Archive for the ‘Incoherent Rambling’ Category

New directions in dementia reversal

Sunday, April 15th, 2018

There is no need to restate the impact of dementia on families, institutions, and the social fabric.  Adult-onset dementia is typically diagnosed as Alzheimer’s when one of two conditions is present:

  • Amyloid-beta plaques (amyloidosis; first observed by Alois Alzheimer in 1907 and biochemically profiled by George Glenner in 1984)
  • Hippocampal atrophy in disproportion to global cortical atrophy

The vast majority of research funding to date has been directed at the theory that amyloid-beta plaque and tau tangle formation, consisting respectively of misfolded amyloid-beta and tau proteins, is the root cause of the observable neurodegeneration (neuron death) and symptomatic presentation of dementia.

Two alternative mechanisms to produce misfolded proteins are proposed in this theory: glutamate excitotoxicity, and attacks by reactive oxidative species.  The hypothesis is then that the disease can be stopped by preventing the misfolding from occurring.

I will not address this disease model or hypothesis of treatment as both have been and continue to be thoroughly explored in the literature. However, as no actionable solutions have yet arisen from the depths of this research, and it does not even attempt to address dementias with a non-Alzheimer’s pathology (i.e.: no amyloidosis) I will attempt to redraw the picture on a blank canvas.

(The following is pure conjecture and subject to revision and feedback)

Inflammation and oxidation

Free radicals (molecules which readily oxidize materials with which they come into contact) can be consumed in contaminated or toxic foods, and they can also be produced by the gut flora.  Free radicals are directly toxic to cells through oxidation attacks that produce reactive oxidative species.  Inflammatory cytokines are produced by the actions of free radicals, as well as directly by hostile periodontal and gut bacteria.  Free radicals directly attack the gut lining, while at the same time inflammatory cytokines induce an autoimmune response that misidentifies the gut lining as the source of inflammation and destroys it, causing gut permeability with respect to the blood and to the vagus nerve.

Inflammation and metabolic diseases are linked to Alzheimer’s.  The gut microbiome can contain pathogens which are a source of inflammationFecal transplantation is used in Europe to treat metabolic syndromeIntestinal inflammation is linked to the development of Parkinson’s disease, with the vagus nerve as the suspect vector.  In Parkinson’s, aromatic compounds are excreted in sebum that can be used to identify sufferers with 100% accuracy.

Excess iron is a major contributor to free radical formation.  An elevated body iron level has been linked to heart attack, stroke, cancer, diabetes, and Alzheimer’sCannabidiol was shown to restore memory and mitochondrial function as well as inhibit apoptosis in the brains of iron-overloaded rats.

While the immediate neurodegeneration during a stroke event is likely due to glutamate excitotoxicity, a process which is also involved in epileptic seizures and is entirely deactivated by cannabidiol, it seems that the ongoing neurodegeneration and cognitive impairment subsequent to a stroke is actually caused by central nervous system inflammation, possibly due to dormant bacterial infection.  Perispinal etanercept administration scavenges the inflammatory cytokine TNF from the central nervous system and produces rapid improvement in stroke victims.

While steroids have been used to suppress inflammation in Alzheimer’s victims, scavenging of the TNF cytokine itself by perispinal etanercept administration produces rapid improvement in aged dementia victims, documented on video, for whom chronic inflammation rather than neurodegeneration is presumably the immediate cause of cognitive impairment — although TNF itself has also been shown to produce cognitive impairment even in the absence of neurodegeneration.  One could surmise that this could be because mitochondria switch from producing energy to producing toxins during inflammation.  Cannabidiol has a potent anti-inflammatory (including anti-TNF) and immunosuppressive effect as well.

TNF has been proposed as the culprit in chronic cognitive dysfunction.  Despite persuasive clinical evidence that eliminating TNF and thus TNF-triggered inflammation restores lost cognitive performance, the theory itself remains unsatisfying because it does not propose a causal mechanism for the overproduction of TNF itself.

Vagal nerve stimulation has been shown to inhibit the production of inflammatory cytokines.

Inflammation from environmental pollution causes Alzheimer precursor anomalies to appear in the brains of infants.

Chronic inflammation is suspected to be the cause of depression and anxiety disorders.

Studies have shown that blueberry powder and blueberry vinegar relieve mild cognitive impairment.  One anecdote further demonstrated that a strict berry, greens, and sweet potato diet initiated a complete recovery of dementia.  Blueberries, as well as blackberries, raspberries, and blackcurrants, contain anthocyanins that have antioxidant effects through mechanisms that are not fully understood.  However, one thing that is known is that blueberries inhibit the production of TNF. Pomegranate extract and juice were independently shown to aid in stroke recovery and to reverse mild cognitive impairment.   One serving of tart cherry juice per day improved sleep and reduced inflammation in only a few days.  Individuals in a study who ate approximately one serving of leafy greens per day performed on average as if they were 11 years younger on a standard cognitive assessment testA number of flavonoids have demonstrated suppression of TNF and TNF secretion at extremely low doses.  Sulforaphane, a flavonoid that can be produced in quantity from broccoli sprouts through an enzymatic process, showed an ability to inhibit amlyoid-beta formation, inflammation, and cognitive deficits in separate Chinese and Korean mouse studies.  Sterubin, the main constituent in Yerba santa, was found to have potent anti-inflammatory and neuroprotective effect in vitro.  Fisein, a flavonoid found in strawberries, apples, grapes, and onions, was found to reduce cognitive deficits and inflammation in mice, to induce autophagy of p-tau as well as to cross the blood-brain barrier effectively.

Sulforaphane, a phytochemical found in broccoli, cabbages and related vegetables, was claimed in a Chinese study to have triggered neural stem cell proliferation and differentiation into new neurons with no toxicity.  Sulforaphane also inhibits secretion of TNF.

The experimental drug J147, a pyrazole derivative of curcumin, was found to prevent and reverse Alzheimer’s in mice genetically engineered to express amyloid-beta.  In mice genetically engineered to rapidly age, J147 was able to halt many aging markers and maintain cognitive and motor performance.  The patent covering J147 and a related curcumin derivative, CNB-001, describes many anti-inflammatory, anti-aging, and anti-Alzheimer’s properties.  J147’s anti-aging and antioxidant properties appear to be due to its ability to bind to and downregulate the mitochondrial ATP synthase complexJ147 is currently in a phase I FDA trial.

B vitamin supplementation slowed AD-typical brain atrophy in patients diagnosed with mild cognitive impairmentGingko biloba extract was found to be as effective as Aricept in slowing the progression of mild cognitive impairment.

An anti-inflammatory medical diet fed to mice genetically engineered to develop Alzheimer’s disease completely eliminated the cognitive symptoms while reducing amyloid-beta levels.

Metabolic factors and autophagy

Autophagy impairment is characteristic of Alzheimer’s and other neurodegenerative disorders.  Intermittent fasting has been shown to induce neuronal autophagy.

Insulin resistance is strongly associated with Alzheimer’s and with the underlying amyloid-beta and tau anomaliesInsulin sensitivity (inverse resistance) is increased with high-intensity interval training.  Tying these threads together, as of 2018 regular exercise is officially recommended and drugs considered ineffective in the treatment of cognitive impairment.  A study showed that simply restoring impaired hearing and eyesight significantly slowed the rate of cognitive decline.

Alzheimer’s has recently been unofficially dubbed “type 3 diabetes“.  Alzheimer’s and type 2 diabetes have both been linked to chronic spirochete infection.  Simple carbohydrates such as sugars are the key dietary factors in the insulin resistance model, and it happens that sugars are also the only energy source for most spirochete bacteria.  There is only one spirochete species, Spirochaeta isovalerica which does not use sugars but rather uses the proteinogenic branched-chain amino acids leucineisoleucine, and valine for food.  In this context, it may be of interest to note that athletic supplementation with branched-chain amino acids is suspected to cause an ALS-like syndrome and that individuals diagnosed with ALS have subsequently died of Lyme disease.

Drugs that are commonly prescribed for metabolic issues, such as statins, are known to produce reversible dementia.

Periodontitis

Since the early 20th century, periodontal pathogens have been implicated in heart disease, originally due to the observations of dentist Weston Price of heart attacks occurring shortly after root canal work.  Since then, periodontitis has been linked to high blood pressurechronic back pain, and, yes, Alzheimer’s disease.  A C-reactive protein (CRP) test can reveal systemic inflammation rooted in periodontitis.

What’s the connection?  Common periodontal bacteria emit inflammatory cytokines which cause autoimmune destruction of gum and bone tissue and subsequent tooth detachment.  Among those periodontal bacteria are spirochetesOral spirochetes have been shown to migrate through gum tissue into the bodySpirochetes are a key suspect in an infectious model of dementia.

Finally, P. gingivalis, the bacterium that causes periodontitis, has been separately implicated in multiple in vitro studies as a cause of Alzheimer’s.  Recently, P. gingivalis has been directly implicated in Alzheimer’s in vivo, with targeted protease inhibitors introduced to eliminate its toxic effects.

Pathogens

Viruses in the herpes simplex family are implicated in recent research as a root cause of dementia, using mice.  Separately, the HSV1 virus was shown to induce Alzheimer’s-typical plaques and tangles in neural tissue, and the plaques and tangles contained viral DNA; subsequent research showed that untreated herpes simplex (HSV1) and varicella zoster (VZV) infections were associated with a significantly greater risk of later senile dementia.  In the HSV hypothesis, the formation of amyloid-beta plaques is a reactive, protective mechanism, rather than an independent pathological mechanism.  It has been known for decades that herpes simplex viruses are unable to replicate in the presence of the cannabinoid THCThe outcome of utilizing cannabinoids seems to depend on whether inflammation is beneficial or pathogenic in a specific case.

Separately, increased loads of the human herpesviruses HHV-6 and HHV-7 have been confirmed in the brains of deceased Alzheimer’s patientsImmune systems of Alzheimer’s patients showed a decreased response to HHV-6.  For various reasons, active HHV-6 brain infection is very difficult to test for.

A controlled study found evidence of fungal infection in the entorhinal cortex/hippocampus (ERH) region of the brains of Alzheimer’s patients.

Influenza infection was linked to the development of Parkinson’s in birds and mice.  HIV brain infection causes the same biological markers implicated in Alzheimer’s.

A new theory divides Alzheimer’s victims into three categories, and identifies inhalational mycotoxins as the cause of neurodegeneration in the third category.  Patients in this category are typically younger and healthier and may comprise as much as 10% of the patient population.  A treatment protocol is available to halt the neurodegeneration and reverse the cognitive decline.

Lyme disease, which is caused by the spirochete borrelia burgdorferi, commonly causes a variety of cognitive impairments, and causes severe dementia in a small number of cases – including that associated with cerebral infarct (global cortical atrophy), which is reversible by clearing the pathogenSpirochete infection has been characterized as a parasitic symbiotic relationship, in contrast to typical pathogenic bacterial infections.

It should be noted that Lyme disease is notoriously difficult to diagnose because in dormancy it produces false negatives with PCR-based assay, and because many people without active infections carry Lyme antibodies, so the presence of Lyme antibodies in blood serum is also inconclusive.

A new theory of Alzheimer’s pathology is that Lyme and periodontal spirochetes infect the central nervous system and cause the symptoms of Alzheimer’s.  In this theory, these spirochetes are able to hide themselves in neural tissue under a protective biofilm while producing the inflammation and autoimmune response that causes amyloid-beta plaque formation and neurodegeneration.  Lyme biofilms and cystic/granular spirochete configurations were directly observed inside amyloid-beta plaques in 100 out of 100 Alzheimer’s postmortem brain tissue samplesThe presence of microbe biofilms in Alzheimer’s plaques was independently confirmed through staining. Alzheimer’s plaques were found to contain both human-derived and spirochete-derived amyloid-beta proteins. Interestingly, the cannabinoid THC both destroys the amlyoid-beta plaques and inhibits the associated inflammatory response, due to THC’s selective anti-TNF activity. It is worth noting that TNF suppression has been shown to interfere with anti-spirochete antibiotic therapy (another report here); however, that could be a useful property to exploit in identifying a concealed and/or unknown pathogen, as spirochetes are notoriously difficult to culture outside of host tissue. That is, one might conduct an anti-inflammatory protocol with drugs or anti-inflammatory herbs as a ruse to entice the spirochete out of dormancy so that the pathogen could be identified. New testing protocols continue to be developed to meet the diagnostic challenge spirochetes present.

Even when the spirochete is eradicated, inflammation can persist long afterwards. Eradication of spirochetes poses two more problems: animals whose spirochete infections were measurably eradicated were still able to pass active infections to ticks (1, 2, 3), and material from destroyed spirochetes is still able to trigger inflammation. However, levels of inflammatory cytokines are lower in chronically infected individuals (>6 mo.). This may be because the biofilm morphology of spirochetes allows the bacteria to persist in a state that does not activate the host immune system, nor respond to typical long-term antibiotic treatment often utilized against “chronic Lyme”. An antibiotic protocol based on daptomycin has been found to destroy biofilms in vitroTraditional herbal medicine such as cinnamon oil, clove bud oil, oregano/thyme oil, ethyl alcohol tinctures of stevia leaf (and — one might surmise — agents which are capable of dissolving amyloid-beta plaques such as cannabinoids) are demonstrated to be capable of destroying spirochete biofilms in vitro and in tissue samples.  Agents which are known to destroy other microbial biofilms may be of particular service: cinnamon oil was found to destroy Candida and MRSA (1, 2) biofilms, while thyme oil was also found to destroy MRSA biofilmsEpsilon-polylysine, a peptide that is used as a natural food preservative, was found to destroy Pseudomonas aeruginosa and aspergillosis biofilms.  While liposomal encapsulations of oils are typically required to cross the blood-brain barrier, oregano oil has psychoactive effects in its default stateA universal protocol remains elusive; however, Alzheimer’s plaques have been attacked with varying success with the antibiotics clioquinol (2001), doxycycline and rifampin (2003), ceftriaxone (2016), and an antibiotic cocktail (2016).

There is a hypothesis that the root cause of the devastating immune syndrome known as AIDS is actually the spirochete that causes syphilis, and that HIV is merely comorbidThe syphilis spirochete is also capable of causing neurodegeneration and dementia that mimics Alzheimer’s. Treatment with the antibiotic doxycycline reduced the number of Alzheimer’s plaques and relieved cognitive impairment in mice. The Lyme spirochete is present in semen and vaginal secretions, raising implications for non-tick-centric epidemiology.  Intestinal spirochete infection is endemic in homosexual men and HIV-infected individuals.

Celebrity Kris Kristofferson suffered dementia for years and was misdiagnosed with Alzheimer’s before the root cause was found to be Lyme diseaseCommentators rejected the diagnosis of chronic Lyme as facially invalid, but failed to propose an alternative (non-iatrogenic) pathogenesis that fit the same facts. Several cases of reversible dementia rooted in Lyme infection have been documented.

To weave an even more intriguing web, Lyme-infected tick-borne nematode parasites have been found in the brains of multiple sclerosis, brain cancer, and Lewy body dementia victimsDoxycycline, which is also the primary antibiotic used in treating Lyme disease, kills filarial nematodes by killing the symbiotic bacterium generally required in their reproductionA filarial Acanthocheilonema nematode infects around 30% of lone star ticks; however, Acanthocheilonema is one of the few filarial nematodes lacking the symbiont.

Schizophrenia has been linked to endogenous retrovirus infection. Intriguingly, treatment with the antibiotic minocycline was found to reverse schizophrenic symptoms in multiple studies in 2010, 2014, and 2017Minocycline was also found to halt the progression of multiple sclerosis.  Although minocycline is most commonly used as an acne medication, it is in the same tetracycline family as doxycycline, the most commonly used antibiotic in treating Lyme disease.  For some reason, the theorized mechanism of effect of minocycline is primarily anti-inflammatory rather than primarily anti-microbial, even though spirochetes have been stained and cultured from the cerebrospinal fluid of MS patients for nearly a century.  Numerous cases of patients suffering from various mental illnesses and subsequently making a full recovery after an infection with a high fever, or after a bone marrow transplant, have been documented.  Common spirochetes cannot survive above 105.8 degrees Fahrenheit, with optimal reproduction occurring at significantly lower temperatures, and induced hyperthermia/’pyrotherapy’ continues to be utilized in management of persistent spirochete infections.

The Lyme spirochete has been documented to cause new-onset panic disorder (1, 2).  Panic disorder comorbidity with schizophrenia has enough distinct features from other schizophrenia manifestations that it has been suggested this comorbidity should be recharacterizedModerate to severe cognitive impairment is characteristic of schizophrenia, while schizophrenia medications are implicated in brain atrophy.  However, recent research demonstrates that at-risk individuals who later develop full psychosis have a steeper rate of gray matter loss; the authors posit that the missing link between schizophrenia and brain atrophy is neuroinflammation rather than medication.  As it happens, a single 600mg daily dose of the cannabinoid cannabidiol given over 40 months eradicated structural brain differences associated with a high risk of psychosis.

A presentation of stroke which turns out to be rooted in infection with the Lyme spirochete is documented again and again in the literature (1, 2, 3).

(Is there further evidence for spirochete-viral coinfections in various chronic neurological diseases?)

A pathogen ensemble could explain the “mixed pathology” often observed in brain tissue autopsies of dementia patients.

Stem cell neurogenesis

A stem cell treatment has been approved in Japan for Alzheimer’s.  A phase I trial is underway in the U.S. with observed restoration of cognitive performance and hippocampal volume subsequent to injection with neural stem cells derived from waist fat.

However, neuroplasticity and mitochrondrial health may be important factors limiting the success of these treatments.

Whole turmeric contains a terpene ar-turmerone which has been shown in rats to increase the proliferation of neural stem cells as well as their differentiation into healthy neurons.

Neuroplasticity and mitochondria

Neuroplasticity refers to the generation of new synapses, the connections between neurons in the brain’s neural network.  A synapse requires a physical point of contact between two neurons.  A typical synapse occurs at the point where a dendrite of one neuron contacts the dendrite of another neuron.  When neuroplastic conditions are present, new connections are being made through a combination of neurogenesis (increasing neuron density) and dendritic outgrowth.

While neuroplasticity is known to decrease with age, loss of existing dendritic spines is characteristic in Alzheimer’s.  Dendrite loss may be an effect of out-of-control synaptic pruning – an otherwise normal process that is mediated by inflammatory cytokines ‘tagging’ a synapse for destructionLoss of dendrites does not necessarily destroy memories embedded in the neural network, but rather prevents access to them, which can be restored.  It has been found that serotonergic psychedelic drugs, commonly referred to as entheogens, stimulate dendritic outgrowth.  Ketamine, a NMDA receptor antagonist with fast-acting antidepressant qualities, stimulates dendritic spine outgrowth and regrowth of spines damaged by chronic stress in mice.

Entheogens as a family are non-specific serotonin receptor agonists, but primarily bind to 5-HT2 receptors5-HT2 receptor loss is characteristic of Alzheimer’s patients and is implicated in the behavioral and psychological symptoms of dementia.  However, 5-HT2 receptor loss precedes the associated neurodegeneration.  The 5-HT2 receptor loss could be due to downregulation subsequent to serotonin misregulation by a third factor.  One study posits a connection between chronic stress and hyperserotonism which then causes the development of a serotonin resistance. Another study showed that low levels of serotonin transporter protein (SERT) is correlated with dementia, implying that impaired serotonin transport is associated with serotonin receptor loss. If impaired serotonin transport and subsequent serotonin resistance is the mechanism by which 5-HT2 receptor loss follows, a supportive therapy is conceivable in which natural serotonin production is suppressed and simultaneously, a non-monoamine 5-HT2 agonist such as LSD is administered to activate 5-HT2 receptors in its place.

Since the sensory-altering effects of entheogens are caused by their binding to the 5-HT2A serotonin receptor, if psychoactive side effects of entheogen administration are too severe, the side effects can be selectively attenuated with a 5-HT2A blocker.  Curiously, it has been shown that activation of the same 5-HT2A receptor with microdose quantities of a drug similar to LSD potently blocks TNF-alpha induced inflammation in the whole body.  The activation of 5-HT2A receptors and not the particular agent that activates them seems to be the key process, as other non-psychoactive 5-HT2A agonists have been shown to block TNF-induced inflammationChronic inflammation is suspected to be the root cause of anxiety and depression disordersLSD itself is currently being studied as a treatment for anxiety and depression pursuant to the quantity of anecdotes indicating its efficacy in those diseases.

Where synaptic paths are present, proper synaptic function is dependent on healthy mitochondriaMitochondrial dysfunction is a precursor to Alzheimer’sThe vitamin NR (nicotinamide riboside) has been shown to restore neural mitochrondria function, destroy amyloid plaques, and restore cognitive performance.

Mitochondrial transplants have been effective in reviving degenerated muscle tissue; the healthy mitochondria need not even be injected directly into the degenerated tissue to find their ‘home’.  One could surmise that neural mitochondrial transplant would have a similar safety profile.

Meditation has been shown to increase the proportion of the hippocampus and areas of the frontal cortex relative to other brain regions.  One could surmise that neurons can thus be recruited to different networks according to utilization, important in the context of mental illness.

Mental illness and sleep quality

Moderate to severe anxietydepression, and chronic stress are independent risk factors for dementia.  Pseudodementia is cognitive impairment that is caused by such mental illness rather than an organic process.  Pseudodementia can be treated.  However, it is unclear whether pseudodementia is a separate process from the observable organic processes in dementia.  What we know is that depression and anxiety are comorbid with dementia, with 54% of dementia patients exhibiting both depression and anxiety.  While cause and effect is unclear, untreated anxiety and depression is detrimental to quality of life, whether or not dementia is present or would otherwise follow.  As with various forms of dementia, harmful gut bacteria are increasingly implicated in mental illnesses as varied as anxiety and schizophreniaSchizophrenia could be predicted from the microbiome of patients’ stool samples in one study.

One could surmise that the ineffectiveness of SSRIs in reversing dementia-related depression and anxiety is due to the aforementioned low levels of serotonin transporter protein (SERT) and serotonin receptor loss that are implicated in dementia, and the resulting inference that serotonin itself is critically low or absent such that the SSRI has no effect.

Furthermore, SSRIs are known to disrupt sleep in the elderly, and poor sleep quality is a risk factor for dementia.  The latter study inexplicably excluded REM sleep as an object of study.  A later study found that REM sleep anomalies are indeed a predictor of dementia.  While several mechanisms for the connection of sleep quality to dementia have been explored, the most promising link is an observed increased flow of cerebrospinal fluid (CSF) due to neuron contraction during sleep.

If SSRIs are inappropriate for people experiencing dementia, what else could terminate anxiety and depression?

A variant of cognitive-behavioral therapy called PATH was successful in reducing depression in a population with cognitive impairment and treatment-resistant depression.

Hypnosis has been shown to be effective in reducing cognitive impairment and improving quality of life in dementia patients.

Transcranial magnetic stimulation has been demonstrated to halt Alzheimer’s-related cognitive decline and is currently in a FDA trial.  While TMS is known to alleviate depression and anxiety in non-Alzheimer’s patients, whether that effect maps to Alzheimer’s patients with their differing serotonin configuration is unknown.

The dissociative anesthetic ketamine has recently been shown to be the most powerful and fastest-acting antidepressant yet known, confirming widespread anecdotes of its efficacy against treatment-resistant depression and relatively minor side effects.  In mice, an immediate antidepressant effect is followed by dendritic spine outgrowth accompanying persisting antidepressant effects.  Interestingly, ketamine is also a NMDA calcium channel blocker; under the glutamate excitotoxicity theory of dementia, it therefore serves the same purpose as the widely prescribed Alzheimer’s drug, memantine, in blocking the calcium ion channel that – the theory holds – excessive levels of glutamate would otherwise overactivate.  However, cannabidiol prevents glutamate excitotoxicity with a much better safety profile and fewer side effects than agents acting on NMDA receptors.

The serotonergic psychedelics psilocybin, LSD, and MDMA have all been shown to alleviate treatment-resistent depression and/or PTSD.  Since they bind directly to serotonin receptors, they can be effective even in individuals with low and/or misregulated serotonin.

Nicotine has been shown to control depression, and its use is widely observed in mentally ill populations as a suspected form of self-medicationNicotine use has been shown to be preventive of Alzheimer’s and Parkinson’s and improves cognitive performance, with studies still ongoing in the areaNicotine is also a known anti-inflammatory and immunosuppressant.  One could surmise that since an autoimmune process triggered by chronic inflammation is implicated in various forms of dementia, nicotine’s benefits are in that it is suppressive of the autoimmune reaction as well as the underlying inflammatory cytokines.

Delivery problems

While several agents like curcumin, resveratrol, cannabidiol, and the steroid etanercept are known to have, variously, effective amyloid-beta destruction and inflammatory cytokine scavenging effects as well as anti-oxidant effects, delivering those agents to the central nervous system poses a challenge because of intestinal absorption, conversion in the liver, and the blood-brain barrier (BBB).  While active systemic inflammation increases the permeability of the blood-brain barrier, and an agent can be engineered to cross a healthy blood-brain barrier, an ingested agent still has to be either properly absorbed by the gut or leak through the gut lining to enter the blood in the first place.

The “Longvida” formulation of curcumin is an example of a liposomal encapsulation.  It is able to deliver curcumin, a powerful antioxidant, anti-inflammatory, amyloid-beta plaque inhibitor, and autophagic stimulator, to the central nervous system via the BBB.  Liposomal encapsulation is also used with resveratrol, a polyphenol found in red wine.  When delivered to the central nervous system across the BBB, liposomal resveratrol is a potent antioxidant and amyloid-beta scavenger.

The vagus nerve is an important nerve that connects the brain stem to the heart, lungs, and gut in order to exercise control of involuntary body functions such as bowel motility.  Constipation is extremely common in older individuals and dementia patients, and one could surmise that neurodegeneration of the vagus nerve or the brain stem is the root cause.  The carotid sheath is a conduit for the vagus nerve.  Topical application of essential oils to the ganglia of the vagus nerve behind the ears is anecdotally effective in delivery of those oils to the nerve.  Since the vagus nerve connection to the gut is also implicated in the development of Parkinson’s disease, with direct observation of Parkinson’s proteins being transported from the gut to the brain, one could reason that beneficial agents could traverse the vagus nerve as well, perhaps via the carotid sheath as a conduit.  A study showed via fluorescent analysis that the cells of the intestinal lining are connected directly to vagal neurons via synapse-like structuresLaser stimulation of the gut lining stimulated the release of brain dopamine in mice, further illustrating a direct gut-brain connection.

As discussed above, etanercept is a steroid, immunosuppressant, and potent TNF scavenger.  Perispinal administration of etanercept is performed via injection into the external vertebral venous plexus, after which it diffuses through the cerebrospinal venous system.  Historically, cocaine was administered in a similar manner.  Perispinal administration can be roughly considered a lower-risk and less complicated form of an epidural injection.

Aromatherapy has seen a variety of applications, with mostly anecdotal results and not much in the way of peer-reviewed, double-blind studies.  However, a plausible mechanism for the delivery of aromatherapy agents to the central nervous system comes in the unlikely form of the brain-eating amoeba, a freshwater pathogen that enters the central nervous system via the nasal olfactory nervous passageways.  One could reason that a vaporized aromatherapy agent could enter the central nervous system in the same manner.

Adventures in a Windows XP hard drive transplant

Thursday, February 14th, 2008

Donor: Intel P4, Intel chipset, SATA disk

Recipient: AMD Opteron, NForce Pro chipset, SCSI disk

  • The first thing that was encountered is a STOP 0x0000007B INACCESSIBLE_BOOT_DEVICE error. This is because the hard disk controller has changed and Windows does not have the new controller in its CriticalDeviceDatabase. See the Knowledgebase article. The best way to avoid this is to install the driver in question before dismantling the donor system, but when the donor system has died, such planning is not possible. There is a way to “fix” the transplanted disk by hooking it up as a temporary slave disk, that is outlined in this article. The basic strategy is to copy over the entire CriticalDeviceDatabase branch from a working installation, and also to be sure that any necessary driver services that it refers to are also added in, and obviously that the appropriate driver files themselves are copied in.
  • The second thing that was encountered was some driver for the donor system was loading, not finding its associated hardware, and barfing a different STOP error. The “ghosted” devices that traditionally are shown in Device Manager in Safe Mode are not shown in Windows XP. There is a way to cause them to be shown so that they can be removed to stop the offending driver from loading.
  • The last thing that was encountered was a piece of dumb luck caused by moving from an Intel to an AMD processor, specifically with Service Pack 2. It turns out that the SP2 Intel processor driver is too stupid to realize that it is being loaded on a non-Intel CPU, and barfs out a STOP 0x0000007E (0xC0000005, …). What’s worse is that Microsoft initially posted an incorrect fix in their KB article, and then instead of correcting the instructions, they removed the fix from the article entirely. Consequently, third party sites had to archive the fix. Basically, in CurrentControlSet as well as the archived ControlSets, change the “Start” value from 1 to 4 for all instances of the ‘Intelppm’ service.

2 frickin’ days! Thanks, Microsoft!

And people ask me why I make such a point of avoiding Microsoft products…

Tall people and success

Thursday, July 26th, 2007

The secret to why tall people seem to be more successful and powerful?

It’s all related to the height of a standard cubicle.

Short people can’t monitor their employees as well because they can’t see over the cubicles as they walk past or stand nearby.

The obvious solution is to cut down the height of a standard cubicle, until it is comparable to the height of a standard picket fence.

Then short people will have true equal opportunity!

Idea for blog spam

Wednesday, July 18th, 2007

This only works if blog spamming is a compute and/or bandwidth intensive activity.

Publish a standard file or URL like robots.txt that blogs can provide in order to notify a robot that comments are moderated.

By market forces, robots should check this so they do not waste their computing time and bandwidth spamming moderated blogs.

Alternatively. Remember those copy protection things in computer games of the 80’s? “Please type in the third word of the second paragraph on the eighth page.”

This could be used in blog captchas too. Make the instructions of which word(s) to find just convoluted enough to avoid machine parsing, and you’re good to go. The instructions can then be generated on the fly.

Proof of concept to follow.

Bank of America “security”

Tuesday, June 26th, 2007

When you’re in a Bank of America online banking session, if your session goes idle for too long, the site pops up an alert box letting you know that your session has timed out due to inactivity. The alert box then redirects to a page which destroys your session and presents a login. This scheme can be easily defeated by immediately refreshing the page after dismissing the alert box, before the redirect occurs… thanks, BOA.

Is it a person or is it not?

Monday, June 25th, 2007

Court documents: Cop killed pregnant woman in her home

Investigators believe policeman Bobby Lee Cutts Jr. killed his pregnant ex-girlfriend Jessie Marie Davis at her home about eleven days ago, according to court documents released Monday.

Cutts faces two counts of murder and is expected to appear in court Monday afternoon.

Unborn Victims of Violence Act

The fundamental moral divide on the issue of abortion is whether the fetus is a part of the mother, giving the mother the exclusive right to determine its fate under the 14th Amendment, or an independent being, giving the state the power to prevent harm to it — even when authorized or committed by the mother.

Yet while it seems that even though Roe v. Wade decided the issue in favor of the fetus being a part of the mother, in that it read an unprecedented right to privacy into 14th Amendment, it seems that in criminal law the fetus is treated as a separate person, invoking a separate charge to the perpretrator equal to that associated with the mother’s death.

Is it possible to really have it both ways in a moral system based on consistent principles?

It’s Stamp Hike Day!

Monday, May 14th, 2007

A tremendously cheap way to show goodwill towards your community on Stamp Hike Day

Buy the 2 cent stamps you need, then buy another quarter’s worth. Hand them out freely to anyone waiting in line just to stamp and mail a few envelopes.

A tremendously easy way to get yourself shot on Stamp Hike Day

Invest $2 in a roll of 100 2 cent stamps, place a sign on the lobby door that says “Out of 2 cent stamps, Come back tomorrow”, and proceed to loiter. Inform any frustrated looking patrons who turn around the moment they read the sign that you have some extra 2 cent stamps you might part with, for the right price.

Idea for seamless VPN use

Tuesday, May 1st, 2007

A network can publish a VPNDB record containing the IPv4 address, IPv6 address, VPN protocol, and other information about the network’s VPN server in its DNS zone.

A modified TCP stack could query the VPNDB record and establish the VPN session with the target network on the user’s behalf, if not already established, before initiating the connection to the target machine as usual.

Running a public VPN server with this scheme would ensure that a user is not inconvenienced with special setup for your network in order to access your network services in a secure fashion. For example, an internal server that requires end-to-end stream security, but uses a protocol that is known to be insecure, can be configured to refuse connections that do not originate from the internal network or the public VPN server. Another potential use would be in encrypting by default as much traffic as possible in order to foil law enforcement data loggers.

Of course, with respect to firewalling, a public VPN server should be treated with the same caution that an open wireless access point would.

Things to do with an idle broadband connection

Tuesday, May 1st, 2007
  • Obtain a La Fonera FON router and install it behind a caching (for speed) and filtering (for illegal material) proxy server for others in your area to use either for a fee or in exchange for sharing their connections. (You could also provide a non-FON router, or use a hacked lafonera firmware, implementing a more strict filtering proxy for unauthenticated access.) Make sure that the router does not allow users to access the rest of your internal network.
  • Run a Freenet or GNUnet node to support anonymous distributed publishing networks. Set up a BitTorrent tracker to host out-of-print video, music, books, and software — heeding all necessary DMCA precautions.
  • Run a Tor onion router to provide others around the world with anonymous surfing.
  • Participate in a distributed computing project that tickles your fancy.
  • Have your router also act as a remote control to send Wake-On-LAN packets to hibernating machines when you need to remotely access them, allowing you to leave your machines in hibernation most of the time to save power.
  • Have your router act as a Asterisk telecommunications server for incoming voice mail, faxes, and remote access modem calls for PPP or for a BBS. Fax and modem calls can be differentiated with adaptive answering built-in to the modem, but voice mail and data calls must be differentiated through software heuristics or through Distinctive Ring service.

A solution to the abuse of obvious patents

Monday, April 30th, 2007

One aspect of patent law reform focuses on the issue that many patents are issued for techniques that are not novel or non-obvious, or for which prior art exists, or the patent is non-specific enough to be more like patenting an idea than a process. Patents are thrown out by the courts on a regular basis.

The problem is that the patent must be thrown out in court once issued, necessitating that the target of a patent lawsuit spends his own money in a gamble to try to convince the court that the patent is invalid. This is compounded by the fact that the USPTO examiner has no interest in closely examining patents to ensure that they are actually valid, because USPTO is paid the same fee whether the patent is valid or not.

So we have the current morass where a bunch of dubious patents are thrown at the USPTO, some of which “stick” and are granted, and then the grantee immediately embarks on a litigation strategy to extract as much money as possible through licensing before one day they pick the wrong fight and the patent is invalidated. Unfortunately, the companies who chose to “pay the piper” instead of fighting just threw their money down a hole.

Proposal

Patent royalties should, by law, be secured in some form so that they may be returned to the licensee if the licensor’s patent is invalidated at any later point.

How it works

This could be accomplished by placing royalties in escrow and only allowing the licensor to access the interest until the end of the patent period. This would not work for companies who depend on license income to sustain their R&D budget.

Alternatively, the licensor should be allowed to purchase patent invalidation insurance from a private party who then possesses bonds covering the sum total of royalties paid out. If the patent is invalidated, the insurance company pays back the licensees and terminates the policy.

Private insurance patent examiners, unlike the USPTO, have a fiscal stake in the validity of the patent. They will exhaustively examine prior art, isolate the novel and non-obvious components of the patent, and ensure that the patent is specific enough to meet the demands of case law. The weaker the patent, the more expensive the insurance will be. The company then has to choose between paying a higher premium or cleaning up their patents.

This idea would be a win for technology firms who can be assured that if another company comes knocking for royalties on an iffy patent, that even if today they make the choice to license, the patent fees will be returned to them later if the patent turns out to be worthless. Several companies in the same industry could even pool their resources to attempt to get patents overturned that they all share a stake in. The more these companies have paid out in royalties, the more desperately they will work to build a case against the patent, and if it is overturned, everybody wins except the former holder of an abusive patent.

This idea is the free market at its best attempting to minimize the harms of the patent monopoly while allowing all of its fruits to continue unabated.