White crystalline powder
Notoginsenoside S is a compound isolated from Panax notoginseng.
Soluble in Chloroform,Dichloromethane,Ethyl Acetate,DMSO,Acetone,etc.
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Approximately 8% of Rift Valley fever (RVF) cases develop severe disease, leading to hemorrhage, hepatitis, and/or encephalitis and resulting in up to 50% of deaths. A major obstacle in the management of RVF and other viral hemorrhagic fever cases in outbreaks that occur in rural settings is the inability to rapidly identify such cases, with poor prognosis early enough to allow for more-aggressive therapies. During an RVF outbreak in Kenya in 2006 to 2007, we evaluated whether quantitative real-time reverse transcription-PCR (qRT-PCR) could be used in the field to rapidly identify viremic RVF cases with risk of death. In 52 of 430 RVF cases analyzed by qRT-PCR and virus culture, 18 died (case fatality rate [CFR] = 34.6%). Levels of viremia in fatal cases were significantly higher than those in nonfatal cases (mean of 105.2 versus 102.9 per ml; P < 0.005). A negative correlation between the levels of infectious virus particles and the qRT-PCR crossover threshold (CT) values allowed the use of qRT-PCR to assess prognosis. The CFR was 50.0% among cases with CT values of <27.0 (corresponding to 2.1 × 104 viral RNA particles/ml of serum) and 4.5% among cases with CT values of ≥27.0. This cutoff yielded 93.8% sensitivity and a 95.5% negative predictive value; the specificity and positive predictive value were 58% and 50%, respectively. This study shows a correlation between high viremia and fatality and indicates that qRT-PCR testing can identify nearly all fatal RVF cases.
Rift Valley fever (RVF) virus is a zoonotic mosquito-borne member of the Phlebovirus genus in the Bunyaviridae family of viruses that was first isolated in Kenya in the 1930s (4, 6). In livestock, the virus is associated with abortions and high levels of mortality in young animals (11, 17). Humans acquire RVF virus through bites from infected mosquitoes or through exposure to the blood, body fluids, or tissue of infected animals or other humans (29). Periodic epidemics of RVF involving both livestock and humans occur following heavy rainfalls, primarily in eastern Africa (Kenya, Somalia, and Tanzania) but also in other African countries (3, 9, 16, 22, 31). In 2000, the virus was introduced to the Arabian Peninsula through the importation of infected livestock from East Africa, causing a severe outbreak in Saudi Arabia and Yemen (1, 2, 15).
At least 80% of human RVF cases are asymptomatic, and less than 8% develop into severe disease characterized by generalized hemorrhagic syndromes, acute hepatitis manifested by jaundice, encephalitis, and retinitis (14, 20). The overall human case fatality rate (CFR) for RVF virus infection has been estimated at 1 to 3%, but the rate can be as high as 50% among cases with severe disease (18, 20). Risk factors and symptoms associated with the development of severe RVF are not clearly elucidated. In the Saudi Arabia outbreak, bleeding abnormalities, neurological symptoms, and jaundice were independently associated with high mortality (2). Jaundice is believed to be the result of acute hepatocellular failure due to virus-induced damage to hepatocytes, while the pathogeneses of meningoencephalitis and retinitis are not understood (14). As is the case with other viral hemorrhagic fevers, the hemorrhagic syndrome from RVF virus is likely the result of injury to the microvasculature and increased endothelial permeability, leading to leakage of blood into tissue and mucosal surfaces (23, 26).
A major obstacle in the management of viral hemorrhagic fever patients is the inability to identify cases with poor prognosis early enough to allow for more-aggressive supportive therapy and possibly the administration of experimental chemotherapeutic drugs. Some studies have suggested a correlation between infectious viral load and the development of severe disease; however, standard laboratory methods for determining infectious viral levels are time-consuming and, for hemorrhagic fever viruses, require laboratories with high-biosafety systems (27). On the other hand, studies have shown that quantitative real-time reverse transcription-PCR (qRT-PCR) is potentially useful for estimating levels of infectious hemorrhagic fever viruses (8, 24, 28). An RVF outbreak occurred in Kenya from December 2006 through March 2007, resulting in more than 700 suspected cases and approximately 150 fatalities, a higher CFR (21.4%) than the historical figure of less that 8%, possibly due to the inability to trace all the RVF cases in the country (5, 30). A risk assessment study found an association between animal contact and the development of severe disease, perhaps because animal exposure resulted in infection with a higher viral load compared to that of the mosquito (S. Amwayi, personal communication). We use laboratory and fatality outcomes from this outbreak to determine the association between the level of viremia and fatality and the usefulness of field qRT-PCR testing to rapidly identify highly viremic RVF cases at elevated risk of death.
Using a Field Quantitative Real-Time PCR Test To Rapidly Identify Highly Viremic Rift Valley Fever Cases▿
M. Kariuki Njenga,1,* Janusz Paweska,2 Rose Wanjala,1 Carol Y. Rao,3 Matthew Weiner,4 Victor Omballa,1 Elizabeth T. Luman,5 David Mutonga,6 Shanaaz Sharif,6 Marcus Panning,7 Christian Drosten,7 Daniel R. Feikin,1 and Robert F. Breiman1
Two strains of Punta Toro virus (PTV), isolated from febrile humans in Panama, cause a differential pathogenesis in Syrian hamsters, which could be a useful model for understanding the virulence characteristics and differential outcomes in other phleboviral infections such as Rift Valley fever virus. Genetic reassortants produced between the lethal Adames (A/A/A) and nonlethal Balliet (B/B/B) strains were used in this study to investigate viral genetic determinants for pathogenesis and lethality in the hamster model. The S segment was revealed to be a critical genome segment, determining lethality with log10 50% lethal doses for each PTV genotype as follows (L/M/S convention): A/A/A, <0.7; B/A/A, <0.7; A/B/A, 1.5; B/B/A, 2.2; B/A/B, 4.7; A/B/B, >4.7; A/A/B, >4.7; B/B/B, >4.7. In addition, the Adames strain inhibits the induction of alpha/beta interferon (IFN-α/β) in vivo and in vitro and inhibits the activation of the IFN-β promoter. Expression of the PTV Adames NSs protein, encoded by the S RNA segment, inhibited the virus-mediated induction of an IFN-β promoter-driven reporter gene, suggesting that PTV NSs functions as a type I IFN antagonist. Taken together, these data indicate a mechanism of pathogenesis in which the suppression of the type I IFN response early during PTV infection leads to early and uncontrolled viral replication and, ultimately, hamster death. This study contributes to our understanding of Phlebovirus pathogenesis and identifies potential targets for immune modulation to increase host survival.
The genus Phlebovirus (family Bunyaviridae) currently consists of 68 antigenically distinct virus serotypes transmitted by arthropods which are distributed into two groups: the Phlebotomus fever and Uukuniemi groups. Of the known human pathogens in the Phlebotomus fever group, Toscana virus, sandfly fever Naples virus, sandfly fever Sicilian virus, Rift Valley fever virus (RVFV), and Punta Toro virus (PTV) are of greatest public health importance. Sicilian and Naples viruses are responsible for most clinically described “sandfly fever” cases on the European continent, and their distribution extends into northern Africa and as far east as China (30, 36, 38). Toscana virus is an important emerging pathogen in Italy and causes a meningoencephalitic disease in European countries bordering the Mediterranean (10). RVFV causes recurrent epidemics in sub-Saharan Africa and was recently implicated in an outbreak of hemorrhagic fever in the Arabian peninsula (1). RVFV is a major veterinary and human pathogen (26, 27). The most medically important Phlebovirus in the Americas is PTV, which has been isolated repeatedly in Panama and Columbia.
Punta Toro virus is transmitted by sand flies and causes an acute febrile illness lasting 2 to 5 days (5, 30, 31, 37). While up to a 35% seroprevalence has been reported in Panama, little is understood about the clinical spectrum of illness (36). Two strains of PTV isolated from febrile patients in Panama were found to produce a differential pathogenesis in the Syrian hamster, with the PTV-Adames (PTV-A) strain infection causing a RVFV-like illness and death, while animals infected with the PTV-Balliet (PTV-B) strain survived infection (3). As reported in a study by Anderson et al. (3), the PTV-A strain was demonstrated to have a hamster 50% lethal dose (LD50) >1 million-fold lower than that of the PTV-B strain. The finding that PTV-A titers were consistently higher than those of the PTV-B strain at early time points during infection indicates that the PTV-A strain may have a growth advantage by efficiently suppressing the early innate immune response.
The viral family Bunyaviridae is composed of 5 genera:Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus. Virions are enveloped and contain three genomic RNA segments in the negative-sense coding orientation. In phleboviruses, the large (L) segment encodes the RNA-dependent RNA polymerase, the medium (M) segment encodes two surface glycoproteins, GN and GC, and a nonstructural protein, NSm. The third small (S) segment of the phleboviruses encodes the nucleoprotein (N) and another nonstructural protein, NSs. The use of genetic reassortants has been critical in determining viral genes involved in host pathogenesis in the Bunyaviridae family (14, 18). While the M and L segments of the California serogroup bunyaviruses have been linked to encephalitis in mice, the inhibition of the early innate immune response has been implicated in the pathogenesis of RVFV infection in mice and is mediated through the NSs gene on the S segment (9, 25, 34, 39). To expand our understanding of Phlebovirus pathogenesis, we utilized genetic reassortants produced between the PTV-A and PTV-B strains to determine segment-associated virulence factors in the hamster model (3, 13). This study reports the finding that the S RNA segment of the PTV genome is a critical factor determining virulence in hamsters and that an inhibition of an early induction of alpha/beta interferon (IFN-α/β) by the PTV-A strain contributes to the lethality in hamsters.
The S Segment of Punta Toro Virus (Bunyaviridae, Phlebovirus) Is a Major Determinant of Lethality in the Syrian Hamster and Codes for a Type I Interferon Antagonist▿
Lucy A. Perrone,1,† Krishna Narayanan,2 Melissa Worthy,2,‡ and C. J. Peters1,2,*
The Rift Valley fever virus (RVFV), a member of the genus Phlebovirus (family Bunyaviridae) is an enveloped negative-strand RNA virus with a tripartite genome. Until 2000, RVFV circulation was limited to the African continent, but the recent deadly outbreak in the Arabian Peninsula dramatically illustrated the need for rapid diagnostic methods, effective treatments, and prophylaxis. A method for quantifying the small RNA segment by a real-time detection reverse transcription (RT)-PCR using TaqMan technology and targeting the nonstructural protein-coding region was developed, and primers and a probe were designed. After optimization of the amplification reaction and establishment of a calibration curve with synthetic RNA transcribed in vitro from a plasmid containing the gene of interest, real-time RT-PCR was assessed with samples consisting of RVFV from infected Vero cells. The method was found to be specific for RVFV, and it was successfully applied to the detection of the RVFV genome in animal sera infected with RVFV as well as to the assessment of the efficiency of various drugs (ribavirin, alpha interferon, 6-azauridine, and glycyrrhizin) for antiviral activity. Altogether, the results indicated a strong correlation between the infectious virus titer and the amount of viral genome assayed by real time RT-PCR. This novel method could be of great interest for the rapid diagnosis and screening of new antiviral compounds, as it is sensitive and time saving and does not require manipulation of infectious material.
The Rift Valley fever (RVF) virus (RVFV), a member of the genus Phlebovirus, belongs to the Bunyaviridae family and possesses a negative-stranded, tripartite RNA genome composed of a large, a medium, and a small (S) segment (for reviews, see references 9 and 37). Like other phleboviruses, the S segment utilizes an ambisense strategy to code for two proteins, the nucleocapsid protein and the nonstructural protein (NSs), which are synthesized from subgenomic viral complementary and viral sense mRNA, respectively.
RVF is a mosquito-borne zoonosis predominantly provoking the death of young animals and abortion (e.g., sheep and goats) (for reviews, see references 24, 39 and 41). The disease was first identified in sheep by Daubney et al. in Kenya in 1931, and it is endemic almost everywhere in subtropical Africa (6). Transmission to humans occurs primarily by contact with infected animal body fluids and by mosquito bites. Infection is usually asymptomatic or associated with a brief self-limited febrile illness. However, complications such as retinitis, encephalitis, or hemorrhagic fever occur in some patients with mortality rates of up to 10 to 12% (21, 28).
The potential of RVF as a disease emerging in new areas was first documented in Egypt in 1977 (16), and since then, epidemics have occurred in Mauritania (1987 to 1988 and 1998), Madagascar (1990 to 1991), Egypt (1993), and eastern Africa (in Kenya, Somalia, and Tanzania) (references 33 and 34 and references therein). Recently, the outbreak on the Arabian Peninsula (in Yemen and Saudi Arabia) represented the first case of RVF outside Africa (2, 4). Epizootics and epidemics are associated with periods of heavy rainfall and the concomitant presence of large numbers of mosquitoes (18). The survival of RVFV during interepizootics is believed to depend on transovarial transmission of the virus in floodwater Aedes mosquitoes (17).
Experimental vaccines are still in development, and no proven specific therapy is available for humans (3, 29). Thus, effective antiviral agents would be useful for treating severe infections or reducing viremia in amplifying hosts, thereby limiting viral propagation by biting arthropods. Currently, diagnosis is based on detection of specific antibodies or virus isolation in animal and mosquito cells (4). Reverse transcription (RT)-PCR techniques have been described and used to detect the RVFV genome in mosquitoes (11) and, recently, in clinical samples (35). In this work we developed a real-time RT-PCR method in order to detect and specifically quantify the virus either from cells or from sera and evaluated the potential of this assay for the diagnosis and screening of antiviral compounds.
Quantitative Real-Time PCR Detection of Rift Valley Fever Virus and Its Application to Evaluation of Antiviral Compounds
Stephan Garcia,1 Jean Marc Crance,1 Agnes Billecocq,2 Andre Peinnequin,1 Alain Jouan,1 Michele Bouloy,2 and Daniel Garin1,*