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51.
E. Niclas Jonsson Rujia Xie Scott F. Marshall Rosalin H. Arends 《British journal of clinical pharmacology》2016,81(4):688-699
AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1), peripheral volume (V2), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day–1, 2.71 l, 1.98 l, 0.371 l day–1, 8.03 μg day–1 and 27.7 ng ml–1, respectively. Inter‐individual variability (IIV) was included on CL, V1, V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit. 相似文献
52.
The level of substance-P-like immunoreactivity (SPLI) in dog paw lymph was determined before and after scalding injury of the paw. At basal conditions, no SPLI could be detected in the paw lymph. Scalding induced an immediate increase of the SPLI-levels. Within 5-10 min after the scalding injury the levels increased up to 28 fmol ml-1 and then gradually decreased within 30-90 min after the injury. It is suggested that scalding injury results in release of substance P from sensory nerve endings, and that this release may contribute to the inflammatory response to scalding injury and, possibly, also wound healing. 相似文献
53.
We have studied the location and mechanism of apoptosis within the granulomas in the lungs at various stages of slowly progressive primary murine Mycobacterium tuberculosis infection. Parallel sections were analyzed for detection of mycobacterial antigens, Fas, and Fas ligand (FasL) by immunohistochemistry, and for apoptotic cells by terminal deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) method. The frequency of apoptosis was high in the macrophage aggregates as compared to the lymphocyte aggregates and at the interface between them. Five to seven percent of the vacuolated macrophages in the granulomas expressed FasL intensely. These cells contained large amounts of mycobacterial antigens. These findings suggest that M. tuberculosis infection can induce increased expression of FasL in a population of infected macrophages. As a consequence the infected macrophages will be protected from the attack of cytotoxic T cells and activation of bactericidal mechanisms by Th1 type lymphocytes. This constitutes a novel evasion mechanism for M. tuberculosis possibly explaining the chronic course of infection. 相似文献
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Virulence of Staphylococcus aureus in a mouse mastitis model: studies of alpha hemolysin, coagulase, and protein A as possible virulence determinants with protoplast fusion and gene cloning. 总被引:5,自引:11,他引:5 下载免费PDF全文
Mutants of a genetically well-characterized strain of Staphylococcus aureus [SA113(83A)] were isolated after mutagenization. Alpha-hemolysin- (hla), coagulase- (coa), and protein A- (spa) negative mutants were characterized by more than 90 biochemical tests for production of extracellular proteins and biochemical profile to exclude pleiotropy. Protoplast fusion was then used to isolate double-defective (hla and coa) recombinants and recombinants with regained properties, i.e., production of alpha-hemolysin and coagulase. Studies of such mutants and recombinants in the mouse mastitis model showed that one alpha-hemolysin [SA113(83A) hla-5] and one coagulase-negative [SA113(83A) coa-147] mutant were lower in virulence compared with the wild-type strain SA113(83A). The double-negative mutant SA113(83A) hla-5 coa-147 showed a drastic decline in virulence and only induced very mild changes, as determined by microscopic examinations of infected mammary gland tissue. The recombinant with regained properties, however, was as virulent as the wild-type strain. This suggests that alpha-hemolysin and coagulase are virulence determinants of S. aureus. A high-level protein A-producing mutant (U300) showed the same virulence as the parent strain SA113(83A) in this model. One low virulence protein A-negative mutant (U320) did not markedly increase in virulence when a plasmid containing the cloned gene for protein A (pSPA15) was introduced into this mutant. By these and earlier observations, it seems likely that protein A is not an important virulence determinant in mastitis of mice. The reduced virulence of the protein A-negative mutant U320 compared with the wild-type SA113(83A) may be due to pleiotropic loss of some other unknown virulence determinant(s). Our data confirm earlier findings that pleiotropic changes are common in protein A-negative mutants. 相似文献
57.
Gilberto Sabino-Santos Jr Felipe Gon?alves Motta Maia Thallyta Maria Vieira Renata de Lara Muylaert Sabrina Miranda Lima Cristieli Barros Gon?alves Patricia Doerl Barroso Maria Norma Melo Colleen B. Jonsson Douglas Goodin Jorge Salazar-Bravo Luiz Tadeu Moraes Figueiredo 《The American journal of tropical medicine and hygiene》2015,93(2):404-406
Hantaviruses are zoonotic viruses harbored by rodents, bats, and shrews. At present, only rodent-borne hantaviruses are associated with severe illness in humans. New species of hantaviruses have been recently identified in bats and shrews greatly expanding the potential reservoirs and ranges of these viruses. Brazil has one of the highest incidences of hantavirus cardiopulmonary syndrome in South America, hence it is critical to know what is the prevalence of hantaviruses in Brazil. Although much is known about rodent reservoirs, little is known regarding bats. We captured 270 bats from February 2012 to April 2014. Serum was screened for the presence of antibodies against a recombinant nucleoprotein (rN) of Araraquara virus (ARAQV). The prevalence of antibody to hantavirus was 9/53 with an overall seroprevalence of 17%. Previous studies have shown only insectivorous bats to harbor hantavirus; however, in our study, of the nine seropositive bats, five were frugivorous, one was carnivorous, and three were sanguivorous phyllostomid bats.Hantaviruses (family Bunyaviridae) are present throughout the globe in rodents, bats, and shrews.1 Humans exposed to rodent excreta from hantaviral reservoirs may develop life-threatening diseases. However, none of the other reservoirs are associated with human illness presently.1,2 Bats (order Chiroptera) are known to harbor a broad diversity of emerging zoonotic pathogens.2 Their ability to fly and social behavior favors maintenance, evolution, and spread of pathogens.1,2 The prevailing hypothesis has been that hantaviruses have coevolved with their rodent reservoirs over millions of years.1,3 With the recognition of new species of hantavirus in bats in Africa and Asia,4 Guo and others5 hypothesized that hantaviruses originated primarily in bats and then spilled over into rodents and shrews, but it seems that shrews are the original hosts from which the viruses jumped into both rodents and bats.3 To determine if New World bats in Brazil may harbor hantaviruses, we screened bat sera for antibodies that react against the recombinant nucleoprotein (rN) of Araraquara hantavirus (ARAQV).Bats were collected at five ecologically distinct sites in the northeast region of São Paulo state (sites 1–3) and north region of Minas Gerais state (sites 4 and 5), southeastern Brazil (Figure 1
and 9 and one specimen per species by trap-night was anesthetized to collect blood by cardiac puncture; blood samples were stored in cryovials and flash-frozen in liquid nitrogen. At sites 4 and 5, five specimens per trap-night were randomly selected for blood collection. All bats were handled and sampled according to Sikes and others10 guidelines. This research project, along with its procedures and protocols, is in accordance with Brazilian environment and wildlife protection laws and regulations, and have been approved by the Chico Mendes Institute of Biodiversity Conservation (Ministry of Environment, Brasília, Distrito Federal, Brazil.), protocols nos. 19838-1 and 41709-3. It has also been approved by the Ethics Committee for Animal Research of University of São Paulo and Federal University of Minas Gerais (nos. 020/2011 and 333/2013, respectively). From 270 captured bats, 53 were bled for detection of immunoglobulin G (IgG) antibodies to rN-ARAQV by indirect enzyme-linked immunosorbent assay (ELISA) using anti-bat (Bethyl Laboratories, Inc., Montgomery, TX) secondary antibody. This ELISA, as previously described, showed 97.2% sensitivity, 100% specificity, 100% positive predictive value, and 98.1% negative predictive value when compared with an IgG-ELISA using rN antigen of Andes virus, which is the serological test for hantavirus most used in South America.11,12Open in a separate windowFigure 1.Study areas, highlighting the states of São Paulo and Minas Gerais in southeastern Brazil. The map shows cities where bats have been captured.
Open in a separate windowJES = Jatai Ecological Station; LGEP = Lapa Grande Ecological Park; MG = Minas Gerais state; NEF = Nova Esperança Farm; SEP = Sapucai Ecological Park; SGF = Santa Gabriela Farm; SP = Sao Paulo state.*Cerrado = Brazilian savanna-like biome.†Dry forest = deciduous seasonal forest.Nine bats had IgG antibodies to ARAQV, which represents an overall seroprevalence of 17%. Five of these bats were from São Paulo state and four were from Minas Gerais state. Of these, five were frugivorous, one was carnivorous, and three were sanguivorous (Family Species Captured Infected/tested Main feeding items Phyllostomidae Artibeus lituratus 41 1/6 Fruits Phyllostomidae A. obscurus 2 1/2 Fruits Phyllostomidae A. planirostris 41 1/3 Fruits Phyllostomidae Carollia perspicillata 43 1/10 Fruits and insects Phyllostomidae Chiroderma villosum 1 1/1 Fruits Phyllostomidae Chrotopterus auritus 1 1/1 Small vertebrates Phyllostomidae Desmodus rotundus 11 3/5 Mammals blood Phyllostomidae Glossophaga soricina 22 0/5 Nectar and pollen Phyllostomidae Lonchophylla spp. 1 0/1 Nectar and pollen Phyllostomidae Micronycteris minuta 1 0/1 Insects Molossidae Molossops neglectus 1 0/1 Insects Molossidae Molossops temminckii 2 0/1 Insects Vespertilionidae Myotis nigricans 13 0/5 Insects Vespertilionidae Myotis albescens 4 0/1 Insects Phyllostomidae Platyrrhinus lineatus 23 0/4 Fruits Phyllostomidae Sturnira lilium 38 0/6 Fruits
Table 1
Trap sites general features6Trap sites/altitude (m) | City/state | Main vegetation | Secondary vegetation | Features | |
---|---|---|---|---|---|
1 | JES/600 | Luis Antonio/SP | Cerrado* | Semideciduous forest | Continuous Cerrado |
2 | NEF/775 | Cajuru/SP | Grassland | Cerrado | Monocultures |
3 | SGF/860 | Batatais/SP | Sugarcane | Cerrado | Monocultures |
4 | SEP/872 | Montes Claros/MG | Dry forest†7 | Cerrado | Karst topography |
5 | LGEP/1,009 | Montes Claros/MG | Cerrado8 | Gallery forest | Caves and shelters |