Ebola Virus Pandemic Shield

Swine Influenza

Swine Influenza

SWINE INFLUENZA frightening you? CONCERNED about the health implications? Coughs and Sneezes Spread Diseases! Stop The Swine Flu from Spreading. Follow the advice to keep your family and friends safe from this virus and not become another victim. These simple cost free guidelines will help you to protect yourself from the swine flu.

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Pandemic Survival

This eBook shows you what it takes to survive the next pandemic. There is no doubt that in the future, the world will be hit with a huge pandemic, either from natural causes or from a terrorist attack. As you look through history, you will be hard-pressed to find any pandemic in history that has killed less than 1 million people. You do not want you or your family to be among those millions. And with the help of the information in this eBook, you have a way to survive the global pandemic that will come. Wishing it won't happen doesn't do anything Preparing for it gives you the tools to survive AND thrive. This book contains the two-pronged approach of John Hartman's years of research in figuring out how pandemics work and living through a dangerous flu outbreak. This gives you the methods to both avoid getting a virus in the first place, and how to strengthen your immune system should you come down with a virus. You don't have to lay down and die. You can fight the next pandemic.

Pandemic Survival Summary


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Inhibitors Of Severe Acute Respiratory Syndrome Sars

Recognizing the potentially high mortality and morbidity associated with SARS, in May 2003, NIAID convened a colloquium entitled SARS Developing a Research Response to help identify research needs in SARS research clinical research, epidemiology, diagnostic, therapeutics, and vaccines and to help coordinate international research efforts.194 There are four areas being considered as SARS therapeutic research priorities (1) drug screening (high throughput screening (HTS) assay and assay of existing compounds), (2) antiviral drug design (identification of viral targets, structural models of viral targets, design and synthesis of candidates), (3) immunomodulation and other therapies, and (4) preclinical (nonhuman primate and small-animal models) and clinical studies. In order to help accelerate the discovery of new leads for effective SARS countermeasures, NIAID offers a SARS Chip'' free to researchers for microarray analysis (see http www.niaid.nih.gov). A number of research initiatives...

Covalent inhibitors of SARSCoV 3CLpro

The design and synthesis of two analogues (3,4) of AG7088 (2) was recently reported 13 . Based upon the reported SARS-CoV 3CLpro structure 9,14 , AG7088 was modified by changing the P2 side chain from a -fluorobenzyl group to the smaller benzyl and prenyl groups. These inhibitors possess a P1 P1'- a,p-unsaturated ester functionality, which can covalently link to the Cys-145. Compound 2 is inactive against SARS-CoV in cell-culture assay. The antiviral activity for 2 was reported to be 100 mg ml 15 . The modified analogues are not only potent against SARS-CoV 3CLpro (kinact values), but are effective in a SARS-CoV cell assay (IC50 values) as well. No toxicity was observed up to 100 mM. Moreover, an X-ray crystal structure of the SARS-CoV 3CLpro covalently linked with the synthetic small molecule inhibitor (4) was reported. In addition to the important covalent bond formed between 4 and the protease, the X-ray structure also showed crucial hydrogen bonding between 4 and His-164 and...

Sars Coronavirus Proteases

The SARS-CoV replicase is encoded in the 5'-most 21 kb of the 29.7kb viral genomic RNA. The genomic RNA is translated to produce two replicase polyproteins, termed ppla and pplab 6,7 . The ppla is a 486 kilodalton (kDa) polyprotein that is predicted to contain a single papain-like protease (PLpro) analogous to the second murine coronavirus PLpro domain, a picornavirus 3C-like protease domain (3CLpro, also sometimes noted as Mpro or main protease), three putative membrane proteins, and several additional products of unknown function. The pplab ( 790 kDa) is generated by ribosomal frameshifting and extends the ppla product to include open reading frame lb, which contains the core RNA poly-merase and helical domains, and additional products of unknown function. The ppla and pplab polyproteins are predicted to be processed to generate l6 protein products (termed non-structural proteins, nspl-nspl6) 8 , which assemble to form a membrane-associated viral replication complex.

Inhibitors Of Ebola Virus

Ebola virus is classified as a select agent. Because of biosafety and biosecurity concerns, antiviral research has been conducted mainly by USAMRIID investigators. Huggins and co-workers recently established a lethal mouse model suitable for evaluation of prophylaxis and therapy of Ebola virus.307 Intraperitoneal administration (2.2-20 mg kg), thrice daily, of C-c3Ado 10 significantly protected BALB c mice from lethal infection with mouse-adapted Ebola Zaire virus, providing

Noncovalent SARSCoV 3CLpro inhibitors

A series of synthetic small molecule, non-covalent inhibitors of SARS-CoV 3CLpro was published in 2004 21 . These investigators previously reported that keto-glutamine analogues with the phthalhydrazido group at a-position are reversible inhibitors of hepatitis A virus (HAV) 3C proteinase. The IC50 values of the inhibitors were in the low micromolar range 22,23 . They synthesized a series of keto-glutamine analogues with the phthalhydrazido group at the a-position and attachment of tripeptide (Ac-Val-Thr-Leu) as the inhibitors (7-14) for SARS-CoV 3CLpro. The combined effect of the p and p' amino groups adjacent to the keto group and intramolecular hydrogen bonding to the carbonyl makes it more elect-rophilic. As a result, the carbonyl group can form a hemithioacetal with the sulfur of Cys-145. The K values of these reversible inhibitors remain to be determined. A diversified library of peptide anilides was prepared and their inhibitory activity was examined against the SARS-CoV 3CLpro...

SARSCoV 3CLpro inhibitors from screening

Extensive screening has been carried out in an effort to find structural leads against SARS-CoV 3CLpro from existing drugs. A major advantage is that approved drugs with minimal modifications may have the possibility of gaining accelerated approval by US Food and Drug Administration. It was reported that Kaletra, a mixture of protease inhibitors - Lopinavir and Ritonavir, approved for treating HIV in 2000, shows some effectiveness against the SARS virus 30 . Based on this observation, the binding affinities of six other drugs were investigated against SARS-CoV 3CLpro 31 . These include Lopinavir, Ritonavir, Niclosamide, Promazine and two other HIV inhibitors, PNU and UC2. The preliminary results indicated that these drugs could be useful as templates for designing SARS-protease inhibitors 32 . A collection of nearly 10,000 synthetic compounds and natural products was screened in an assay using SARS-CoV and Vero E6 cells 6,33 . For the SARS-CoV 3CLpro inhibiton assay, a C2-symmetric...

Sarscov 3clpro Inhibitors

Coronavirus Chemistry

Proteolytic processing of the coronavirus replicase polyproteins is essential for ongoing viral RNA synthesis. Therefore, the SARS-CoV proteases are attractive targets for the development of antiviral drugs to reduce viral replication and pathogenicity. The structure and activity of the coronavirus 3CLpro has already been elucidated and the design of inhibitors to 3CLpro as therapeutics has been proposed 9,10 . SARS-CoV 3CLpro has three domains I (residues 8-101), II (residues 102-184), and III (residues 201-301). Domains I and II, which contain the active site region, are p-barrel domains and III is an a-helical domain. In the active site, a cysteine residue (Cys-145) acts as a nucleophile and a histidine residue (His-41) acts as the general acid base. The X-ray crystal structure of the related enzyme from porcine transmissible gastroenteritis coronavirus (TGEV 3CLpro) and a substrate-analogue hexapeptidyl chloromethyl ketone (CMK) inhibitor 1 (Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK) has...

Contributions Of Virus And Host To Disease Severity

Once infection has become established, host inflammatory responses may make major contributions to disease severity and, in some instances, may be principally responsible for a fatal outcome. Many viruses that pose a bioterror threat infect monocytes, macrophages, and related cells, causing the release of large quantities of cytokines, chemokines, and other immunological mediators. In the case of Ebola virus, for example, macrophages are the principal target of infection, and their release of interleukin-1, tumor necrosis factor-alpha, and other proinflammatory mediators appears to be the direct cause of the increased vascular permeability, hypotension, and shock seen in severe or fatal illness.17-19 Infected cells also trigger another major component of hemorrhagic fever disseminated intravascular coagulation by producing tissue factor on their surfaces.20 The fact that a number of other RNA viruses cause a similar syndrome suggests that they evoke similar sets of host responses....

Inhibitors Of Avian Influenza A Viruses

In 1997, an outbreak of H5N1 avian influenza in Hong Kong caused considerable concern about a potential pandemic.312 Since then, several influenza A viruses of avian origin that cause human disease have been isolated (see Table 3.6). In addition, such a naturally occurring lethal virus as well as recombinant viruses generated in the lab would be potential bioterrorist weapons.313

SAH Hydrolase Inhibitors

SAH hydrolase is an intracellular enzyme that regulates biological transmethylation in general. Since many animal viruses require SAH hydrolase in the methylation of the 5'-terminal residue of viral mRNA for forming the cap structure necessary for viral protein translation and replication, this enzyme has been recognized as a suitable antiviral target.112-116 3-Deazaneplanocin A 9 (c3-NPC A) and carbocyclic 3-deazaadenosine 10 (C-c3Ado) are two representative inhibitors. Their in vitro activity is summarized in Table 3.5. SAH inhibitors are inactive against togaviruses and flaviviruses.11 However, they have demonstrated potent activity against Ebola virus in cell cultures and in mice (see Section 3.9).

Viruses As Weapons

Although biological weapons were abandoned as impractical by most military forces, they may unfortunately be much better suited to the needs of terrorists. The environmental factors that were a major obstacle to military planning would not be an impediment to a terror attack, since the effects of wind and weather could be avoided, either by carrying pathogens directly to their targets or by releasing them as aerosols in indoor spaces. In addition, terrorist groups may be less interested in attempting to infect a broad target area or causing a large number of deaths than in inducing fear and insecurity through small, unpredictable clandestine attacks. Thus, even if the release of aerosolized Ebola virus into an urban setting, such as a subway station, were to cause only a few cases of disease, such an event might still produce widespread anxiety and extensive social disruption. Countermeasures that would be expected to deter a nation-state from carrying out biological attacks, such as...

Miscellaneous Inhibitors

Several compounds have been identified that have shown inhibitory activity against SARS-CoV. However, no information regarding their mechanism of action or the corresponding target is known. Glycyrrhizin showed inhibitory activity for SARS-CoV replication with EC50 300mg l after virus absorption in Vero cells 60 . Some glycyrrhizin acid derivatives were found to inhibit SARS-CoV replication in vitro with EC50 values ranging from 5 to 50 mM. Unfortunately, these compounds show high cytotoxity 61 . The viral entry step was suspected to be inhibited by these derivatives. Nitric oxide (NO) has shown an inhibitory effect on some virus infections 62 . An organic NO donor, S-nitroso-N-acetylpeniciUamine was shown to inhibit the replication cycle of SARS-CoV in a concentration-dependent manner, probably during the early steps of infection 63 . HIV protease inhibitor nelfinavir 64 , antihelminthic drug niclosamide 65 and antimalarial agent chloroquine 66 all showed strong inhibitory activity...

Viral Entry Inhibitors

Virtual screening aided in identifying structural leads for viral entry inhibitors of SARS-CoV. Compound 27, which emerged from a 50,240 compound screen and inhibited pseudovirus entry and SARS-CoV plaque formation with EC50 values of 3 mM and 1.6 mM, respectively 37 . A two-step screening of Chinese herbal medicine-based, novel small molecules which bind avidly with the S protein was performed as well. Two virus entry inhibitors, tetra-O-galloyl-p- D-glucose (28) and luteolin (29) were identified and showed anti-SARS-CoV activities with EC50 values of 4.5 and 10.6 mM, respectively 58 . After binding with ACE2, SARS-CoV is taken up into a vesicle inside the cell. Special cellular enzymes (cathepsins) act in the acidic environment inside the vesicle, facilitating fusion of the viral membrane and the vesicle membrane, so that viral proteins and nucleic acids can enter the cell where viral replication occurs 59 . Thus, the cathepsin L inhibitor, MDL28170 (30) represents an attractive...

The doublemembraned vesicles induced by arteriviruses and CoVs may be related to autophagosomes

SARS-CoV extend from the ER and can be labeled with antibodies specific for replicase proteins. This suggests that, in common with MHV, the vesicles are a site of replication (Snijder et al., 2006). Even though all SARS-CoV replicase proteins tested colocalize to punctate structures that accumulate near the nucleus, there are conflicting reports about their relationship with autophagosomes. In monkey Vero cells, the replicase proteins colocalize with autophagosomes identified using antibodies against LC3 (Prentice et al., 2004a). However, when autophagosomes are identified by expression of GFP-LC3, the replicase proteins do not coloca-lize with the GFP signal (Snijder et al., 2006). The vesicles induced by SARS-CoV are smaller at 100- to 300-nm diameter than autophagosomes (500-1000 nm) and are labeled with ER markers. This has lead Snijder and colleagues to suggest that they are virus-induced extensions to the ER, rather than bona fide autophagosomes (Pedersen et al., 1999 Snijder et...

Antimicrobialresistant Microorganisms

The severe acute respiratory syndrome (SARS) first emerged in Guangdong Province, China, in November 2002. SARS is caused by a novel coronavirus (SARS-CoV) that may have originated from an animal reservoir.81 It is characterized by fever, chills, cough, dyspnea, and diarrhea and radiologic findings suggestive of atypical pneumonia.82 As of August 7, 2003, a total of 8,422 probable cases, with 916 deaths (11 ), had been reported from 29 countries.83 The incubation period is estimated to be 10 days, and patients appear to be most infectious during the second week of illness.83 Available evidence suggests that SARS-CoV is spread through contact, in droplets, and possibly by airborne transmission.83 Accordingly, health care workers must adhere to contact, droplet, and airborne precautions when caring for SARS patients. Included in such precautions are the use of gloves, gowns, eye protection, and the N95 respirator.83 A comprehensive review of SARS is available at the WHO web site

AIDS Rhetoric and Medical Knowledge

This book examines the formation of scientific knowledge about the AIDS epidemic in the 1980s and shows the broader cultural assumptions on which this knowledge is grounded. Alex Preda highlights the metaphors, narratives, and classifications that framed scientific hypotheses about the nature of the infectious agent and its means of transmission and compares these arguments with those used in the scientific literature about SARS. Through detailed rhetorical analysis of biomedical publications, the author shows how scientific knowledge about epidemics is shaped by cultural narratives and categories of social thought.

The Nidovirus replicase is generated from two polyproteins

The Nidovirales order comprises the Arteriviridae, Coronaviridae, and Roniviridae families. The replicase gene is composed of two open reading frames termed ORF1a and ORF1b. ORF1b is generated from a frameshift in 1a, and both reading frames encode complex polyproteins processed by viral proteases (Gorbalenya et al., 2006 Ziebuhr, 2006). The arterivirus ORF1b encodes NSPs 9-12, including the RdRp (NSP9) and helicase (NSP10). The ORF1b, however, lacks hydrophobic domains able to target the replicase to membranes. Interestingly, the hydrophobic domains necessary for membrane targeting are encoded by ORF1a in NSP2, 3, and 5, suggesting that ORF1a proteins produce a scaffold to locate the viral replication-transcription complex to membranes (Fig. 1D) (Pedersen et al., 1999 van der Meer et al., 1998). A similar strategy is used by CoV, for example mouse hepatitis virus (MHV) and severe acute respiratory syndrome-CoV (SARS-CoV) (Prentice etal., 2004a,b), where transmembrane domains are...

Sites of arterivirus and CoV replication are separate from sites of envelopment and budding

Several studies have investigated the intracellular sites of replication of equine arterivirus (EAV), MHV, and SARS-CoV. Such studies are difficult because during nidovirus infection, the processes of replication and envelopment occur on different membranes, and these may merge during encapsidation. Furthermore, late during infection cells infected with MHV can form syncitia. Newly synthesized MHV viral RNA has been found in perinuclear sites colocalized with the RdRp (Shi et al., 1999), and depending on whether human or murine cells were infected, these sites colocalized with Golgi or ER membranes, respectively. Similar studies in mouse L cells report that the polymerase and newly synthesized RNA locate to late endosomes and endocytic carrier vesicles (van der Meer et al., 1999). This discrepancy is in part reconciled by later work showing that the subcellular distribution of the replicase proteins can change during the course of infection, since replicase proteins move to sites of...

Regulation of Gene Expression

To the nuclear envelope (for review, see Qumsiyeh 1999). Lamins as well as many INM integral proteins directly interact with chromatin (Stierle et al. 2003, Ye and Worman 1996), being potentially able to affect its structure at the nuclear periphery. Moreover, lamins and some of their molecular partners can specifically bind the genomic sequences called MARS (matrix attachment regions) and SARS (scaffold attachment regions Luderus et al. 1994 Zhao et al. 1996), very likely contributing to the higher-order organization and partitioning of chromatin into functional loops in the nuclear matrices. Several pieces of evidence suggest that nucleoplasmic lamins form an internal skeleton that could also support different nuclear activities, such as the replication and repair of DNA and the splicing of pre-mRNAs, through interactions with molecular partners such as nuclear actin, which could have motor functions in this cellular compartment as well (Sasseville and Langelier 1998 Shumaker et al....

Chemogenomics knowledge space

The chemogenomics knowledge space, integrated by Paolini et al. identified chemical tools, leads and drugs for nearly 900 human proteins. Annotated chemical libraries of chemical tools that can be derived from such databases can be applied to target validation and chemical biology 20,21 . Importantly, Paolini et al. have demonstrated that new knowledge space can be created by analyzing SAR data in its entirety by mapping the interaction network between proteins in chemical space 17 . Thus, mapping the chemogenomics knowledge space enables the development of methods for the rational design of polypharmacology drugs 22,23 . The chemogenomics knowledge space also enables the ideas proposed by Frye 24 and Fliri et al. 25-27 of comparing the homology of SARs across a wide range of molecular targets to determine the relationship between structure, selectivity, efficacy and safety. The data in the chemogenomics knowledge space are not just a repository of previous experimental observation...

Regulation of Transcription in Eukaryotes

During interphase the genetic material in association with proteins is dispersed throughout the nucleus in the form of chromatin. At the onset of mitosis, chromatin condensation takes place and during prophase it undergoes further compression into recognizable chromosomes. The associated proteins are basic, positively charged (lysine- and arginine-containing) histones and less positively charged nonhistones including high-mobility group (HMG) proteins. Histones play a key role in chromatin structural organization and are subject to various posttranslational modifications like acetylation, phosphorylation, and ubiquitination. Histones constitute nearly half of all the chromatin protein by weight and can be divided into six types HI, H2A, H2B, H3, H4, and H5. DNA is incorporated into a 100 A nucleosomal fiber comprising of two molecules each of H2A, H2B, H3, and H4 which form the core histone octamer along with one linker histone HI or H5. The nucleosome core particle consists of 146...

Regulation of membrane traffic in the early secretory pathway

By a hydrophobic region at the N-terminus of P1. P1 also acts as the methyltransferase (yellow). P2 encodes the helicase (purple) and P4 is the RdRp (red). The P123 precursor associates with P4 and generates negative-stranded RNA. Further processing produces a complex of separate P1, 2, 3, and 4 proteins that produce positive-stranded RNA. (D) Nidoviruses. The Nidovirales order comprises the Arteriviridae, Coronaviridae, and Roniviridae families. The replicase gene is composed of two open reading frames termed ORF1a and ORF1b, both of which encode complex polyproteins. Arterivirus ORF1b encodes NSPs 9-12 including the RdRp (NSP9, red), helicase (NSP10, purple). The ORF1b reading frame lacks hydrophobic domains able to target the replicase to membranes. Proteins necessary for membrane targeting (brown and blue) are encoded by ORF1a (NSP2, 3, and 5). For the CoVs, for example, MHV and SARS-CoV transmembrane domains are located in NSP3, 4, and 6, and helicase and polymerase proteins are...

Respirovirus A genus in the family

Reston Ebola virus (EBOV) Filoviridae. In 1989 an outbreak of hemorrhagic fever occurred in a non-human primate facility in Reston, Virginia, USA involving Cynomolgus monkeys imported from the Phillipines. Ebola virus was diagnosed as the cause of the outbreak and all monkeys were destroyed. At least one case of demonstrated human infection occurred, but with no associated disease symptoms. Two further outbreaks occurred in association with monkeys imported from the same facility in the Phillipines, in Siena, Italy in 1992, and in Texas, USA in 1996. The company providing the monkeys has now ceased trading. The Reston Ebola virus is highly pathogenic for monkeys, and whilst it has been suggested that it may be less pathogenic for humans this has not been put to the test, for obvious reasons. The following strains of Reston Ebola virus are recognized Reston Ebola virus Philippines Reston Ebola virus Reston Reston Ebola virus Siena Reston Ebola virus Texas.

Subacute myeloopticoneuropathy virus

Sudan Ebola virus (SEBOV) A species in the genus 'Ebola-like viruses', which caused a major outbreak of Ebola hemor-rhagic fever in Sudan in 1976. See Ebola virus. Sudan Ebola virus Boniface An isolate of Sudan Ebola virus from a patient named Boniface. Sudan Ebola virus Maleo An isolate of Sudan Ebola virus from a patient named Maleo.

The wildlife resource

By the end of the 1990s, there was one issue that brought debates about sustainable use into focus, and that was 'bushmeat' hunting in tropical forests. Bushmeat is an umbrella term for all wild-caught mammal meat, and it can range from cane rats to gorillas. The subject is extremely complex. There are obvious ethical issues associated (particularly in the minds of adequately-nourished Westerners) with both killing and eating apes, for example as explored by the Great Ape Project.58 There are also health issues, since the inter-species transmission of viruses such as Ebola is a major problem for people (and indeed apes). There are issues of poverty and malnutrition (for much bushmeat is consumed by people for whom there is no immediate alternative protein source). There are issues of political representation, since the majority of those campaigning on bushmeat are white Americans and Europeans, and bushmeat consumers are mostly not. And there are, of course, issues of biodiversity and...

Use of Functional Genomics to Understand Influenza Host Interactions

In healthy individuals however, it is responsible for 30,000-40,000 deaths each year in the United States. In extreme cases, such as the influenza pandemic of 1918, tens of millions of people have died from the infection. To prepare for future influenza outbreaks, it is necessary to understand how the virus interacts with the host and to determine what makes certain strains of influenza highly pathogenic. Functional genomics provides a unique approach to this effort by allowing researchers to examine the effect of influenza infection on global host mRNA levels. Researchers are making

Postencephalitic Parkinsonism

Following the pandemic of encephalitis lethargica (von Economo's disease), in the early part of the 20th century, a large proportion of individuals who survived the acute encephalitic phase developed parkinsonism, after a latency of several years or decades. PEP was therefore common in the 1940s and 1950s but is now rarely encountered. Although a viral etiology (possibly influenza A) has long been suspected, this remains to be proven (164,165).

Estimated Exposure Risks

Heterosexually acquired HIV infections in the UK, including those among pregnant women, and the numbers of new HIV diagnoses reflect the focus of the pandemic in sub-Saharan African countries with close links to the UK. In England, Wales and Northern Ireland, of the HIV-infected heterosexual patients receiving care in 2003 (and for whom ethnicity was reported), 70 per cent were black-African. Over two-fifths of the HIV-infected heterosexuals receiving care reside and are treated outside London most of these are black-African. Among women who were born in sub-Saharan Africa and who subsequently gave birth in the UK, an estimated one in 42 were HIV-infected in 2003. However, the transmission of HIV from mother to child in the UK has been reduced greatly since the universal offer and recommendation of HIV testing in pregnancy was introduced. Despite this, undiagnosed HIV infection and late diagnosis of longstanding HIV infection continue to be a feature of the treatment histories of...

Human endogenous retroviruses HERV

Human enterovirus 70 (HEV70) A serotype of Human enterovirus D in the genus Enterovirus. Isolated in 1971 from epidemics of acute hemorrhagic conjunctivitis in Japan, Singapore and Morocco. These outbreaks were part of a pandemic involving millions of humans in Africa, South-East Asia, Japan, India and England during 1969-71. The virus can adsorb in vitro to cells from a wider range of species than most enteroviruses. In some it produces no CPE but in others, such as RK 13 (rabbit cells) and BK 1 (bovine cells), it produces virus and CPE. Prototype strain is AHC(J670 71). human microvascular endothelial cell line (HMEC-1) A cell line that has proved useful for propagation of filoviruses, such as Marburg and Ebola virus.

Postsurgical Infections

Ironically, the evolution of the hospital into a center for medical education and research may have been a major factor in the appalling mortality rates of the large teaching hospitals. Changes in the hospital's social role may also have contributed to the pandemic of hospitalism. By the nineteenth century, the reputation of many urban hospitals was so low that no horror story seemed too implausible. Impoverished slum dwellers were convinced that hospital patients were doomed to death and dissection to satisfy the morbid curiosity of doctors. Hospital managers in France were confronted by terrifying rumors of secret dissection rooms where human fat was collected to light the lamps of the Faculty of Medicine.

Goals and Impacts of Health Policies

Less frequently, policies are advanced that may not be based on careful scientific consideration. For example, the 1975 campaign to immunize the American population against the swine flu was advanced without adequate consideration of the scientific evidence (Ibrahim 1985). Even though the policy was halted shortly after implementation, it led to substantial legal liability for the US government because of the potential link between swine flu vaccination and Guillain-Barre syndrome (Christoffel and Teret 1991). More recently, the ban on silicone breast implants in the United States and

Avian influenza vaccine

Traditionally, vaccination has been the principal approach to protecting individuals against influenza. Currently, no influenza A H5N1 vaccine is available although several candidate vaccines are being developed. Preliminary data suggest that either higher concentrations of antigens than used in seasonal influenza vaccines and or addition of adjuvants to these vaccines will be necessary to induce protective responses 8 . Gearing production, to rapidly make necessary quantities, of such a vaccine in the event of pandemic spread will be a great challenge to the vaccine industry. Thus, although great progress has been made in understanding the biology of avian influenza H5N1 and although the virus is not presently capable of efficient human-to-human transmission there is reason for concern as noted above. Continued surveillance in animal and human populations and infection control measures to limit its spread are critical, while we learn to better combat this virus (or some other future...

Fetal rhesus kidney virus Synonym for

Filoviridae A family consisting of a single genus Filovirus, containing two genera, 'Marburg-like viruses' and 'Ebola-like viruses'. Both Marburg and Ebola viruses cause severe hemorrhagic fevers in humans and other primates, with extremely high mortality (up to 90 ). Marburg virus so far appears to be a single virus type, whereas four subtypes of Ebola virus have been recognized Zaire, Sudan, Reston and C te d'Ivoire. Except for their extreme length, the viruses have a morphology somewhat similar to that of members of the family Rhabdoviridae. They are filamentous, with U-shaped, 6-shaped or circular forms produced in cell culture. The length is highly variable and can be as great as 14000 nm but it is usually about 800-1000 nm the diameter is 80 nm. The particles are enveloped with spikes ca. 7 nm in length and 10nm apart. The virus RNA is 19.1 kb in length, negative-sense and is therefore non-infectious. There are at least seven virus proteins with mol. wt. of ca. 267 (RNA Klenk...

Evolution of B burgdorferi sl

The pattern of distribution of LB is comparable with a multifocal worldwide epidemic with the endemic regions extending over the continents. However, most species of the B. burgdorferi s.l. complex have a relatively limited distribution, the only exception being B. burgdorferi s.s., which is found both in Europe and in the USA. The question is, from where and how have the LB Borrelia spp. migrated The larger genetic variability and the clinical polymorphism seen in the Old World suggest that the B. burgdorferi s.l. complex emanated from this geographical area. However, in a series of experiments Baranton and co-workers compared the genetic polymorphism of B. burgdorferi s.s. strains isolated in Europe or the USA, using several molecular methods (Foretz et al., 1997 Marti Ras et al., 1997). A genetic distance method and a parsimony method were used to perform phylogenetic analysis of each of the two sets of data. The results were consistent and showed that the American B. burgdorferi...

The 3 and 4R Tauopathies

As the chronic form of the episode, could appear years after the acute episode (175). Most salient clinical characteristics of PEP are onset below middle age, symptom duration lasting more than 10 yr, presence of oculogyric crisis, and obviously a history of encephalitis (176). The disease has been linked to the Spanish influenza pandemic that occurred at approximately the same time. The influenza virus responsible for the Spanish flu has been isolated from an archival 1918 autopsy lung sample its RNA was not detected in archival brain tissues from acute encephalitis lethargica. These data make the connection between Spanish flu and encephalitis lethargica doubtful (177).

Sources of Public Health Surveillance Data

Langmuir's credo of rapid reporting, analysis, and action now applies to over 100 infectious diseases and health events of noninfectious etiology nationally (Osterholm et al. 1996). Some ongoing systems of reporting have resulted from national emergencies such as contaminated lots of polio vaccine (Lang-muir 1987), the Asian influenza epidemic of 1957, shellfish-associated hepatitis type A in 1961, and toxic-shock syndrome in 1980. Following the investigation of L-tryptophan-associated eosinophilia-myalgia syndrome (EMS) in 1990, within days a national surveillance system was put into place (Philen et al. 1993).

Artifical Intelligence In Drug Design

Whilst there is a strong tacit dimension to the medicinal chemist's knowledge, many of the tactics and techniques used to navigate chemical space that derive from experience can be articulated and therefore potentially formalized. If we can articulate the tactics used to explore SARs efficiently then the next step is to formalize and codify such knowledge. Codifying medicinal chemistry knowledge enables the goal of evolving from computer-aided drug design (CADD) to knowledge-aided drug design (KADD).


For centuries, influenza virus has plagued humankind. While influenza infection typically causes mild-to-moderate illness in healthy individuals, it still results in 30,000-40,000 deaths per year in the United States. Those most susceptible to influenza infection are infants, the elderly, and those individuals that are immunocompromised due to HIV AIDS infection or organ tissue transplant (CDC, 2006). In extreme cases, such as the 1918 pandemic, it is estimated that 50 million people died as a result of influenza infection (Taubenberger and Morens, 2006). What was unique about this pandemic is that the most susceptible to this disease were young, otherwise healthy, individuals. Since 1918, multiple influenza pandemics have occurred, although none nearly as deadly. Another influenza pandemic is inevitable and much effort is being placed on disease surveillance and monitoring of transmission across species (Pandemic Flu, 2007 Subbarao and Joseph, 2007). Of particular concern is the H5N1...

Technical Aspects

Of the vector genome resulting in concatamerization of a starting monomer has been the rule in several studies in which small expression cassettes were rescued as deleted adenoviral vectors. The vector preparations consisted of viral particles that contained both monomeric and dimeric genomes and frequently were mixtures of particles with head-to-head, head-to-tail, or tail-to-tail DNA concatemers 6, 14, 28, 29 . This size-dependence of stable vector production was confirmed with the loxP production system that was used to rescue and propagate HC-Ad vectors with differently sized vector genomes as starting material. Only vectors with genome sizes of at least 27 kb allowed efficient and stable vector amplification 30 . Thus, stuffer DNA has to be added to the therapeutic gene cassette to bring the total vector genome size to at least 27 kb. Some practical considerations are outlined here. Since approximately 30-kb plasmids are typically used for vector construction, the stuffer DNA...

Natures degradation

On the ground, however, as conservationists know only too well, the natural world is a mess. Rates of ecosystem change and rates of fossil energy use are high, and not slowing. The implications of anthropogenic climate change for biodiversity are profound, with the prospect of the world's species being reduced to a weedy fast-dispersing subset of the recent whole.6 Even leaving aside the well-known problems of habitat destruction and pollution, the interactions of humans and other species hold novel threats to both, as the recent outbreaks of Ebola haemorrhagic fever in the forests of Central Africa, demonstrate. Neither people nor wild gorillas and chimpanzees can survive this killer, which they have the misfortune to share.7

Avian Influenza

The influenza virus genome is composed of 8 segmented pieces of RNA with each coding for a separate viral protein. These viral proteins may change slowly (antigenic drift) through point mutations occurring during viral replication or suddenly (an-tigenic shift). The latter occurs only in influenza A strains and it results from a combination of the segmented genome described above and the ability of influenza A strains of human and avian origin to co-infect the same host (typically, pigs or swines are most receptive), and share their genetic information. During this process of re-assortment a new strain acquiring one of the avian surface protein genes (H or N) may emerge. Such a novel strain then eludes pre-existing immunity in people previously infected with influenza and may spread rapidly among the entire population. This defines the potential for worldwide spread or an influenza pandemic. A number of influenza pandemics were documented over the 20th century with the most notable...

Murine models

Of all the influenza viruses that have surfaced in the last century, very few have caused as much intrigue as the 1918 pandemic strain. Among the most perplexing questions surrounding the influenza pandemic of 1918 is what made this virus so deadly. Environmental, biological, or demographic factors could have contributed to its virulence however, the most pertinent factors may be related to how this virus interacts with the host innate immune response. As mentioned in the previous section, we used functional genomics to study the effect of the 1918 NSi on global gene expression using a cell culture system. While this study provided an important first step in understanding this deadly virus, it only hints at what might be occurring in the whole host.


From the functional genomics experiments published so far, we have been able to gain invaluable insight into influenza pathogenesis. Perhaps the most critical use of this technology has been in the study of the virus responsible for the deadly 1918 influenza pandemic. In regards to highly pathogenic influenza, future experiments should also focus on the effect of avian H5N1 infection on global gene expression, using multiple model systems such as those that are being used to study the 1918 virus.

PLpro Inhibitors

Numerous studies on the structural and mechanistic aspects of SARS-CoV 3CLpro have provided multiple avenues for structure-based design of antiviral compounds targeted against the 3CLpro active site 9,16,44,45 . On the other hand, structure-based design against the membrane-associated PLpro enzyme, either from SARS-CoV or related coronaviruses, has remained elusive due to lack of structural information. Unlike many coronaviruses that encode two PLpro paralogs (PLP1 or PLP2), SARS-CoV has a single copy of PLpro that cleaves ppla at three sites at the N terminus to release nspl, nsp2 and nsp3, respectively 10,46 . Interestingly, these cleavage sites bear strong resemblance to the C-terminal tail of ubiquitin (consensus sequence LXGG). As a result, it was hypothesized that SARS-CoV PLpro may have de-ubiquitinating activity 47 . Recently, the catalytic domain of PLpro was purified and it was shown that it efficiently disassembles di- and branched polyubiquitin chains, cleaves...

Future Outlook

It is with unprecedented rapidity that a basic understanding of SARS-CoV life cycle has been achieved. Already, a number of targets including SARS-CoV 3CLpro and SARS-CoV PLpro appear very promising for anti-SARS-CoV chemotherapy. Since the global outbreak of SARS ended in 2003, only a small number of cases of SARS associated with laboratory exposures have been reported. However, with the identification of Chinese horseshoe bats as an animal reservoir for SARS-CoV, the potential danger of the transfer of this virus to humans still exists. To date, there is no effective therapy for the treatment of SARS in humans. While structure-based design and the screening of compounds have provided a number of promising structural leads for SARS-CoV 3CLpro, potent, low molecular weight inhibitors with less toxicity are needed for development. Interest in structure-based design and screening of SARS-CoV PLpro will increase since the X-ray structure of SARS-CoV PLpro was recently determined....

Possession Of Facts

Interestingly, in both categories, the number of available relevant facts, both known a priori and generated in situ during the course of drug discovery project, can be very large, and yet chemists never quite have complete information to make their choices with certainty. During the course of a drug discovery project the laboratory measurements for a series of compounds reveal the structure-activity relationships (SARs) and the structure-property relationships (SPRs). These relationships then provide a priori information for the next generation of drug discovery projects to learn from. New knowledge is created within a project by exploration of the SARs and the testing of the compound through the hierarchy of biological and toxicity assay through to the clinic. However, the previous experience of medicinal chemistry also provides a rich source of information from which to derive new knowledge, useful to selecting and guiding drug-design programs. Prior knowledge provides an ontology...

Bubonic Plague

Bubonic Plague Resistance

Astrologers blamed the Black Death on a malign conjunction of Saturn, Jupiter, and Mars. Epidemiologists have traced the cause of epidemic plague to a catastrophic conjunction of Yersinia pestis, fleas, and rats. A brief overview of the complex ecological relationships of microbes, fleas, rodents, and human beings will help us understand the medieval pandemics, the waves of plague that continued well into the seventeenth century, and the status of plague today. Studying the components of this web of relationships should help dispel the notion that discovering the cause of epidemic disease is a simple matter of finding a specific microbial agent. Even if a specific pathogen can be linked to epidemic disease, that microbe is only one strand in the complex web of life, along with fleas, mosquitoes, lice, ticks, wild animals, domesticated animals, and human beings. Moreover, the relationship between human beings and epidemic disease is affected by many factors biological, climatic,...