2009-11-24

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 206S206T 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.

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2009-11-23

Hemorrhagic Pneumonia: CDC Issues Alert to Physicians for Heightened Surveillance

This report is preliminary and will be reviewed for corroboration as the official documents become available.

Although confirmation is not yet complete on this item, the American CDC has apparently issued an alert to physicians concerning hemorrhagic pneumonia in the United States.  The North Carolina Medical Society has published a description of the CDC alert and has identified a reporting point in their state. 

The PF11 viral reservoir is extending and revising in important areas concerning trait enhancements.  Since the early part of the pandemic, this viral reservoir has exhibited exceptional abilities to damage the human body due to Influenza Flux; however, we may now be moving into deeper water if this alert is validated.  While no one may say exactly where this virus is going, we are able to track the genetics and the human clinical outcomes correlated to those genetics.

Deep lung involvement appears to be supported as a trait enhancement via the D225G polymorphism on the viral Hemagglutinin.  225G is not a new incursion into ΣPF11, but now paired with 206T is becoming a higher concern.  The US and Mexico demonstrated 225G with 206S early in the pandemic.  206T, as predicted, has now become fixed or consensus in many geographies.  Recent studies on the Ukraine, Russia, China and Norway show 225G in the Hemagglutinin to be circulating alongside the dangerous 225E and the wildtype 225D bearing strains.

Heightened surveillance is being required from the medical community while the general public is receiving communications with an alternate message?  Moms and Dads will want to get ahead of this issue by gathering accurate and complete information as soon as possible.  PF11 will be with us for a long time.

Gather and Solve.

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.

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2009-11-22

TamiFlu Resistant Cluster of 4 at Duke Medical Center, North Carolina, US

As the thirteenth TamiFlu Resistant sequence was released publicly by Italy demonstrating a hypermorphic progression to another novel strain, the Duke University Medical Center contemporaneously described a group of patients acquiring PF11 Influenza in an isolated ward of their hospitalFour of the patients from this isolated ward were found to be infected with a TamiFlu Resistant strain.  Transmission is suspected and may be verified by publication of all sequences from that ward over a time period covering two weeks prior, during and two weeks after the event.  Three of the four patients had fatal outcomes (75%).

Antiviral resistance has now been documented in 50 instances, when investigated, including North America, Europe and widely across Asian countries.  The 13 sequences that are available are, for the most part, incomplete for research into cross-segment linking of Hemagglutinin (HA) polymorphisms correlative to the antiviral-resistance conferring H275Y Neuraminidase (NA).  Investigators are left at bare benches staring into empty beakers waiting for catalyst. 

The resistance marker is now found on numerous backgrounds potentially demonstrating an ability to travel as a silent sub-species.  Up to this current stage of the pandemic virus progression, this resistance trait, in several cases, appears to arise in an individual as the prominent super-infection (co-infecting silent H275Y PF11 strain) based on some unidentified characteristic of the individual's host-pathogen meshing, including immune dysregulation or other existing Cytokinic Dysregulation morbidities.

Publication of the remaining 37 sequences, including the Duke University Medical Center clinicals from this prestigious research institution, may benefit worldwide understanding of the efficacy and longevity of currently promulgated mediation measures for PF11.

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.

GeneWurx.com

2009-11-06

Ukraine Expected to Surpass 1 Million Infections in Only 10 Days; the U.S. took 10 weeks.

A day in the Ukraine is like a week in the United States . . .

for Pandemic Influenza spread, that is.

On October 29, the Ukraine officially reported an uptick in Influenza-like-Illness (ILI) and a surge in hospitalisation.  Concomitant deaths were reported from hemorrhagic pneumonia and four doctors were soon included in the fatality pool.  The situation was recognised and immediate action was taken.  Very early in the process, a nationwide alert was issued and the situation came under central management.  In mere days, the healthcare infrastructure was stressed and supplies were exhausted.  Resources have been redirected and escalations continue.  Citizens are cutting their own clothing to make masks.

Tomorrow will mark 10 days since that spark. 

Based on the most recent daily case increases trending upward from 32% to 37%, we expect the Ukraine to surpass one million reported infections by Saturday afternoon, November 7, 2009.  If the reporting trend continues with the weekend and the rates hold, just under 1.2 million cases will be cataloged.  We cannot speculate if a report will be made publicly available on Saturday.

The official reports from the United States indicated that 1 million infections were reached in late June 2009, 10 weeks after the initial sparks of PF11 began to ignite the populations and burn through the major cities.

The Ukraine progression defines a new method for PF11.  In the early phases of any catalyst event, all statistics are suspect, but the trending is often useful.  Official numbers, upon some minor calculations, demonstrate that the daily increase in hospitalisation and deaths is rapidly climbing.  Yesterday the increase in daily hospitalisations was 20% and today the increase is 37%, almost a doubling in day-to-day velocity.  Yesterday the increase in deaths was 17% and today the increase is 42%, more than a doubling in day-to-day velocity. 

Data reporting cut-offs are always at issue in these early inflows, but over the next two weeks an exacting pattern will be defined.  Researchers must be given access to the raw data to determine causality and vectoring.  A significant library of samples has been received and sequenced in a prestigious European coordinating laboratory.  No data at this time has been released. 

Timeliness is essential when a virus has marched to 1 million suspect cases in only 10 days in one country of less than 50 million people.  1 of 50 ill across 10 days.  Clinical and environmental data matching the sequences will be critical to deduce and weight the parameters driving this regional escalation.  Those who will writeoff these flashpoints as medical infrastructure failures and sub-standard housing problems endemic to the third world are not intellectual Titans.  A pandemic is by definition unpredictable in phase shift timing and degree.  To discount this Ukrainian surge in suffering to poverty is simply academically irresponsible in a pandemic era.  These data points requested, if made public today, may save the lives of many in the area and exponentially more in the coming months around the globe.

The Ukraine is bordered by the countries of Russia, Belarus, Poland, Slovakia, Hungary, Romania and Moldova.  The southern area of the Ukraine is involved in several bird migration routes being bordered by the Black Sea.  Sequence examination of late summer specimens from these bordering areas and Eastern Europe demonstrates a trend equal to the United States with a significant Hydra Effect and substantial Antigenic Diversity delivered via Influenza Flux.  US sequences certainly match and even advance the polymorphisms in Eastern Europe and these border nations.

Our studies clearly demonstrate a one to three week lag at maximum in transport time and acquistion into new geographic areas of trait-enhancing genetic material within ΣPF11.  The stage is already set with similar sequences existing in most parts of the world.  225E has continued to penetrate in dozens of nations and is a factor in our present working hypothesis for this Ukraine spark. 

If the Ukraine has variant genetic specimens, the information is primary to world health.  Singapore was recently courageous enough to release 600 sequences that widely demonstrate movement in the reservoir.  Only an immediate evaluation of the full dataset of Ukrainian sequences and matched clinical information will provide countries the opportunity to prepare if this incident does mark an inflection point or catalyst event in the pandemic.

Is the US only one cold winter week from the situation today in the Ukraine?  Is the base of Pandemic 2.0 now widening in countries that have some point of susceptability?  If so, the landing strips are presently in place for these new polymorphisms to land on the existing PF11 strains in every basic geographic area of the world. 

We may all be one week from seeing a million new cases in our homelands or, worse yet, watching 2% of our population stricken in only 10 days. You do the math for your nation and then decide if we need data transparency and academic honesty.


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.

GeneWurx.com