A few months ago I submitted an abstract to the committee planning the upcoming Days of Molecular Medicine Conference, which will be held this April in Karolinska Sweden. A week ago, I was quite happy to learn that my abstract was accepted and that I will be giving a poster presentation at the conference. The subject: “Cognitive dysfunction in women with Chronic Fatigue Syndrome: examining the role of the endometrium, the nuclear receptors, and the antimicrobial peptides.” So if all goes as planned, I’m headed to Sweden in about a month. I’m excited for many reasons, one of them being that before starting the Marshall Protocol I never thought I’d be able to board a plane again – the pressure changes and noise were too much for my head to tolerate. Yet, two 3/4 years later, here I am traveling half-way across the world, talking about many cognitive issues that were once a problem for me – a problem that has largely subsided.

In the following article, I discuss what I will be presenting at Karolinska.

In 2001, Alayne B. spent 8 months staring at a wall. “I went from being a company executive to barely being able to read above a 4th grade level,” states Alayne. “I couldn’t focus/concentrate on anything. My short-term memory turned into about 15 seconds – my nickname was ‘Memento Girl’ after the movie Memento.” The L.A. native would have to write notes immediately after a conversation or she’d forget what had been discussed. She also had to write herself notes in order to remember where she was driving. If she didn’t, she’d forget where she was going and get lost. “Ultimately I had to stop driving because I’d also forget that the notes were on the seat next to me and it’d take me ages to find my way home,” Alayne confesses. “I no longer had any mathematical figuring abilities either.”

Eventually, she started teaching at a private school – a job that was physically demanding, not to mention required increased brain use. “I made it through a few sessions, but would catch pneumonia, etc. and my energy levels were dropping again,” states Alayne. “Plus, I started forgetting words, how to spell, couldn’t understand my own lesson plans, couldn’t figure out the basic math I was also teaching, etc. When students caught a mistake, I’d pretend I’d been trying to catch them up – which they thought was fun. However, that only goes so far. I started teaching exclusively one-on-one in homes, but that also petered out, as I just couldn’t remember what the heck I was doing there.”

In 2005, Alayne was finally properly diagnosed with CFS. Her reading levels fell again to elementary/junior high level, her mathematical abilities to about 0, and her short term memory left her once again. She suffered from high levels of fear and anxiety, her word recall was horrible, and her reasoning abilities were greatly reduced. “I had no choice but to stop teaching even little one-hour tutoring sessions because I was confusing my students AND it would take me 5 days to recover from 3 hours spent away from home (driving, teaching, driving),” states Alayne.

Upon starting the Marshall Protocol in 2005, she was able to grasp enough of the treatment to “see it was the missing puzzle piece.” However, she could not explain it to anyone else, nor remember what she’d read. “I wrote a few notes down and went with it,” she describes. “By that time, I was bed-bound, emaciated, and my boyfriend and I thought I was dying.”

Although the CDC has recently recognized Chronic Fatigue Syndrome (CFS/ME) as a physiological disease, doctors and researchers are only beginning to understand the severe cognitive effects of the illness, such as those described by Alayne.

Alayne

Case histories like Alayne’s are supported by numerous studies that have tested the cognitive abilities of patients with CFS.

Take, for example, a 2007 twin study conducted by researchers at the University of Hawaii. After controlling for genetic and environmental influences, female identical twins, in which one twin met strict criteria for CFS and the co-twin was healthy, underwent a structured psychiatric interview and comprehensive neuropsychological assessment that evaluated 6 cognitive domains. Results indicated that twin groups had similar intellectual and visual memory functioning, but fatigued twins exhibited decreases in motor functions, speed of information processing, verbal memory, and executive functioning.[1]

Similarly, researchers at the Department of Physical Medicine and Rehabilitation, University of Medicine and Dentistry of New Jersey, recently compared the cognitive performance of subjects with chronic fatigue syndrome (11 female subjects, 1 male subject), multiple sclerosis (MS), and healthy controls. After matching subjects for age, education, and verbal intelligence, subjects were given a battery of neuropsychological tests and scores were compared among the groups. Subjects with CFS and MS scored significantly below control subjects on five different tests that examined memory, concentration, word recall, information processing, and other cognitive abilities (CFS subjects scored worse than MS subjects on two of the tests).

“These results indicate that subjects with CFS and subjects with MS show significant impairment on a test of complex concentration when compared with appropriate controls,” state the research team. “The data suggest that subjects with CFS and subjects with MS have difficulty on tasks that require the simultaneous processing of complex cognitive information.”[2]

Interestingly, the vast majority of studies that have tested for various forms of cognitive dysfunction in CFS patients, including those described above, contain only/mostly women as subjects. For starters, more women than men are diagnosed with the disease. In fact, CFS victims are twice as likely to be women.

But while males also suffer from CFS, the cognitive symptoms of women are, for the most part, reported to be more severe then those experienced by their male counterparts. This is not to say that some men with CFS can’t and don’t suffer from severe cognitive dysfunction, only that most of the studies that describe serious cognitive decline in CFS patients focus on women.

While I can’t deny that these studies may suffer from some forms of bias, the notion that women with CFS are more likely to suffer from severe cognitive dysfunction held up when I started research for this paper/presentation. Because I wanted to speak with cognitively impaired CFS patients on a one to one basis, I posted on the Marshall Protocol study site, asking if CFS patients who had suffered or were suffering from cognitive problems could send me an email describing their symptoms. While eight women contacted me, only one male patient volunteered information.

The endometrium

What might explain the hypothesis that women with CFS are more likely to experience serious cognitive dysfunction than their male counterparts? In what ways do men and women differ?

One obvious and rather large difference between men and women is that women have a uterus – an organ that has several internal membranes. One of these layers is the endometrium.

The endometrium is the inner membrane of the mammalian uterus.

The endometrium is the inner membrane of the mammalian uterus. It functions as a lining for the uterus, keeping the walls of the middle layer of the uterine wall separated – thereby maintaining the expanded shape of the uterine cavity.

During the menstrual cycle, the endometrium grows to a thick, blood vessel-rich, tissue layer that is filled with glands. This represents an optimal environment for the implantation of a blastocyst – the mass of cells that eventually forms an embryo if it arrives safely to the uterus.

If no blastocyst is detected, levels of the hormone progesterone (which is secreted in the endometrium) drops, and the endometrial lining is shed during what is known as the menstrual cycle. In the latter case, the process of shedding involves the breaking down of the lining, the tearing of small connective blood vessels, and the loss of the tissue and blood that had constituted it through the vagina. In humans, the cycle of building and shedding the endometrial lining lasts an average of 28 days.

If a blastocyst is able to implant, pregnancy results. In this case, the endometrial lining is neither absorbed nor shed. Instead, it remains as decidua. The decidua becomes part of the placenta; it provides support and protection for the embryo.

The endometrium produces certain hormones which affect other portions of the reproductive system and participate in important feedback pathways. This means that the endometrium is also home to a plethora of receptors whose activity is controlled by these hormones and other molecules.

The vitamin D system in the endometrium

In what is believed to be the first study to investigate the vitamin D system in human cycling endometrium, researchers at the Fondazione Policlinico-Mangiagalli-Regina Elena Hospital at the University of Milano in Italy have recently identified that one of the hormones produced in excess in the endometrium is the active vitamin D metabolite 1,25-D. Not surprisingly then, the research team also confirmed that both cycling and early pregnant endometrial cells express the Vitamin D Receptor (VDR), which is activated by 1,25-D.[3]

One of the body’s most fundamental receptors, the VDR controls the activity of the innate immune system, or the body’s first line of defense against infectious agents. It also transcribes many antimicrobial peptides – peptides that kill bacteria, viruses, and fungi by a variety of mechanisms including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell.[4]

Furthermore, the receptor activates the transcription of hundreds and possibly thousands of genes. Researchers at McGill University have compiled two lists of genes transcribed by the Vitamin D Receptor including 913 genes on the confirmed list and over 20,000 on the putative list. These genes are associated with genes ranging from cancers to multiple sclerosis.[5]

The Italian team was able to gauge the presence and quantity of 1,25-D in the endometrium by using several different molecular methods to track levels of the enzyme 1{alpha}-hydroxylase (1-OHase) – or the enzyme that catalyzes the production of 1,25-D.

The team, under the leadership of P. Vigano, found that the endometrium harbors abundant quantities of 1,25-D, independent of the phase during which it is cycling under normal conditions. They also discovered that the hormone rises to even higher levels during pregnancy when the decidua is formed.

Expression of the Vitamin D Receptor in endometrial stromal cells and early pregnancy decidual cells, as evaluated by the molecular technique, Western blot.

A molecular technique called Western blot analysis showed a 40% increase in the expression of 1-OHase (which correlates with 1,25-D production) in the early pregnant decidua versus the percentage of 1,25-D created in the endometrium under normal conditions that lead to menstruation. The team confirmed these results by using another molecular technique called immunohistochemistry.

In order to confirm that not just 1,25-D, but also the VDR is found in the endometrium, the Italian team used Western blot analysis to look for the presence of nuclear receptor VDR protein. The protein was identified in both proliferate and secretory cells of the endometrium as well as in the decidua. The team confirmed their results by using a rat antibody to the human VDR that, as expected, reacted with both endometrial and decidual samples.

The team also tested whether the endometrium is a site where 25-D – the secosteroid precursor form of vitamin D – can be energetically converted to 1,25-D (the active form of the substance). The team found that the endometrium does indeed “represent a site of local conversion from the precursor to the active form” of vitamin D, and that levels of 1,25-D produced in this manner were similar to those detected in other areas of the body except for the kidneys, where conversion occurs at an even greater rate.

Cellular localization of 1-OHase in the human cycling endometrium and early pregnant decidua as evaluated by immunohistochemistry.

The functional consequences of 1,25-D production and the presence of the VDR in the endometrium were tested by evaluating the expression level of two genes that are transcribed when the VDR is activated – CYP24 and osteopontin. Levels of the genetic material that make up these genes were negligible or very low in unstimulated endometrial or decidual cells (cells that had no 1,25-D). However a “significant and strong increase” was observed in the expression of both genes after 1,25-D was added to the cells. In endometrial cells transcription levels of CYP24 went up to about 2000-fold after about a 1000nM concentration of 1,25 was added; in decidual cells this increase was also very strong. This same addition of 1,25-D stimulated osteopontin expression levels by about 60–70% in both types of cell culture.

The results of the study make one thing clear: because 1,25-D and the VDR are produced at high levels in the endometrium, the substances are over-expressed in women. Why might this be?

Truth be told, nobody knows why the VDR is over-expressed in the endometrium. One possible explanation is that since 1,25-D is the vitamin D metabolite that activates the VDR, it could be that early in human evolution, women acquired the ability to produce more 1,25-D and more VDRs because interactions between the hormone and the receptor would offer them an advantage during pregnancy. Think about it. When the Vitamin D Receptor is activated, the AMPs are produced at a greater rate, causing them to become increasingly active against viral, fungal, and bacterial infection in the fetus.

Furthermore, the innate immune system is strengthened, and hundreds, possibly thousands, of genes are expressed at a prolific rate. This provides an ideal situation for women who are preparing to bear a fetus and eventually conceive a child. Both mother and child should find it easier to fend off new infectious agents encountered during the pregnancy, and genes controlled by the VDR that may affect the success of the pregnancy should work at an optimal level.

Vigano and team seem to agree, stating, “The presence of the enzyme that catalyzes the synthesis of the active form of vitamin D in cycling endometrium and its up-regulation in first trimester decidua, support the possibility that this hormone might be involved in some mechanisms of pregnancy establishment or maintenance.”

Researchers at Children’s Hospital Medical Center in Ohio published a study in Endocrinology confirming that 1,25-D and the VDR are also expressed at high quantities in the placenta. The team found that the extra levels of the hormone and its receptor stimulate the synthesis and release of human placental lactogen – a hormone that modifies the metabolic state of the mother during pregnancy to facilitate the energy supply of the fetus. This supports the hypothesis that elevated 1,25-D and VDR expression are intended to optimize success during pregnancy.[6]

Pathogens hijack the system

But at some point in the history of man, chronic idiopathic pathogens evolved a way to take advantage of the VDR receptor – by creating ligands that block its activity.

Biomedical researcher Trevor Marshall was the first to identify a species of bacteria that creates a ligand capable of binding and blocking the activity of the VDR. After reading a paper that discusses the characteristics of a bacterial species isolated from biofilm deposits on surgically removed human prosthetic hip joints, Marshall noted that the chronic pathogen under study creates a substance – a sulfonolipid called Capnine – that is able to bind the VDR and substantially slow its activity.[7]

A molecular model of capnine blocking the Vitamin D Receptor.

This discovery strongly suggests that other pathogens can create similar substances, each of which can potentially block the VDR and diminish the body’s ability to keep bacteria in check. “There is now proof of concept that bacterial genomes are capable of producing at least one ligand which acts as a strong VDR antagonist,” says Marshall.

One must admit that creating a ligand or other substance capable of blocking the VDR is an exceptionally logical survival mechanism for any form of pathogen. By creating one single substance to block the VDR, they can, in a knockout blow, disable the receptor that would otherwise activate numerous pathways to interfere with their ability to persist in the body – pathways that are activated to an even greater extent by the extra 1,25-D produced in the endometrium, particularly during pregnancy.

“Think about it for a minute,” says Marshall. “If you were a persistent pathogen, wouldn’t it seem a good idea to disable your host’s ability to produce the antimicrobial peptides? And if you discovered that disabling just one receptor, the VDR, would get rid of [many types of AMPs], wouldn’t you try to evolve a mechanism for doing that?”[4]

Because blocking the VDR is such a logical survival mechanism, the idea that most, if not all, of the L-form and biofilm bacteria (collectively called the Th1 pathogens) that cause chronic disease create these substances, is not far-fetched. This suggests that, as a person acquires more and more of these bacteria, their VDRs become increasingly blocked. As the innate immune system slows, it’s much easier for new species of Th1 pathogens, that probably also create VDR blocking substances, to accumulate and enter the body – causing somewhat of a VDR-blocking snowball effect.

Has this bacterial survival mechanism turned what was intended to be a protective situation for a woman (particularly during pregnancy and menstruation) into an environment that now allows pathogens rather than humans to gain the upper hand?

If a woman has acquired a sufficient number of Th1 pathogens, the over-expression of the VDR in the endometrium could suddenly put her at a disadvantage. Since women have more VDRs, they should, in theory, be more impacted by the effects of VDR blockage – a slower innate immune system, fewer AMPs, and reduced gene transcription. “The dysfunction caused by the Th1 pathogens affect women disproportionately,” states Marshall.

Of course, some may argue that the Th1 pathogens cannot cross the placental barrier and enter the endometrium, but evidence is growing that L-form bacteria and other pathogens are able to pass through this protective membrane.

Researchers at Peking University in Beijing recently discovered that the H5N1 bird flu virus can pass through a pregnant woman’s placenta to infect her fetus.[8] Other studies have revealed that other bacterial species such as Borrelia burgdorferi and Mycobacterium tuberculosis are also capable of crossing the placental barrier during pregnancy.[9] If these pathogens can be passed from mother to child during gestation, then why not species of biofilm bacteria and other forms of bacteria that are capable of transforming into the L-form?

Furthermore, if bacteria are unable to infect the endometrium and the placenta, then why do many women who have hysterectomies in order to treat diseases such as cancer or endometriosis find that the procedure affords them symptomatic relief?

For example, the 1994 Maine Women’s Health Study followed approximately 800 women with similar gynecological problems – pelvic pain, urinary incontinence due to uterine prolapse, severe endometriosis, excessive menstrual bleeding, large fibroids, and painful intercourse – for around 12 months. Approximately half of the women had had a hysterectomy while the other half did not. The study found that a substantial number of those who had a hysterectomy had marked improvement in their symptoms following hysterectomy, as well as significant improvement in their overall physical and mental health one year out from their surgery. The study concluded also that, for those who had intractable gynecological problems that had not responded to non-surgical intervention, a hysterectomy was beneficial to their overall health and wellness.[10]

Since the removal of the uterus seems so effective at alleviating Th1 symptoms (an average of 622,000 hysterectomies a year have been performed for the past decade), one can infer that in cases where women feel better after a hysterectomy, the organ was infected – again suggesting that the endometrium is not immune to the effects of L-form and biofilm bacteria.

How might this contribute to the severe cognitive decline seen among women with CFS? It’s possible that women with VDR blockage, who subsequently have a decreased number of AMPs to kill bacteria, and a slowed innate immune system, find that the Th1 pathogens can infect their brains with greater ease. This infectious model seems logical, as nearly all females with CFS report a gradual onset of their mental symptoms – correlating to a gradual increase of bacteria in the brain.

Patients on the Marshall Protocol with diseases ranging from depression to ADD, OCD, anxiety, bipolar disorder, and schizophrenia, are reporting symptomatic improvement after taking bacteriostatic antibiotics aimed at killing the Th1 pathogens. Similarly, almost every patient on the Marshall Protocol is reporting mental as well as physical immunopathology – the name given to the rise in disease symptoms that results from the cytokine and toxin release that occurs when the Th1 pathogens are killed. Symptoms of anxiety, depression, anger, numerous kinds of brain fog, and cognitive deficits are reported along with physical symptoms, confirming that the Th1 pathogens infect the brain as easily as they do the body.

L-form bacteria have also been detected on several occasions in the brains of patients with Alzheimer’s disease.[11] Rolf Zinkernagel at the Institute of Experimental Immunology in Switzerland demonstrated that viruses are able to persist for decades in the brain, so why not other pathogens?

Since, as described by researcher Josep Casadesus in a recent BioEssays paper, every known species of bacteria is probably capable of transforming to the L-form,[12] this means that a plethora of different species of L-form and biofilm bacteria could be causing the neurological symptoms observed in women with CFS, explaining why symptoms are so diverse and differ substantially among individuals.

Of course cognitive decline and “brain fog” are not by any means phenomena unique to CFS. The same type of cognitive deficits observed in patients with CFS are also noted in patients with other Th1 diseases such as sarcoidosis, Lyme disease, and rheumatoid arthritis. Since the basic pathogenesis of these diseases appears to be the same as that of CFS, cognitive decline in these cohorts of patients likely results from the same mechanisms observed in CFS.

PKA

VDR blockage may also directly affect the brain through a pathway that Dr. Marshall will be discussing in his own presentation at the Days of Molecular Modeling conference. This pathway involves the enzyme CYP27B1, which plays a role in the body’s one and only pathway known to produce 1,25-D.

Under conditions where the VDR is activated, this pathway works to carefully limit (through what is known as trans-repression) the amount of transcribed CYP27B1 gene, and in turn the amount of 25-D that is converted into 1,25-D.[4]

Researchers at the University of Tokyo recently published a paper that eloquently describes this feedback pathway in detail, pointing out other molecules involved in the process of limiting the production of CYP27B1. One of these molecules is Camp-dependent protein kinase A (PKA).[13]

Eric Kandel

In his 2000 Nobel Lecture “The Molecular Biology of Memory Storage: A Dialog between Genes and Synapses”, Nobel Prize winner Eric Kandel (who happens to be the person who will be giving the opening talk at the upcoming DMM conference), describes how PKA is involved in broadening action potentials – spikes of energy that allow for communication between neurons in the brain. It also works to strengthen synapses, or specialized junctions through which the cells of the nervous system are able to signal to each other and non-neuronal cells such as those in muscles or glands. These findings provide direct evidence for the role of PKA in the formation of short-term memory.[14]

When one molecule in a pathway is affected, other molecules in the pathway must adjust in order to accommodate new levels of the substance. In cases where high levels of VDR blockage disrupt the trans-repression element that keeps levels of CYP24B1 in a normal range, other molecules in the same pathway, such as PKA are also affected. As levels of PKA are modulated by higher than normal levels of CYP24B1, it is quite possible that PKA can become dysregulated – causing problems in communication between neurons that result in short-term memory loss and other cognitive symptoms.

“We have determined that activation of PKA is regulated by the process of VDR homeostasis in chronic immune disease, pointing towards a putative mechanism whereby immune dysfunction can directly suppress short-term memory,” states Marshall.

However, patients on the Marshall Protocol, who use pulsed, low-dose antibiotics to kill the Th1 pathogens, along with a VDR-agonist, to restore function of the VDR, are reporting not just the return of short-term memory, but also of mid-term and long-term memory. Consequently, it is very important that researchers continue to further investigate the connection between VDR blockage and other forms of cognitive decline besides those associated with short-term memory.

The nuclear receptors

As the Th1 pathogens take hold, the fact that women express more 1,25-D in the endometrium also becomes a problem. As the VDR becomes increasingly blocked, the receptor slows transcription of the gene for CYP24A1- an enzyme that inactivates 1,25-D. “[The production of CYP24A1] is the best documented of the feedback control systems used by the body to limit the concentration of 1,25-D to just that amount needed for proper transcription and activation of the VDR,” states Marshall.[4]

The feedback pathways that control vitamin D metabolism. Graphic by Janet Foutin, taken from a paper by Trevor Marshall

But with a diminishing level of CYP24A1 to keep the body’s level of 1,25-D in check, the level of 1,25-D in patients with VDR blockage starts to rise. Unfortunately, when 1,25-D reaches a certain threshold, it binds many of the body’s other nuclear receptors, displacing the metabolites that are meant to be in the receptors under normal conditions. The receptors affected by 1,25-D include the glucocorticoid receptor, and the alpha and beta thyroid receptors, the adrenal receptors, and the progesterone receptors.

This means that when 1,25-D is high, it competitively displaces cortisol, T3, and other metabolites from their target nuclear receptors. Indeed, in the book Vitamin D: New Research, researcher Joyce Waterhouse PhD and team describe how patients with high levels of 1,25-D do indeed tend to suffer from hormonal abnormalities.[15]

Furthermore, since each of these nuclear receptors transcribes various families of antimicrobial peptides,[16] the displacement of their normal metabolites by 1,25-D causes a decrease in AMP production, generating an immunosuppressive effect (the body’s ability to kill bacteria is slowed without the help of the AMPs).

By “different families of antimicrobial peptides” I mean that there are many different types of AMPs. Although all AMPs are natural antibiotics produced by the body, each family of these peptides works to kill bacteria in different ways, and in different areas of the body.

In a recent article published in BMC Bioinformatics, a team of researchers (who are on the cutting edge of studying the role of the nuclear receptors in the transcription of different families of antimicrobial peptides) found that the glucocorticoid receptor, the androgen receptor, and the Vitamin D Receptor, seem to be in control of 20, 17 and 16 families respectively, out of 22 analyzed.[17]

Excessive levels of 1,25-D affect the progression of chronic disease in both women and men, as 1,25-D is produced in other tissues of the body, including cells of the skin known as keratinocytes, intestinal cells, and in macrophages (macrophage-like differentiated THP-1 cells.) But since the substance is over-expressed in the endometrium, women are again disproportionately susceptible to the immunosuppression that takes place when the hormone displaces ligands from the nuclear receptors, causing a decrease in the production of so many different families of AMPs. Once again, this immunosuppression likely makes it easier for the Th1 pathogens to infect the brain, where they can cause a host of neurological symptoms.

On a similar note, researchers at Tampere University Hospital in Finland have found that several of the nuclear receptors are expressed at different levels throughout the menstrual cycle – for example the androgen receptor, the estrogen receptors, and the progesterone receptor are expressed more abundantly during the proliferative phase of the endometrium than in the secretory phase of the endometrium.[18]

Since the expression of these receptors waxes and wanes during the menstrual cycle, even in healthy women, the activity of the AMPs that they transcribe may fluctuate over the course of a month – allowing for periods when some women may be less able to kill invading pathogens. While men aren’t affected by this surging and waning, it could be part of the reason why women appear to pick up the Th1 pathogens that cause CFS and the neurological symptoms associated with the disease at a greater rate then men.

It could also be hypothesized that women tend to acquire the Th1 pathogens that cause cognitive dysfunction more easily than men because they don’t produce as much testosterone as their male counterparts. Although on average women are more sensitive to testosterone, an adult human male body produces about forty to sixty times more testosterone than an adult female body.

Since males produce more testosterone, the hormone should activate its target nuclear receptor, the androgen receptor, to a greater extent in men than in women. Since the androgen receptor controls 20 families of antimicrobial peptides, this could mean that men produce many of these natural antibiotics at a greater rate than women – giving them an advantage when it comes to fending off infection and targeting the Th1 pathogens.

Then again, the case history of a Marshall Protocol patient suggests that the progesterone receptor may also transcribe antimicrobial peptides – albeit possibly not in the same high quantities as the androgen receptor.

The possibility that the progesterone receptor may also transcribe antimicrobial peptides is supported by the case of Jane T, an MP patient who suffers from a great number of Th1 conditions. One of the symptoms that results from her immunopathology is endometrial bleeding.

A few months ago, Jane’s doctor reported that, after being given a prescription for supplemental synthetic progesterone, her bleeding became stronger and more severe.

Could it be that upon taking the extra progesterone, her progesterone receptors stimulated the production of AMPs? If this were the case, the AMPs might have facilitated her ability to kill more of the bacteria causing the bleeding, leading to a rise in immunopathology in the area. This hypothesis is supported by the fact that her bleeding was reduced when her progesterone dose was cut in half.

Interestingly, the extra synthetic progesterone did not just affect the level of immunopathology in her endometrium. Her symptoms of obsessive-compulsive disorder increased tremendously after her initial dose of high progesterone and also decreased when the progesterone dose was lowered.

This suggests that if AMPs are produced by the progesterone receptor, they are also able to cause an increase in the death of bacteria in the brain. This case history not only sheds light on how intricately different body systems are connected and how easy it is to disrupt the body’s delicate feedback pathways, but also calls for more research into the actions of the nuclear receptors and the AMPs.

Pregnancy

Unfortunately, because of the fact that 1,25-D levels rise to their highest point during pregnancy, the hormone’s ability to cause immunosuppresion by affecting the nuclear receptors is quite prevalent during this time. The subsequent ease at which the Th1 pathogens are able to spread, thanks to the drop in AMP production, may account for part of the reason why many women with CFS often find that occasionally during pregnancy, and almost always after giving birth, they struggle with an increase in cognitive and other symptoms.

According to New York University gynecologist Frederick R. Jelovsek MD, symptoms in CFS and fibromyalgia tend to become worse during the third trimester of pregnancy and during the postpartum period, when women with CFS often report worsening of pain and other symptoms. A 1998 New England Journal of Medicine article also found that in women with multiple sclerosis (a Th1 disease similar to CFS), rates of relapse tend to increase during the first three months postpartum.

However, the majority of women with CFS feel better during pregnancy (at least during the first two trimesters) and report that their disease symptoms seem to improve. Such women are reaping the palliation derived from the decrease in bacterial die-off that occurs when less of the antibmicrobial peptides target the Th1 pathogens. Because less bacteria are killed, immunopathology drops, leading to fewer inflammatory symptoms. However such feelings of “wellness” are short-lived, as after giving birth, such women feel the effects of the new bacteria they have almost surely accumulated during the previous months when AMP production was particularly low.

It doesn’t help that most women are told to take prenatal vitamins that contain vitamin D, which only adds to the excess amount of the substance in the body. “Pregnancy is a time when (these days) the mother is being laced with prenatal vitamins, even though the endometrium is expressing lots of extra 1,25-D during pregnancy itself. So in mothers who start off carrying a sufficient bacterial load, the first pregnancy might well allow proliferation to a point that the subsequent pregnancies could be affected,” states Marshall.

Indeed, a recent study by researchers the University of Hong Kong found that anxiety and depression often increase during pregnancy and are highly prevalent and strongly associated with postpartum depression.[19]

Among a consecutive sample of 357 pregnant women, Lee and colleagues found that more than half (54 percent) had anxiety and more than one third (37 percent) had signs of depression at some point during their pregnancies. Anxiety was more prevalent than depression at all stages of pregnancy.

Between 12 and 17 percent of women in the study were found to have both anxiety and depression at various stages of pregnancy, the researchers report in the medical journal Obstetrics and Gynecology. “Both antenatal anxiety and antenatal depression were found to be more prevalent and severe in the first and third trimesters,” Lee told Reuters Health. Anxiety and depression levels decreased from early to mid-pregnancy, but increased again late in pregnancy.

Since the mechanisms involved in pregnancy are incredibly complex and involve myriad changes – including the production of endorphins, cortisol, and many hormones – the rise in cognitive symptoms in women with CFS cannot be attributed solely to elevated 1,25-D. Yet, it certainly seems to be part of the puzzle.

The cognitive decline seen in women with CFS is serious and must be treated by killing the Th1 pathogens in the brain

While this paper probably raises more questions than it answers, several things are certain. The VDR is at the heart of chronic disease and it is doubtful that the overexpression of the VDR in the endometrium and the tendency of women with Th1 disease to suffer from a greater degree of cognitive dysfunction is simply due to chance.

Furthermore, the cognitive symptoms observed in women with CFS are incredibly debilitating and can only be reversed by a treatment such as the Marshall Protocol that targets the Th1 pathogens in the brain. This means that treatments such as cognitive behavioral therapy, which fail to address the root cause of cognitive symptoms, cannot be used to effectively treat cognitive decline in CFS.

A recent pilot study (Koolhaas, et al., 2008, Netherlands) reported that only 2% of CFS patients are “cured” by cognitive behavioral therapy (CBT), while the greatest share (38%) are actually adversely affected – most reporting substantial deterioration. The study proved to be a stark contrast to claims of psychiatrists and the Dutch Health Council that 70% of CFS patients improve after CBT. Previous studies have also ignored or denied the negative affects of CBT on ME/CFS patients. The pilot study, recently published in the Dutch medical magazine, Medisch Contact, concludes that the previously reported claims of 70% improvement in ME/CFS patients receiving CBT are vastly overstated and misleading.

In contrast, today, after a little over two years on the Marshall Protocol, Alayne feels that her cognitive function is a “gazillion times better.” According to Alayne, her improvements thus far have been absolutely stunning and very obvious.

“On the MP, my brain has been steadily healing over the past 26 months. My parents (academics) see me every 6 months or so and are able to describe the changes for me, which is great,” states Alayne. “I can read books again, although if they’re too intense or convoluted, it takes me time to understand them fully. My reasoning abilities are FAR improved as well, my math skills have returned (although I’m not sure I could teach it now), word recall is FAR better and I find myself at times uttering words I haven’t used for years.”

Alayne finds she can also spell much better again, and despite the occasional dyslexic moment, she no longer has to spell words phonetically.

She’s also able to understand and grasp new concepts far more easily, plus remember them and old ones she never really understood. “My ability to learn new software (that I couldn’t possibly do last summer), has suddenly opened up,” explains Alayne. “I was able to learn three new complicated programs within a few days last fall – ones that had completely stumped me a few months prior.”

Alayne’s level of motivation has increased greatly, up from levels of zero before the MP. “I set myself a schedule or list of ‘things to do’ and actually get them accomplished,” she states. “This is a big change. I still have some difficulties following through with some ‘things’ or projects on a timely basis, but all in all, it’s a lot better.”

In fact, Alayne is now starting a part-time job that will require her to do some freelance work that will stem from her own motivation. She’s also joined another writing group and is taking one of their courses. Since she can now remember numbers and percentages, she’s also able to do small business contracts for other people again.

“Finally, I think I’m more fun to be with,” confesses Alayne. “I’m more social and I’m eager to give feedback during conversations in my classes. I haven’t felt this way for so long.”

“We have seen no sign that the brain doesn’t heal,” says Marshall, who created the Protocol. “The adults recover all their lost faculties as they heal on the MP, and the several children on the MP, who have had a variety of difficulties, also are recovering fully. So our data (at this point) shows that the body heals as bacteria are killed and immune function is restored. All of the body. Including the brain.”

In order to emphasize the severity of cognitive dysfunction experienced by women with CFS, I leave you with the following reports from women who are using the Marshall Protocol to treat their CFS and the cognitive issues that accompany the disease. Happily, these women and others on the Marshall Protocol are experiencing strong immunopathology in the brain and some are at the point where symptoms are beginning to disappear. Complete recovery is expected once all the Th1 pathogens are targeted – a process that takes up to 3-5 years.

Name: Natalie
Age: 21
Location: Melbourne, Australia
Date of CFS/ME diagnosis: September 2006 tested positive for glandular fever/Epstein-Barr virus in august of 2005 & it never went away.
Marshall Protocol patient since: July 2007

At her worst, Natalie was unable to watch television. Even if she could stand to watch it on a rare occasion, she couldn’t process what was going on or follow a story line or, for example, why one character would respond to another character with a particular phrase. “I couldn’t listen to music (if music was switched on near me I would literally start to feel my physical symptoms get worse; if it kept playing I would end up paralyzed & unable to speak for several hours) or read at all,” states Natalie. “It would just look like words on a page. I could read the word, but I could not get my head around how the word I just read related to the last one.”

Natalie was also completely unable to use the computer. Before falling ill with CFS she had worked on computers all day at a nearby university where she was striving for a double degree in multimedia/e-commerce. “All of a sudden I couldn’t understand how to find anything,” Natalie describes. “I couldn’t write an email because I couldn’t construct a sentence.”

The Australian native also had difficulty understanding people who would speak to her. “Their sentences were like a bunch of words jumbled in the air,” Natalie confesses. “I would pick up about every 4th or 5th word, and try to piece it together, like when you’re learning a new language. To understand I had to either get the person to speak really slowly or get them to repeat what they said so I could pick up the other words.”

Natalie’s cognitive dysfunction reached a point where she was lying down flat on her back each day, trying to focus on her roof & using her hands to block out her light hanging from the roof, “because the more color I saw, or the more clutter, the harder my brain had to work just to see. Looking at my messy desk was a nightmare, so, understandably, night was the easiest time for me.. all black.”

“Now I am a lot better,” states Natalie. “When I say a lot better, I can now watch TV for about an hour at night (during the day tires me too much), I can use the PC from bed 3 or so hours a day on average, I can listen to about 1 music track a week and I can read short articles in magazines, etc.”

Natalie finds that it’s a lot easier to listen to music she knows by heart, rather than listen to new music she’s never heard before, because the different tunes are much more difficult to process.

She also still finds it very difficult to process two things at once. “If the TV is on, and someone is talking to me, I can’t isolate one from the other.. it’s two blasts of information coming at me at once & all I hear is noise,” states Natalie.

Name: Claire
Age: 52
Location: Virginia
Date of CFS/ME diagnosis: 1999 (but started having noticeable symptoms in 1963-4; disabled totally in 2003)
Marshall Protocol start date: December 2006

“At age 3, I was adding double digit numbers in my head,” states Clare. Then, at 7, Clare began to have CFS symptoms. She had difficulty learning how to tell time. Later, she could not memorize the multiplication tables or understand long division, which she had to teach herself later on her own. Despite these handicaps, she tested into advanced placement for English, Science, and Math in middle and high school. She stopped advance math classes just shy of calculus because her math understanding seemed to be mainly intuitive–that is, she could arrive at a solution without understanding or being able to explain how she was able to solve the problem.

Academically, throughout life, Clare could not memorize names and dates, although she could memorize a series of numbers. “The only reason I successfully navigated college and then a prestigious law school at age 35 was because I possessed excellent reasoning ability and the ability to memorize concepts–I could temporarily memorize just about anything but names and dates for the brief period needed to take exams,” states Clare.

In my 20s, I started “losing the nouns”, states Clare, “although I could describe the thing I could not name. Then, I started mixing up 3s with 8s and Es with Is when typing or using a calculator. And my reading speed slowed even more and I noticed that I was transposing not only letters but also words.” However, Clare’s reading comprehension remained high. But it became obvious that if someone provided her directions along with a list explaining what they were providing at the same time, she could not understand either command. “Explanations and directions or lists had to be carefully separated into full explanations first, followed by the details needing to be remembered,” Clare describes.

Then, a couple of years before becoming totally disabled at age 48, she noticed much to her dismay that her non-attorney co-workers – she had become a corporate attorney – were pointing out legal issues in meetings while giving her credit for having schooled them all so well in corporate law. “I say ‘much to my dismay’ because the legal issues they were pointing out were now eluding me,” states Clare.

Her vocabulary began to drop, as did the grade level at which she wrote, dropping from a post doc level, which she is unable to do now no matter the effort, to an 8th to 12th grade level. She could no longer beat any reasonably smart person at Scrabble.

Worst of all, she lost her ability to problem solve. “When considering a legal issue, it was like I was standing at the edge of a vast city neighborhood that I used to know like the back of my hand,” states Clare. “Before I lost my ability to problem solve, I could see in my mind’s eye many ways to get from one side of the neighborhood. After that skill slipped away, I would stand there helplessly on the edge of the neighborhood while remembering that I used to know the way. Making any decision became increasingly difficult.”

Then, Clare took an online IQ test that she had scored ridiculously high on just two years before and found that she could not get beyond the first set of questions. “I could not think my way out of a wet paper bag,” she confesses.

Within weeks, her energy was completely gone and it became obvious that she could not go on working. Within a month or two of that, she had cause to look at a deed of a piece of rental property she owned. “I couldn’t find my name in the deed and out of courtesy a local attorney looked up my deed in the courthouse to tell me the contents,” Clare recalls. “Later, when my mind was a bit clearer, I looked at my deed and saw that my name was all in caps and bolded.”

Her reading comprehension fell through the floor. Worse was her ability to comprehend anything that contained numbers in the text. She couldn’t fill out an EZ tax form. “I couldn’t remember my last name when the new receptionist in my doctor’s office asked me for it; I feigned deafness while I got out my checkbook to look up my name. I also got lost while driving in my own neighborhood a few times and had to pull over until I could figure out where I was,” she states.

When writing not only did Clare begin making all sorts of typographical errors, but she started substituting “to” for “two” and “too,” “there” for “their,” “do” for “due,” and started dropping “ed,” “ing,” “s” and many words from sentences, including consistently omitting the word “not” from sentences. Most of the time, she was unable to change a passive sentence into an active one.

“Sometimes when people are talking, it is as if with some words they are speaking in a foreign language,” says Clare. “I hear the words, but they don’t make sense. If feels like a form of age-related deafness, having to do with the inability to comprehend due to the loss of stereophonic sound (if that’s what it is called–I really can’t remember), but seems to be mainly word specific.”

“Surprisingly, I am still able to get the big picture from scanning some kinds of documents, and am surprised by my ability (i.e., most of the time when I am at my best) to get things at a conceptual level, although I find even scanning difficult or even not so difficult text very tiring and cannot attend to much of what I used to be able to attend to.’”

Name: Kathleen
Age: 53
Location: New York, New York
Date of CFS/ME diagnosis: 1986
Marshall Protocol start date: July 2004

As a child, Kathleen had no cognitive problems except for the fact that she had trouble telling time. In her 20’s, she worked as a pattern maker for Perry Ellis in New York City and Italy. Her work required challenging cognitive tasks since her intricate patterns had to be drawn to 32nd of an inch and her models had to work precisely when transposed from 2D to 3D.

However, after falling ill with CFS, Kathleen began to notice an extreme disconnect between her brain and her ability to communicate in both verbal and written form. “When I first fell ill with CFS, I felt like a scrim (the dark semi-transparent curtain that blocks the stage at some theaters) had fallen between my ability to communicate and my brain.”

She soon found that she “could think normally inside her head”, but could simply not write commands or give instructions. “It’s as if I don’t have access to utilize my brain, as if it simply isn’t connected to my hand and mouth,” states Kathleen. “I’m alive inside my own mind but can’t communicate that to the world.”

Kathleen soon found that she was constantly losing her train of thought. She struggled to answer questions or write down numbers in succession. She took an IQ test and found that her score had dropped by 30 points. “I started crying 3/4 way through the IQ test,” she confides. “I could tell how badly I was doing, but the most frustrating part was that I still felt smart inside my head but could still not answer the questions.”

Over time, her cognitive symptoms got worse. She finds it extremely difficult to write by hand because of the fact that she often inserts letters incorrectly between other parts of a word, and leaves spaces between words in the wrong places. “It takes me twice as long as a healthy person to compose an email,” states Kathleen. She is able to read, but when reading cannot remember names and dates, although she can retain concepts.

She is extremely bothered and exhausted by noise in general, and can only tolerate one source of noise at a time. “Multiple sources of input shut me down,” she states. “Whereas other people can filter out background noise at a restaurant, my brain doesn’t have the capacity to do that. All the different noises exhaust me to the point where sometimes I faint.”

Kathleen is still experiencing strong levels of neurological immunopathology, but has experienced a few periods of time during the MP where her cognitive function returned as never before. After taking an antibiotic break before getting dental surgery she “felt like Einstein”, and could think much more clearly, causing her to marvel, “my brain is still there!”

This past November her immunopathology toned down and she “felt inklings of herself that she hadn’t felt for 20+ years.” “I felt sort of extra confident,” she states and “as if the scrim in my brain had been lifted and I could peek through.”

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