National Institute of Health

NIH Roadmap for Medical Research

Director’s Transformative R01 (T-R01) Awards

Pioneer Awards 2009

New Innovator Awards 

NIH Administrative Supplement (Economy Stimulus Funding)

NIH Small Business Funding Opportunities

Small Business Innovation Research (SBIR)

SBIR Coach

SBIR Resource Center

Community of Science (COS) Funding Opportunities

The National Institute of Standards and Technology (NIST) Funding Opportunities

NIST Information Related to the American Recovery and Reinvestment Act of 2009

Department of Defense Funding Opportunities

The Bill & Melinda Gates Foundation Grant Opportunities

The Michael J. Fox Foundation for Parkinson’s Research

Multiple Myeloma Research Foundation (MMRF)

John Templeton Foundation

The European Commission and The European Federation of Pharmaceutical Industries and Associations (EFPIA)

Innovative Medicines Initiative: €246 Million to Support Public-Private Research Cooperation for a Fast Development of Better Medicines 

Leading venture capital firms focusing on life-science R&D according to FierceBiotech listing.

Domain Associates
Founded in 1985, Domain Associates, L.L.C. is a venture capital firm with an exclusive focus on life sciences. With $2.5 billion of capital under management, Domain is headquartered in Princeton, NJ with a second office in San Diego, CA. Domain’s three major investment segments are pharmaceuticals, specialty pharmaceuticals, and medical devices, while additional areas of interest include biomaterials, bioinstrumentation, and diagnostics. The Partners of Domain have a total of close to 200 person-years of experience among them in the healthcare/venture capital industries and have been involved in the formation and growth of more than 220 life-sciences companies. The highly focused network, experience, and reputation of this team have made it one of the top private-equity groups participating in the healthcare field.

HealthCare Ventures
HealthCare Ventures is a leading life science venture capital firm investing in pre-clinical or early clinical stage, project-focused companies with potential to transform patient care. HCV approach is to identify high potential products within academia or pharmaceutical companies, develop them to clinical proof-of-concept within capital efficient, semi-virtual organizations, and generate superior returns through acquisitions by pharmaceutical and biotechnology companies

Polaris Venture Partners
Polaris Venture Partners is a partnership of experienced venture capital investors and technology executives. Our mission is to identify and invest in seed, first round, and early stage technology and life science businesses with exceptional promise and help them grow into sustainable, market-leading companies. In addition, Polaris is committed to providing growth equity and shareholder liquidity to established companies in the technology, healthcare, manufacturing, media, communications, and business services sectors. As a national venture capital firm with offices in the high-tech centers of Boston and Seattle, we’re able to invest in businesses throughout the United States and around the world. The firm has over $3 billion under management and current investments in more than 100 companies.

MPM Capital
MPM Capital is one of the world’s largest life science-dedicated venture investors. With committed capital under management in excess of $2 billion, MPM Capital is uniquely structured to invest globally in healthcare innovation.

Alta Partners
Alta Partners is a leading venture capital firm in life sciences, funding over 130 companies in the industry since 1996. The diverse and integrated team brings together a powerful depth of knowledge and experience, delivering tangible results for our companies and our investors.
Alta is committed to building successful businesses through deep collaborative partnerships with outstanding entrepreneurs. Alta invests only in those areas where it has specific domain expertise.

ARCH
ARCH invests primarily in companies co-founded with leading scientists and entrepreneurs, concentrating on bringing to market innovations in life sciences, physical sciences, and information technology. The firm enjoy special recognition as a leader in the successful commercialization of technologies developed at academic research institutions and national laboratories.

Flagship Ventures
Flagship Ventures is a venture capital firm focused on creating, financing and building innovative companies. Founded in 2000, Flagship manages over $600 million in early-stage funds and operates from its offices at Kendall Square in Cambridge, MA. With an active portfolio of over 40 companies, the firm’s strategy is to balance its investments across three principal business sectors: Therapeutics, Life Science Tools & Diagnostics, and BioEnergy/Cleantech.

SV Life Sciences
SV Life Sciences is a leading international life sciences venture capital firm. SVLS affiliated funds have been investing in life sciences companies since the early 1980s and the firm closed its first dedicated life sciences fund in 1994. The SVLS team manages six venture capital funds and a publicly traded investment trust with approximately $2 billion of capital under management. The firm employs a diversified strategy within life sciences in order to selectively capitalize on an expanding opportunity in biotech, medical devices and health-care services. SVLS has offices in Boston, London and San Francisco.

Sanderling
Founded in 1979, Sanderling is among the oldest investment firms dedicated to building new biomedical companies. Sanderling demonstrates that significant companies are best built in close working partnerships with entrepreneurs. Sanderling’s unique approach combines a specialized investment focus with active management and long-term commitment to ensure the highest rates of return for both its entrepreneurs and investors. Biomedical investing has been a viable sector in the technology markets for more than thirty years, and in the past ten years has experienced accelerated growth. Since its inception, Sanderling has supported over 90 biomedical companies from very early stage start-ups, through commercial development, earning consistently high rates of return on its venture investments.

Kleiner Perkins Caufield & Byers
Kleiner Perkins Caufield & Byers are passionately committed to helping their portfolio companies succeed. Entrepreneurs gain access to their matched portfolio of companies and associations with global business leaders. These relationships are the foundation for strategic alliances, partnership opportunities and the sharing of insights to help build new ventures faster, broader and with less risk.

InterWest Partners
For more than 30 years InterWest has partnered with exceptional entrepreneurs to build winning technology and life sciences companies. With more than 200 years of combined operating and investing experience, our team has raised $2.8B, completed more than 70 IPOs, and participated in nearly 60 upside acquisitions. As we invest InterWest X, a $650M fund, Partners continue to believe that providing capital is just the beginning of a long-term collaboration with entrepreneurs to turn their vision into a thriving company.

Sofinnova Ventures
Sofinnova Ventures has over 30 years of experience building start-ups and spin-outs into market leaders. With $1 billion under management, the firm applies capital and expertise to guide early stage companies to successful exits.

Burrill Venture Capital
The Burrill family of venture capital funds includes funds with more than $950 million under management. These funds were formed to capitalize on Burrill’s unique investment platform and the opportunities created by today’s intersection of the genomic/proteomic and biologic revolution, and capital market inefficiency occurring within the life science field.

New Enterprise Associates
For more than 30 years, NEA has been helping to build great companies. NEA’s committed capital has grown to $11 billion and it’s funded more than 650 companies in the Information Technology, Energy Technology and Healthcare sectors. With more than 65 investment professionals working out of offices in the US, India, and China and investing across the globe—NEA is the entrepreneur’s venture capital firm, consistently ranking among the top firms in portfolio IPOs each year. Since its founding, the firm has backed more than 165 companies that have gone public and invested in more than 255 companies that have been successfully merged or acquired—more liquidity events than any other venture capital firm.

OrbiMed
OrbiMed is the world’s largest healthcare-dedicated investment firm, with approximately $5 billion in assets under management. OrbiMed’s investment advisory business was founded in 1989 with a vision to invest across the spectrum of healthcare companies: from private start-ups to large multinational companies. OrbiMed manages the Caduceus Private Investments series of venture capital funds and a family of public equity investment funds. OrbiMed’s investment team includes over 35 experienced professionals with backgrounds in science, medicine, industry, finance, information technology and law.

Quaker BioVentures
Quaker BioVentures is a venture capital firm investing in life science companies. The firm leads investments across the spectrum of the life science industry, including biopharmaceuticals, medical devices, human diagnostics, specialty pharmaceuticals, and healthcare services. Quaker BioVentures invests in companies at all stages of development, from early stage start-ups to public companies. Founded in 2003, the firm is currently investing Quaker BioVentures II, a $420 million fund formed in 2007. Quaker BioVentures manages over $700 million in committed capital.

Venrock
Venrock was founded in 1969 as the venture capital arm of the Rockefeller Family and we have $2.2 billion under management. Venrock provides funding and services for entrepreneurs with breakthrough ideas in technology, healthcare, media and energy. Venrock’s entrepreneurs have charted new advancements in cancer and HIV treatments, powered semiconductors and the digital era, secured our information technology infrastructure, pioneered on-line advertising, delighted consumers and most recently, generating power through alternative means. Venrock’s 22 investment professionals currently back 117 ventures out of offices in Palo Alto, New York City, Cambridge, and Israel.

More venture companies:

Aberdare Ventures
Abingworth
Aeris CAPITAL
Aisling Capital
Anthem Capital
Alliance Technology Ventures
Apple Tree Partners
Edmond de Rothschild Investment Partners
Bay City Capital
Bessemer Venture Partners
Care Capital
Caxton Advantage Life Sciences Fund
Chicago Growth Partners
Clarus Ventures
DAG Ventures
Delphi Ventures
Devon Park Bioventures
Enterprise Partners Venture Capital
Essex Woodlands Health Ventures
Excel Medical Fund
Frazier Healthcare Ventures
Grupo Cornelio Brennand
HBM BioCapital
HBM BioVentures
Highland Capital Partners
Intersouth Partners
Khosla Ventures
McNerney & Partners
MDV-Mohr Davidow Ventures
Morningside Venture
MVM Life Science Partners
Naxos
Northgate Capital
Novo A/S
Osage Partners
OVP Venture Partners
Oxford Finance Corporation
Panorama Capital
ProQuest Investments
Prospect Venture Partners
Rho Capital Partners
Scale Venture Partners
Sectoral Asset Management
SR One, the corporate venture fund of GlaxoSmithKline
Sutter Hill Ventures
Teachers’ Private Capital
The Column Group
Thomas
TPG Biotech
Venrock Associates
Ventech
Versant Ventures
Votorantim Novos Negocios
Wellcome Trust
Ysios Capital Partners

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The inhibitory effects of gossypol on human prostate cancer cells-PC3 are associated with transforming growth factor beta1 (TGFbeta1) signal transduction pathway.

Jiang J, Sugimoto Y, Liu S, Chang HL, Park KY, Kulp SK, Lin YC.

Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.

BACKGROUND: Racemic gossypol [(+/-)-GP], a naturally occurring polyphenolic yellow pigment present in cottonseed products, inhibits in vitro proliferation of Dunning prostate cancer cells (MAT-LyLu), human prostate cancer cells derived from a bone marrow metastasis (PC3), MCF-7 and primary cultured human prostate cells. (+/-)-GP also has the ability to inhibit the metastasis of lung and lymph nodes of the androgen-independent rodent prostate cancer cell line, MAT-LyLu, after implantation into Copenhagen rats. MATERIALS AND METHODS: The effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells were determined by thymidine incorporation assay and doubling-time (DT) determination. The mechanisms of action of (+/-)-GP on the proliferation of PC3 cells were determined by RT-PCR analysis, ELISA assay and Western blot analysis. RESULTS: The results show that (+/-)-GP caused reductions in DNA synthesis and prolonged the DTs in PC3 cells. RT-PCR and ELISA results show that (+/-)-GP elevate the mRNA expression and protein secretion of transforming growth factor beta1 (TGFbeta1) in PC3 cells. Consistent with these findings, (+/-)-GP has been shown to decrease the cyclin D1 mRNA expression and protein expression in PC3 cells. Furthermore, the growth inhibition of PC3 cells by conditioned media collected from the (+/-)-GP-treated-PC3 cells was completely reversed by addition of 25 microg/ml of mouse monoclonal anti-TGFbeta1, -beta2, -beta3 antibody, suggesting the involvement of TGFbeta1 in (+/-)-GP-induced growth inhibition of PC3 cells. CONCLUSION: These results indicate that the inhibitory effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells are associated with induction of TGFbeta1, which in turn influences the expression of the cell cycle-regulatory protein, cyclin D1, in prostate cancer cells.

PMID: 15015581 [PubMed – indexed for MEDLINE]

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Cottonseed Drug Boosts Cancer Treatment in Mice

Gossypol, a drug refined from cottonseed oil, and previously tried and abandoned as a male contraceptive, could boost the effectiveness of treatment for prostate cancer and possibly other common cancers as well.

New York /PSA Rising/ October 5, 2004 — Gossypol, a drug made from a toxic yellow pigment in cottonseed, for about a decade has been tested for use against prostate and other cancers.

Gossypol in cotton is a natural toxin present in the plant that protects it from insects. Its name is derived from the scientific name of cotton ( Gossypium spp.) and phenol, its main chemical structure.

Cottonseed can poison cattle yet gossypol is an old, abandoned male contraceptive used in China in the 1920s. After studies in the 1970s it was abandoned because some men remained infertile after stopping treatment and some developed hypokalemia (potassium shortage in the blood, which can lead to serious heart problems). Although in 1998 the World Health Organization said research on its use for contraception should be abandoned, Chinese researchers are still testing low-doses.

New interest has developed in gossypol as an anti-cancer drug. Gossypol is able to inhibit growth of a wide range of cancer cells both in a lab dish (in vitro) and in mice and other lab animals (in vitro). A study in Ohio in 1996 of the effect of gossypol on the growth of human androgen-independent prostate cancer cell line (PC3) found that gossypol “is a potent inhibitor of prostate cancer cell growth.”

Natural gossypol (GP) is made up of two mirror image molecules (enantiomers) — (+)GP (plus gossypol) and (-)GP (minus gossypol). Tests on breast cancer cells have shown that (-)GP is the more potent inhibitor of cancerous breast cell growth (Anticancer Res. 2002 Jan-Feb).

Now researchers at the University of Michigan Comprehensive Cancer Center say that minus gossypol (-)GP inhibits the function of Bcl-2/xL in human prostate tumors implanted in mice and makes the cancer more sensitive to radiation therapy and chemotherapy. The drug increased apoptosis, or programmed cell death.

“The significance of this is that anti-apoptotic proteins Bcl-2 and Bcl-xL are over expressed in many cancers, making them resistant to drug and radiation treatment. So, it is not just prostate cancer that our findings are relevant to, but also other cancers with BcL-2/xL expression, such as those of the lung, breast, ovary, pancreas, skin, brain and head and neck, where (-)-gossypol may also sensitize cancer cells to chemotherapy or radiation,” says Liang Xu, M.D., Ph.D., research assistant professor in hematology and oncology at the U-M Medical School.

Based on the cell and animal data, the (-)-gossypol form of the drug was likely to be more active than the same doses of natural gossypol used in previous studies. Furthermore, cell and animal data show that (-)-gossypol would make radiation and chemotherapy more powerful and overcome the resistance to drug and radiation treatment caused by high levels of Bcl-2/xL.

Gossypol is not the first drug investigated as a contraceptive to find a potential role in treating cancer. Tamoxifen was first developed as a female contraceptive and failed, only to become the world’s most successful breast cancer drug.

Will gossypol follow in the footsteps of tamoxifen? “There is a lot of research still to do, but we certainly hope so,” Xu says. “The natural form of gossypol has been extensively tested in humans and is well tolerated for long-term use. If we use the more active form, (-)-gossypol, correctly and wisely – for example, in combination with radiation or chemotherapy – gossypol may soon find its new role in our fight against cancer.”

Xu says he hopes to see the findings clinically tested soon and a Phase I trial is planned.

The research team is led by Marc Lippman, M.D., John G. Searle Professor and chair of internal medicine, and Shaomeng Wang, Ph.D., associate professor of internal medicine and co-director of the U-M Comprehensive Cancer Center Experimental Therapeutics Program, in collaboration with Theodore Lawrence, M.D., Ph.D., Isadore Lampe Professor and chair of Radiation Oncology.

Results of the Michigan study were reported Oct. 1 at the Symposium on Molecular Targets and Cancer Therapeutics in Geneva, Switzerland. The symposium is sponsored by three major cancer organizations: European Organization for Research and Treatment of Cancer, the National Cancer Institute and the American Association for Cancer Research.

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Gossypol is an herbal medicine used to treat cancer and a female problem called endometriosis. It may also be used by women and men to prevent pregnancy.

Other names for Gossypol include: Gossypium hirsutum and Cottonseed oil.

Ask your doctor, nurse, or pharmacist if you need more information about this medicine or if any information in this leaflet concerns you.

Before Using: Tell your doctor if you.

* are taking medicine or are allergic to any medicine (prescription or over-the-counter (OTC) or dietary supplement)
* are pregnant or plan to become pregnant while using this medicine
* are breastfeeding
* have other health problems, such as high blood pressure or heart or blood vessel disease

Dosage: There are many doses for this medicine. The most common doses for Gossypol are listed below. Ask your doctor if your health problem is not on the list or if the dose is not given for a product you want to use.

* Cancer (adrenal), tablet: 40 to 60 milligrams daily, by mouth (1)
* Cancer (glioma), tablet: Racemic Gossypol 10 milligrams twice daily, by mouth (2)
* Female birth control, gel: put application of a Gossypol acetic acid gel 0.5 milligram/milliliter into vagina before having sex (3)
* Male birth control, tablet: 10 to 20 milligrams (mg) daily for 75 to 180 days or until adequate reduction in sperm count is reached, followed by 35 to 65 mg weekly, by mouth (4-8)

To store this medicine: Keep all medicine locked up and away from children. Store medicine away from heat and direct light. Do not store your medicine in the bathroom, near the kitchen sink, or in other damp places. Heat or moisture may cause the medicine to break down and not work the way it should work. Throw away medicine that is out of date or that you do not need. Never share your medicine with others.

Drug and Food Interactions: Do not take Gossypol without talking to your doctor if you are taking:

* Chloroquine (9)
* Digoxin (1,7,10-12)
* Diuretic (1,7,11)
* Ethanol (13-15)
* Iron (16)
* Isoproterenol (10,17,18)
* Nonsteroidal anti-inflammatory medicine (1,19,20)
* Potassium (7,11,12)

Warnings:

* Do not take Gossypol if you are pregnant or breastfeeding

Side Effects: Stop taking your medicine right away and talk to your doctor if you have any of the following side effects. Your medicine may be causing these symptoms which may mean you are allergic to it.

* Breathing problems or tightness in your throat or chest
* Chest pain
* Skin hives, rash, or itchy or swollen skin
* Severe tiredness (21)
* Muscle weakness or paralysis (21)
* Dry mouth or skin, nausea (upset stomach), vomiting (throwing up), hair loss, bowel problems (1)

References:
1. Flack MR, Pyle RG, Sullen NM et al: Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab 1993; 76:1019-1024.
2. Bushunow P, Reidenberg NM, Wasenko J et al: Gossypol treatment of recurrent adult malignant gliomas. J Neuro-Oncology 1999; 43(1):79-86.
3. Ratsula K, Haukkamaa M, Wichmann K et al: Vaginal contraception with gossypol: a clinical study. Contraception 1983; 27(6):571-576.
4. Coutinho EM, Athayde C, Atta G et al: Gossypol blood levels and inhibition of spermatogenesis in men taking gossypol as a contraceptive. A multicenter, international, dose-finding study. Contraception 2000; 61(1): 61-67.
5. Gu ZP, Mao BY, Wang YX et al: Low dose gossypol for male contraception. Asian J Androl 2000; 2(4):283-287.
6. Coutinho EM & Melo JF: Clinical experience with gossypol in non-Chinese men: a follow-up. Contraception 1988; 37(2):137-151.
7. Liu GZ, Lyle KC & Cao J: Clinical trial of gossypol as a male contraceptive drug. Part I. Efficacy study. Fertil Steril 1987; 48(3):459-461.
8. Liu GZ, Lyle K & Cao J: Experiences with gossypol as a male pill. Am J Obstet Gynecol 1987a; 157(4 pt 2):1079-1082.
9. Nwoha PU & Aire TA: The effects of gossypol and chloroquine interaction on serum electrolytes of protein-malnourished rats. Contraception 1995a; 52(4):255-259.
10. Ye YX, Akera T & Ng YC: Modification of the positive inotropic effects of catecholamines, cardiac glycosides and Ca2+ by the orally active male contraceptive, gossypol, in isolated guinea pig heart. Life Sci 1989; 45(20): 1853-1861.
11. Liu GZ, Ch’iu-Hinton K, Cao J et al: Effects of potassium salt or a potassium blocker on gossypol-related hypokalemia. Contraception 1988; 37(2):111-117.
12. Shaozhen A, Guangwei J, Xiaoyun W et al: Gossypol related hypokalemia: clinicopharmacologic studies. Chin Med J 1980; 93:477-482.
13. Akingbemi BT, Rao PV & Aire TA: Chronic ethanol intake may delay the onset of gossypol-induced infertility in the male rat. Andrologia 1997; 29(4):201-207.
14. Messiha FS: Effect of gossypol on kinetics of mouse liver alcohol and aldehyde dehydrogenase. Gen Pharmac 1991; 22(4):573-576.
15. Messiha FS: Behavioral and metabolic interaction between gossypol and ethanol. Toxicol Lett 1991a; 57(2):175-181.
16. Herman DL & Smith FH: Effect of bound gossypol on the absorption of iron by rats. J Nutr 1973; 103(6):882-889.
17. Wu DF, Yu YW, Tang ZM et al: Pharmacokinetics of (+/-)-,(+)-, and (-)-gossypol in humans and dogs. Clin Pharmacol Ther 1986; 39(6):613-618.
18. Ye YX, Akera T & Ng YC: Direct actions of gossypol on cardiac muscle. Eur J Pharmacol 1987; 136(1):55-62.
19.Wagner H, Hikino H & Farnsworth NR (eds): Economic and Medicinal Plant Research. Academic Press, London, England; 1985.
20. DeSmet PAGM, Keller K, Hansel R et al (eds): Adverse Effects of Herbal Drugs 2. Springer-Verlag, Berlin, Germany; 1993:195-208.
21. Wooley RJ: Contraception-a look forward, part II: Mifepristone and gossypol. Contraception 1991; 4:103-113.

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By: Dr. Harriet Burge and Dave Gallup

Endotoxin
Endotoxins are bacterial products that are ubiquitous in the environment and, although they do take part in some disease processes, exposure at some level is probably essential for the normal development of the human (and animal) immune systems.

The nature of endotoxin
Bacteria produce two general types of toxins: exotoxins and endotoxins. Exotoxins are soluble proteins that are excreted from the bacterial cell. Anthrax, tetanus, botulism, and toxic shock syndrome are a few of the diseases caused by bacterial exotoxins. Endotoxins, on the other hand, are lipopolysaccharides (LPS) that are part of the bacterial cell structure. The toxin is minimally soluble and effects occur directly from contact with the bacteria. Endotoxins are produced by Gram negative bacteria such Escherischia coli, Salmonella, Shigella, Pseudomonas, Neisseria, Haemophilus, and many others. All Gram negative bacteria have lipopolysaccharides as part of the cell wall. However, the lipopolysaccharides are not always toxic and those that are vary in potency.

Health Effects
Endotoxins are potent inflammatory agents, stimulating the release of many chemicals that activate the immune system. In high concentrations, such as would occur during a Gram negative bacterial infection, fever, inflammation, coagulation of platelets, hemorrhage, and shock may result. At the much lower concentrations encountered during inhalation exposures, inflammation is the primary outcome.

In some work environments in which organic material is handled or large amounts of water are used (e.g., swine confinement, fiberglass manufacturing) work-related respiratory illnesses may occur. These illnesses are characterized by fever, chills, muscle aches, shortness of breath, and cough. These symptoms may be worse on Monday and may gradually abate during the week, only to return following a weekend of no exposure. In residential and office environments, effects are less clear. Some studies relate dust or air levels of endotoxin to respiratory inflammation.

In residential environments, endotoxin exposure appears to be related to a decrease in the risk of developing asthma. This effect is called the hygiene hypothesis, which considers that the reduction in exposure to endotoxin caused by increasing standards for home hygiene has led in part to the rising incidence of asthma.

Sampling and measurement technologies

Analytical methods

The most commonly used analytical method for endotoxin detection and measurement is the Limulus amoebocyte assay. This assay measures endotoxin in units of toxic activity as measured by the ability to clot the blood of Limulus (the horseshoe crab). Results from this assay are highly dependent on the lot of Limulus lysate being used, and the assay is affected by many factors, including materials that may be present in a sample. In general, this means that data from different laboratories cannot be directly compared and, even within a laboratory, data from different days or different batches of chemicals are difficult to compare. The ACGIH Bioaerosols Committee has proposed a relative standard for airborne endotoxin based on the Limulus assay that requires outdoor measurements for comparison. The comparisons are made on data produced by the same assay using the same lot of reagents.

Total lipopolysaccharides can be measured using gas chromatography. This method is stable and interlaboratory comparisons can be made. However, the method measures both toxic and non-toxic lipopolysaccharides. Since the non-toxic forms may be immunostimulants, this approach may actually be the most relevant in the long run. LPS is measured in concentration of the actual compound (e.g., nanograms/gram of dust). Endotoxin is measured in units of potency-endotoxin units (EU). In some literature, endotoxin concentrations are listed as nanograms (ng) or micrograms (ug)/ unit of measure. In these cases, either GCMS has been used to measure total LPS, or the authors are referring to units of the reference LPS standard used in the assay. However, because the type of lipopolysaccharide in the unknown sample may differ from the standard, EU is the preferred unit for Limulus assay data.

Sampling methods
Samples for endotoxin analysis can be collected from air or dust. For air samples, endotoxin-free membrane filters can be used. For dust, a variety of vacuum-based methods have been used with variable results. It is important to use the method by which any reference data that is to be used for comparison was collected.

Distribution in the environment

Outdoor air
Endotoxin is always present in outdoor air. Measured levels have ranged from 0.01-more than 5 EU/m³ of outdoor, with geometric means generally in the 0.02-0.5EU/m³. Endotoxin concentrations in outdoor air near farming activities can be much higher, reaching levels in excess of 1,000 EU/m³. In residential and other supposedly “clean” environments, measured levels of airborne endotoxin are rare. Concentration ranges for the few available studies are in the range 0.5-2,500 EU/m³, with the higher part of the range possibly indicating unusually high levels. Most residential measures are dust concentrations, which range from 8,000-250,000 EU/g of dust. Repeated measurements of endotoxin in residential dust tend to be correlated. The presence of a dog in the house tends to be strongly correlated with endotoxin concentrations in dust.

Most of the data on endotoxin exposure comes from occupational environments where organic material or water is used in the manufacturing process. In these types of environments, extremely high endotoxin concentrations have been measured. A summary of measured levels are listed in Table 1.

Air Samples EU/m³ of air
Outdoors 0.01-5
Residential 
Office .5-3; 350-460; 2500
Aircraft 1.5
Outdoor Feedlots (USA) 26-83
Soybean harvest 460-4438
Farms 2534-3175
Machining fluid mist 16-234
Fiberglass manufacturing 139000-278000

Table 1

Role in environmental investigations
In occupational environments where organic material is handled, or water is a part of the manufacturing process, airborne endotoxin measures are important and air samples should be collected in both the occupational environment and in outdoor air. There is a large amount of literature on such occupational exposures, and reference to the medical literature is an important component of interpretation. The National Library of Medicine is a free and very useful resource: www.pubmed.org.

There is little indication that endotoxin levels in residential and office environments are likely to be related to ongoing problems. Measuring endotoxin in house dust has been done often enough that there is reference data that can be used for interpretation of whether levels are low, moderate, or high. How the data is interpreted with respect to health is less clear.

Lipopolysaccharides from BuyReagents.com 

Liquid ( aqueous solution )
Lipopolysaccharide from E.coli O157 1ml 400,000 EU/ml01772-41 -20ºC
Lipopolysaccharide(LPS) from Salmonella serover paratyphi-A(O antigen 2+) 1ml 400,000 EU/ml 02453-91 -20ºC
Lipopolysaccharide(LPS) from Salmonella serover paratyphi-B(O antigen 4+) 1ml 400,000 EU/ml 02454-81 -20ºC
Lipopolysaccharide(LPS) from E.coli O2 1ml 400,000 EU/ml 02452-01 -20ºC
Lipopolysaccharide(LPS) from E.coli O18 1ml 400,000 EU/ml 02451-11 -20ºC
Lipopolysaccharide(LPS) from E.coli O145 1ml 400,000 EU/ml 02450-21 -20ºC
Lipoarabinomannan (LAM) from M.TB Aoyama-B 1ml 1mg/ml 02449-61 -20ºC
Lyophilized powder
Lipopolysaccharide (LPS) from E.coli O2 10mg 500,000 EU/mg 20386-34 2-8ºC
Lipopolysaccharide (LPS) from E.coli O18 10mg 500,000 EU/mg 20387-24 2-8ºC
Lipopolysaccharide (LPS) from E.coli O145 10mg 500,000 EU/mg 20388-14 2-8ºC
Lipopolysaccharide (LPS) from E.coli O157 10mg 500,000 EU/mg 20389-04 2-8ºC
Lipopolysaccharide (LPS) from E.coli O55:B5 100mg 500,000 EU/mg 20382-74 2-8ºC
Lipopolysaccharide (LPS) from E.coli O111:B4 100mg 500,000 EU/mg 20383-64 2-8ºC
Lipopolysaccharide (LPS) from E.coli O127:B8 100mg 500,000 EU/mg 20384-54 2-8ºC
Lipopolysaccharide (LPS) from E.coli O128:B12 100mg 500,000 EU/mg 20385-44 2-8ºC
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Acca
In the context of molecular modelling or chemical informatics, Acca is a program which assists in conformation searching, by transferring information between related conformation searches.

ACID
In the context of databases, ACID stands for Atomic, Consistent, Isolated and Durable. The ACID test for a database transaction requires: (i) Atomic – a transaction either succeeds completely, or fails completely, so the database is not left in a half-updated state. (ii) Consistent – a transaction always leaves the database in a correct state. (iii) Isolated – executing transactions do not affect other transactions (iv) Durable – the data should survive

ADME
ADME stands for Absorption, Distribution, Metabolism and Excretion. These four aspects of a drug’s action are all important.

AM1
Austin Model 1. A semi empirical molecular orbital method

AMBER
A molecular mechanics force field

API
Application Program Interface: many computer programs (including operating system) are designed so that other programs can access some of their functionality. The specification of how to do this is the API.

ASP
Application Service Provider: Applications can be delivered over the internet as well as data. Is this the future? Many companies are looking into this evolving delivery model. More information is available from the ASP Industry Consortium. (October 2000)

ASP
Active Server Pages: a web page which contains a script to be which works out what information to send to the user. Typically it is used to process a request for some information from a database. For more information see the ASP toolbox or LearnASP (September 2001)

BDNR
Block Diagonal Newton Raphson. A minimisation algorithm

BFGS
Broyden-Fletcher-Goldfarb-Shanno. A minimisation algorithm

BLAST
Basic Local Alignment Search Tool: a set of similarity search programs for DNA and protein sequences, originally published in the Journal of Molecular Biology (1990, 215(3):403-10 Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ). Several web resources are available including the NCBI – NIH and Washington University.

BLYP
A functional for density functional calculations

BRENDA
A collection of enzyme functional data

CADPAC
Cambridge Analytical Derivatives Package. An ab initio molecular orbital theory package

CAOS
Computer-Aided Organic Synthesis

CAS
Chemical Abstracts Service. An organisation connected with the American Chemical Society which abstracts the world’s chemical literature.

CCD
Cambridge Crystallographic Database (also called CCDC for Cambridge Crystallographic Data Centre)

CFF93
A molecular mechanics force field

CHARMm
A molecular mechanics force field

Chemical Informatics
‘Computer-assisted storage, retrieval and analysis of chemical information, from data to chemical knowledge.’ (Chem. Inf. Lett. 2003, 6, 14.) This definition is distinct from ‘Chemoinformatics’ (and the synonymous cheminformatics and chemiinformatics) which focus on drug design.

Chemiinformatics
See Chemoinformatics and Chemical Informatics

Cheminformatics
See Chemoinformatics and Chemical Informatics

Chemoinformatics
‘The mixing of those information resources [information technology and information management] to transform data into information and information into knowledge for the intended purpose of making better decisions faster in the arena of drug lead identification and optimization.’ (Frank K Brown ‘Chemoinformatics: what is it and how does it impact drug discovery.’ Ann. Rep. Med. Chem. 1998, 33, 375-384.) This article also says that chemometrics is a subset of chemoinformatics. See also Chemical Informatics, which includes chemoinformatics and also encompasses areas of chemistry outside drug design.

Chemometrics
Statistical analysis of chemical data

CIF
Crystallographic Information File. A standard format to exchange crystallographic information

CML
Chemical Markup Language; a SGML for chemistry, designed by Peter Murray-Rust. A browser is available, called JUMBO

CNDO
Complete Neglect of Differential Overlap. A semi-empirical molecular orbital method

CODATA
Committee on Data for Science and Technology

COMFA
Comparative Molecular Field Analysis: a 3D-QSAR technique, which explores molecular fields around a molecule. (Cramer, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc. 1988, 110, 5959-5967.

Concord
A program, developed by Robert Pearlman for generating 3D structures from 2D, distributed by Tripos.

CORBA
Common Object Request Broker Architecture

CORINA
A program from the Gasteiger Group at Erlangen, which automatically generates 3D molecular structures from 2D information

COSMIC
A molecular mechanics force field, and also a molecular modelling program

CPK
Corey, Pauling and Kulton design for plastic models of molecules

CVFF
Consistent Valence Force Field. See CFF93

DFT
Density Functional Theory. A new approach to molecular orbital theory

DNA
Deoxyribonucleic acid

DOM
Document Object Model

DOS
Disk Operating System. MicroSoft’s operating system for PCs which has grown into Windows.

DOS
Denial of Service: Computers can be attacked to prevent them providing access to their resources. More information is available from CERT.

DREIDING
A molecular mechanics force field

dtd
Document Type Definition. This is an explanation of all the label that may be used in a SGML.

Dublin Core
The Dublin Core is a set of core elements which can usefully be used to structure metadata. The name comes from a workshop in Dublin, Ohio.

Eadfrith
Eadfrith is a free program which produces high-quality pictures of molecules.

ECEPP
A molecular mechanics force field

ExPASy
ExPASy (Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB)

FEP
Free Energy Perturbation

GAMESS
An ab initio molecular orbital theory package

Gaussian
An ab initio molecular orbital theory package

Global minimum
The lowest energy point on a potential energy surface

Globus
The Globus project provides a toolkit, software tools that make it easier to build computational grids and grid-based applications.

GPL
GNU General Public License. How can a program be licensed as free software? GPL is one answer.

GRID
A program for finding binding sites on biologically important macromolecules, developed by Peter Goodford (J. Med. Chem. 1985, 28, 849-857).

GRID
Computational Grids enable computation as well as data to be shared over a network of computers.

GROMACS
A molecular dynamics package, primarily designed for biochemical molecules like proteins and lipids

GROMOS
A molecular mechanics force field

Hessian
A matrix of the second derivatives of energy with respect to molecular coordinates. The Hessian can be used to determine whether a stationary point is a minimum, a transition state with one negative normal mode or a higher order saddle point.

HOMO
Highest Occupied Molecular Orbital

HTML
Hyper Text Mark up Language. This is the language that WWW browsers understand

http
Hypertext Transfer Protocol

ICSTI
International Council for Scientific and Technical Information

IUBMB
International Union of Biochemistry and Molecular Biology

IUPAC
International Union of Pure and Applied Chemistry

Java
A computer language which was designed with World-Wide web-applications particularly in mind

Javascript
A A client-side HTML embedded scripting language for World-Wide Web browsers, which is not closely related to Java.

Journal Abbreviations
Chemistry journals have standard abbreviations, which are listed at the University of British Columbia website

JCAMP
The Joint Committee on Atomic and Molecular Physical Data developed standard data formats. The work has now been taken over by IUPAC. JCAMP formats are used for NMR, Mass Spectrometry and other spectral data.

KEGG
Kyoto Encyclopedia of Genes and Genomes

LCAO
Linear combinations of atomic orbitals. A technique used to build up molecular orbitals.

LDA
Lithium diisopropylamide: a strong, non-nucleophilic base

LDAP
Lightweight Directory Access Protocol. See, for example, the OpenLDAP project

Lhasa
Lhasa is a program to help plan organic syntheses, originally developed by E J Corey at Harvard.

Local minimum
A structure that is minimised with respect to all its coordinates, but higher in energy than the global minimum

LUMO
Lowest Unoccupied Molecular Orbital

MacroModel
A molecular modelling program (Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. “MacroModel- an Integrated Software System for Modeling Organic and Bioorganic Molecules using Molecular Mechanics” J. Comp. Chem. 1990, 11, 440-467.)

Magnus
Magnus is a group of programs for doing chemical calculations and handling chemical information. Most of the programs will run within a web browser.

MC
Monte Carlo. The name for any of a wide range of stochastic methods which involve random numbers, or even a mountain with a casino. The meaning may be clear from the context.

MD
Molecular Dynamics

MIME
Multipurpose Internet Mail Extension. A MIME-type describes the sort of information that a mail message, or other computer file, contains, and so a computer knows whether to expect an image, a molecule, or a spectrum, for example.

MINDO/3
A semi-empirical molecular orbital method

MM2, MM3, MM4
Molecular mechanics force fields

MM2*
MM2 as implemented in MacroModel

MMFF
A molecular mechanics force field

MNDO
A semi-empirical molecular orbital method

MOL
The MOL file format is defined by MDL (Molecular Design Ltd). A MOL file can describe a chemical structure, but no properties and references. For further detail, see the manual ‘MDL CTfile Formats’ provided by MDL. MOLFile Structure/Data File is a file format from MDL

MOPAC
A semi-empirical molecular orbital program

MP2
Second order Mшller-Plesset correction to a Hartree Fock calculation

mSQL
A lightweight database engine developed by David Hughes

Multiplicity
A measure of the number of unpaired electrons in a molecule. Singlet multiplicity means that all the electron spins are paired, a doublet must have one unpaired spin.

MySQL
An open-source database management system, available under GPL (Gnu General Public License), developed by Monty Widenius.

NCE
New Chemical Entity

NCI
National Cancer Institute: a part of the NIH (qv)

NIH
National Institutes of Health, USA

NIST
National Institute of Standards and Technology, USA

NSF
National Science Foundation

nOe
Nuclear Overhauser Effect. Used in NMR spectroscopy to determine which atoms are close to each other

OASIS
Organization for the Advancement of Structured Information Standards (OASIS), is a non-profit, international consortium that creates interoperable industry specifications based on public standards such as XML and SGML (See OMG).

OMG
The Object Management Group (OMG) is an open membership, not-for-profit organisation that produces and maintains computer industry specifications. Its specifications include CORBA and UML.

OPLS
A molecular mechanics force field

Oracle
The world’s leading supplier of software for information management, and the world’s second largest independent software company. The Oracle database, which uses SQL, is being made increasingly internet aware.

P2P
Peer-to-peer: a concept for networking computers, used by Gnutella and other applications.

P3P
Platform for Privacy Preferences Project (P3P), not to be confused with P2P, is a simple, automated way for users to gain more control over the use of personal information, developed by the World Wide Web Consortium.

PCA
Principal Component Analysis. A set of variables which may be correlated are transformed to a smaller set of uncorrelated variables.

PCR
Polymerase Chain Reaction

PCR
Principal Component Regression. A combination of principal component analysis (PCA) with a regression analysis.

PDB
Protein Data Bank, formerly the Brookhaven Protein Data Bank

PDF
Portable Document Format.

Perl
Perl is a interpreted language optimized for scanning text files, extracting information and printing reports.

PHP
PHP: Hypertext Preprocessor. A server-side HTML embedded scripting language, closely connected to database access. PHP offers compatibility witha number of SQL database servers. Its syntax is borrowed from C, Java and Perl.

PLS
Partial Least Squares. A fitting algorithm closely related to principal component regression (PCR)

PM3
Parameterised Model 3. A Semi-Empirical Molecular Orbital Theory Hamiltonian, developed by Stewart

PostgreSQL
PostgreSQL is an open-source object-relational database management system.

PRCG
Polak-Ribiere Conjugate Gradient algorithm for minimisation

QM
Quantum Mechanics

QSAR
Quantitative Structure Activity Relationship

RDBMS
Relational Database Management System

RDF
Radial Distribution Function

RDF
Resource Description Framework: a foundation for processing metadata providing interoperability between applications that exchange machine-understandable information on the Web

RDF
RDFile (reaction-data file) is a file format from MDL.

RFP
Request for proposals. The OMG periodically issues requests for proposals for standards in data exchange and interoperable applications

RHF
Restricted Hartree Fock. Useful approximation in ab initio molecular orbital theory, forcing all electrons to be paired

SCF
Self Consistent Field. Use in molecular orbital theory

SDF
The SDF file format is defined by MDL (Molecular Design Ltd). A SDF file can contain multiple compounds together with properties and references. For further detail, see the manual ‘MDL CTfile Formats’ provided by MDL. SDFile Structure/Data File is a file format from MDL

SELF
Standard Electronic Data Files: developed at a IUCOSPED meeting, a IUPAC task group chaired by Dr Henry Kehiaian

SGML
Standard Generalised Mark-up language. HTML is an SGML with a particular dtd.

SHAKE
A method of speeding up molecular dynamics simulations by constraining C-H bond lengths

Simplex
A simple, minimisation algorithm which does not require the calculation of derivatives

SNP
Single Nucleotide Polymorphisms. DNA sequence variations

SN1
Substitution, Nucleophilic, Unimolecular

SN2
Substitution, Nucleophilic, Bimolecular

SOMO
Semi-occupied molecular orbital – Used instead of HOMO or LUMO when the highest occupied orbital contains only one electron.

Spartan
An ab initio molecular orbital theory package

SQL
Structured query language: a language for interacting with relational databases including Oracle, MySQL, PostgreSQL, and mSQL. There are several dialects of SQL, and a standardisation process. SQL can be used for a variety of tasks including: querying data, updating and deleting rows in a table, altering objects, controlling access to a database and ensuring database consistency.

STO
Slater Type Atomic Orbital: An early basis set for molecular orbital theory. These are close in shape to atomic orbitals, but much harder to manipulate mathematically than gaussian functions, so the latter are now used almost exclusively.

SVG
Scalable Vector Graphics, a graphics format from Adobe.

SWISS-PROT
A curated protein sequence database which strives to provide a high level of annotations (such as the description of the function of a protein, its domains structure, its domains structure, post-translational modifications, variants, etc.), a minimal level of redundancy and high level of integration with other databases

TIP3P, TIP4P
Models for the properties of water molecules (Jorgensen, W. L.; Chandrasekhar, J.; Madura, J. D.; Impey, R. W.; Klein, M. L. “Comparison of Simple Potential Functions for Simulating Liquid Water” J. Chem. Phys. 1983, 79, 926-935.)

Tripos
A molecular mechanics force field

UFF
A molecular mechanics force field

UHF
Unrestricted Hartee-Fock. Unlike RHF, this permits a system to have any multiplicity. Can lead to spin contamination

URL
Uniform Resource Locator- the address of a WWW page

WWW
World Wide Web

XED
Extended Electron Distribution (Vinter, J. G. Extended electron distributions applied to the molecular mechanics of some intermolecular interactions J Comp.-Aided. Mol. Design 1994, 8, 653-668.)

XML
Extensible Markup Language: a unified format for structured documents and data on the web. A less general, and perhaps more useful, SGML.

Z-matrix
An internal coordinate description of a molecule

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The Disease In Birds: Impact And Control Measures

Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. The disease, which was first identified in Italy more than 100 years ago, occurs worldwide.

All birds are thought to be susceptible to infection with avian influenza, though some species are more resistant to infection than others. Infection causes a wide spectrum of symptoms in birds, ranging from mild illness to a highly contagious and rapidly fatal disease resulting in severe epidemics. The latter is known as “highly pathogenic avian influenza”. This form is characterized by sudden onset, severe illness, and rapid death, with a mortality that can approach 100%.

Fifteen subtypes of influenza virus are known to infect birds, thus providing an extensive reservoir of influenza viruses potentially circulating in bird populations. To date, all outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7.

Migratory waterfowl – most notably wild ducks – are the natural reservoir of avian influenza viruses, and these birds are also the most resistant to infection. Domestic poultry, including chickens and turkeys, are particularly susceptible to epidemics of rapidly fatal influenza.

Direct or indirect contact of domestic flocks with wild migratory waterfowl has been implicated as a frequent cause of epidemics. Live bird markets have also played an important role in the spread of epidemics.

Recent research has shown that viruses of low pathogenicity can, after circulation for sometimes short periods in a poultry population, mutate into highly pathogenic viruses. During a 1983–1984 epidemic in the United States of America, the H5N2 virus initially caused low mortality, but within six months became highly pathogenic, with a mortality approaching 90%. Control of the outbreak required destruction of more than 17 million birds at a cost of nearly US$ 65 million. During a 1999–2001 epidemic in Italy, the H7N1 virus, initially of low pathogenicity, mutated within 9 months to a highly pathogenic form. More than 13 million birds died or were destroyed.

The quarantining of infected farms and destruction of infected or potentially exposed flocks are standard control measures aimed at preventing spread to other farms and eventual establishment of the virus in a country’s poultry population. Apart from being highly contagious, avian influenza viruses are readily transmitted from farm to farm by mechanical means, such as by contaminated equipment, vehicles, feed, cages, or clothing. Highly pathogenic viruses can survive for long periods in the environment, especially when temperatures are low. Stringent sanitary measures on farms can, however, confer some degree of protection.

In the absence of prompt control measures backed by good surveillance, epidemics can last for years. For example, an epidemic of H5N2 avian influenza, which began in Mexico in 1992, started with low pathogenicity, evolved to the highly fatal form, and was not controlled until 1995.

A Constantly Mutating Virus: Two Consequences

All type A influenza viruses, including those that regularly cause seasonal epidemics of influenza in humans, are genetically labile and well adapted to elude host defenses. Influenza viruses lack mechanisms for the “proofreading” and repair of errors that occur during replication. As a result of these uncorrected errors, the genetic composition of the viruses changes as they replicate in humans and animals, and the existing strain is replaced with a new antigenic variant. These constant, permanent and usually small changes in the antigenic composition of influenza A viruses are known as antigenic “drift”.

The tendency of influenza viruses to undergo frequent and permanent antigenic changes necessitates constant monitoring of the global influenza situation and annual adjustments in the composition of influenza vaccines. Both activities have been a cornerstone of the WHO Global Influenza Programme since its inception in 1947.

Influenza viruses have a second characteristic of great public health concern: influenza A viruses, including subtypes from different species, can swap or “reassort” genetic materials and merge. This reassortment process, known as antigenic “shift”, results in a novel subtype different from both parent viruses. As populations will have no immunity to the new subtype, and as no existing vaccines can confer protection, antigenic shift has historically resulted in highly lethal pandemics. For this to happen, the novel subtype needs to have genes from human influenza viruses that make it readily transmissible from person to person for a sustainable period.

Conditions favourable for the emergence of antigenic shift have long been thought to involve humans living in close proximity to domestic poultry and pigs. Because pigs are susceptible to infection with both avian and mammalian viruses, including human strains, they can serve as a “mixing vessel” for the scrambling of genetic material from human and avian viruses, resulting in the emergence of a novel subtype. Recent events, however, have identified a second possible mechanism. Evidence is mounting that, for at least some of the 15 avian influenza virus subtypes circulating in bird populations, humans themselves can serve as the “mixing vessel”.

Human Infection With Avian Influenza Viruses: A Timeline

Avian influenza viruses do not normally infect species other than birds and pigs. The first documented infection of humans with an avian influenza virus occurred in Hong Kong in 1997, when the H5N1 strain caused severe respiratory disease in 18 humans, of whom 6 died. The infection of humans coincided with an epidemic of highly pathogenic avian influenza, caused by the same strain, in Hong Kong’s poultry population.

Extensive investigation of that outbreak determined that close contact with live infected poultry was the source of human infection. Studies at the genetic level further determined that the virus had jumped directly from birds to humans. Limited transmission to health care workers occurred, but did not cause severe disease.

Rapid destruction – within three days – of Hong Kong’s entire poultry population, estimated at around 1.5 million birds, reduced opportunities for further direct transmission to humans, and may have averted a pandemic.

That event alarmed public health authorities, as it marked the first time that an avian influenza virus was transmitted directly to humans and caused severe illness with high mortality. Alarm mounted again in February 2003, when an outbreak of H5N1 avian influenza in Hong Kong caused 2 cases and 1 death in members of a family who had recently travelled to southern China. Another child in the family died during that visit, but the cause of death is not known.

Two other avian influenza viruses have recently caused illness in humans. An outbreak of highly pathogenic H7N7 avian influenza, which began in the Netherlands in February 2003, caused the death of one veterinarian two months later, and mild illness in 83 other humans. Mild cases of avian influenza H9N2 in children occurred in Hong Kong in 1999 (two cases) and in mid-December 2003 (one case). H9N2 is not highly pathogenic in birds.

The most recent cause for alarm occurred in January 2004, when laboratory tests confirmed the presence of H5N1 avian influenza virus in human cases of severe respiratory disease in the northern part of Viet Nam.

Why H5N1 Is Of Particular Concern

Of the 15 avian influenza virus subtypes, H5N1 is of particular concern for several reasons. H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species. Its ability to cause severe disease in humans has now been documented on two occasions. In addition, laboratory studies have demonstrated that isolates from this virus have a high pathogenicity and can cause severe disease in humans. Birds that survive infection excrete virus for at least 10 days, orally and in faeces, thus facilitating further spread at live poultry markets and by migratory birds.

The epidemic of highly pathogenic avian influenza caused by H5N1, which began in mid-December 2003 in the Republic of Korea and is now being seen in other Asian countries, is therefore of particular public health concern. H5N1 variants demonstrated a capacity to directly infect humans in 1997, and have done so again in Viet Nam in January 2004. The spread of infection in birds increases the opportunities for direct infection of humans. If more humans become infected over time, the likelihood also increases that humans, if concurrently infected with human and avian influenza strains, could serve as the “mixing vessel” for the emergence of a novel subtype with sufficient human genes to be easily transmitted from person to person. Such an event would mark the start of an influenza pandemic.

Influenza Pandemics: Can They Be Averted?

Based on historical patterns, influenza pandemics can be expected to occur, on average, three to four times each century when new virus subtypes emerge and are readily transmitted from person to person. However, the occurrence of influenza pandemics is unpredictable. In the 20th century, the great influenza pandemic of 1918–1919, which caused an estimated 40 to 50 million deaths worldwide, was followed by pandemics in 1957–1958 and 1968–1969.

Experts agree that another influenza pandemic is inevitable and possibly imminent.

Most influenza experts also agree that the prompt culling of Hong Kong’s entire poultry population in 1997 probably averted a pandemic.

Several measures can help minimize the global public health risks that could arise from large outbreaks of highly pathogenic H5N1 avian influenza in birds. An immediate priority is to halt further spread of epidemics in poultry populations. This strategy works to reduce opportunities for human exposure to the virus. Vaccination of persons at high risk of exposure to infected poultry, using existing vaccines effective against currently circulating human influenza strains, can reduce the likelihood of co-infection of humans with avian and influenza strains, and thus reduce the risk that genes will be exchanged. Workers involved in the culling of poultry flocks must be protected, by proper clothing and equipment, against infection. These workers should also receive antiviral drugs as a prophylactic measure.

When cases of avian influenza in humans occur, information on the extent of influenza infection in animals as well as humans and on circulating influenza viruses is urgently needed to aid the assessment of risks to public health and to guide the best protective measures. Thorough investigation of each case is also essential. While WHO and the members of its global influenza network, together with other international agencies, can assist with many of these activities, the successful containment of public health risks also depends on the epidemiological and laboratory capacity of affected countries and the adequacy of surveillance systems already in place.

While all these activities can reduce the likelihood that a pandemic strain will emerge, the question of whether another influenza pandemic can be averted cannot be answered with certainty.

Clinical Course And Treatment Of Human Cases Of H5N1 Avian Influenza

Published information about the clinical course of human infection with H5N1 avian influenza is limited to studies of cases in the 1997 Hong Kong outbreak. In that outbreak, patients developed symptoms of fever, sore throat, cough and, in several of the fatal cases, severe respiratory distress secondary to viral pneumonia. Previously healthy adults and children, and some with chronic medical conditions, were affected.

Tests for diagnosing all influenza strains of animals and humans are rapid and reliable. Many laboratories in the WHO global influenza network have the necessary high-security facilities and reagents for performing these tests as well as considerable experience. Rapid bedside tests for the diagnosis of human influenza are also available, but do not have the precision of the more extensive laboratory testing that is currently needed to fully understand the most recent cases and determine whether human infection is spreading, either directly from birds or from person to person.

Antiviral drugs, some of which can be used for both treatment and prevention, are clinically effective against influenza A virus strains in otherwise healthy adults and children, but have some limitations. Some of these drugs are also expensive and supplies are limited.

Experience in the production of influenza vaccines is also considerable, particularly as vaccine composition changes each year to match changes in circulating virus due to antigenic drift. However, at least four months would be needed to produce a new vaccine, in significant quantities, capable of conferring protection against a new virus subtype.

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Flu drugs exist that may be used both to prevent people from catching bird flu and to treat those who have it. The virus appears to be resistant to two older generic flu drugs, amantadine and rimantadine. However, the newer flu drugs Tamiflu and Relenza are expected to work – though supplies could run out quickly if an outbreak occurs.

Currently there is no vaccine, although scientists are working to develop one. It probably will take several months to complete and may not be ready in time to stop a widespread human outbreak, if one occurs.

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In rural areas, the H5N1 virus is easily spread from farm to farm among domestic poultry through the feces of wild birds. The virus can survive for up to four days at 71 F (22 C) and more than 30 days at 32 F (0 C). If frozen, it can survive indefinitely.

So far in this outbreak, human cases have been blamed on direct contact with infected chickens and their droppings. People who catch the virus from birds can pass it on to other humans, although the disease is generally milder in those who caught it from an infected person rather than from birds.

If the virus mutates and combines with a human influenza virus, it could be spread through person-to-person transmission in the same way the ordinary human flu virus is spread.

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Bird flu can cause a range of symptoms in humans. Some patients report fever, cough, sore throat and muscle aches. Others suffer from eye infections, pneumonia, acute respiratory distress and other severe and life-threatening complications.

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