RESUMO
Recent findings suggest that tau oligomers, which form before neurofibrillary tangles (NFTs), are the true neurotoxic tau entities in neurodegenerative tauopathies, including Alzheimer's disease (AD). Studies in animal models of tauopathy suggest that tau oligomers play a key role in eliciting behavioral and cognitive impairments. Here, we used a novel tau oligomer-specific monoclonal antibody (TOMA) for passive immunization in mice expressing mutant human tau. A single dose of TOMA administered either intravenously or intracerebroventricularly was sufficient to reverse both locomotor and memory deficits in a mouse model of tauopathy for 60 d, coincident with rapid reduction of tau oligomers but not phosphorylated NFTs or monomeric tau. Our data demonstrate that antibody protection is mediated by extracellular and rapid peripheral clearance. These findings provide the first direct evidence in support of a critical role for tau oligomers in disease progression and validate tau oligomers as a target for the treatment of AD and other neurodegenerative tauopathies.
Assuntos
Doença de Alzheimer/terapia , Imunização Passiva , Emaranhados Neurofibrilares/imunologia , Tauopatias/terapia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Progressão da Doença , Camundongos , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Fosforilação , Tauopatias/genética , Tauopatias/imunologia , Tauopatias/metabolismo , Proteínas tau/genéticaRESUMO
Over the last several years, there has been a great deal of progress in characterizing the role of dendritic cells (DCs) in the activation and modulation of B cells. DC-secreted chemokines can induce B cell trafficking to the lymph nodes. DC-produced survival factors such as B cell-activating factor of the TNF family and a proliferation-inducing ligand have been shown to be essential for B cell maturation, but have also been implicated in class-switch recombination and B cell lymphoma survival. Recently added to this list of DC-derived factors effecting B cells is IgA-inducing protein (IGIP). In this study, we characterize production of IGIP by human DCs, and examine its capacity to induce IgA class switching and differentiation of naive B cells in vitro. Monocyte-derived DCs were cultured in vitro with TLR agonists (TLR3, 4, 5, and 9) and other factors, including CD40 ligand, GM-CSF, and IL-4 as well as the neuropeptide vasoactive intestinal peptide. Under in vitro stimulation with vasoactive intestinal peptide and CD40L, IGIP mRNA expression could be up-regulated as much as 35-fold above nonstimulated samples within 12-48 h. Naive B cells cultured with exogenous recombinant human IGIP produced IgA in greater quantities than nonstimulated controls. Finally, we demonstrate that IGIP stimulation drives the production of mu-alpha switch circles from IgM(+)IgD(+) naive human B cells, indicating its role as an IgA switch factor.
Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Imunoglobulina A/biossíntese , Ativação Linfocitária/imunologia , Proteínas/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/imunologia , Humanos , Switching de Imunoglobulina/imunologia , Imunoglobulina D/imunologia , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Mycobacterium tuberculosis and M. bovis share >99% genetic identity and induce similar host responses and disease profiles upon infection. There is a rich history of codiscovery in the development of control measures applicable to both human and bovine tuberculosis (TB) including skin-testing procedures, M. bovis BCG vaccination, and interferon-γ release assays. The calf TB infection model offers several opportunities to further our understanding of TB immunopathogenesis. Recent observations include correlation of central memory immune responses with TB vaccine efficacy, association of SIRPα(+) cells in ESAT-6:CFP10-elicited multinucleate giant cell formation, early γδ T cell responses to TB, antimycobacterial activity of memory CD4(+) T cells via granulysin production, association of specific antibody with antigen burden, and suppression of innate immune gene expression in infected animals. Partnerships teaming researchers with veterinary and medical perspectives will continue to provide mutual benefit to TB research in man and animals.
Assuntos
Vacinas contra a Tuberculose , Tuberculose Bovina , Tuberculose , Animais , Animais Recém-Nascidos , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Biomarcadores/análise , Bovinos , Perfilação da Expressão Gênica , Humanos , Imunidade/genética , Memória Imunológica , Macaca fascicularis , Masculino , Camundongos , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/imunologia , Receptores Imunológicos/agonistas , Linfócitos T/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/genética , Vacinas contra a Tuberculose/imunologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/prevenção & controle , Vacinação/métodosAssuntos
Antígenos de Plantas/imunologia , Epitopos Imunodominantes/imunologia , Imunoglobulina E/imunologia , Juniperus/imunologia , Proteínas de Plantas/imunologia , Rinite Alérgica Sazonal/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos de Plantas/química , Humanos , Hibridomas , Epitopos Imunodominantes/química , Conformação Molecular , Proteínas de Plantas/química , Pólen/imunologiaRESUMO
BACKGROUND: Burkholderia mallei is a zoonotic Gram negative bacterium which primarily infects solipeds but can cause lethal disease in humans if left untreated. The effect of two antibiotics with different modes of action on Burkholderia mallei strain ATCC23344 was investigated by using in vitro and in vivo studies. RESULTS: Determination of minimal inhibitory concentrations (MICs) in vitro was done by the agar diffusion method and the dilution method. The MICs of levofloxacin and ceftazidime were in the similar range, 2.5 and 5.0 microg/ml, respectively. Intracellular susceptibility of the bacterium to these two antibiotics in J774A.1 mouse macrophages in vitro was also investigated. Macrophages treated with antibiotics demonstrated uptake of the drugs and reduced bacterial loads in vitro. The efficacy of ceftazidime and levofloxacin were studied in BALB/c mice as post-exposure treatment following intranasal B. mallei infection. Intranasal infection with 5 x 10(5) CFUs of B. mallei resulted in 90% death in non-treated control mice. Antibiotic treatments 10 days post-infection proved to be effective in vivo with all antibiotic treated mice surviving to day 34 post-infection. The antibiotics did not result in complete clearance of the bacterial infection and presence of the bacteria was found in lungs and spleens of the survivors, although bacterial burden recovered from levofloxacin treated animals appeared reduced compared to ceftazidime. CONCLUSION: Both antibiotics demonstrated utility for the treatment of glanders, including the ability for intracellular penetration and clearance of organisms in vitro.
Assuntos
Antibacterianos/farmacologia , Burkholderia mallei/efeitos dos fármacos , Ceftazidima/farmacologia , Levofloxacino , Ofloxacino/farmacologia , Animais , Linhagem Celular , Farmacorresistência Bacteriana , Feminino , Mormo/tratamento farmacológico , Mormo/microbiologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade MicrobianaRESUMO
Burkholderia mallei is a facultative intracellular pathogen that survives and replicates in phagocytic cell lines. The bacterial burden recovered from naïve BALB/c mice infected by intranasal delivery indicated that B. mallei persists in the lower respiratory system. To address whether B. mallei invades respiratory non-professional phagocytes, this study utilized A549 and LA-4 respiratory epithelial cells and demonstrated that B. mallei possesses the capacity to adhere poorly to, but not to invade, these cells. Furthermore, it was found that B. mallei was taken up by the murine alveolar macrophage cell line MH-S following serum coating, an attribute suggestive of complement- or Fc receptor-mediated uptake. Invasion/intracellular survival assays of B. mallei-infected MH-S cells demonstrated decreased intracellular survival, whilst a type III secretion system effector bopA mutant strain survived longer than the wild-type. Evaluation of the potential mechanism(s) responsible for efficient clearing of intracellular organisms demonstrated comparable levels of caspase-3 in both the wild-type and bopA mutant with characteristics consistent with apoptosis of infected MH-S cells. Furthermore, challenge of BALB/c mice with the bopA mutant by the intranasal route resulted in increased survival. Overall, these data suggest that B. mallei induces apoptotic cell death, whilst the BopA effector protein participates in intracellular survival.
Assuntos
Infecções por Burkholderia/patologia , Burkholderia mallei , Adenocarcinoma , Animais , Aderência Bacteriana , Burkholderia mallei/citologia , Burkholderia mallei/genética , Burkholderia mallei/isolamento & purificação , Burkholderia mallei/patogenicidade , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Primers do DNA , Humanos , Pulmão/microbiologia , Neoplasias Pulmonares , Macrófagos Alveolares/microbiologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Reação em Cadeia da Polimerase , Mucosa Respiratória/microbiologia , VirulênciaRESUMO
Tuberculosis (TB) remains a major threat to public health. The identification of safe TB vaccine candidates beyond Mycobacterium bovis BCG, is an exciting prospect for control of human TB and necessary in the context of the human immunodeficiency virus (HIV) pandemic. Selection of vaccine candidates for human trials which are ultimately targeted for use in children less than 5 years of age or in newborns will require an animal model that closely approximates immune function and disease. We propose that the bovine neonate and adolescent is a robust animal model for preclinical safety and efficacy evaluation of TB candidate vaccines targeting this special human population. Parallel studies conducted in bovine neonates and non-human primates with a leading auxotrophic mutant with demonstrated efficacy/safety in a rodent TB model of TB demonstrated similar findings with respect to gross pathology scoring relative to BCG. The findings indicated more numerous and severe lesions in the lung in addition to higher levels of IFN-gamma producing cells. BCG vaccinates demonstrated higher levels of FoxP3 transcripts and lower levels of IL-4 mRNA.
Assuntos
Vacinas contra a Tuberculose/imunologia , Tuberculose Pulmonar/prevenção & controle , Animais , Biomarcadores , Bovinos , Modelos Animais de Doenças , Humanos , Linfócitos/fisiologia , Mycobacterium bovis , Vacinas contra a Tuberculose/efeitos adversos , Tuberculose Bovina/imunologiaRESUMO
A series of N-heterocyclic carbene silver complexes have been synthesized and tested against the select group of bio-safety level 3 bacteria Burkholderia pseudomallei, Burkholderia mallei, Bacillus anthracis, methicillin-resistant Staphylococcus aureus and Yersinia pestis. Minimal inhibitory concentrations, minimal bactericidal and killing assays demonstrated the exceptional efficacy of the complexes against these potentially weaponizable pathogens.
RESUMO
BACKGROUND: We performed initial cell, cytokine and complement depletion studies to investigate the possible role of these effectors in response to vaccination with heat-killed Burkholderia mallei in a susceptible BALB/c mouse model of infection. RESULTS: While protection with heat-killed bacilli did not result in sterilizing immunity, limited protection was afforded against an otherwise lethal infection and provided insight into potential host protective mechanisms. Our results demonstrated that mice depleted of either B cells, TNF-alpha or IFN-gamma exhibited decreased survival rates, indicating a role for these effectors in obtaining partial protection from a lethal challenge by the intraperitoneal route. Additionally, complement depletion had no effect on immunoglobulin production when compared to non-complement depleted controls infected intranasally. CONCLUSION: The data provide a basis for future studies of protection via vaccination using either subunit or whole-organism vaccine preparations from lethal infection in the experimental BALB/c mouse model. The results of this study demonstrate participation of B220+ cells and pro-inflammatory cytokines IFN-gamma and TNF-alpha in protection following HK vaccination.
Assuntos
Vacinas Bacterianas/imunologia , Burkholderia mallei/imunologia , Mormo/imunologia , Imunidade Ativa , Vacinas de Produtos Inativados/imunologia , Animais , Anticorpos Bloqueadores/imunologia , Linfócitos B/imunologia , Vacinas Bacterianas/administração & dosagem , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinação , Vacinas de Produtos Inativados/administração & dosagemRESUMO
BACKGROUND: Allergic airway diseases are more common in females than in males during early adulthood. A relationship between female hormones and asthma prevalence and severity has been suggested, but the cellular and molecular mechanisms are not understood. OBJECTIVE: To elucidate the mechanism(s) by which estrogens enhance the synthesis and release of mediators of acute hypersensitivity. METHODS: Two mast cell/basophil cell lines (RBL-2H3 and HMC-1) and primary cultures of bone marrow derived mast cells, all of which naturally express estrogen receptor-alpha, were examined. Cells were incubated with physiological concentrations of 17-beta-estradiol with and without IgE and allergens. Intracellular Ca(2+) concentrations and the release of beta-hexosaminidase and leukotriene C(4) were quantified. RESULTS: Estradiol alone induced partial release of the preformed, granular protein beta-hexosaminidase from RBL-2H3, BMMC and HMC-1, but not from BMMC derived from estrogen receptor-alpha knock-out mice. The newly synthesized LTC(4) was also released from RBL-2H3. Estradiol also enhanced IgE-induced degranulation and potentiated LTC(4) production. Intracellular Ca(2+) concentration increased prior to and in parallel with mediator release. Estrogen receptor antagonists or Ca(2+) chelation inhibited these estrogenic effects. CONCLUSION: Binding of physiological concentrations of estradiol to a membrane estrogen receptor-alpha initiates a rapid onset and progressive influx of extracellular Ca(2+), which supports the synthesis and release of allergic mediators. Estradiol also enhances IgE-dependent mast cell activation, resulting in a shift of the allergen dose response.
Assuntos
Asma/imunologia , Sinalização do Cálcio/imunologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/imunologia , Mastócitos/imunologia , Caracteres Sexuais , Alérgenos/imunologia , Alérgenos/farmacologia , Animais , Asma/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/genética , Linhagem Celular , Estradiol/imunologia , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Imunoglobulina E/imunologia , Imunoglobulina E/farmacologia , Leucotrieno C4/imunologia , Leucotrieno C4/metabolismo , Masculino , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Ratos , beta-N-Acetil-Hexosaminidases/imunologia , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
BACKGROUND: Prevalence and morbidity of allergic diseases have increased over the last decades. Based on the recently recognized differences in asthma prevalence between the sexes, we have examined the effect of endogenous estrogens on a key element of the allergic response. Some lipophilic pollutants have estrogen-like activities and are termed environmental estrogens. These pollutants tend to degrade slowly in the environment and to bioaccumulate and bioconcentrate in the food chain; they also have long biological half-lives. OBJECTIVES: Our goal in this study was to identify possible pathogenic roles for environmental estrogens in the development of allergic diseases. METHODS: We screened a number of environmental estrogens for their ability to modulate the release of allergic mediators from mast cells. We incubated a human mast cell line and primary mast cell cultures derived from bone marrow of wild type and estrogen receptor alpha (ER-alpha)-deficient mice with environmental estrogens with and without estradiol or IgE and allergens. We assessed degranulation of mast cells by quantifying the release of beta-hexosaminidase. RESULTS: All of the environmental estrogens tested caused rapid, dose-related release of beta-hexosaminidase from mast cells and enhanced IgE-mediated release. The combination of physiologic concentrations of 17beta-estradiol and several concentrations of environmental estrogens had additive effects on mast cell degranulation. Comparison of bone marrow mast cells from ER-alpha-sufficient and ER-alpha-deficient mice indicated that much of the effect of environmental estrogens was mediated by ER-alpha. CONCLUSIONS: Our findings suggest that estrogenic environmental pollutants might promote allergic diseases by inducing and enhancing mast cell degranulation by physiologic estrogens and exposure to allergens.
Assuntos
Poluentes Ambientais/toxicidade , Estrogênios não Esteroides/toxicidade , Mastócitos/efeitos dos fármacos , Animais , Antígenos de Dermatophagoides/farmacologia , Arocloros/toxicidade , Asma/imunologia , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Diclorodifenil Dicloroetileno/toxicidade , Dieldrin/toxicidade , Dinitrofenóis/farmacologia , Endossulfano/toxicidade , Estradiol/farmacologia , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Humanos , Imunoglobulina E/imunologia , Mastócitos/imunologia , Mastócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Praguicidas/toxicidade , Fenóis/toxicidade , Soroalbumina Bovina/farmacologiaRESUMO
Burkholderia mallei, the etiologic agent of the disease known as glanders, is primarily a disease affecting horses and is transmitted to humans by direct contact with infected animals. The use of B. mallei as a biological weapon has been reported and currently, there is no vaccine available for either humans or animals. Despite the history and highly infective nature of B. mallei, as well as its potential use as a bio-weapon, B. mallei research to understand the pathogenesis and the host responses to infection remains limited. Therefore, this minireview will focus on current efforts to elucidate B. mallei virulence, the associated host immune responses elicited during infection and discuss the feasibility of vaccine development.
Assuntos
Burkholderia mallei/imunologia , Burkholderia mallei/fisiologia , Mormo/imunologia , Mormo/microbiologia , Animais , Armas Biológicas , Cavalos , Humanos , VirulênciaRESUMO
PURPOSE: The risk of developing breast cancer is positively correlated with exposure to increased levels of estrogen and/or an increased duration of estrogen exposure. Many different mechanisms have been proposed to explain the association of estrogens with breast cancer risk; however, the well-documented immune modulatory properties of estrogen have received little attention. In part, this is due to a lack of suitable models for studying this relationship. EXPERIMENTAL DESIGN: We have developed an animal model using estrogen receptor (ER)-negative human breast cancer cell line, MDA-MB-468, xenografted into severe combined immunodeficient (SCID) mice. We also generated the ER-alpha knockout (ER-alphaKO) mice on the SCID background and then tested the ability of 17beta-estradiol to stimulate growth of xenografted ER-negative human breast cancer tumors in wild-type and ER-alphaKO SCID mice. We quantified vascularization of tumors, macrophage recruitment to the tumor site by immunocytochemistry, and inflammatory cytokine production. RESULTS: We show that estrogen treatment of C57BL/6/SCID mice promotes the growth of xenografted ER-negative tumors in wild-type mice and this estrogen-induced tumor growth is abrogated in ER-alphaKO mice. Tumor neovascularization of estrogen-treated mice was unchanged versus control; however, estrogen treatment of the C57BL/6/SCID host suppressed macrophage recruitment to and inflammatory cytokine production at the tumor site. CONCLUSIONS: These data are consistent with estrogen modulation of the inflammatory response as a contributing factor in estrogen-stimulated growth of an ER-negative tumor. This effect on the host innate immune response was mediated by ER-alpha.
Assuntos
Neoplasias da Mama/imunologia , Estradiol/farmacologia , Receptores de Estrogênio/metabolismo , Animais , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Feminino , Humanos , Imunidade Inata , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Bovine natural killer (NK) cells were recently identified by positive selection of a NK cell-activating receptor p46 (NKp46)+ CD3- lymphocyte population, which expresses CD25 and CD8 and lyses tumor cell lines following stimulation with recombinant interleukin-2. In the current work, we characterize the cytotoxic/effector potential of a CD3(-)CD8(-)CD11b- population isolated through negative selection of bovine peripheral blood leukocytes. This population is CD25(lo)CD62(hi) when isolated and becomes CD25hiCD62L(lo) following cytokine stimulation. Activated bovine NK cells increase expression of granulysin, interferon-gamma, and perforin and have cytotoxic activity against human tumor cells and Mycobacterium bovis bacillus Calmette-Guerin-infected alveolar and monocyte-derived macrophages. Expression of a bovine homologue of the CD56 neural adhesion molecule expressed by human NK cells was detected in mRNA from brain tissue but was not detected in peripheral blood mononuclear cells or purified NK cell mRNA. Analysis of mRNA from nonstimulated peripheral blood NK cells demonstrates the constitutive expression of homologues of human NK receptors NKp46, CD244, and CD94 and the granule proteins granulysin and perforin. Phorbol ester-stimulated CD8+ T cells also expressed CD244 and CD94, and CD4+ T cells expressed CD94. These NK cell receptors bearing T lymphocytes may represent memory subsets characterized in humans. The results of these studies demonstrate that bovine NK cells may play an important role in the innate immune responses of cattle.
Assuntos
Interleucina-12/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Macrófagos Alveolares/imunologia , Mycobacterium bovis/imunologia , Tuberculose Bovina/imunologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Bovinos , Células Cultivadas , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Interleucina-12/farmacologia , Interleucina-15/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Macrófagos Alveolares/microbiologia , Glicoproteínas de Membrana/imunologia , Perforina , Proteínas Citotóxicas Formadoras de PorosRESUMO
BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD > 90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250 mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI = 21-58 days). One year overall survival (OS) was 21% (95% CI = 6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma de Células Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Idoso , Carcinoma de Células Pequenas/patologia , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The purpose of this study was to investigate SCID-bg mice engrafted with bovine haematolymphoid tissues (SCID-bo) as a model for studying bovine Mannheimia haemolytica serotype 1- induced pneumonia, in which leucotoxin (LKT) plays a major role. In experiment A, SCID-bo and SCID-bg mice were inoculated intratracheally with either (1) phosphate-buffered saline (PBS), (2) M. haemolytica wild-type strain 89010807N ("LKT(+)WT"), (3) a M. haemolytica leucotoxin-deficient mutant of strain 89010807N ("LKT(-)mutant"), or (4) the M. haemolytica wild-type Oklahoma strain. Mice were killed for examination at intervals between 20 and 44h after inoculation. Lung lesions consisted of thickened alveolar septa and neutrophil and macrophage infiltrates in the bronchioles and alveoli. Lung lesion scores in the SCID-bo mice inoculated with LKT(+)WT or LKT(-) mutant were significantly (P<0.05) greater than those of the PBS control group, but the two bacterial strains produced results that did not differ significantly. M. haemolytica was isolated from lung, liver and spleen after inoculation but less frequently as time progressed. In experiment B, SCID-bg mice were inoculated intratracheally with live LKT(+)WT or formalin-killed LKT(+)WT and killed 24, 48 or 96 h later. Lung lesions were histologically similar to those observed in experiment A; however, there were no significant differences in the lung lesion scores between groups. It was concluded that the lesions seen in this study were probably not due to LKT, and that the SCID-bo mouse does not provide a good rodent model for bovine pneumonia.
Assuntos
Toxinas Bacterianas/genética , Broncopneumonia/patologia , Exotoxinas/genética , Pulmão/patologia , Mannheimia haemolytica/patogenicidade , Infecções por Pasteurella/patologia , Animais , Toxinas Bacterianas/imunologia , Broncopneumonia/imunologia , Broncopneumonia/microbiologia , Bovinos , Modelos Animais de Doenças , Exotoxinas/deficiência , Exotoxinas/imunologia , Feminino , Pulmão/imunologia , Pulmão/microbiologia , Mannheimia haemolytica/genética , Mannheimia haemolytica/imunologia , Camundongos , Camundongos SCID , Infecções por Pasteurella/imunologia , Infecções por Pasteurella/microbiologiaRESUMO
Abnormal procainamide pharmacokinetics (prolonged half-life and decreased volume of distribution) and pharmacodynamics (decreased threshold for the suppression of premature ventricular complexes) have been suggested in patients with acute myocardial infarction or congestive heart failure, or both. To better define procainamide kinetics, 37 patients in the acute care setting received intravenous procainamide (25 mg/min, median dose 750 mg) with peak and hourly blood samples taken over 6 hours. Compared with the 10 control patients, the 12 patients with acute myocardial infarction and the 15 patients with congestive heart failure had normal procainamide pharmacokinetics with respect to half-life (2.3 +/- 1.0, 2.5 +/- 0.9 and 2.6 +/- 0.8 hours, respectively), volume of distribution (1.9 +/- 0.7, 1.8 +/- 0.4 and 1.8 +/- 0.5 liters/kg, respectively), clearance (11.3 +/- 7.5, 9.3 +/- 3.6 and 9.1 +/- 3.5 ml/min per kg, respectively) and unbound drug fraction (66 +/- 9, 66 +/- 9 and 69 +/- 4%, respectively). Low thresholds for greater than 85% premature ventricular complex suppression were confirmed in these patients (median 4.7 micrograms/ml in patients with acute myocardial infarction and 3.3 micrograms/ml in patients with congestive heart failure). Thus, differences in the response of premature ventricular complexes to procainamide reflect electropharmacologic differences dependent on clinical setting rather than pharmacokinetic abnormalities. Furthermore, the reduction of procainamide dosing in patients with acute myocardial infarction or congestive heart failure, based solely on prior kinetic data, may result in inappropriate antiarrhythmic therapy.
Assuntos
Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Procainamida/metabolismo , Idoso , Feminino , Insuficiência Cardíaca/sangue , Humanos , Cinética , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Procainamida/sangueRESUMO
Previous studies of outcome as a function of the initial electrophysiologic mechanisms recorded at the scene of prehospital cardiac arrest have demonstrated that bradyarrhythmias and asystole have the worst prognosis. In this report, our observations in bradyarrhythmic and asystolic arrests occurring from 1980 to 1982 are compared with those from 1975 to 1978. From 1980 to 1982, 61 (27%) of 225 cardiac arrest events meeting entry criteria for the study were bradyarrhythmic or asystolic. Only 2 (8%) of 24 patients with asystole and 1 (20%) of 5 patients with sinus bradycardia survived prehospital intervention. Only 1 of these 29 patients was discharged from the hospital alive. In contrast, 15 (47%) of 32 patients who presented with idioventricular rhythm at initial contact survived prehospital intervention and were hospitalized, and 8 (25%) of these 32 were ultimately discharged alive. When compared with the 1975 to 1978 patients with bradyarrhythmia and asystole, both prehospital survival (8 versus 30%, p less than 0.001) and survival after hospitalization (0 versus 15%, p less than 0.05) significantly improved, but the improvement occurred predominantly in the subgroup with idioventricular rhythm. Survivors within this subgroup tended to have a prompt response to prehospital pharmacologic interventions that were not available to the 1975 to 1978 group. The response was manifested by return to a sinus mechanism or increase in the rate of idioventricular rhythm. In conclusion, outcome has improved for a specific subgroup of victims of prehospital cardiac arrest with bradyarrhythmia or asystole; the improved outcome may relate to field interventions by rescue personnel at the scene of arrest but the mortality rate is still high.
Assuntos
Arritmias Cardíacas/mortalidade , Bradicardia/mortalidade , Parada Cardíaca/mortalidade , Ressuscitação , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
In this series of studies, we determined the potential role of intracellular estrogen receptors (ER), ERalpha and ERbeta, on macrophage function in response to bacterial stimuli. The sex hormone 17beta-estradiol (E(2)) and ER have been shown to modulate inflammatory responses as well as T helper cell type 1 (TH1)/TH2 responses. The mechanisms E(2) and its receptors use to alter these immune functions remain largely unknown. ERalpha and ERbeta possess complex actions in tissues where they are expressed. We have characterized the receptor repertoire of murine dendritic cells and thioglycollate-elicited peritoneal macrophages (PM). Both cell types express mRNA for ERalpha. Neither cell type expressed detectable amounts of ERbeta mRNA, as determined by reverse transcriptase-polymerase chain reaction using exon-specific primers spanning each of the seven intron/exon junctions. Primary macrophages from ERalpha- and ERbeta-deficient severe combined immunodeficiency mice [ERalpha knockout (KO) and ERssKO, respectively] were used to delineate the effects and potential mechanisms via which steroid receptors modulate macrophage function. ERalpha-deficient PM exposed ex vivo to lipopolysaccharide or Mycobacterium avium exhibited significant increases in tumor necrosis factor alpha (TNF-alpha) secretion as well as reduction in bacterial load when compared with wild-type (WT) PM. In contrast, ERbeta-deficient PM possessed no significant difference in TNF-alpha secretion or in bacterial load when compared with WT littermates. These studies suggest that ERalpha, but not ERbeta, modulates murine PM function.
Assuntos
Macrófagos Peritoneais/metabolismo , Mycobacterium avium/fisiologia , Receptores de Estrogênio/deficiência , Fator de Necrose Tumoral alfa/metabolismo , Animais , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Feminino , Técnicas In Vitro , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCIDRESUMO
African trypansosomes are tsetse-transmitted parasites of chief importance in causing disease in livestock in regions of sub-Saharan Africa. Previous studies have demonstrated that certain breeds of cattle are relatively resistant to infection with trypanosomes, and others are more susceptible. Because of its extracellular location, the humoral branch of the immune system dominates the response against Trypanosoma congolense. In the following study, we describe the humoral immune response generated against T. congolense in SCID mice reconstituted with a bovine immune system (SCID-bo). SCID-bo mice infected with T. congolense were treated with an agonistic anti-CD40 antibody and monitored for the development of parasitemia and survival. Anti-CD40 antibody administration resulted in enhanced survival compared with mice receiving the isotype control. In addition, we demonstrate that the majority of bovine IgM+ B cells in SCID-bo mice expresses CD5, consistent with a neonatal phenotype. It is interesting that the percentage of bovine CD5+ B cells in the peripheral blood of infected SCID-bo mice was increased following anti-CD40 treatment. Immunohistochemical staining also indicated increased numbers of Ig+ cells in the spleens of anti-CD40-treated mice. Consistent with previous studies demonstrating high IL-10 production during high parasitemia levels in mice and cattle, abundant IL-10 mRNA message was detected in the spleens and peripheral blood of T. congolense-infected SCID-bo mice during periods of high parasitemia. In addition, although detected in plasma when parasites were absent or low in number, bovine antibody was undetectable during high parasitemia. However, Berenil treatment allowed for the detection of VSG-specific IgG 14 days postinfection in T. congolense-infected SCID-bo mice. Overall, the data indicate that survival of trypanosome-infected SCID-bo mice is prolonged when an agonistic antibody against bovine CD40 (ILA156) is administered. Thus, stimulation of B cells and/or other cell types through CD40 afforded SCID-bo mice a slight degree of protection during T. congolense infection.