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possible involvement of endogenous beta-endorphin in the pathophysiological mechanisms of pichinde virus-infected guinea pigs.previously, we demonstrated that naloxone, an opiate antagonist, prolonged survival of strain 13 guinea pigs infected with pichinde virus. thus, endogenous opiates may be involved in the pathogenesis of this viral disease. to determine whether endogenous opiate levels were affected by pichinde viral infection, beta-endorphin concentrations in plasma and cerebrospinal fluid (csf) of normal and infected strain 13 guinea pigs were measured by radioimmunoassay. cerebrospinal fluid beta-endorphin con ...19921319583
increased platelet-activating factor (paf) concentrations in hearts and lungs of pichinde virus-infected guinea pigs.platelet-activating factor (paf) has been implicated as a cause of cardiopulmonary disturbances in certain diseases. in the present study, concentrations of paf in hearts, lungs, whole blood, and other organs of control and pichinde virus-infected guinea pigs on post-inoculation days (pid) 10 and 14 were measured by radioimmunoassay. results were further confirmed by bioassay after separation and purification with thin-layer chromatography. paf concentration in the hearts and lungs of virus-infe ...19921334721
metabolism of platelet-activating factor in neutrophils isolated from pichinde virus-infected guinea pigs.metabolism of platelet-activating factor (paf) was studied in cultured polymorphonuclear neutrophils (pmns) obtained from pichinde virus-infected strain 13 guinea pigs. neutrophils obtained from control and infected guinea pigs on postinoculation days 10 and 14 were incubated with [3h]lyso-paf, [3h]paf, or [3h]acetate. after incubation for 1 h at 37 degrees c, formation of [3h]acyl-paf from either [3h]lyso-paf or [3h]paf increased significantly in pmns from infected guinea pigs compared to contr ...19921541904
pulmonary responses of conscious strain 13 guinea pigs to pichinde viral infection.a laboratory animal model for studying pulmonary responses to arenaviral infection was established with advanced technologies. tidal volume (tv), respiratory rate (rr), minute volume (mv), expiratory time (te), inspiratory time (ti), peak expiratory flow (pef), and specific pulmonary airway resistance (res) were measured with a double plethysmograph and a computer data-acquisition system in six conscious, strain 13 guinea pigs. using the same animal, experiments were conducted before and after s ...19911667202
influence of volume expansion on capillary transport in the gut of pichindé virus infected strain 13 guinea pigs.hydropenic strain 13 guinea pigs (gp13) injected with pichindé virus show marked jejunal capillary disruption determined by a reduction in protein reflection coefficient (sigma) [katz and starr, 1990]. these studies examined whether this is reversed by a 2% ringer's expansion, and whether anorexia may contribute to reduced sigma. gp13 were either infected or given a 60% expected ad lib diet, and were studied while under a 2% ringer's expansion. the results showed 1) infected gp13 separated into ...19911940885
the effect of an arenavirus infection on liver morphology and function.patients with severe lassa fever have high serum levels of liver enzymes. studies of the histology of the liver have shown only minor alterations, seemingly insufficient to account for death. pichinde virus is an arenavirus which causes severe illness similar to lassa fever in strain 13 guinea pigs, but does not cause severe illness in man. this can serve as a relatively safe model for studying the pathology and pathophysiology of fatal arenaviral infection. we used this infection to evaluate th ...19901974392
pichinde virus infection in strain 13 guniea pigs reduces intestinal protein reflection coefficient with compensation.pichinde virus inoculation into strain 13 guinea pigs is a model with features reputed to be similar to hemorrhagic fever in humans. although the infection is lethal by day 13-19, guinea pigs of approximately 600 g do not show edema or effusions. this raises the questions of whether capillary damage is present in such infected animals and, if it is, why edema is absent. the effects of pichinide virus on protein transport across jejunal capillaries were examined in 38 normal and 7 infected strain ...19902230259
arenavirus infection in the guinea pig model: antiviral therapy with recombinant interferon-alpha, the immunomodulator cl246,738 and ribavirin.human arenaviral infections have a high mortality, and are dangerous to work with in the laboratory. there is a need for good antiviral agents to treat these infections. pichinde virus infection of the inbred strain 13 guinea pig is a relatively safe, good animal model for human arenavirus infections. mortality is consistently 100% between days 12 and 25 (mean 14.8) days after infection. when infected animals were treated with recombinant human interferon alpha a, or with cl246,783, an immunomod ...19892561334
pathogenesis of viral hemorrhagic fevers: rift valley fever and lassa fever contrasted.although many viral infections have on occasion been associated with hemorrhagic complications, infection with any of several rna viruses regularly results in vascular involvement and the syndrome called viral hemorrhagic fever (vhf). in spite of clinically useful similarities among various vhfs, there are significant differences in their pathogenesis and clinical evolution; these are often related to characteristics of their viral taxon. infection with rift valley fever (rvf) virus, a phlebovir ...19892665011
observation of the in situ contracting heart of guinea pigs infected with pichinde virus.the in situ beating hearts from anesthetized control and pichinde virus-infected strain 13 guinea pigs, between days 7 and 19 postinoculation, were directly observed and video recorded. although some hearts from pichinde virus-infected animals were visually depressed and had altered contraction patterns, such a pronounced cardiac dysfunction was not associated with any marked histopathological changes in the cardiac tissue. the manifestations of cardiac dysfunction were limited mainly to the rig ...19872824949
changes in body weight and body surface area in strain 13 guinea pigs infected with pichinde virus.in studying pathogenetic mechanisms of pichinde virus-induced disease in strain 13 guinea pigs, a large decrease of body weight (approximately 28%) observed within 14 days postinoculation raises a question concerning the validity of standardizing body or organ functions in terms of body weight. this study was to examine changes in body weight and body surface area of pichinde virus-infected strain 13 guinea pigs after various days postinoculation. control guinea pigs were also subjected to the s ...19892915597
evidence for the involvement of sulfidopeptide leukotrienes in the pathogenesis of pichinde virus infection in strain 13 guinea pigs.strain 13 guinea pigs inoculated subcutaneously with pichinde virus developed fever, lost body weight, decreased water and food consumption, and died at 14 +/- 0.6 days. after fpl-55712, a leukotriene d4 antagonist, was administered beginning on pid (post-inoculation day) 3 for 18 days, the magnitude of body weight loss decreased and food intake increased, despite a persistent fever. the treated guinea pigs also survived significantly longer than infected animals receiving placebo injection (21 ...19863025893
studies of the coagulation system in arenaviral hemorrhagic fever: experimental infection of strain 13 guinea pigs with pichinde virus.significant coagulation abnormalities were associated with experimental infection of strain 13 guinea pigs with pichinde virus, an arenavirus related to the virulent human pathogens junin, machupo, and lassa viruses. infected animals developed decreased activity of multiple coagulation factors, decreased antithrombin iii levels, high levels of fibrin-fibrinogen degradation products, impaired platelet function, and thrombocytopenia. testing for the presence of a coagulation inhibitor revealed a p ...19873030150
pathogenesis of a pichinde virus strain adapted to produce lethal infections in guinea pigs.a model for studying the pathogenesis of virulent arenavirus infection was developed by adapting pichinde virus to produce lethal infections of inbred guinea pigs. this adapted pichinde virus retained low virulence for primates, thus potentially reducing the biohazard to investigators. whereas all inbred (strain 13) guinea pigs were infected and killed by 3 plaque-forming units or more of adapted pichinde virus injected subcutaneously, outbred (hartley strain) guinea pigs were relatively resista ...19816265367
antiviral efficacy of pyrazofurin against selected rna viruses.the antibiotic pyrazofurin, 3-(beta-d-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide, markedly inhibited the in vitro replication of a number of rna viruses including rift valley fever (rvf), venezuelan equine encephalomyelitis (vee), sandfly, pichinde, lassa and lcm virus. plaque formation was reduced by 80% or more with 2-10 micrograms/ml of pyrazofurin while 2 micrograms/ml reduced by 1000-fold the yield of lassa and lcm virus in a yield reduction assay. in vivo, pyrazofurin failed to protect ...19826299188
differential alterations in host peripheral polymorphonuclear leukocyte chemiluminescence during the course of bacterial and viral infections.previous studies have shown that stimulation of the oxidative metabolism in polymorphonuclear leukocytes (pmn) by in vitro phagocytosis of various microorganisms results in photon emission, termed chemiluminescence (cl). studies were conducted to determine whether bacterial and viral infections induce enhanced basal endogenous host peripheral pmn cl in the absence of in vitro phagocytic stimulation. nonimmune rats and guinea pigs as well as immune rats were inoculated with various doses (10(5) t ...19807228389
tumor necrosis factor and the pathogenesis of pichinde virus infection in guinea pigs.pichinde virus (pic) is a reticuloendothelial arenavirus of the new world tropics. a guinea pig passage-adapted strain of this virus (adpic) is uniformly lethal for inbred guinea pigs, while the related, prototype strain (pic3739) has attenuated virulence. the abilities of adpic and pic3739 to induce tumor necrosis factor (tnf) in vivo and in cultured macrophages were compared. infection with adpic, but not pic3739, was associated with detectable serum tnf that peaked in week 2 of infection. tum ...19957694969
cardiovascular and pulmonary responses to pichinde virus infection in strain 13 guinea pigs.in fatal human lassa fever, severe hypotension, circulatory shock, and pulmonary edema develop as terminal events. we examined cardiovascular and respiratory functions in strain 13 guinea pigs infected with pichinde virus, an animal model for studying human lassa fever. cardiovascular functions were studied in anesthetized and conscious guinea pigs, whereas pulmonary functions were measured only on animals under anesthesia. in anesthetized animals, cardiovascular disturbances were severe and pro ...19947898034
pathological and virological features of arenavirus disease in guinea pigs. comparison of two pichinde virus strains.a guinea pig passage-adapted strain of the arena-virus pichinde (adpic) is highly virulent in inbred guinea pigs, whereas the related strain pic3739 is attenuated. both viruses were macrophage tropic and infected peritoneal, splenic, liver, and alveolar macrophages during experimental pichinde virus infection. infection with the virulent strain was associated with unlimited viral replication in the face of exaggerated delayed-type hypersensitivity response, manifested by the macrophage disappear ...19948030751
changes in platelet-activating factor, catecholamine, and serotonin concentrations in brain, cerebrospinal fluid, and plasma of pichinde virus-infected guinea pigs.brain concentrations of platelet-activating factor (paf), catecholamines, and serotonin were measured in control and pichinde virus-infected strain 13 guinea pigs on postinoculation day (pid) 12. after virus inoculation, paf concentrations increased 81% in cerebrum, 147% in diencephalon-brain stem, and 110% in cerebellum from baseline values of 2.6 +/- 0.3, 4.3 +/- 0.2, and 6.1 +/- 0.5 (ng/g wet tissue), respectively. dopamine concentrations in the infected cerebrum and diencephalon-brain stem i ...19938158981
pichinde virus-induced respiratory failure due to obstruction of the small airways: structure and function.respiratory distress that leads to death is seen in patients with lassa fever. the development of this respiratory problem was studied using a pichinde virus model (10(4) plaque forming units, ip, survival time 20 +/- 1 days) in strain 13 guinea pigs (n = 35, 229-353 g) of this lethal human contagious infectious disease. extravascular lung water to bloodless dry lung weight (evlw/bdlw) ratio showed a modest yet significant increase in animals 13 and 18-21 days postinoculation (pi). in contrast, ...19938281916
haemostatic derangements associated with arenavirus infection in the guinea-pig: radioimmunoassay of fibrinopeptide a to assess thrombin action in infected animals.pichinde virus infection of inbred guinea-pigs is a model for arenaviral infections in humans. infected animals experience reduced levels of multiple coagulation factors caused by either consumption coagulopathy or impaired factor synthesis. a radioimmunoassay (ria) of guinea-pig fibrinopeptide a (gfpa) has been developed to measure the degree of thrombin action in vivo. gfpa was synthesized via the solid-phase method and conjugated to bovine serum albumin (bsa). a double antibody ria was establ ...19938384497
death after pichinde virus infection in large and small strain 13 guinea pigs.the lethal events of pichinide virus infections were studied in large (> 36-week-old), small (4- to 6-week-old), and uninfected strain 13 guinea pigs. time to death was shorter and the rate of body weight loss greater for large than for small virus-infected guinea pigs. severely ill large guinea pigs developed a life-threatening, nonlactate metabolic acidemia with an increased anion gap, hypokalemia, and renal failure. small infected guinea pigs near death demonstrated a modest increase in blood ...19938387562
pathogenesis of pichinde virus infection in strain 13 guinea pigs: an immunocytochemical, virologic, and clinical chemistry study.pichinde virus has been adapted to produce lethal infection of strain 13 guinea pigs. viral replication and presence of viral antigen in frozen tissues stained by immunofluorescence has been previously described. further investigation into the pathogenesis of this disease has been hampered by the lack of a light microscopic method for correlating histologic lesions and the presence of pichinde viral antigens. for this purpose, we developed a sensitive immunocytochemical technique for staining pi ...19938394659
role of atrial natriuretic peptide in disturbed water and electrolyte metabolism of guinea pigs infected with pichinde virus.daily intake and output of water and electrolytes (na+, k+, and cl-) were determined for 14 days in control and pichinde virus-infected strain-13 guinea pigs. although water intake began to decrease 7 days after virus inoculation, total daily water output (insensible water loss, urine excretion, plus fecal water loss) had little change. however, insensible water loss alone increased markedly in the virus-infected animals. both intake and excretions of urinary and fecal electrolytes decreased at ...19958569144
sequence analysis of the small rna segment of guinea pig-passaged pichinde virus variants.the established animal model for lassa fever is based on the new world arenavirus pichinde (pic). natural isolates of pic virus are attenuated in guinea pigs, but serial guinea pig passage renders them extremely virulent in that host. we have compared the nucleotide sequences of the small rna segments of two attenuated, low-passage variants of the pic virus munchique strain (coan 4763) and two virulent, high-passage derivatives. missense mutations in the glycoprotein precursor (gpc) gene at codo ...199910463670
alterations in nf-kappab and rbp-jkappa by arenavirus infection of macrophages in vitro and in vivo.pichinde virus is an arenavirus that infects guinea pigs and serves as an animal model for human lassa fever. an attenuated pichinde virus variant (p2) and a virulent variant (p18) are being used to delineate pathogenic mechanisms that culminate in shock. in guinea pigs, the infection has been shown to begin in peritoneal macrophages following intraperitoneal inoculation and then spreads to the spleen and other reticuloendothelial organs. we show here that infection of the murine monocytic cell ...200211773391
reassortant analysis of guinea pig virulence of pichinde virus variants.the new world arenavirus pichinde (pic) is the basis of an accepted small animal model for human lassa fever. pic (munchique strain) variant p2 is attenuated in guinea pigs, whereas variant p18 is extremely virulent. previous sequence analysis of the s segments of these two viruses indicated a small number of possible virulence markers in the glycoprotein precursor (gpc) and nucleoprotein (np) genes. in order to determine the role of these s segment genes in guinea pig virulence in this system, ...200111883003
differential signaling networks induced by mild and lethal hemorrhagic fever virus infections.the family arenaviridae includes several national institutes of allergy and infections diseases category a select agents which cause hemorrhagic fever. there are few vaccines available, and treatment is limited to ribavirin, which varies in efficacy. development of new antiviral compounds has been hindered by a lack of understanding of the molecular basis of pathogenesis. we used two variants of pichinde virus, one attenuated and one virulent in the guinea pig model, to delineate the host determ ...200617005702
identification of differentially activated cell-signaling networks associated with pichinde virus pathogenesis by using systems kinomics.phosphorylation plays a key role in regulating many signaling pathways. although studies investigating the phosphorylated forms of signaling pathways are now commonplace, global analysis of protein phosphorylation and kinase activity has lagged behind genomics and proteomics. we have used a kinomics approach to study the effect of virus infection on host cell signaling in infected guinea pigs. delineating the host responses which lead to clearance of a pathogen requires the use of a matched, com ...200717151108
thioaptamer decoy targeting of ap-1 proteins influences cytokine expression and the outcome of arenavirus infections.viral haemorrhagic fever (vhf) is caused by a number of viruses, including arenaviruses. the pathogenesis is believed to involve dysregulation of cytokine production. the arenaviruses lassa virus and pichinde virus have a tropism for macrophages and other reticuloendothelial cells and both appear to suppress the normal macrophage response to virus infection. a decoy thioaptamer, xby-s2, was developed and was found to bind to ap-1 transcription factor proteins. the p388d1 macrophage-like cell lin ...200717325372
genome comparison of virulent and avirulent strains of the pichinde arenavirus.a virulent (p18) strain of the pichinde arenavirus produces a disease in guinea pigs that somewhat mimics human lassa fever, whereas an avirulent (p2) strain of this virus is attenuated in infected animals. it has been speculated that the composition of viral genomes may confer the degree of virulence in an infected host; the complete sequence of the viral genomes, however, is not known. here, we provide for the first time genomic sequences of the s and l segments for both the p2 and p18 strains ...200818506572
cytokine patterns in a comparative model of arenavirus haemorrhagic fever in guinea pigs.arenaviruses such as lassa virus cause a spectrum of disease in humans ranging from mild febrile illness to lethal haemorrhagic fever. the contributions of innate immunity to protection or pathogenicity are unknown. we compared patterns of expression of cytokines of innate immunity in mild versus severe arenavirus disease using an established guinea pig model based on the macrophage-tropic arenavirus pichinde virus (picv). cytokine transcripts were measured by using real-time rt-pcr in target or ...200818796726
analysis of the differential host cell nuclear proteome induced by attenuated and virulent hemorrhagic arenavirus infection.arenaviruses are important emerging pathogens and include a number of hemorrhagic fever viruses classified as niaid category a priority pathogens and cdc potential biothreat agents. infection of guinea pigs with the new world arenavirus pichindé virus (picv) has been used as a biosafety level 2 model for the lassa virus. despite continuing research, little is known about the molecular basis of pathogenesis, and this has hindered the design of novel antiviral therapeutics. modulation of the host ...200919004951
targeting inside-out phosphatidylserine as a therapeutic strategy for viral diseases.there is a pressing need for antiviral agents that are effective against multiple classes of viruses. broad specificity might be achieved by targeting phospholipids that are widely expressed on infected host cells or viral envelopes. we reasoned that events occurring during virus replication (for example, cell activation or preapoptotic changes) would trigger the exposure of normally intracellular anionic phospholipids on the outer surface of virus-infected cells. a chimeric antibody, bavituxima ...200819029986
molecular determinants of pichinde virus infection of guinea pigs--a small animal model system for arenaviral hemorrhagic fevers.arenaviruses are enveloped single-strand rna viruses that mostly have natural hosts in rodents. upon infection of humans, several arenaviruses can cause severe hemorrhagic fever diseases, including lassa fever that is endemic in west africa. the virulence mechanism of these deadly arenaviruses can be studied in a safe and economical small animal model-guinea pigs infected by a nonpathogenic arenavirus pichinde virus (picv), a virulent strain of which can cause similar disease syndromes in guinea ...200919751405
proteomic analysis of pichindé virus infection identifies differential expression of prothymosin-alpha.the arenaviruses include a number of important pathogens including lassa virus and junin virus. presently, the only treatment is supportive care and the antiviral ribavirin. in the event of an epidemic, patient triage may be required to more effectively manage resources; the development of prognostic biomarker signatures, correlating with disease severity, would allow rational triage. using a pair of arenaviruses, which cause mild or severe disease, we analyzed extracts from infected cells using ...201020706531
Effective oral favipiravir (T-705) therapy initiated after the onset of clinical disease in a model of arenavirus hemorrhagic Fever.Lassa and Junín viruses are the most prominent members of the Arenaviridae family of viruses that cause viral hemorrhagic fever syndromes Lassa fever and Argentine hemorrhagic fever, respectively. At present, ribavirin is the only antiviral drug indicated for use in treatment of these diseases, but because of its limited efficacy in advanced cases of disease and its toxicity, safer and more effective antivirals are needed.201122022624
low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses.favipiravir is approved in japan to treat novel or re-emerging influenza viruses, and is active against a broad spectrum of rna viruses, including ebola. ribavirin is the only other licensed drug with activity against multiple rna viruses. recent studies show that ribavirin and favipiravir act synergistically to inhibit bunyavirus infections in cultured cells and laboratory mice, likely due to their different mechanisms of action. convalescent immune globulin is the only approved treatment for a ...201626711718
identification of virulence determinants within the l genomic segment of the pichinde arenavirus.several arenaviruses are responsible for causing viral hemorrhagic fevers (vhf) in humans. lassa virus (lasv), the causative agent of lassa fever, is a biosafety level 4 (bsl4) pathogen that requires handling in bsl4 facilities. in contrast, the pichinde arenavirus (picv) is a bsl2 pathogen that can cause hemorrhagic fever-like symptoms in guinea pigs that resemble those observed in human lassa fever. comparative sequence analysis of the avirulent p2 strain of picv and the virulent p18 strain sh ...201323552411
characterization of the glycoprotein stable signal peptide in mediating pichinde virus replication and virulence.arenaviruses can cause lethal hemorrhagic fevers in humans with few preventative and therapeutic measures. the arenaviral glycoprotein stable signal peptide (ssp) is unique among signal peptides in that it is an integral component of the mature glycoprotein complex (gpc) and plays important roles not only in gpc expression and processing but also in the membrane fusion process during viral entry. using the pichinde virus (picv) reverse genetics system, we analyzed the effects of alanine substitu ...201627630230
in vitro and in vivo characterizations of pichinde viral nucleoprotein exoribonuclease functions.arenaviruses cause severe hemorrhagic fever diseases in humans, and there are limited preventative and therapeutic measures against these diseases. previous structural and functional analyses of arenavirus nucleoproteins (nps) revealed a conserved deddh exoribonuclease (rnase) domain that is important for type i interferon (ifn) suppression, but the biological roles of the np rnase in viral replication and host immune suppression have not been well characterized. infection of guinea pigs with pi ...201525878103
characterization of virulence-associated determinants in the envelope glycoprotein of pichinde virus.we use a small animal model, based on guinea pigs infected with a non-pathogenic pichinde virus (picv), to understand the virulence mechanisms of arenavirus infections in the hosts. picv p2 strain causes a mild febrile reaction in guinea pigs, while p18 causes severe disease with clinical and pathological features reminiscent of lassa hemorrhagic fever in humans. the envelope glycoproteins (gpc) of p2 and p18 viruses differ at positions 119, 140, and 164, all localized to the receptor-binding g1 ...201222877842
protective effect of anti-phosphatidylserine antibody in a guinea pig model of advanced hemorrhagic arenavirus infection.host derived markers on virally infected cells or virions may provide targets for the generation of antiviral agents. recently, we identified phosphatidylserine (ps) as a host marker of virions and virally-infected cells.201729290843
virulent infection of outbred hartley guinea pigs with recombinant pichinde virus as a surrogate small animal model for human lassa fever.arenaviruses, such as lassa virus (lasv), can cause severe and fatal hemorrhagic fevers (e.g., lassa fever, lf) in humans with no vaccines or therapeutics. research on arenavirus-induced hemorrhagic fevers (ahfs) has been hampered by the highly virulent nature of these viral pathogens, which require high biocontainment laboratory, and the lack of an immune-competent small animal model that can recapitulate ahf disease and pathological features. guinea pig infected with pichinde virus (picv), an ...202032799623
pichinde virus infection of outbred hartley guinea pigs as a surrogate animal model for human lassa fever: histopathological and immunohistochemical analyses.lassa virus (lasv) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic lassa fever (lf) disease. currently, there are no fda-approved vaccines or therapeutics against lasv. development of treatments against lf and other related arenavirus-induced hemorrhagic fevers (ahfs) requires relevant animal models that can recapitulate clinical and pathological features of ahf diseases in humans. laboratory mice are generally resistant to lasv infect ...202032708789
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