but ALS TDI is currently one of the most comprehensive.


LIPID ABNORMALITIES LINKED TO ALS
Abnormal accumulation of two common lipids (fats) in motor nerve cells could play a critical role in the development of ALS, according to investigators at the National Institution Aging - NIA. The finding could help scientists develop drugs and other treatments that might one day slow or arrest the disease's progression.

NIA scientists unearthed several new clues through a complex, multi-step investigation. After comparing spinal cord tissue extracted from people who had ALS with those who didn't, the investigators discovered that levels of ceramides, cholesterol esters and several other lipids were significantly elevated in the spinal cords of people with ALS.

To test whether these elevated levels of ceramides, a cell wall component, and cholesterol esters, a form of cholesterol, cause motor neuron degeneration associated with ALS, the investigators studied mice with copper/zinc-superoxide dismutase (Cu/Zn-SOD), incorporated into their genome. As in humans, analysis of the spinal cords of these animals revealed increased levels of ceramides and cholesterol esters.

To determine what might cause these abnormalities in lipid metabolism, investigators exposed mouse motor neurons to free radicals because previous studies suggested that increased production of oxygen free radicals is involved in the onset and progression of ALS. As a result, ceramides and cholesterol esters are increased in the exposed cells, just as was found in motor neurons affected by ALS.

Experiments were conducted to determine if accumulation of ceramides and cholesterol esters in these neurons could be blocked when treated with a drug called ISP-1.

The drug prevents the formation of large membrane molecules called sphingolipids, which produce ceramides. When exposed to oxygen free radicals, motor neurons treated with ISP-1 did not accumulate ceramides and cholesterol esters, nor did they degenerate. Untreated motor neurons that were exposed directly to ceramides did deteriorate.

Ceramide accumulation appears to be both necessary and sufficient to explain the degeneration of spinal cord motor neurons in ALS. This knowledge is now being used to develop drugs that potentially could prevent these abnormalities.

In addition to drugs, the NIA scientists are investigating whether changes in dietary intake of cholesterol and lipids involved in the formation of membrane sphingolipids might have an impact on an individual's susceptibility to ALS.

*Cutler RG, Pedersen WA, Camandola, S, Rothstein, JD, and Mattson, MP, "Evidence That Accumulation of Ceramides and Cholesterol Esters Mediates Oxidative Stress -- Induced Death of Motor Neurons in Amyotrophic Lateral Sclerosis," 'Annals of Neurology', vol. 52 (2002).


ALS Cell Death Route

Researchers at the Robert Packard Center for ALS Research reported uncovering the "death pathway" that's switched on when neurons die from the disease. They've also highlighted the key role of a specific molecule in the chemical cascade, called Apoptosis Inducing Factor (AIF). They are now looking specifically for things that prevent AIF release.

Cultures of animal brain cells exposed to a neurotoxin that simulates ALS's end stages in cells, dramatically resisted death when their AIF was blocked.

Two cell pathways, apoptosis and necrosis, bring about death of cells. Usually, things that trigger the cell death process activate one path or the other,
though both may be involved in later stages when a point of no return is reached and the cell dies.

A third pathway turns on when a cell is heavily stressed, as nerve cells are in ALS. Stress-initiated shifts in internal chemistry trigger the over-activation of a normally helpful repair enzyme called PARP-1 and excessive PARP-1 brings about a rapid and dramatic drop in cell energy.

Major drops in energy cause release of AIF from the mitochondria that produce it. AIF travels to the nucleus and triggers destruction of chromosomal material, causing rapid cell death. Several molecules that block AIF have already been found and researchers are exploring their use.

AIF's move to the nucleus is easily tracked and an automated system reports on the state of hundreds of cells at a time enabling the accurate screening of potential AIF-blockers.

The Robert Packard Center for ALS Research at Johns Hopkins has the latest information on ALS research and treatment.


Minocycline prevents neurotoxicity

Source: Brain 2002 Apr;125(Pt 4):722-31 Author(s): Tikka TM, Vartiainen NE, Goldsteins G, Oja SS, Andersen PM: Marklund SL, Koistinaho J. Institute: A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland. Published: 04/01/02

CSF from patients with motor neurone disease (ALS/MND) has been reported to be toxic to cultured primary neurones. We found that CSF from MND patients homozygous for the D90A CuZn-superoxide dismutase (CuZn-SOD) mutation, patients with sporadic MND and patients with familial MND without CuZn-SOD mutations significantly increased apoptosis and reduced phosphorylation of neurofilaments in cultured spinal cord neurones when compared with the effects of CSF from patients with other neurological diseases.

Exposure of spinal cord cultures to MND CSF also triggered microglial activation. The toxicity of MND CSF was independent of the presence of the CuZn-SOD mutation, and it did not correlate with gelatinase activity or the presence of immunoglobulin G autoantibodies in the CSF.

The concentrations of glutamate, aspartate and glycine in MND CSF were not elevated. Antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid/kainate receptors prevented the toxic CSF-induced neuronal death but not microglial activation, whereas minocycline, a tetracycline derivative with anti-inflammatory potential independent of antimicrobial activity, reduced both the apoptotic neuronal death and microglial activation.

We conclude that the cytotoxic action of CSF is prevalent in all MND cases and that microglia may mediate the toxicity of CSF by releasing excitotoxicity-enhancing factors. PubMedID: 11912107


Hirano bodies could shed light on ALS/MND.

Source: National Science Foundation Published: 04/30/02


A new study describes for the first time a method of culturing important but poorly understood cell structures called Hirano bodies. The report by cellular biologists at the University of Georgia could shed light on numerous diseases in which Hirano bodies may play some role, including ALS/MND, Alzheimer's disease and cancer.

The research was published in the May issue of the Journal of Cell Science. Hirano bodies - named for their discoverer - have been known for several decades and their presence in autopsy tissue of Alzheimer's patients has led to speculation that they may play a role in disease processes. Studying Hirano bodies has been difficult because they have been resistant to culturing in the laboratory.

The new study, led by cellular biologist Marcus Fechheimer, reports a novel way to create Hirano bodies in the lab, giving scientists their first tool to understand how the bodies may aid-or hinder the progress of disease. Scientists have found Hirano bodies in the post-mortem examination of brain tissue from patients with neurodegenerative diseases, diabetes, alcoholism and cancer.

Understanding just what Hirano bodies do remains unclear. They may change cells to make them more vulnerable to disease, but it's just as likely that they help battle disease; nobody knows.

Until now, Hirano bodies have been found by autopsy most often in the hippocampus region of the brain, though the bodies are not restricted to neurons. Still, the bodies appear to have some association with numerous diseases. The presence of Hirano bodies in association with these diseases has led scientists to speculate that they have some role in neurological deterioration.

Fechheimer and his colleagues propose that a range of conditions may generate signals that induce the formation of Hirano bodies. Some researchers had speculated that the bodies played a role in apoptosis or so-called "programmed cell death," in which cells signal for their own demise, often for the good of the entire organism.

However, Fechheimer's work shows that Hirano bodies are not necessarily linked to a stage in cell death. The new ability to create Hirano bodies in the lab will allow researchers to explore their mechanisms with greater understanding.


Mechanisms of Neurodegeneration in ALS
Cluskey S, Ramsden DB. Dpt. of Medicine, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.

...Experiments using both transgenic mice and ALS tissues have been useful in delineating other genetic defects in ALS. However, because only a subset of cases can be attributed to one particular molecular defect (such as mutation of SOD1 or the gene encoding neurofilament H),
the aetiology of ALS is likely to be multifactorial. [See My Theory page SS]

This review discusses the major mechanisms of neurodegeneration in ALS, such as oxidative stress, glutaminergic excitotoxicity, damage to vital organelles, and aberrant protein aggregation.
Mol Pathol 2001 Dec;54(6):386-92 PMID: 11724913

AND
Amyotrophic Lateral Sclerosis: the Toxic Exposure Connection
Bernie Windham(Ed.)
...The majority of ALS cases do not appear to be genetic but rather have primarily environmental related causes. Some of the mechinisms of neural damage found in ALS include increased free radical generation/oxidative damage, impaired electron transport, disrupted calcium channel function,neurotoxicity, oxidative damage to mitochondrial DNA inhibition of the mitochondrial respiratory chain, and generalized disruption of metabolism of neuroexciotoxic amino acids like glutamate, aspartate,NAAG. The mechanisms by which exposure to mercury and other neurotoxic substances cause all of this will be documented.

Some of the toxic exposures which have been found to be a factor in ALS other than mercury include lead, pesticides (especially pyretherins), Lyme disease, failed root canaled teeth, and smoking. All have been demonstrated to cause the some of the mechanisms of damage listed above seen in ALS and since such exposures are common as is exposure to mercury, such exposures appear to synergistically cause the types of damage seen in ALS. [nb The original paper cites numerous references. I have been proposing a multifactorial aetiology for ALS/MND for many years. ]



Stem Cells Harvested Directly From Adult Brain Tissue 

Please note that stem cell therapy may soon be able to replace dead or damaged motor neurones but the reason the neurones die in the first place must also be discovered and halted for a complete "cure" for ALS/MND to be achieved.


In the Journal Nature, August 2001, Dr Perry Bartlett of the Walter & Eliza Hall Institute in Melbourne, Australia, revealed that his research team has isolated stem cells within the human brain. As a result of this research, stem cells may be harvested from many parts of the body, including, skin and blood and not just embryonic or placental cells.

These cells seem to have the ability to give rise to other tissue types. This should put an end to the ethical debates surrounding early stem cell research, which required cells harvested from human fetuses.

Patients could potentially regrow parts of their damaged brain by having neural stem cells stimulated by a molecule that will cause them to grow new nerve cells rather than scar tissue. This would mimic what already happens in healthy parts of the brain, notably the areas of memory and smell where cells are routinely replaced with new ones.

The research should confirm that some adult stem cells could hold the same capabilities as stem cells from embryos, thus solving the problem of rejection. This will be a great step forward in the process of treating neurodegenerative illnesses, including ALS/MND.


Umbilical Stem Cells Used to Treat Spinal Cord Damage

In November 2004 Hwang Mi-Soon, a Korean woman with spinal cord damage regained the use of her legs after 20 years. Stem cells taken from umbilical cord blood developed to replace damaged nerve cells.

The placenta and umbilicus are normally discarded after childbirth but cells taken from the umbilical cord, so called multi potent stem cells, can develop into a limited number of specialised cells, including nerve cells.

Undifferentiated stem cells that may have been derived from embryos are far more versatile but can sometimes trigger an immune response, which does not occurs with umbilical stem cells.

Stem cells injected directly into the damaged area of the Hwang's spine have enabled her to walk again with the aid of a walking frame. Doctors caution that more research must be done before this treatment becomes generally accepted.


Information on the effect of drugs ALS patients currently take.

ALS Therapy Development Foundation has released its first round of drug tests on SOD mice at its Treatment Production Factory.


The results are now posted on ALS-TDI's website and offer concrete information on the therapeutic effect of some drugs ALS patients currently take, and includes other FDA-approved drugs that may benefit patients.


Lentiviral Vectors for the Treatment of Neurodegenerative Diseases

Curr Opin Mol Ther 2001 Oct;3(5):476-81 Martin-Rendon E, Azzouz M, Mazarakis ND. Oxford BioMedica, UK.

A number of potential gene therapy applications in the adult nervous system include neurodegenerative disorders, such as ALS. During the last five years, lentiviral vectors have developed into extremely efficient gene transfer vehicles to the nervous system, revealing a wide range of possibilities for the treatment of neurological disorders


HIV Linked to Condition Resembling ALS

By Nicolle Charbonneau HealthScoutNews Reporter  MONDAY, Sept. 24 (HealthScoutNews)


The AIDS virus could cause a type of ALS, which could be treated successfully with anti-retroviral drugs, according to the studies published in Neurology Magazine Research reinforces the idea that ALS/MND can have a viral origin. Many researchers suspect a virus, but evidence in this direction was merely circumstantial until AIDS related studies revealed a connection.

Doctors have discovered a link between the virus that causes AIDS and a condition resembling ALS, and have found that drugs can help the disorder.

In two separate studies, American and French researchers describe rare cases of HIV infected patients who develop a syndrome similar to ALS.

But although drugs can only modestly slow the course of conventional ALS, the multi-drug therapy used to treat AIDS patients appears to improve and even reverse this virus-related, ALS-like syndrome.

The findings, which appear in the Sept. 25 issue of Neurology, bolster an existing theory that some cases of ALS are the result of viral infections. Moreover, the effect of AIDS drugs in these rare cases raises hopes for an effective treatment for ALS patients.

In October 1997, doctors at the Beth Israel Medical Center in New York City encountered a 32-year-old woman who for three months had struggled with painless but progressive muscle weakness, speech problems, and weight loss, along with other reflex abnormalities similar to those seen in ALS patients.

Within three weeks of her admission to the hospital, the woman was bed-bound, and lead author Dr. Daniel MacGowan, an assistant professor of neurology, found evidence of motor neuron loss on a brain imaging scan.

After a battery of tests, MacGowan discovered that the woman was HIV-positive, and she was started on a cocktail of AIDS drugs known as highly active antiretroviral therapy (HAART).

Six months later, levels of HIV were undetectable in the patient's blood. She was out of bed and able to walk with assistance, and she could also swallow and speak normally and had returned to her normal weight. Four years later, there were only trace signs of weakness and other abnormal reflexes.

But MacGowan says that despite the effect of therapy in this patient, it's not clear from this study whether HIV is directly responsible for the ALS-like symptoms or if another virus is involved.

HIV is known to affect inflammatory immune cells called macrophages, which then invade the brain and spinal cord, causing nerve cell damage. But it has never been shown to damage motor neurons.

"Maybe there's another virus that could be causing ALS," says MacGowan.

The study also raises questions about why HAART reversed the symptoms. "We know that [AIDS drugs] have activity [not] just against HIV itself," says MacGowan. "They seem to block a process called apoptosis [cell death] in lymphocytes in the blood.

"Apoptosis is one of the primary mechanisms for motor neuron death in ALS," MacGowan continues. "So that raises an issue: Maybe the drugs were working by that action as well."

In the French study, researchers at the Adolph Rothschild Foundation and the Infectious and Tropical Disease Service in Paris studied 1,700 HIV-positive people with neurological symptoms, and identified five men and one woman with symptoms similar to ALS. Their ages ranged from 22 to 61.

Unlike patients with conventional ALS, their symptoms worsened rapidly, progressing within just a few weeks.

But after treatment with AIDS drugs, two of the patients recovered completely, while three improved and the sixth patient stabilized.

Dr. Burk Jubelt, a neurovirologist at the State University of New York Upstate Medical University in Syracuse, says that researchers must continue to look for other viruses that may be responsible for other cases of ALS.

At the same time, he adds, these studies suggest that doctors considering a diagnosis of ALS should make sure the patient is tested for HIV, especially if he or she is young. "Maybe HIV is allowing some other virus to infect the nerve cells," he says.

"There had been some cases where HTLV [human T-cell lymphotrophic virus type I] had caused some [ALS-like] cases reported back in the 1980s." HTLV, like HIV, is part of the retrovirus family.

MacGowan says that not every patient who visits a doctor with ALS symptoms is tested for HIV, although the test is done on anyone with risk factors for the virus.

The American researchers are now preparing a trial of the HAART drug indinovir on conventional ALS cases, where they will also examine fluid from the patients' spinal columns for signs of any viruses, as well as any effect of the therapy on motor cell death.

What To Do : You can find out more about ALS from the Web sites for the ALS Association, the Les Turner ALS Foundation, or the National Institute of Neurological Disorders and Stroke.


Glutamine and Glutamate

To be used effectively by the body the amino acid glutamine must be converted by cellular enzymatic processes. In people with ALS/MND these enzymatic processes are often inhibited and neurone-damaging glutamate is a common breakdown component.


RICIN & ALS/MND

Ricin, the toxic component of the castor bean plant, may cause or contribute to ALS. It's used in a surprising number of products, from hydrolic brake fluid to fertilizers, so there are many possible routes of exposure.


I have had ALS for about 4 years.  About 8 months ago I started on allopurinal and grape seed extract because what I read on your study.  About 2 weeks ago I stopped both of them because I didn't think they were doing any good. 


To my amazement my legs became tighter and the spasticity increased.  Therefore I went back on both of them.  The very next morning I could tell the difference.  Thank You Very Much,”

Ken in Peoria, IL. May 1999


A book explaining ALS/MND in clear and understandable terms is now available. "ALS - Lou Gehrig's Disease" by Mary Dodson Wade, explores the history of the disease from diagnosis to sophisticated techniques used to treat and help patients cope.


Real life stories from PALS and CALS make this book a valuable resource for understanding this illness. This book is available online.


The Brain Wellness Plan

Medical, Nutritional, and Immune-Boosting Therapies  by Carl Germano, Dr. Jay Lombard was the Health and Fitness Editor's Recommended Book. Published by Kensington Books.


You know you're in for some tough sledding when you encounter this sentence on page 27: "These tiny organelles are often referred to by biologists as 'the powerhouses of the cell' because mitochondria are so important to oxidative phosphorylation."

The authors go on to explain what oxidative phosphorylation is, but still, you have to really care about that noggin of yours to keep reading until you get to the good stuff: the foods and nutritional supplements that make your brain work better.

Once you get past the exotic roster of amino acids, antioxidants, and other substances that may improve or maintain brain function--(s-adenosyl methionine, tocotrienols, n-acetyl-cysteine, among others)--the bulk of the book focuses on specific problems (Alzheimer's, attention deficit hyperactivity disorder, depression) and ways to deal with them nutritionally.

Synopsis
The link between the brain and the body's immune and digestive systems is such that, when there is a breakdown between them, neurological diseases result. Using the latest research, the authors show how the foods we eat, combined with over-the-counter nutritional supplements, not only successfully address both the symptoms and root causes of disease, but also enhance our health.

A Reader from Dana Point, California
"A must-read for anyone knowing anyone afflicted.

Depression, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Lou Gehrig's Disease, Attention Deficit Disorder, and Chronic Fatigue Syndrome are the diseases the authors tackle in this book.

The latest in nutritional and immune-boosting therapies in a concise and well organized format. Considering the millions affected by these diseases and the lack of consistent treatment in the medical community, this book truly offers a complete plan".

The Brain Wellness Plan is also available from Amazon.com

I have read this book and recommend it as a source of information on the effects of diet, supplements and medications on the nervous system, brain function and biochemistry. The authors seem to have independently come to many of the conclusions offered by me on this website. Steve Shackel


Excess Calcium Damage?

Motor neuron dysfunction and loss in ALS have been attributed to several different mechanisms, including increased intracellular calcium, glutamate excitotoxicity, oxidative stress and free radical damage, mitochondrial dysfunction, and neurofilament aggregation and dysfunction of transport mechanisms.

These alterations are not mutually exclusive, and increased calcium could be a common denominator. Furthermore, the selective vulnerabilityof spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and familial ALS.

There is evidence that calcium homeostasis is altered in ALS and that low levels of the calcium binding proteins parvalbumin and calbindin-D28K contribute to selective vulnerability by decreasing the ability of motor neurons to handle an increased calcium load, with cell injury and death as the consequence.

PMID: 11465925 [PubMed - in process] ALS & Other Motor Neuron Disorders 2001 Mar;2 Suppl 1:S47-54: Appel SH, Beers D, Siklos L, Engelhardt JI, Mosier DR.: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.



The Mercola.com website contains information about treatment of chronic illnesses (primarily arthritis) with low dose antibiotics. As I believe many chronic illnesses may be different manifestations of the same group of infective organisms, this type of treatment may prove to be relevant to ALS/MND.



Study Uncovers Cell's Role in Wiring the Brain

The Associated Press January 25,2001, Thursday, BC cycle: LAURAN NEERGAARD

Stanford University scientists have filled an important gap in understanding how the brain works, discovering what prompts nerve cells to build the vital connections they need to communicate.

Glial cells, long thought to be passive scaffolding for the brain's all-important neurons, are directly responsible for how many connections neurons form so they can talk to each other, scientists report in the Journal: Science, 19 Jan 2001.

The discovery could lead to understanding of how memory forms and perhaps shed new light on what causes certain brain diseases such as epilepsy or ALS/MND.

Understanding how glial cells affect those vital neuron connections called synapses is important. To understand how the brain computes, we have to understand how they form.

Glial cells make up most of the brain's cells- for every single neuron there are 10 glia. The scientific dogma was that they only supported neurons, perhaps by providing nutrition. Research was conducted to uncover the function of a main glial cell called an astrocyte.

Neurons send and receive messages by swapping chemical signals, such as signals to move a leg to walk or to retrieve a memory. To communicate those messages, neurons must first form synapses.

Scientists once thought neurons were wired to simply build as many synapses as needed. It has now been discovered that young neurons form only a few immature synapses when there are no astrocytes nearby.

Add astrocytes to neurons in laboratory dishes and suddenly they form seven times more strong, healthy synapses. In another experiments astrocytes were taken away and the synapses promptly started shrivelling.

Results clearly show that environmental signals can have a profound effect on how many synapses neurons can have.

Under the microscope, numerous brain diseases how "gliosis," an abnormal accumulation of glia in the brain-injured area. Perhaps glia overreact to an injury, causing neurons to form too many synapses and thus triggering unwanted neurological responses.

With ALS overreacting glia may kill additional neurons by over stimulating them.

Astrocytes signal neurons to build synapses by secreting a protein. If that protein can be isolated then scientists could test current theories.


Lab-made Stem Cells May Be Key to Transplants

Scientists at Johns Hopkins in 1998, showed that human pluripotent stem cells (hPSCs) - our earliest, undifferentiated "full potential" cells - could develop into the basic embryonic tissues that make up human beings. Researchers have now engineered hPSCs to form embryoid body derived cells (EBDs) that may develop into different tissues. EBDs reproduce readily and are easily maintained and thus eliminate the need to use foetal tissues as a source.

This should quell many political and ethical concerns about previous stem cell studies. EBD cells will be the workhorses of new tissue-transplant therapies and their first applications should include treating ALS. Researchers are testing EBDs on animal models of ALS and other neurodegenerative diseases.

Injected into the body, stem cells can produce tumours but EBDs readily divide, producing millions of cells without any apparent chromosomal abnormalities typical of tumour cells. No tumors appeared in three cancer-prone test mice injected with the new cells. EBD cells appear to accept foreign genes readily, which is necessary if scientists are to produce large quantities of cells for human transplants.

Cells were grown in cultures that favour growth of nerve cells, then allowed to divide undisturbed for many generations. Researchers recognized in EBD cells a sort of biologic raw material which, when placed within specific environments in the body, can be made to differentiate into specific tissues.


Australian newspapers reported that researchers are a step closer to a treatment for ALS/MND.  Dr. Elizabeth Coulson, of the Walter and Eliza Hall Institute, Melbourne, Australia believes she has developed a molecule to stop the mechanism that kills off motor neurones. She has been awarded the inaugural Sealey Research Fellowship. 


The money will help Dr.Coulson continue testing the compound in animals, with a view to developing a compound for humans.  "At this stage, no one knows why motor neurones die", Dr.Coulson said. "But if the mechanism we've identified stops deaths in animals, it may also do the same for humans.  If the process is the same for humans, we may have opened a new direction for research into potential ALS/MND therapies".


SOD Immunoreactivity in Sporadic ALS

Cu/Zn superoxide dismutase (SOD) like immunoreactivity (LI) was found within Lewy body-like inclusions (LBIs) in the spinal cords of patients with sporadic amyotrophic lateral sclerosis (ALS) by using an antibody to human Cu/ZnSOD. LBIs were detected in the anterior horn cells in 10 of 20 patients with sporadic ALS.

In each of these patients, 7 to 60% of LBIs showed Cu/ZnSOD-LI.No Cu/ZnSOD-LI was detected in intact neurons and glia in the 20 ALS patients, as well as in these cells in 10 normal control individuals. The skein-like inclusions and Bunina bodies, which were found in all of the 20 ALS cases, showed no Cu/ZnSOD-LI. Thus, Cu/ZnSOD appears to play roles in the production and/or degradation process of LBIs.

Neurosci Lett 1994 Sep 26;179(1-2):149-52 Cu/Zn superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis. Shibata N, Hirano A, Kobayashi M,Sasaki S, Kato T, Matsumoto S, Shiozawa Z, Komori T, Ikemoto A, UmaharaT, et al Department of Pathology, Tokyo Women's Medical College, Japan.


Study supports virus link to MS


Although Multiple Sclerosis and ALS/MND are different neurodegenerative disorders it is possible that research findings relating to one may ultimately impact on the other. As it has been suggested that ALS/MND may be caused or triggered by a virus it is interesting to note that a similar possibility has been proposed for Multiple Sclerosis.

A study appears to support the theory that multiple sclerosis (MS) maybe linked to infection with herpes virus 6 (HHV-6), and at least one patient with MS who is infected with HHV-6 is being treated with antiviral medication.

The National MS Society cautioned: "Although this is one of several reports over several years suggesting a possible link between HHV-6 and MS, there is not enough evidence to say that HHV-6 is a causal factor in MS."

A young woman with MS had a chronic  HHV-6 infection. Treated with an antiviral agent to suppress HHV-6 she has been well for about 6 to 8 months but this is "an anecdotal story of one individual undergoing such therapy, with unsubstantiated claims of benefit.

There is no evidence that treatment with agents effective against HHV-6 will have a role in treatment of multiple sclerosis," the Society cautioned.

Researchers found signs of herpes virus 6 infection in central nervous system samples from 7 out of 10 patients with MS. 90%, or 17 of 19 samples with active demyelination - the loss of the sheath surrounding nerve cells - had signs of HHV-6, compared with just 5%, or 1 of 19 samples of tissue free of active disease.

The study cannot conclusively determine whether HHV-6 is a cause or effect of the disease. From the limited data available,  there is an  association between the presence of active, replicating HHV-6 in the white matter of patients with MS.

To demonstrate  a causal role for this virus patients who have active, ongoing infection could be treated with an antiviral agent to see if the infection can be cleared.


Protein That Prevents Cell Death

WASHINGTON - Scientists have delayed the onset of [ALS/MND] by giving genetically engineered mice a protein that prevents cell death ( Bcl-2), suggesting a new approach to fight the disease.

The protein delayed the inherited form of ALS from striking mice that carried the disease, suggesting this type of therapy might one day prove "beneficial to ALS patients in whom treatment can be started before the onset of symptoms, "wrote co-author Dr. Serge Przedborski of Columbia University.

Cell death can be similar in both inherited and noninherited ALS, suggesting cell-protective therapies be investigated for both types. ALS experts cautioned that the work needs confirmation. "But it's very, very interesting that the disease is postponed. This is encouraging," said Dr. Teepu Siddique of Northwestern University, who created the ALS-carrying mouse breed that Columbia used.

He is studying people with familial ALS to see if doctors can predict when they will get sick. The human proto-oncogene called Bcl-2 produces a protein that regulates cell death.

Przedborski cross-bred ALS mice with mice that produced high levels of human Bcl-2, to see if it would postpone this new generation's illness. Bcl-2 delayed the onset of [ALS/MND] by 19 percent. Consequently, the Bcl-2 mice lived 15 percent longer than the original ALS mice -though once their symptoms began, the protein could not slow the disease's inevitable progression.


Growth Factors Hold Possibilities For Treating ALS

Research from University of Houston scientists may lead to techniques for jump-starting the faulty "wiring" in damaged nerve cells, and suggests possible avenues for treating ALS/MND.

University of Houston scientists have found that growth factors play a key role in regulating how embryonic nerve cells acquire the ability to start processing information.

In some cases, when nerves succumb to neurodegenerative diseases such as ALS, they don't die but quit working and may actually revert to an immature embryonic-like state. Embryonic nerve cells fire electrical impulses shortly after the cells have divided for the last time - after they are "born." But these impulses are extremely generic, and not necessarily specialized for the kind of information the cell is going to eventually process.

Initially, the cells are becoming connected, like the individual circuit elements in a computer, and the message that gets through is one that says 'I'm hooking up' rather than 'I'm processing information'. The developing embryonic cells must somehow acquire the ability to discharge and route electrical impulses in a coordinated, highly specialized fashion.

If damaged cells have indeed entered a kind of immature state, perhaps we can kick-start them back to their proper function using the natural pathways embryonic cells take to become fully functioning nerve cells. Nerve cells, or neurons, connect to each other in complex networks, carrying electrical and chemical signals through the body to other cells, or "target" tissues, allowing muscles to move and the brain to think.

Growth factors may be the trigger that allows embryonic nerve cells to become specialized. Growth factors secreted by the target tissue signal the embryonic nerve cells to make ion channel proteins.

These ion channel proteins then attach to certain places on the nerve cell's membrane, where they "channel" electrically charged particles called ions in and out of the neuron. This enables the cells to conduct electrical impulses.

In their most recent study, Dr Stuart Dryer and post-doctoral fellow Miguel Martin-Caraballo found that as the number of ion channels increases, the electrical properties of the developing neuron change.

Once a certain density of ion channels in the embryonic nerve cell are in place, the cell exhibits mature electrical behavior, functioning with the specialized electrical patterns needed to allow them to function normally.

Growth factors associated with the target tissue spur the ion channel formation. This study is the first attempt to look at how growth factors control the electrical properties of embryonic spinal motor neurons. Dryer's study is published in the Jan. 1 issue of the Journal of Neuroscience.


Anti inflammatory drugs may slow neurodegeneration

Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are neuroprotective, although the mechanisms underlying their beneficial effect remain largely unknown.

Given their well-known adverse effects, which of the NSAIDs is the best for neurodegenerative disease management remains a matter of debate.

As microglia play an important role in CNS inflammation and pathogenesis of neurodegenerative diseases, we investigate the effect of paracetamol on rat microglial cultures. Although less potent than other NSAIDs, paracetamol completely inhibited the synthesis of [several neuroinflammatory substances].

Paracetamol effectively reduces prostaglandin E2 synthesis in brain macrophages by inhibiting enzymatic activity of cyclooxygenase but not phospholipase and prostaglandin E synthase.Source: J Neurosci Res 2003 Mar 15;71(6):844-52 Author(s): Greco A, Ajmone-Cat MA, Nicolini A, Sciulli MG, Minghetti L. Institute: Laboratory of Pathophysiology, Istituto Superiore di Sanita, Rome, Italy. Published: 03/15/03

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders... Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells, the microglia, which produce proinflammatory and neurotoxic factors including cytokines, reactive oxygen intermediates, nitric oxide and eicosanoids that impact on neurons to induce neurodegeneration.

Hence, identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases...

Dextromethorphan Protects Dopaminergic Neurons against Inflammation-mediated Degeneration through Inhibition of Microglial Activation.Source: J Pharmacol Exp Ther 2003 Jan 21; [epub ahead of print] Author(s): Liu Y, Qin L, Li G, Zhang W, An L, Liu B, Hong JS. Published: 01/21/03


Metallothionein in ALS Motor Neurons

Authors: Kasarskis, Edward J., M.D., Ph.D. Source: Department of Veterans Affairs_Research and Development, 810 Vermont Ave. N.W., Washington, D.C., United States of America. (IRB #91-22026) 

MOTOR NEURONS; METALLOTHIONEIN; MERCURY; AMYOTROPHIC LATERAL SCLEROSIS
 
... The pathological hallmark of ALS is a selective death of motor neurons in the spinal cord and motor cortex. These features of ALS, however, fail to provide insight into its etiology with the result that several theories of etiopathogenesis have been advanced.

Our research focus is upon the potential involvement of toxic trace metals in causing the death of motor neurons. Heretofore, studies of toxic metals have only considered the possibility of excessive accumulation of a metal in the brain and spinal cord.

Our own work advanced the notion that mercury is present to excess in ALS patients when compared to age-matched controls based on a multi-element analytical study using neutron activation analysis of several types of tissue.

Further studies have suggested that mercury may be localized within spinal motor neurons using photoemulsion histochemistry. Thus it appears that mercury accumulates within the very cells which degenerate in ALS, suggesting that mercury may be a necessary precondition for ALS-type degeneration to occur.

OBJECTIVE: To investigate one aspect of mercury detoxification in ALS. As a prelude, we have ascertained the distribution of metallothionein (MT) in spinal cord by immunocytochemical methods using a polyclonal antibody to a defined epitope present in all forms of human MT.

The MTs are a family of structurally-similar, soluble, cysteine-rich, 6-7 kD proteins which detoxify heavy metals by sequestration and also regulate copper and zinc homeostasis.

In control subjects, we found MT immunoreactivity localized to the nucleus, cytoplasm, and axonal extensions of spinal motor neurons. In ALS spinal motor neurons, MT immunoreactivity was absent (or greatly reduced) in the nucleus.

These findings open the possibility that abnormalities of MT may be involved in the pathogenesis of ALS. According to this formulation, MT may be structurally altered in ALS, greatly reduced in amount, or diverted from its normal nuclear localization as a result of toxic metal exposure.

PLAN and METHODS: The overall goal of this study is to isolate and sequence the MTs from the spinal cord of controls and compare the results to ALS patients to determine if MTs are altered in composition in ALS.

The issue is a complicated one because: a) 6 MT isoforms have been sequenced from human tissues; b) 11 separate, but closely-related MT genes have been found; and c) MT has not been characterized from human spinal cord.

To date, we have partially purified MT from bulk samples of control human spinal cord. Methods are in place to complete the purification of MT isoforms and determine their sequence.

After dissection of the anterior horn region and subcellular fractionation, we propose to isolate and identify the nuclear-associated MT isoform in control spinal cord.

Strategies have been developed to deal with collateral issues such as the newly described MT-related protein, "GIF". Guided by the results in controls, we will isolate the nuclear-associated MT(s) from ALS spinal cord.

As a final test of the hypothesis, we will compare MT isoforms in motor cortex, the other region in which motor neuron degeneration occurs in ALS.

The results of these studies will evaluate the hypothesis that MT is altered in ALS. Finding an abnormality in MT would give considerable support to the concept that toxic metals are involved in the pathogenesis of ALS.

STATUS:  Results/Findings: We have localized metallothionein and mercury to human and rat spinal motorneurons using both monoclonal and polyclonal antibodies. To date, we have identified MT-3 and MT-2 by direct protein sequencing after isolation.
Entry Month: August, 1999 Initial Project Year: 19931001 Secondary Source ID: FEDRIP/200003/004055


"Cocktail" to Slow ALS/MND?

 "Scientists have found a new drug that could become part of a drug cocktail capable of preventing the spinal cord neuronal damage associated with ALS/MND.


The substance, called pigment epithelium-derived factor, or PEDF, offered "nearly complete protection" against spinal cord nerve cell degeneration in laboratory animal models, according to Ralph Kunci, a Johns Hopkins University neurologist and lead author of the study.


PEDF is a naturally occurring substance in eye tissue and is a "neurotrophic factor" - molecules that typically encourage the re-growth of damaged nerve cells. 

Researchers discovered its protective effect on the spinal cord by chance, after hearing about a colleague's work on neurotrophic factors in the eye.  "If we had this same level of protection in patients with ALS, they'd experience slight muscle weakness at most," said Kunci.

It is likely that PEDF and another recently discovered neurotrophic factor, neurturin, will be used as a "cocktail" to dampen the sensitivity of the nerve transmitter glutamate, which figures prominently in ALS."
-Johns Hopkins Medical Institutions


Scleronet Clinical Trial
The Scleronet trials in Sydney, Australia were discontinued due to "poor results". It is possible that further trials may be held in the future as some PALS requested to remain on the drug as they felt it was helping them. No date has been set for future trials.


Toxic Cleaning Products

Many PALS feel that minimising environmental toxins will assist in slowing neurodegeneration. There is evidence that toxic compounds used in and around the home and workplace stress the immune system and may even be the cause of many illnesses.


If one's body is not constantly forced to eliminate and protect against toxins from household cleaning products and other sources it will be better able to deal with illness and infection.


Many websites now suggests non-toxic and environmentally friendly alternatives to normal cleaning products.



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