LEI 11416 DE 2006 PDF

This study investigated the prevalence of serological markers for causative agents of transfusion-transmissible infections TTI , i. We collected data on the seroprevalence of TTI agents among volunteer blood donors. Although the risk of TTI is low in China compared to that in some developing countries, sensitive screening methods and recruitment of regular donors are still very important for blood safety and availability. Despite significant progress made over the last few decades in the prevention of transfusion-transmissible infections TTI through blood transfusion, transmission of pathogens such as hepatitis B virus HBV , hepatitis C virus HCV , human immunodeficiency virus HIV and Treponema pallidum TP via transfusion still poses a great threat to blood safety. In the global view, the risk of TTI has been drastically reduced by the introduction of routine donor laboratory screening for blood-borne pathogens and by volunteer donations 1 , 2. As a consequence of continuous implementation and improvement of more sensitive serological methods and nucleic acid amplification tests NAT , in the European Union and the United States the residual risk of HIV and HCV among all allogeneic donations is currently below 1 per 1 million donations, and that of HBV is close to 1 per , donations 3 , 4.

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Surveillance of coronaviruses in many animal species has increased the number on the list of coronaviruses to at least The explosive nature of the first SARS epidemic, the high mortality, its transient reemergence a year later, and economic disruptions led to a rush on research of the epidemiological, clinical, pathological, immunological, virological, and other basic scientific aspects of the virus and the disease.

This research resulted in over 4, publications, only some of the most representative works of which could be reviewed in this article. The marked increase in the understanding of the virus and the disease within such a short time has allowed the development of diagnostic tests, animal models, antivirals, vaccines, and epidemiological and infection control measures, which could prove to be useful in randomized control trials if SARS should return.

The findings that horseshoe bats are the natural reservoir for SARS-CoV-like virus and that civets are the amplification host highlight the importance of wildlife and biosecurity in farms and wet markets, which can serve as the source and amplification centers for emerging infections. The rapid economic growth in southern China has led to an increasing demand for animal proteins including those from exotic game food animals such as civets.

Large numbers and varieties of these wild game mammals in overcrowded cages and the lack of biosecurity measures in wet markets allowed the jumping of this novel virus from animals to human , Its capacity for human-to-human transmission, the lack of awareness in hospital infection control, and international air travel facilitated the rapid global dissemination of this agent. The acute and dramatic impact on health care systems, economies, and societies of affected countries within just a few months of early was unparalleled since the last plague.

The small reemergence of SARS in late after the resumption of the wildlife market in southern China and the recent discovery of a very similar virus in horseshoe bats, bat SARS-CoV, suggested that SARS can return if conditions are fit for the introduction, mutation, amplification, and transmission of this dangerous virus 45 , , , Here, we review the biology of the virus in relation to the epidemiology, clinical presentation, pathogenesis, laboratory diagnosis, animal models or hosts, and options for treatment, immunization, and infection control.

Members of the Coronaviridae are known to cause respiratory or intestinal infections in humans and other animals Fig. Primary isolation of SARS-CoV was achieved by inoculation of patients' specimens into embryonal monkey kidney cell lines such as FRhK-4 or Vero E6 cell lines, which produced cytopathic changes at foci, where cells become round and refractile within 5 to 14 days These initial cytopathic changes spread throughout the cell monolayers, leading to cell detachment within 24 to 48 h.

Transmission electron microscopy of infected cell lines showed characteristic coronavirus particles within dilated cisternae of rough endoplasmic reticulum and double-membrane vesicles. Clusters of extracellular viral particles adhering to the surface of the plasma membrane were also seen.

Negatively stained electron microscopy showed viral particles of 80 to nm with characteristic surface projections of surface proteins from the lipid envelope 89 , , SARS-CoV has a higher degree of stability in the environment than other known human coronaviruses 91 , It can survive for at least 2 to 3 days on dry surfaces at room temperature and 2 to 4 days in stool Similar to other coronaviruses, it is an enveloped positive-sense single-stranded RNA virus with a genome size of almost 30 kb Fig.

The genome is predicted to have 14 functional open reading frames ORFs The two proteases are involved in posttranslational proteolytic processing of the viral polyprotein 5 , 15 , , , The surface S protein is involved in the attachment and entry of the host cell and is therefore the main target for neutralizing antibody and antiviral peptides , , , , N together with M, E, and Orf7a are involved in the assembly of the virion 97 , , , , Orf3a is an ion channel protein that is likely to be involved in viral budding and release Deletions of 82 and nucleotides in Orf8 were found in some human isolates, whereas a unique nucleotide signature insertion in Orf8 can be found in animal isolates 64 , Therefore, the more conserved Orf1b is generally chosen to be the molecular target for the design of clinical diagnostic tests rather than these less conserved regions.

Phylogenetic tree of 28 coronaviruses with complete protein sequences of helicase. Their accession numbers are shown in parentheses. Italic type indicates the complete genome accession numbers since helicase protein sequence accession numbers of these coronaviruses are not available. The helicase of another eight coronaviruses of spotted hyena, cheetah, ferret, puffinosis, rat, pigeon, goose, and duck are not included because no complete protein sequence is available.

The classification of Asian leopard cat coronavirus is undefined. The tree was constructed by the neighbor-joining method using clustalX 1. The scale bar indicates the estimated number of substitutions per 50 nucleotides. Data are from references , , , , , and Nomenclature and functional characteristics of SARS-CoV gene products and their interactions with host cells in disease pathogenesis. Trimers of the S protein form the peplomers that radiate from the lipid envelope and give the virus a characteristic corona solis-like appearance under an electron microscope.

S is a class I fusion protein that consists of the amino-terminal S1 and carboxyl-terminal S2 subunits connected by a fusion peptide. The two subunits are indispensable for receptor binding and membrane fusion, respectively. The receptor binding domain of S1 has been mapped to residues to 9 , The binding of S1 to the cellular receptor will trigger conformational changes, which collocate the fusion peptide upstream of the two heptad repeats of S2 to the transmembrane domain, and, finally, fusion of the viral and cellular lipid envelopes.

Moreover, this process could be facilitated by the infected cell membrane-associated protease, such as factor Xa, which can cleave S into S1 and S2. This proteolytic cleavage is specifically inhibited by a protease inhibitor, Ben-HCl The key receptor of the host cell attached by S is angiotensin-converting enzyme 2 ACE2 , which is a metalloprotease expressed in the cells of the lung, intestine, liver, heart, vascular endothelium, testis, and kidney Since ACE2 was shown to protect against acute lung injury in a mouse model and since the binding of the S protein to host cells results in the downregulation of ACE2, this mechanism may contribute to the severity of lung damage in SARS Nonsusceptible cells expressing these lectins in the absence of ACE2, such as dendritic cells, were able to promote the cell-mediated transfer of SARS-CoV to susceptible cells Although lysosomotropic agents can block viral entry, which indicates that endosomal acidification is required for entry, the activation of the S protein by protease can bypass this inhibition and result in cell-to-cell fusion.

Despite the role of the pH-sensitive endosomal protease cathepsin L in the entry pathway , , viral culture does not require pretreatment with trypsin. However, this pH-sensitive cathepsin L may be a target for agents such as chloroquine, which elevates endosomal pH , The process of viral disassembly in the cytoplasm for the release of viral RNA for translation and replication remains elusive.

Translation starts with two large polyproteins from Orf1a and Orf1ab , which are posttranslationally cleaved by the two viral proteases into nsp1 to nsp As in other coronaviruses, SARS-CoV may attach by the hydrophobic domains of their replication machinery to the limiting membrane of autophagosomes and form double-membrane vesicles. Once sufficient viral genomic RNA and structural proteins are accumulated, viral assembly by budding of the helical nucleocapsid at the endoplasmic reticulum to the Golgi intermediate compartment occurs.

Here, the triple-membrane-spanning M protein interacts with the N protein and viral RNA to generate the basic structure. It also interacts with the E and S proteins to induce viral budding and release. The N protein is the most abundantly expressed viral protein in infected cells in which the mRNA levels were amplified 3 to 10 times higher at 12 h postinfection than other structural genes and is therefore an important target for immunohistochemistry and antigen detection in clinical specimens.

Various diagnostic tests, antiviral agents, and vaccines are designed on the basis of our understanding of the structure and function of the various viral proteins involved in the life cycle of this virus. SARS was the first known major pandemic caused by a coronavirus. During the epidemic in , 8, cases with deaths had occurred in over 30 countries among five continents 89 , , , , , , , , , , , , , , , Retrospective surveillance revealed severe cases of the disease in five cities around Guangzhou over a period of 2 months The index case was reported in Foshan, a city 24 km away from Guangzhou.

The second case involved a chef from Heyuan who worked in a restaurant in Shenzhen. The patient had regular contact with wild game food animals. His wife, two sisters, and seven hospital staff members who had contact with him were also affected. From 16 November to 9 February , a total of cases were reported in mainland China, with of those cases involving health care workers.

Within a day, he transmitted the infection to 16 other people in the hotel where he resided. His brother-in-law, one of the secondary cases, underwent an open lung biopsy from which the etiological agent was discovered and first isolated Carlo Urbani's description of the disease, to which he later succumbed, alerted health authorities throughout the world and accelerated collaborative research to identify the virus and combat the disease As a result, massive numbers of palm civets were culled to remove sources for the reemergence of SARS in Guangdong in January The virus was found in many civets and raccoon dogs from the wildlife market prior to culling but not in over 1, civets later sampled at 25 farms in 12 provinces The evolutionary starting point was a prototype group consisting of three viral genome sequences of animal origin.

This prototype group representing low-pathogenicity virus has seven single-nucleotide variation SNV sites that caused six amino acid changes, at positions , , , , , and of the S protein, which were involved in generating the early phase of the and epidemic. One of these was found in the first SARS patient in the subsequent epidemic of to A further 14 SNVs caused 11 amino acid residue changes, at positions , , , , , , , , , , and This resulting high-pathogenicity virus group caused the middle phase of the epidemic of Finally, the remaining six SNVs caused four amino acid changes, at positions , , , and , which resulted in the group of viruses responsible for the late phase and the global epidemic The most recent common ancestor was estimated to be present around mid-November, which is epidemiologically compatible with the first case of SARS found in Foshan.

After the epidemic was over, a second interspecies-jumping event occurred in late to early , resulting in the reemergence of four human cases in China 45 , These four cases were believed to be due to an independent interspecies transmission event, instead of residual cases of the major epidemic, because of the much lower affinity for human ACE2 hACE2 of the S proteins of SARS-CoV isolated from these patients and palm civets than that of the major epidemic isolates from SARS patients, which utilized both human and palm civet ACE2 efficiently Since S contains the receptor binding domain for the host receptor and is immunogenic, it is under selection in the host and becomes the most rapidly evolving protein, with most mutations located in the S1 domain and especially the receptor binding domain.

Bioinformatic analysis has identified three key amino acid residues at positions , , and that are responsible for host-specific binding The low affinity of the S proteins bearing K and S combinations for hACE2 was confirmed by pseudotype binding assays. However, the human and civet isolates of the outbreak of to had N and S, which suggested that this is an intermediate stage of mutation of the S protein.

Further change to the N and T combination will allow efficient human-to-human transmission Apart from the subsequent minor outbreak, three laboratory-associated outbreaks were reported in Singapore, Taiwan, and Beijing from September to May , , , In Beijing, the outbreak also involved secondary and tertiary cases. Phylogenetic analysis of the S protein of SARS-CoV isolates in the Hong Kong outbreak showed that several introductions of viruses had occurred but that only one of them was associated with the major outbreak in HKSAR and the rest of the world Some of the strains found in the early stages of the outbreak were phylogenetically distinct from the major cluster and were closer to some of the Guangdong and Beijing strains.

Another molecular epidemiological study of the Guangdong outbreak suggested that the disease spread from Guangdong to HKSAR and the rest of the world, and the index case was a chef who handled game animals Subsequent animal surveillance in China recovered coronavirus isolates that had A characteristic bp insertion between Orf8a and Orf8b also initially known as Orf10 and Orf11 was found in these animal isolates , This nucleotide segment was deleted either before or soon after crossing the species barrier to humans.

The biological effect of this deletion remains elusive. Two independent molecular epidemiological studies comparing the complete genomes of 12 and 63 virus isolates also found evidence of strong positive selection at the beginning of the epidemic, which was followed by a purifying selection, as indicated by the amino acid substitution rate at S, Orf3a, and nsp3 64 , , Both studies suggested that molecular adaptation of the virus had occurred after interspecies transmission from animals to humans.

In the small outbreak in Guangzhou in , all four human isolates belonged to a separate sublineage of the concurrent animal isolates that were distinct from the human pandemic or animal viruses in Although SARS-CoV is distinct from the three existing groups of coronaviruses, it may be closer to group II because 19 out of 20 cysteines found in the S1 domain of the S protein are spatially conserved compared with the group II consensus sequence, whereas only five cysteine residues are conserved compared with those of groups I and III 93 , Since coronaviruses are believed to have coevolved with their animal hosts, it is possible that rats, mice, and cattle harboring group II coronaviruses are more likely to be the animal host for SARS-CoV than cats, which harbor group I coronavirus.

However, when a comparison of the phylogenetic trees for 11 known host species and nucleocapsid sequences of 36 coronaviruses was done using an inference approach with sliding-window analysis, there was statistical incongruence, which indicates multiple host species shifts between the coronaviruses of many animals that are phylogenetically distant


Severe Acute Respiratory Syndrome Coronavirus as an Agent of Emerging and Reemerging Infection

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Proteins regulating the mammalian target of rapamycin mTOR , as well as some of the targets of the mTOR kinase, are overexpressed or mutated in cancer. Rapamycin, the naturally occurring inhibitor of mTOR, along with a number of recently developed rapamycin analogs rapalogs consisting of synthetically derived compounds containing minor chemical modifications to the parent structure, inhibit the growth of cell lines derived from multiple tumor types in vitro , and tumor models in vivo.


mTOR and cancer therapy

Please, help me to find this lei atualizada em pdf printer. Lei n. Marchese, Mark Lautens J. Supplement to Comprehensive Asymmetric Catalysis The effect of the acidifying group on the regioselectivity of the base-induced ring opening of hetero-oxabicyclic [3. Palladium catalyzed hydrostannation-cyclization of 1,6-diynes. Organoselenium-Catalyzed Mild Dehydration of Aldoximes: Enantioselective synthesis of chiral 1,2-diamines by the catalytic ring opening of azabenzonorbornadienes: Synthesis of 1,2-dihydropyridines using vinyloxiranes as masked dienolates in imino-aldol reactions Brunner, B; Stogaitis, N; Lautens, M Org.


LEI 11416 DE 2006 PDF




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