The Overblown Cytokine Storm and 225G from 1918

225G is not new and this "Cytokine Storm" phraseology is overblown.

The public perception of 225G and the media linkage to hemorrhagic pneumonia is new. 

These Hydra Effect viral backgrounds carrying 225G within ΣPF11 are, in fact, very dangerous strains for what they are doing now and, more importantly, for where they are going . . . no question exists about that risk tendency.  The only question is why hasn't the science community driven the clinical linkages to the forefront before this week?  Fatal outcomes have been documented on record since July in multiple cases from Brasil.

Obverse speculation is also dangerous, especially risky when speculating based on poorly defined terms.  Banter and rant occur with much vitriol and then everyone who needs the data stops listening.  Few conversations are more demoralising that the ones where you have no anchor point on the major terms.

A primary topic of concern is Cytokinic Dysregulation.  Reliance on inspecific phrases like "Cytokine Storm" in the media will only continue to misinform the public on a process that is far less understood than the lead investigators would like to admit.

All of which returns us to the basic categories:

• What we do know?
• What we don't know?

What we do know?

Now that 225G matched clinical data is available, however limited, a potential correlation is being drawn on lung tropism. The standing bench studies, including the Palese and JKT team collaboration in 2006, detailing variant tropism based on differential HA reception at α2-3 and α2-6-linked sialic acids evaluated correlative to aa225 lend evidence to the concept of deep lung involvement though the experiments were conducted by varying permutations of aa190 and aa225 on 1918 variants.  Whereas, we stand in 2009 with quite different genetics that require cross-validation prior to citation with applicability to PF11.

Tissue type targets are compelling studies and this particular superarray protocol may prove even more useful on PF11 than 1918 samples.  We note that though 1918 and PF11 now share 190D and 225G, that all 1918 public sequences show 206S.  206T continues to emerge and conserve regionally in PF11.  All 225G bearing strains after April show 206T, except the July CatNS1706 and the undated Vladivostok01.

Reproducing the glycan microarray procedure with the contemporary and ideal dataset including Brasil and Catalonia may bring a tigher focus onto today's issues.  We couldn't ask for a more balanced set of control factors with Catalonia offering sequences less than one week apart demonstrating both important pairings: 206S/225G and 206T/225G . . . a bench review made to order.

We also do know that a proper immune response, that is a timely and regulated innate immune response, is not occurring in certain of these patients. When the n +1 generations of the virus progeny begin to lyse the host cells, that failure of innate immune function to have responded early leads to an undetected and massive viral load due to the rapid replication trait of PF11. The cell detritus and the density of moving viral particles elicit a host-driven, limited “self-destruct” series of events because the multiple levels of early detection parameters have been bypassed leaving the core essentially defenseless.

What we don’t know?

Much of what we need to know today about Cytokinic Regulation is yet to be studied. 

The systems of feedback loops are extensive with individual effectors often having multiple functions, in some cases, opposing functions.  So please bear in mind that we are looking into an instantaneously self-modifying system that not only self-revises the systemic parameters, but recruits and removes players in the middle of the game and then encourages them to change sides without even changing jerseys.  And to top the difficulties, Heisenberg applies.  Tighten down the screws to look at one molecule and his best friend will no longer stand anywhere near him, though they were conversing with verve before we attempted to measure.

That disclaimer in place, you may still note important aspects of proper cell-to-cell signaling systems from the following discussion as you keep in mind that the presentation is highly compressed for educational purposes.

Though Cytokinic Dysregulation is occurring in most PF11 cases at some level of interchange, the 225G and 225E strains may potentially interfere at a more profound level with the early innate response by amplifying the PF11 conserved effect of the NS1 paired Glutamates at aa96 & 97 that constrains the IFN synthesis instantiation cycle by binding TRIM25, an early catalyst to RIG-I ubiquination.  Influenza bench researchers don’t know exactly where the failure is occurring or at which combination of cell-to-cell signalers in PF11 or the PF11 225G strains.  Until those identification studies are designed, undertaken and reproduced, discussion at this point is stark hypothesis based frequently on the speaker’s sheer lack of present research content mastery. Apparently, saying “I don’t know?” and then returning to the bench to design and gather a proper foundation of data is a skill rarely encouraged in our “Science for Hire” era.

Our team is unimpressed that the wider science community, with such broad analytical skills and exceptional equipment, relies on pseudo-explanation, this cloud of diversion, by invoking the “Cytokine Storm” phrase.  More than 20 well-characterised and 100 identified distinct molecular signal functions are at work in the early immune response, including cytokines, but not limited to that class of communicators.  Tagging a term for PR purposes is much simpler than tagging a molecule for tracking, but you received your instruments because you can think, not for your ability to improvise inventive talk.

Think.

Eighty billion dollars in research should arrive at a better answer with higher specificity and actionability than the blanket “Cytokine Storm” tome.  Data and procedure discover Facts.  Anything less is purely Public Relations.

Our team continues to hold an opinion that we first described in 2006 concerning Cytokinic Dysregulation and the NS1 protein of Influenza.  Succinctly, the viral ability to suspend innate immunity for up to two days post-infection, as characterised by Mount Sinai this year, prevents the early and required pro-inflammatory Cytokinic Response to viral detection.  That blunting, taken in conjunction with detailed studies around adaptive immunity, may result not only in failure to clear the virus from some patients in a timely fashion, but also in failure to produce a useful quantity and competence of memory T-cells and Ab.  The early failure to clear a rapidly replicating virus like H5N1 or PF11 results in a frank trauma to the immune system when the first generations of viral progeny lyse their host cells after being undetected and flood the tissues with virii and toxic cell detritus.  That disorderly surge of human and viral proteins en masse activates a late and cascading pro-inflammatory response that frequently fails to down-regulate properly.

This explanation is contrary to "pop" science reports that a normal and robust immune response over-generates cytokines and attacks self indiscriminately.  We hold that, by the time the virus has lysed thousands of cells and released millions of virii, that most adjacent tissue areas are "fair game" for immune response due to toxic cell detritus and viral travel.  That flooding of antigen and waste matter, widespread and instantaneous to the immune system, may further interact with some virally induced derangement of the alternative pathway of complement and generate the intensive up-regulation of signaling, pro-inflammation cascades and the resultant tissue damage described in the clinicals as DIC, DAH and ARDS.

Ergo, the findings of massive tissue damage on necropsy is the result of a failed early innate immune response, not a normal robust response.  A normal, properly up- and down-regulated robust innate response clears infection in more than 90% of various infections (viral, fungal and bacterial) and proceeds to generate Ab in short order via the adaptive arm of immunity.

When viral hosting cells properly detect intrusion, flag themselves for apoptosis (cell death) and are then assisted by cytotoxic T-cells, the injection of fragmentins via perforin "tubes" induces an endogenous apoptotic program literally cutting DNA into 200 base multimers (fragments) and eventually condensing chromatin.  That organised molecular result is far less inflammatory and far more useful for antigen identification than the disorderly outcome of a virally "exploded" cell.  Now you can see why proper genetic expression during each phase of this programmed cell death guarantees a lower pathology than the chaotic and toxic outcome of lytic host cell destruction resulting from viral NS1-induced, delayed genetic expression. 

A confluence of PF11 traits (failed early detection, multi-tropism and rapid replication) against the host-pathogen interface may force a limited "self-destruct" in the host upon eventual detection in an attempt to save the organism.  That limited "self-destruct" is not the desired outcome of a normal and robust immune response, but occurs due to a failure of the immune system to detect and respond early in the process.

Timing matters. 

Individual viral genetics and individual host immune genetic expression are primary effectors that must no longer be discounted under the clouds of some nebulous "Cytokine Storm" or Mysterious Mutation.

Cytokinic Dysregulation is wider than immunity. 

Johns Hopkins School of Public Health estimates that half of all Americans suffer from chronic illness.  150 million in one country.  Cytokinic Dysregulation is a very real situation occurring daily in the lives of a significant group of chronic illness sufferers as a component of asthma, chronic joint damage, digestion tract insult, diabetes, endocrine dysfunction, vascular inflammation of undisclosed cause, detoxification pathway insult (renal/hepatic), immune dysfunction, obesity and numerous sub-clinical, but accumulative pathologies.  Each of these suffering individuals is at an increased PF11 risk based on the types and levels of cell-to-cell signaling failures across their systems.

So let's stop talking about this overblown "Cytokine Storm" and begin candid discussions with specificity about causality.


For additional background on the clinical and epidemiological observational facts concerning Pandemic Influenza H1N1, please refer to the Table of Contents for PF11 Trends & Issues, Mid-Term.

Please visit GeneWurx.com for insight into the latest published studies.

Use Low and Slow Exposure to Make Hungry Antibodies Fast

We produced this article on 2009-05-03 for members of our community in response to questions surrounding the then epidemic which soon became PF11.  The information remains useful as a general guide though the Hydra Effect is more pronounced today.

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As the number of PF11 infections increase within a community, the average newest-exposed or most recently exposed individual in the population will have multiple and, more importantly, persistent viral exposures, significantly more than the individual effect early in the pandemic.

As an epidemic grows, the NEI (Newest Exposed Individual) and their naïve immune system will initially be presented with a substantial particle count from a multitude of variants.  The virus will have made moderate adaptations to the new host, humans, and may, therefore, be more capable due to Influenza Flux.  Many labs have now demonstrated that passage of a novel virus through a new host and / or new host tissue type will lead to selection for host-matching genetics.  Upon this more substantial initial exposure, the NEI’s immune system will naturally have an immediate requirement to mount an innate response and, if successful, to subsequently mature a separate line of antigen-matching B cells for each variant strain of community Influenza (PF11 Hydra Effect).

A separate and important consideration today is that much of the population is immune depleted due to genetic damage and may be missing significant feature functionality in the cell-mediated and humoural responses.  Any heavy taxing may overwhelm the system of the immune-suppressed.

As the boundaries shrink between the non-exposed and the exposed, we may see a higher death rate among the NEI population because their Multiplicity of Exposure and total intake of infective viral particles will be high and variant.

We’ll now examine the idea strictly on a particle count example that is tempered for ease of communication.  These numbers, though simplified, are conservative.

Early in any epidemic, presume that exposed individuals get 1,000 particles to start an infection.  Later individuals will have at least a dozen of their close community who are infected, thus, 12,000 input particles.  Influenza delays and partially disables innate response, so 12,000 input particles is far worse than the small number may seem.  The synergy of 12,000 initial virions attacking a body may have a stultifying effect on immune response, especially on a delayed or late stage immune response. Twelve thousand particles each entering 1,000 on the copy machine within each infected cell may result in twelve million virions circulating freely in one replication cycle, certainly in less than a day. 

Your body is doing a lot of heavy lifting for an unappreciative guest.

Bear in mind that even the early specimens from ΣPF11 have been found to replicate 1,000 times faster in mammals than standard H1N1 Seasonal Influenza, so our very simplified example is vastly underplayed from the reality of what actually occurs in the human body.  Now that the trait-enhancing genetic marker of PB2 E627K has been identified across several geographies in this reservoir, we can expect the additional increase in replication speed to become fixed.

I’m not so sure that anyone’s humoural response can make the required 12 million antibodies for the dozens of genetically variant inputs that will be part of that initial 12,000 particle exposure, at least not in a useful timeframe.  Due to proximity and transport requirements, the NEI may need to make 60 million or more antibodies to accomplish neutralisation of that initial 12 million Influenza variants.  A properly regulated, innate immune response will always be the driving factor in successful clearance of an IDRREAV like PF11.

Then you have the Elimination challenge.  Without an early and powerful macrophage and inflammatory up and down-regulating process, any Cytokinic Dysregulation due to delayed cell-mediated immune response may leave the tissues filled with plasma and the small blood vessels effectively clotted closed, setting off another chemokine cascade to flood the system with anti-clotting agents (DIC).   A well-timed and even response is essential so that elimination may occur on a manageable schedule.

Remember that three phases must be fulfilled sequentially to clear any toxin or pathogen from a biological system.

1. Detect
2. Destruct
3. Eliminate

Failure to operate at maximum potential during any stage means practical failure of the entire system.

Initial exposure reduction may be noted as the most important factor in reducing Influenza severity in a previously healthy host individual.  Slow and Low Exposure protocols ensure that your NEI (n+1) are provided the greatest opportunity for survival and reduced severity.  Communities will fail or succeed in this pandemic based on their Multiplicity of Exposure.  In this pandemic, choices made by each individual may have long-term health implications for that individual and for their community.

How do we establish a Slow and Low Exposure protocol?

In the event of a rapidly replicating Influenza virus, a community’s highest priority must be on social distancing to reduce the number of exposure episodes and the per exposure viral count.  A prominent secondary priority must be to supply the community members with the materials, catalysts and protective time umbrella necessary to make genetically accurate antibodies in a sufficient count to neutralise and defeat those new strains of Influenza.  These two priorities when executed in tandem will create the Low and Slow exposure that allows members of a community to make accurate antibodies fast.

Everyone will eventually be exposed, though not everyone will display outward symptoms.

Each exposed and infected individual becomes a risk at some point to others in the community due to viral shedding.  The initial symptomatic host (index = n) within a community (family, workgroup, school, day care, etc) will be forced to rely almost entirely on innate immune function to overcome a rapidly replicating virus.  A weak innate response puts that individual in the unenviable position of being a rapid viral shedder.  The first exposure in a community is a sentinel to the others.

On the other hand, any subsequently exposed individuals [(n + 1), family members, professional peers, fellow students, et al] may have another route if they are properly managed and supplied.  If the remaining community (n+1) is following hygiene and social distancing protocols to reduce total exposure episodes and viral concentration (per exposure infective particle count), those members may discourage the rabid community burn and promote a Low and Slow Exposure.  Given the additional time due to the lower total infective particle input, the immune systems of the (n+1) individuals may have the opportunity to produce an array of vibrant antibodies before the virus manifests an extensive reproductive cycle and attains the minimum viral count required to produce interior spread and outward host symptoms.

An early and robust innate response to PF11 may be followed by an equally broad antibody build.  That early response, in sufficient numbers, controls the virus in the host and reduces viral shedding, limiting further community illness.  The antibody build, if competent, provides an additional memory function for that individual’s future exposures to genetically matched viral assaults.

Everyone will be exposed.  Work for safety in your community by making your exposure Low and Slow to build hungry antibodies fast.



For additional background on the clinical and epidemiological observational facts concerning Pandemic Influenza H1N1, please refer to the Table of Contents for PF11 Trends & Issues, Mid-Term.

Please visit GeneWurx.com for insight into the latest published studies.

E627K from July Discovered Retrospectively, Tied to Vacation Island off the Netherlands in Diabetic Patient and Adolescent Female

Though the sequences have not been released, the team at Erasmus MC in Rotterdam has done us all a great service by providing an early report of 627K in the Netherlands. 

The multiple cases all vector from visits to a popular vacation island between July 13 and August 9.  Two of the cases do not appear to be related via direct contact, potentially indicating an endemic and silent spread of a minor PF11 population carrying the human-fit virulence factor 627K in a sub-clade that may match the major circulating sub-clade there but for the Lysine recombination.  Ten of twelve (83%) sample specimens from this geography fall into this sub-clade indicating the potential for dominant circulation in that area.

As this release of information via Promed is very limited, additional evalution and insight will require amendment and revision to this article as the matter is clarified on several accounts, including specification of the E627K sequence count and the various ratios confirming the certain Hydra Effect demonstrated in the study population.

In our reading, 4 distinct cases are discussed in the Osterhaus release. Which two of the four are described as having the E627K is questionable and will determine the H2H transmission assumptions.  The researchers may have mentioned “two patients” because the family contact and the younger sister may have been directly evaluated by them in a clinical setting?

• Male Diabetic who may have shared activities with ill female camper, onset 2009-08-09
• Female camper, onset after returning home 2009-07-20 
• Female family contact of ill camper, onset after camper returned on 2009-07-20
• Younger sister of female family contact, onset 2009-07-23

This highly interpretive post is preliminary based on inconclusive language in the press release.
No mention is made of the correlating PB2 virulence of aa701N and aa703K at this time in the information released.  We suspect these to be absent due to the non-fatal clinical outcomes; however, confirmation would be useful.

As the samples were examined retrospectively, little new observational evidence will be forthcoming.  Rational projections due to this 627K mid-Summer emergence in the Netherlands and the late May emergence in Shanghai71T could cause us to expect a geographically-dispersed, wild-type sub-population carrying this virulence factor.

Tenacious sub-clonal evaluation of current sequences in the United States will likely indicate mixed peaks at the PB2 residue coding for the Lysine at 627.



For additional background on the clinical and epidemiological observational facts concerning Pandemic Influenza H1N1, please refer to the Table of Contents for PF11 Trends & Issues, Mid-Term.

Please visit GeneWurx.com for insight into the latest published studies.

How Long Will the Pandemic Last?

The Road to Post-Omega PF11

How long will the Pandemic last?

Process: Predictions involving the outcomes of unprecedented or entirely new events must utilise theory.  Very few outside the scientific community revel in the joys of Theory, but today you may come to appreciate the practical value of theoretical reasoning.  Theory, the primary tool to explore anything unknown, generally begins with new tags or agreed definitions so that the discussion may embark.  The present framework of discussion, of theory, around PF11 appears to be lacking several important terms, specificity, control variables, causality determination and scientific rigour. 

So let's make an attempt to plant some markers and comport a discussion on one simple and important area of measurement, PF11 Timing.  Let's call today's virus, PF11_β, and a future tipping point, PF11_Ω, for ease of discussion.  Let's agree that we must progress beyond that future event of PF11_Ω before the Pandemic will dissipate.  (Glossary)

The distance between PF11_β and PF11_Ω is unknown.

And that delta, that difference, will remain unknown until some point in the distant future when we can retrospectively measure the closing event. Today, we'll talk about the road that everyone will travel from this moment until that closing event.

The journey between the two points will be progressively inundated with higher levels of impediment to the traveler. The traveler may not declare an optional routing. Due to decisions made by others, the traveler’s only available option is to agree and undertake the journey as given.

We all are driving the only highway (ΣPF11) between this small town of Bad (PF11_β) and the metropolis of Worst (PF11_Ω).  We know that no one knows the rate of speed we are traveling because no speedometer may be calibrated for a non-uniform progression.  Measurement is incomplete for all practical purposes. Fits and starts will be the norm.  We also know that each family will be affected by various types of collisions along the way.  In the veritable infinity of infectious vectors, few will emerge without themselves, their family or some important person in their lives being impacted.  Density, proximity and movement guarantee collision in any bounded system and this system is distinctly bounded.

As the traveler succeeds in passing each mile with the almost certain collisions and if they are able to survive the increasing number of attack vehicles (recombinants from the Influenza Flux), the lost segments of road (poorly chosen mediation measures) and the dwindling availability of fueling stations, eventually they will arrive at a better place. Though PF11_>Ω, this first city on the other side of Worst, is not the ultimate destination, any relief after that pandemic journey will be appreciated and any glimmer of light will be a sight for sore eyes.

Eventual arrival is the key concept. How long will this journey last and what must you do to eventually arrive are the important questions.

Someday long hence, you may rate this trip as “Somewhat Unpleasant” or “Utterly Devastating” depending on how well you’ve equipped your individual journey with actionable Knowledge and viable provisions. Though a fully intact arrival might be your goal, the most capable and well-Led travelers will realise that completion of this journey with only minor impact is a deep blessing because you’re going to need to see around corners to get there at all. While others planned your route straight through renegade territory, the responsibility now falls on you to cross this expanse of impediments and the ostensible rest areas are unprotected.

Renegades abide no law and a virus abides no social messaging campaign. A virus does not care and a virus does not feel. A virus just makes copies and reacts to the environment by acquiring new genetics. A virus escapes and evades. You are now being forced to drive your family directly into a hundred-mile wide, bone-dry forest in a three-year drought that has been primed by summer heat. From the moment you enter the expanse, you can feel the dryness of the stick wood and you know the logical outcome, but your route planners have given you no exit from this road. You can’t race this virus. One stray spark and everything changes.

On what type of journey do you wish to lead your family? Where on the scale between “Somewhat Unpleasant” and “Utterly Devastating” do you wish for your future rating to stand? Your actions today select your rating for tomorrow. This article provides you the initiative you need to act.

The route has been decided by our lack of determination, by our abdication of responsibility to untrustworthy people. Continue to Follow or Start to Lead, but be certain to load your vehicle well because your journey is beginning.

Glossary

For additional background on the clinical and epidemiological observational facts concerning Pandemic Influenza H1N1, please refer to the Table of Contents for PF11 Trends & Issues, Mid-Term.

Please visit GeneWurx.com for insight into the latest published studies.