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A/Hong Kong/213 recognizes SA 2,3Gal & SA 2,6Gal

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Jhetta View Drop Down
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    Posted: June 12 2006 at 12:14am
Influenza virus receptors in the human airway
Note: The PDF version is much easier to read and has photos and illustrations. You can download Adobe Reader which opens pdf files here.  http://www.adobe.com/products/acrobat/readstep2.html

Vol 440|23 March 2006

"It is interesting that the A/Hong Kong/213/03 (H5N1) virus, which was isolated from a human and recognizes both SA 2,3Gal and SA 2,6Gal....
 
...unimpeded transmission of the virus might require acquisition of the ability to recognize SA 2,6Gal. This change would enable the virus to replicate in the upper region of the respiratory tract, where it could be read-ily spread by sneezing and coughing.
 
Muta-tions in the viral haemagglutinin molecule would be necessary to confer SA 2,6Gal-bind-ing ability on H5N1 avian viruses, although amino-acid substitutions in other viral pro-teins, including PB2 (refs 7, 8), may be required to confer pandemic potential on avian viruses that can efficiently replicate in humans. "

Influenza virus receptors in the human airway Avian and human flu viruses seem to target different regions of a patient’s respiratory tract. Although more than 100 people have beeninfected by H5N1 influenza A viruses, human-to-human transmission is rare1.
 
What are the molecular barriers limiting human-to-humantransmission? Here we demonstrate ananatomical difference in the distributionin thehuman airway of the different binding mol-ecules preferred by the avian and human influenza viruses. The respective molecules are sialic acid linked to galactose by an -2,3linkage (SA 2,3Gal) and by an -2,6 linkage(SA 2,6Gal)2. Our findings may provide arational explanation for why H5N1 viruses at present rarely infect and spread between humans although they can replicate efficientlyin the lungs. SA 2,3Gal molecules have been found on cells artificially differentiated from isolated human tracheal and bronchial cells in vitro3. But the anatomical distribution and preva-lence of SA 2,3Gal and SA 2,6Gal in the human airway was unknown. Using lectinsspecific for SA 2,3Gal and SA 2,6Gal, we found that SA 2,6Gal is dominant on epi-thelial cells in nasal mucosa, with SA 2,3Galbeing occasionally detected (for details and methods, see supplementary information).Epithelial cells in the paranasal sinuses, thepharynx, the trachea4and the bronchi mainly express SA 2,6Gal In the terminal andrespiratory bronchioles, epithelial cells also express SA 2,6Gal sialyloligosaccharides. SA 2,3Gal was found on non-ciliatedcuboidal bronchiolar cells at the junction between the respiratory bronchiole and alveo-lus, however, and a substantial number of cells lining the alveolar wall also expressed this mol-ecule. The SA 2,3Gal-positive alveolar cells also reacted to an antibody against surfactant protein A; this suggests that they were alveolar type-II cells (which express surfactant proteinA). Alveolar type-II cells have been shown to be infected with H5N1 virus in a patient5. Human-derived viruses that preferentially recognize SA 2,6Gal bound extensively to epithelial cells in the bronchi and, to a lesser degree, to alveolar cells; by contrast, avian viruses that preferentially recognize SA 2,3Gal bound extensively to alveolar cells but less widely to bronchial epithelial cells (see supple-mentary information). It is interesting that the A/Hong Kong/213/03 (H5N1) virus, which was isolated from a human and recognizes both SA 2,3Gal and SA 2,6Gal (ref. 6), bound BRIEF COMMUNICATIONS Figure 1 | Reactivity of human respiratory tissues with lectins specific for different sialic acid linkages.a, Nasal mucosa; b, paranasal sinuses; c, bronchus; d, bronchiole; e, alveolus. Res, respiratory bronchiole (adjacent to alveoli); Ter, terminal bronchiole (distal to alveoli); Alv, alveolus. Green,reaction with Sambucus nigra lectin, indicating the presence of sialic acid linked to galactose by an 2,6-linkage (SA 2,6Gal). Red, reaction with Maackia amurensis lectin, indicating the presence of SA 2,3Gal. Cells were counter stained with DAPI (4,6-diamidino-2-phenylindole). abcedTerResAlv Figure 2|Infection of human respiratory tissue by influenza A viruses. a, Extensive infection of bronchial epithelial cells by human A/Kawasaki/173/01 (H1N1) virus. b,Infection of alveolar cells by the human virus.c, Bronchial epithelial cells are not infected byA/duck/Mongolia/301/01 (H3N2) virus. d,I nfection of alveolar cells by the avian virus. The results obtained with other human viruses, A/Yokohama/2057/03(H3N2) and A/Kawasaki/176/02 (H1N1), were similar to those obtained with A/Kawasaki/173/01, and those obtained with the avian viruses A/duck/Czechoslovakia/56 (H4N6) and A/duck/Vietnam/5001/05(H5N1) were similar to those obtained with A/duck/Mongolia/301/01. Infected cells are stained brown extensively to both bronchial and alveolar cells. Human-derived viruses preferentially rec-ognizing SA 2,6Gal efficiently infected epi-the lial cells lining the bronchi and alveolar cells (Fig. 2a, b), whereas avian viruses prefer-entially recognizing SA 2,3Gal infected alve-olar cells but not bronchial epithelial cells (Fig. 2c, d, and see supplementary informa-tion). As shown in a virus-binding assay,A/Hong Kong/213/03 infected both alveolar cells and epithelial cells in bronchi (see supple-mentary information). Although not quanti-tative, these results indicate that there could be functional significance in the preferential expression of SA 2,3Gal and SA 2,6Gal mol-ecules on human airway cells.
 
Our findings indicate that although H5N1 viruses preferentially recognizing SA 2,3Gal can be transmitted from birds to humans, they can replicate efficiently only in cells in the lower region of the respiratory tract, where the avian-virus receptor is prevalent.

This restriction may contribute to the inefficient human-to-human transmission of H5N1 viruses seen so far, and indicates that unimpeded transmission of the virus might require acquisition of the ability to recognize SA 2,6Gal. This change would enable the virus to replicate in the upper region of the respiratory tract, where it could be read-ily spread by sneezing and coughing.
 
Muta-tions in the viral haemagglutinin molecule would be necessary to confer SA 2,6Gal-bind-ing ability on H5N1 avian viruses, although amino-acid substitutions in other viral pro-teins, including PB2 (refs 7, 8), may be required to confer pandemic potential on avian viruses that can efficiently replicate in humans.
 
Kyoko Shinya*†‡§, Masahito Ebina||, ShinyaYamada†, Masao Ono¶, Noriyuki Kasai‡,Yoshihiro Kawaoka*†#✩*Department of Pathobiological Sciences, Schoolof Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USAe-mail: kawaokay@svm.vetmed.wisc.edu†Division of Virology, Department ofMicrobiology and Immunology, #InternationalResearch Center for Infectious Diseases, Instituteof Medical Science, University of Tokyo,Tokyo 108-8639, Japan‡Institute for Animal Experimentation,||Respiratory Oncology and Molecular Medicine,Institute of Development, Aging, and Cancer,in 1998 (ref. 5), in 2002 (ref. 5) and in 2003(ref. 6), respectively.
 
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This is the other change H5N1 needs to become efficient... mentioned in the article above it have been documented to occur and a researcher in Indonesia claims to have found SA 2,6Gal... though that has not been documented to date in any scientific publication that I have been able to find.  It is important to note that they are still learning and additional changes may be needed as well.
 
 
PB2 amino acid at position 627 affects replicative efficiency of Hong Kong H5N1 influenza A viruses in mice.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15016548

Shinya K, Hamm S, Hatta M, Ito H, Ito T, Kawaoka Y.

Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706, USA.

A single amino acid substitution, from glutamic acid to lysine at position 627 of the PB2 protein, converts a nonlethal H5N1 influenza A virus isolated from a human to a lethal virus in mice. In contrast to the nonlethal virus, which replicates only in respiratory organs, the lethal isolate replicates in a variety of organs, producing systemic infection.
 
Despite a clear difference in virulence and organ tropism between the two viruses, it remains unknown whether the dissimilarity is a result of differences in cell tropism or the reduced replicative ability of the nonlethal virus in mouse cells in general. To determine how this single amino acid change affects virulence and organ tropism in mice, we investigated the growth kinetics of the two H5N1 viruses both in vitro and in vivo. The identity of the PB2 amino acid at position 627 did not appreciably affect viral replicative efficiency in chicken embryo fibroblasts and a quail cell line; however, viruses with lysine at this position instead of glutamic acid grew better in the different mouse cells tested. When the effect of this substitution was investigated in mice, all of the test viruses showed the same cell tropism, but infection by viruses containing lysine at position 627 spread more rapidly than those viruses containing glutamic acid at this position.
 
Further analysis showed a difference in local immune responses: neutrophil infiltration in lungs infected with viruses containing lysine at position 627 persisted longer than that associated with viruses lacking a glutamic acid substitution.
 
Our data indicate that the amino acid at position 627 of the PB2 protein determines the efficiency of viral replication in mouse (not avian) cells, but not tropism among cells in different mouse organs. The presence of lysine leads to more aggressive viral replication, overwhelming the host's defense mechanisms and resulting in high mortality rates in mice.

PMID: 15016548 [PubMed - indexed for MEDLINE]"
 
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What makes E627K dangerous?
http://realage.typepad.com/avian_flu/2006/05/anniversary.html

"Human influenza viruses do not spread in birds, and bird influenza viruses generally do not cause disease in humans. (Beare & Webster, 1991)[4] One reason is that typical bird flu viruses need temperatures of about 40 – 41 degrees Celsius to replicate. These temperatures are normal in bird intestines, the typical site of infection in birds. Human influenza viruses are adapted to a lower temperature range, down around 33 degrees Celsius, which is typical for the human upper respiratory tract. The PB2 gene contains instructions for making copies of the virus, and the instruction located at the 627 th  amino acid helps determine at which temperatures this replication functions best. (Massin et al, 2001)[5] 

The E627K version of PB2 is found in human H1, H2, and H3 flu virus strains where it supports faster replication at low temperatures. After Qinghai, the E627K mutation shows up regularly in the H5N1 bird flu strain that has migrated with wild birds westward to Europe and Africa.

 
When mammals get infected with this strain, the disease is more serious than with H5N1 infections that do not have the E627K mutation."
 
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Kataku™ Automatic Translation Demonstration
This free service enables you to translate English to Indonesian and Indonesian to English, up to 300 words.

I believe the word antarmanusia should be efficiently or efficient

Flu of Burung
 Teka
Teki gazed at the Pandemic Although officially the spread antarmanusia in the level kluster still became the mystery, spesifitas the receptor alfa 2,6 that enabled the bird flu virus to move from humankind to humankind has been found.

Must be attentive seriously so that the pandemic that usually claims many casualties could be avoided.

The influenza VIRUS H5N1 the first time infecting humankind in Hong Kong in 1997.

In December 2003 began to be determined this virus infection in humankind that had contact with the poultry was sick.
A official from the Health Service of the Bandung City took the sample of blood from one of the patient's neighbours "suspect" bird flu, the RN (22 months), in the Cigagak Kel Village.
Cipadung Kec.

Cibiru the Bandung City, on Monday (27/2).
M. the SAPTA TUMULT/HOMEWORK Since That Time till June 6 2006 WHO accepted the report 225 cases of the spread of the virus H5N1 with 128 died in 10 Asian countries, Africa as far as Europe.

Indonesia was in the second level of the number of most cases in the world after Vietnam with 49 cases and 37 died. From 49 patients who it was confirmed were infected by the bird flu virus, 17 among them was in the West Javanese Province. As many as 15 people from 49 patients died.

Now from 17 patients in West Java, seven including being treated in the Handsome Sadikin Hospital (RSHS) Bandung, two people were stated recovered.

Saw this reality, did at this time the world head the new pandemic?
The organisation of the health of the world (WHO) stated the spread of bird flu at this time was to stage 3: pandemic alert.
Meaning that, has had the infection in humankind but was not yet proven had the spread antarmanusia. Needed two stages more before being categorised experienced the pandemic.

The stage 4 was proven had the spread antarmanusia in the group (cluster) small and the stage 5 spreads antarmanusia in the big group (larger). The world had experienced three influenza pandemics in this age.
Spanish influenza happened in 1918 that killed 40-50 million people all over the world.

Asian influenza in 1957 killed 2 million world's populations and Hong Kong influenza (1968) with 1 million fatalities. The pandemic happened when emerging a new virus and spread semudah normal influenza. The chairman Tim the Control of Bird Flu of RSHS Bandung, Dr. Hadi Jusuf Sp.

P. D (K), KPTI mentioned the condition as "spreading semudah normal flu by sneezing and deadly was as cruel as bird flu".
Dr. drh.

C. A. Nidom, M. Sc, the researcher of the bird flu virus from the University of Airlangga Surabaya, said the spread of bird flu antarmanusia very possibly happened.

Was based on the research that the implementation since last March 2006, spesifitas the receptor alfa 2,6 available to humankind could spread antarmanusia.

And spesifitas the receptor has been found in the field (read: the special interview). (link not found)

Moreover the characteristics of this virus really were easy to adapt and stable in the human body.

Nidom had in fact carried out the isolation and results not all that was infected by this virus experienced was sick.

"Therefore, I had the hypothesis if the Jakarta citizen was done surveilans by means of isolating the virus (not the antibodies test), not not all that the figure 70% brought this virus without caused was sick."

I believed that Jakarta was the epicentre of bird flu.

For Bandung, only gods that knew, he said.The matter of the spread antarmanusia in the group (kluster), also still became the mystery.
The case kluster that it was reported happened in the Sembilang Fortification Village, the Subdistrict of three bows, the Regency Karo the North Sumatran Province was that biggest in the world till at this time. Nine people who had affinity relations were infected by the bird flu virus and 7 including dying.

WHO said continued to research the possibility of the spread of bird flu antarmanusia in Indonesia including the existence kluster this.
The statement was hurriedly denied Menkes RI, Siti Fadilah Supari and the Director General of the Control of the Illness and environmental Sanitation Department of Health RI I Nyoman Kandun.

Since July 2005 Indonesia had six cases kluster.

"According to me, something that naive if the number cluster that happened already a large number of in Indonesia and the form of the virus already 2,6 still was said the spread did not happen antarmanusia and still was said only tertular from the poultry," said Nidom
.

Slow him the handling of the government especially in the poultry breeding arrangement was said by Nidom to one of the starting points continued to expand him this illness.

As far as this is concerned, apparently the handling in the sector of poultry breeding still was reactive including the clear rule lack about the vaccine that was used.

Up to the middle of this year, has 19 regencies/the city in West Java that his poultry tertular the bird flu virus.

Six regencies/the other city was threatened because was pressed by the area was infected.

Drh.
Sri Mudjiartiningsih from Labkesda West Java in the training of coverage of bird flu that was spread out by Internews acknowledged the indolence.
According to the veterinary surgeon who had been treated as suspect this bird flu, the handling that did not touch the community happened because of his motor only the Service of province Livestock Breeding.

"Disnak the regency/the city did not have the colleague's fund for that," he said.

The matter of the vaccination also did not yet spread everywhere was done.

In fact, the poultry that has divaksin then only had maximal optimal immunity four months.

That was significant, the vaccination must be repeated routinely minimal three times in a year.

"Must him together like the PIN," he said again. Apart from the vaccine H5N1, to the front Disnak will also use the vaccine H5N2.

The same vaccine kind that currently often is worn by the poultry breeding industry in the homeland.

The matter, Nidom also commented loud.
According to him, the vaccine that was used must be matched with the available virus in the field. "If the available virus in the field was the virus H5N1 that seed the vaccine, yes must H5N1."

Except if indeed has changed his virus, his vaccine must then change.
Likewise seed the vaccine vaccine must be always controlled, he said.Government indolence was also observed in the insignificance of the socialisation against the community.

Blocked (35) villagers Cinunuk the Bandung Regency that lost his two nephews of AT (10) and AC (18) that was stated positive bird flu, claimed confused.

He admitted to not knowing the characteristics of the poultry that was infected by bird flu and the sign of the deadly illness.

"If from the beginning knew his sign like that, let alone having nine chickens that died, definitely we anticipation," he said.

In fact, the distance of the residence Block and the NY family.
C that his two sweethearts were "achieved by" bird" flu with the village office and the community health centre not more than 15 trip minutes by the taxi bike.

But, knowledge concerning the illness that diributkan all the worlds were not obtained by them.

Various bitter realities that happened ought to make the government more efficient took the step.

The sector arrangement of poultry breeding, the comprehensive research with the sample 49 positive cases available until giving the upper answer of millions of the community's questions.The occurrence opportunity of the spread antarmanusia with the discovery spesifitas the receptor alfa 2,6 in the field, the number of cases kluster, pointed out the pandemic already in front of the eyes.
 
Would and when the pandemic happened, indeed could not be predicted.
If in the pandemic beforehand the virus surrounded the earth in time 6-9 months together with the international trip through the ship.

WHO said, it was at this time not impossible for the virus to be able to spread faster in fact infected all the continents only in three months.
Saw the history, the death rate for the pandemic really varied depended the number of people that was infected, the virulence of the virus, the character, and the sensitivity was infected from the population and the effectiveness from the step in the prevention.

So, before the report on the case from 10 countries changed to the pandemic, let's began to do the prevention.

(Wilda Nurlianti/HOMEWORK)
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Guests Quote  Post ReplyReply Direct Link To This Post Posted: June 12 2006 at 9:25am
Jjetta, what do you think the odds are that this strain can be contained? I understand now, finally, what this means. Is it possible that the strain Dr Nidom isolated with these changes has died out, not spread? I think I may be starting to freak out. I'm going to take a break for a while.
Christy
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Jhetta Quote  Post ReplyReply Direct Link To This Post Posted: June 12 2006 at 9:34am
Christy,
 
It looks like he is trying to get the info out... the translation is very poor.  It looks like he may think that many people have it and some are not showing severe disease... my biggest question should his assertions be true.. would be does it have the PB2 627 change as well.
 
I believe we will see a good article soon in Nature... if it is not censored.  H5N1 is very wide spread, and there are so many possible changes that could occur that we really do not understand well.  I am hoping that it will become less lethal as time goes on.
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Originally posted by Jhetta Jhetta wrote:

Influenza virus receptors in the human airway
Note: The PDF version is much easier to read and has photos and illustrations.

Vol 440|23 March 2006

"It is interesting that the A/Hong Kong/213/03 (H5N1) virus, which was isolated from a human and recognizes both SA 2,3Gal and SA 2,6Gal....
 
...unimpeded transmission of the virus might require acquisition of the ability to recognize SA 2,6Gal. This change would enable the virus to replicate in the upper region of the respiratory tract, where it could be read-ily spread by sneezing and coughing.

 


Jhetta, thank you for these detailed informational posts. There is a lot of speculation, but this is clear, no nonsense, documentation that we have a potential URI spreader here, which has indeed mutated in a way which makes it a serious threat.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote NZ er Quote  Post ReplyReply Direct Link To This Post Posted: June 12 2006 at 9:55am
 Thanks Jhetta.... not sure that I am quite understanding this correctly..  I find the translation really difficult..is someone please able to post the 'plain english gist' of this article, unable to load the simpler PDF version ..thanks Confused
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Jjetta, I guess I couldn't stay away, hmm.. anyway I hope you're right and it will weaken, like you said, we don't know everything about influenza.
I took some deep breaths and worked a little, now I feel better.
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Fluprepper found this... quite interesting.
 
Thanks fluprepper!

Hemispherx Biopharma Advances Influenza Vaccine/Immunopotentiation Clinical Trials Designed to Increase Vaccine Dosage Supply and Increase Cross-Protection; Australian Clinical Protocol Complete

6/12/2006 8:30:00 AM EST

BIOWIRE

Hemispherx Biopharma, Inc. (AMEX: HEB) announced that the Company had completed final design of a well-controlled, Ampligen(R) vs. placebo, immunopotentiation trial of seasonal influenza vaccinations. The design follows closely newly published FDA guidelines for determining potential efficacy. The clinical study seeks to extend the findings from the preclinical models, including primates, being conducted in collaboration with the Japanese National Institute for Infectious Diseases, to determine the extent to which Ampligen(R) may increase the effectiveness of vaccines and thereby broaden the availability of flu vaccine doses to treat more at-risk groups, such as senior citizens.

Ongoing preclinical studies suggest that Ampligen(R), an experimental immunotherapeutic for which an NDA is being prepared for chronic fatigue syndrome (CFS), may achieve two major therapeutic benefits when co-administered with influenza vaccines. First, in studies conducted by the Japanese National Institute of Infectious Diseases (JNIID), protective antibody levels increased up to 100-fold against seasonal influenza viruses. Second, using highly pathogenic lethal avian influenza viruses (HPIV) JNIID found that when co-administered with HPIV vaccines, Ampligen(R) provided cross-protection against variant HPIV strains 100-300 fold.

These are the first scientific reports of potentiation and cross-protection of this magnitude with human or avian influenza viruses.

Variant HPIV has recently been isolated in Indonesia, and may account for the relative ineffectiveness of current vaccines. Specifically, the World Health Organization (WHO) has also noted the increased level of H5N1 in the patients' throat, which is a property associated with more efficient transmission of the virus, and may account for the 100% death rate recently in an Indonesian village.

Indonesian H5N1 deaths averaged one human bird flu death every 2.5 days in May. There are growing concerns for increased bird flu deaths in the wake of the recent earthquake.

Hemispherx Biopharma's clinical programs in flu vaccine use are designed to eliminate and/or mitigate the growing vaccine supply problems and to make the existing vaccines more effective in combating a potential pandemic. Success in this arena will require novel immunological strategies not part of the traditional worldwide vaccine procurement programs.

About Hemispherx

Hemispherx Biopharma, based in Philadelphia, is a biopharmaceutical company engaged in the manufacture and clinical development of new drug entities for treatment of viral and immune-based disorders. Hemispherx Biopharma's flagship products include Alferon(R) and the experimental immunotherapeutics/antivirals Ampligen(R), Alferon LDO and Oragens(TM). Alferon(R) is approved for a category of STD infection, and Ampligen(R) and Oragens(TM) represent experimental nucleic acids being developed for globally important viral diseases and disorders of the immune system. Hemispherx's platform technology includes large and small agent components for potential treatment of various viral infections. Hemispherx has in excess of 100 patents comprising its core intellectual property estate, a fully commercialized product (Alferon(R) N) and GMP certified manufacturing facilities for its novel pharma products. For more information please visit www.hemispherx.net

Information contained in this news release other than historical information, should be considered forward-looking and is subject to various risk factors and uncertainties. For instance, the strategies and operations of Hemispherx involve risk of competition, changing market conditions, change in laws and regulations affecting these industries and numerous other factors discussed in this release and in the Company's filings with the Securities and Exchange Commission. Any specifically referenced investigational drugs and associated technologies of the company (including Ampligen(R), Alferon(R) LDO and Oragens) are experimental in nature and as such are not designated safe and effective by a regulatory authority for general use and are legally available only through clinical trials with the referenced disorders. The forward-looking statements represent the Company's judgment as of the date of this release. The Company disclaims, however, any intent or obligation to update these forward-looking statements. Clinical trials for other potential indications of the approved biologic Alferon(R) do not imply that the product will ever be specifically approved commercially for these other treatment indications.

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Specifically, the World Health Organization (WHO) has also noted the increased level of H5N1 in the patients' throat, which is a property associated with more efficient transmission of the virus

Wow. This is what we've been talking about for months. I'm surprised that WHO is putting this out.
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Jhetta Quote  Post ReplyReply Direct Link To This Post Posted: June 12 2006 at 1:21pm
Originally posted by aurora aurora wrote:

Specifically, the World Health Organization (WHO) has also noted the increased level of H5N1 in the patients' throat, which is a property associated with more efficient transmission of the virus

Wow. This is what we've been talking about for months. I'm surprised that WHO is putting this out.
 
I do not believe WHO released this... the vaccine maker did!  I bet this gets pulled from the article today. 
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Well, that certainly makes sense..
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Zondar Quote  Post ReplyReply Direct Link To This Post Posted: June 12 2006 at 3:05pm
It's still in there as of 3:00...
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