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1.
IDCases ; 14: e00460, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30370224

RESUMO

Treatment of enterococcal endocarditis in patients with history of renal transplantation is complicated. Treatment failure and/or drug toxicities are not uncommon. Treatment with ampicillin and daptomycin in a renal transplant patient has been rarely reported. Here we report a patient who was successfully treated with this novel combination.

2.
Clin Chest Med ; 39(3): 561-568, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30122180

RESUMO

Pulmonary embolism remains a leading cause of morbidity and mortality in the United States. However, with improved recognition and diagnosis, the risk of death diminishes. The diagnosis depends on the clinician's suspicion. Pulmonary emboli are categorized into low, intermediate, or high risk based on the scoring scales and patients' hemodynamic stability versus instability. Imaging plus biomarkers help stratify patients according to risk. With the advent of the computed tomography multidetector scanners, the improved imaging has increased the detection of subsegmental and incidental pulmonary emboli. Treatment of low-risk as well as subsegmental and incidental pulmonary embolism is evolving.

3.
J Wound Care ; 27(Sup4): S24-S28, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29641341

RESUMO

OBJECTIVE: Necrotising soft tissue infections (NSTIs) progress rapidly and mortality remains high, ranging from 10% to 30%, representing a significant challenge for health professionals. Early accurate diagnosis is crucial because timely and aggressive surgical intervention remains the number one indicator for a better clinical outcome. Understanding the microbial background of NSTIs would aid early diagnosis. PRESENTATION: We present a case of NSTI, in a seemingly healthy adult male, originating from a tooth abscess. The NSTI progressed rapidly, and eventually covered the patient's chest and abdominal skin and underlying soft tissue. RESULTS: Traditional blood and tissue culture only found Group C Streptococcus where 16S sequencing detected abundant Prevotella spp., a more likely causal organisms of the NSTI. The use of antibiotics with the approriate anaerobe coverage, in combination with timely surgical intervention, contributed to the ultimate successful clinical outcome. Complete wound healing and successful graft was achieved within one month of diagnosis of the microbes present. CONCLUSION: While surgical intervention remains the most important consideration in treatment of NSTI, correct identifcation of the microbial flora could also contribute to successful treatment.

4.
Sci Rep ; 6: 38466, 2016 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-27929129

RESUMO

Perfluorooctanesulfonate (PFOS) has been widely detected in the environment, wildlife and humans, but few studies have ever examined its mutagenic effect in vivo. In the present study, we use a transgenic fish model, the λ transgenic medaka, to evaluate the potential mutagenicity of PFOS in vivo following a subchronic exposure of 30 days. The mutant frequency of cII target gene was 3.46 × 10-5 in liver tissue from control fish, which increased by 1.4-fold to 4.86 × 10-5 in fish exposed to 6.7 µg/L PFOS, 1.55-fold to 5.36 × 10-5 in fish exposed to 27.6 µg/L PFOS, and 2.02-fold to 6.99 × 10-5 in fish exposed to 87.6 µg/L PFOS. This dose-dependent increase of mutant frequency was also accompanied with mutational spectrum changes associated with PFOS exposure. In particular, PFOS-induced mutation was characterized by +1 frameshift mutations, which increased from 0% in control fish to 13.2% in fish exposed to 27.6 µg/L PFOS and 14.6% in fish exposed to 87.6 µg/L PFOS. Our findings provide the first evidence of PFOS's mutagenicity in an aquatic model system. Given the fact that most conventional mutagenic assays were negative for PFOS, we propose that PFOS-induced mutation in liver tissue of λ transgenic medaka may be mediated through compromised liver function.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Carcinógenos/toxicidade , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , Mutação/efeitos dos fármacos , Animais , Animais Geneticamente Modificados/genética , Fígado/patologia , Testes de Mutagenicidade , Mutação/genética , Oryzias/genética
5.
Proc (Bayl Univ Med Cent) ; 29(2): 181-2, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27034562

RESUMO

Infective endocarditis caused by Klebsiella species is rare, with most isolates being K. pneumoniae. We report the case of a 24-year-old intravenous drug user with newly diagnosed seminoma who developed K. oxytoca endocarditis. In addition to having K. oxytoca isolated from blood culture, cultures of that species were obtained from a retroperitoneal metastasis found on original presentation.

6.
Hum Vaccin Immunother ; 10(3): 640-7, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24374377

RESUMO

Sm-p80, the large subunit of Schistosoma masoni calpain, is a leading antigen candidate for a schistosome vaccine. Prophylactic and antifecundity efficacy of Sm-p80 has been tested using a variety of vaccine approaches. However, the mechanism of Sm-p80-mediated killing is still unknown. In this study, potential role of complement in Sm-p80-mediated protection was studied using both in vitro (cobra venom factor inhibition) and in vivo using mice deficient in C3 (C3 -/-; B6.129S4-C3tm1Crr/J). In the absence of C3, Sm-p80-based vaccine was able to provide significant reduction in adult worm burden following challenge with schistosome cercariae in mice suggesting the effector functions of complement may be limited in this vaccine-induced protection.


Assuntos
Antígenos de Helmintos/imunologia , Calpaína/imunologia , Complemento C3/imunologia , Schistosoma mansoni/imunologia , Animais , Complemento C3/deficiência , Modelos Animais de Doenças , Imunização/métodos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Carga Parasitária , Esquistossomose mansoni/imunologia
7.
Cancer Immunol Immunother ; 62(2): 371-82, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22926061

RESUMO

The central role of CD4+ T lymphocytes in mediating DNA vaccine-induced tumor immunity against the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory. In the present study, we extend our previous findings by examining the roles of IFN-γ and Th1-associated effector cells within the context of DNA immunization in a murine model of pulmonary metastasis. Immunization of BALB/c mice with plasmid DNA encoding SV40 Tag (pCMV-Tag) generated IFN-γ-secreting T lymphocytes that produced this cytokine upon in vitro stimulation with mKSA tumor cells. The role of IFN-γ as a mediator of protection against mKSA tumor development was assessed via in vivo IFN-γ neutralization, and these experiments demonstrated a requirement for this cytokine in the induction immune phase. Neutralization of IFN-γ was associated with a reduction in Th1 cytokine-producing CD4+ and CD8+ splenocytes, as assessed by flow cytometry analysis, and provided further evidence for the role of CD4+ T lymphocytes as drivers of the cellular immune response. Depletion of NK cells and CD8+ T lymphocytes demonstrated the expendability of these cell types individually, but showed a requirement for a resident cytotoxic cell population within the immune effector phase. Our findings demonstrate the importance of IFN-γ in the induction of protective immunity stimulated by pCMV-Tag DNA-based vaccine and help to clarify the general mechanisms by which DNA vaccines trigger immunity to tumor cells.


Assuntos
Antígenos Transformantes de Poliomavirus/imunologia , Interferon gama/imunologia , Infecções por Polyomavirus/imunologia , Vírus 40 dos Símios/imunologia , Infecções Tumorais por Vírus/imunologia , Vacinas de DNA/imunologia , Animais , Antígenos Transformantes de Poliomavirus/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Células Cultivadas , Feminino , Interferon gama/metabolismo , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Endogâmicos BALB C , Plasmídeos , Infecções por Polyomavirus/genética , Baço/imunologia , Células Th1/imunologia , Infecções Tumorais por Vírus/genética
8.
Clin Rheumatol ; 32(1): 135-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23065146

RESUMO

Progressive disseminated histoplasmosis is a disease where Histoplasma capsulatum affects multiple organs due to the inability of host cellular immunity to control the infection. Progressive disseminated histoplasmosis mainly involves the bone marrow, liver, and lungs. We report an unusual initial presentation of progressive disseminated histoplasmosis presenting as acute tenosynovitis in a systemic lupus erythematosus (SLE) patient. This report highlights the point that H. capsulatum may present as focal lesions and a high level of suspicion is needed to make the diagnosis, especially in SLE patients. We specifically reviewed reported cases of progressive disseminated histoplasmosis in SLE patients, and a review of the literature is presented.


Assuntos
Histoplasmose/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Tenossinovite/diagnóstico , Doença Aguda , Adulto , Antifúngicos/uso terapêutico , Medula Óssea/microbiologia , Medula Óssea/patologia , Diagnóstico Diferencial , Quimioterapia Combinada , Feminino , Histoplasma/isolamento & purificação , Histoplasmose/complicações , Histoplasmose/tratamento farmacológico , Humanos , Itraconazol/uso terapêutico , Fígado/microbiologia , Fígado/patologia , Pulmão/microbiologia , Pulmão/patologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/microbiologia , Tenossinovite/microbiologia , Tenossinovite/terapia
9.
J Virol ; 85(14): 7216-24, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21593176

RESUMO

A mechanistic analysis of tumor immunity directed toward the viral oncoprotein simian virus 40 (SV40) large tumor antigen (Tag) has previously been described by our laboratory for scenarios of recombinant Tag immunization in BALB/c mice. In the present study, we performed a preliminary characterization of the immune components necessary for systemic tumor immunity induced upon immunization with plasmid DNA encoding SV40 Tag as a transgene (pCMV-Tag). Antibody responses to SV40 Tag were observed via indirect enzyme-linked immunosorbent assay following three intramuscular (i.m.) injections of pCMV-Tag and were typified by a mixed Th1/Th2 response. Complete tumor immunity within a murine model of pulmonary metastasis was achieved upon two i.m. injections of pCMV-Tag, as assessed by examination of tumor foci in mouse lungs, without a detectable antibody response to SV40 Tag. Induction-phase and effector-phase depletions of T cell subsets were performed in vivo via administration of depleting rat monoclonal antibodies, and these experiments demonstrated that CD4(+) T lymphocytes are required in both phases of the adaptive immune response. Conversely, depletion of CD8(+) T lymphocytes did not impair tumor immunity in either immune phase and resulted in the premature production of antibodies to SV40 Tag. Our findings are unique in that a dominant role could be ascribed to CD4(+) T lymphocytes within a model of DNA vaccine-induced tumor immunity to Tag-expressing tumor cells. Additionally, our findings provide insight into the general mechanisms of vaccine-induced tumor immunity directed toward tumors bearing distinct tumor-associated antigens.


Assuntos
Antígenos Virais de Tumores/imunologia , Linfócitos T CD4-Positivos/imunologia , Neoplasias Experimentais/imunologia , Plasmídeos , Vírus 40 dos Símios/imunologia , Vacinas de DNA/imunologia , Animais , Anticorpos Antivirais/biossíntese , Ensaio de Imunoadsorção Enzimática , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Vacinas de DNA/administração & dosagem
10.
Autoimmun Rev ; 10(4): 181-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20920612

RESUMO

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has remarkable pathogenicity and can cause severe infections, such as necrotizing pneumonia, necrotizing fasciitis, and sepsis. To our knowledge, no case of CA-MRSA resulting in catastrophic antiphospholipid syndrome (CAPS) has been reported. Furthermore, no specific pathogenic link between these two disorders has been described. Staphylococcal sequence homologies and binding capabilities to plasma protein ß2-glycoprotein I (ß2-GPI) may result in anti-ß2-GPI antibody production. These antibodies represent the critical prothrombotic factor in pathogenesis of antiphospholipid syndrome and CAPS. However, the development of CAPS requires additional prothrombotic activities. In our case, sepsis and CA-MRSA-induced leukocytolysis likely represent the activity required to transform a hypercoagulable state into the life threatening, diffusely thrombotic CAPS. The presence of anti-ß2GPI-antibodies and diffuse microvascular occlusion are characteristic of CAPS. However, other life threatening syndromes cause microvascular thrombi and multiorgan failure, and more studies are needed to determine the frequency of antiphospholipid antibodies and clinical syndromes consistent with CAPS in patients with staphylococcal infections.


Assuntos
Síndrome Antifosfolipídica/etiologia , Síndrome Antifosfolipídica/fisiopatologia , Infecções Comunitárias Adquiridas/complicações , Staphylococcus aureus Resistente à Meticilina/fisiologia , Mimetismo Molecular/imunologia , Infecções Estafilocócicas/complicações , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/mortalidade , Síndrome Antifosfolipídica/terapia , Autoimunidade , Infecções Comunitárias Adquiridas/diagnóstico , Humanos , beta 2-Glicoproteína I/imunologia
11.
Clin Dev Immunol ; 2010: 697158, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20936120

RESUMO

The employment of the immune system to treat malignant disease represents an active area of biomedical research. The specificity of the immune response and potential for establishing long-term tumor immunity compels researchers to continue investigations into immunotherapeutic approaches for cancer. A number of immunotherapeutic strategies have arisen for the treatment of malignant disease, including various vaccination schemes, cytokine therapy, adoptive cellular therapy, and monoclonal antibody therapy. This paper describes each of these strategies and discusses some of the associated successes and limitations. Emphasis is placed on the integration of techniques to promote optimal scenarios for eliminating cancer.


Assuntos
Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Citocinas/administração & dosagem , Citocinas/imunologia , Células Dendríticas/imunologia , Cães , Humanos , Camundongos
12.
Surg Neurol Int ; 12010 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-20847921

RESUMO

BACKGROUND: A paucity of data exists concerning the prognostic usefulness of preoperative and postoperative imaging after resection of glioblastoma multiforme (GBM). This study aimed to connect outcome with imaging features of GBM. METHODS: Retrospective computer-assisted volumetric calculations quantified central necrotic (T0), gadolinium-enhanced (T1) and increased T2-weighted signal volumes (T2) in 70 patients with untreated GBM. Clinical and treatment data, including extent of resection (EOR), were obtained through chart review. T1 volume was used as a measure of solid tumor burden; and T2 volume, as an indicator of invasive isolated tumor cell (ITC) burden. Indicators of invasiveness included T2:T1 ratios as a propensity for ITC infiltration compared to solid tumor volumes and qualitative analysis of subependymal growth and infiltration of the basal ganglia, corpus callosum or brainstem. Cox multivariate analysis (CMVA) was used to identify significant associations between imaging features and survival. RESULTS: In the 70 patients studied, significant associations with reduced survival existed for gadolinium-enhancing tumor crossing the corpus callosum (odds ratio, 3.14) and with increased survival with gross total resection (GTR) (GTR median survival, 62 weeks versus 37 and 34 weeks for sub-total resection and biopsy, respectively). For a selected "GTR-eligible" subgroup of 52 patients, prolonged survival was associated with smaller preoperative gadolinium-enhancing volume (T1) and actual GTR. CONCLUSION: Some magnetic resonance (MR) imaging indicators of tumor invasiveness (gadolinium-enhancing tumor crossing the corpus callosum) and tumor burden (GTR and preoperative T1 volume in GTR-eligible subgroup) correlate with survival. However, ITC-infiltrative tumor burden (T2 volume) and "propensity" for ITC invasiveness (T2:T1 ratio) did not impact survival. These results indicate that while the ITC component is the ultimate barrier to cure for GBM, the pattern of spread and volumes of gadolinium-enhancing solid tumor are more robust indicators of prognosis.

13.
Cryobiology ; 61(2): 211-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20654608

RESUMO

Medaka Oryzias latipes is a well-recognized biomedical fish model because of advantageous features such as small body size, transparency of embryos, and established techniques for gene knockout and modification. The goal of this study was to evaluate two critical factors, cryoprotectant and cooling rate, for sperm cryopreservation in 0.25-ml French straws. The objectives were to: (1) evaluate the acute toxicity of methanol, 2-methoxyethanol (ME), dimethyl sulfoxide (Me(2)SO), N,N-dimethylacetamide (DMA), N,N-dimethyl formamide (DMF), and glycerol with concentrations of 5%, 10%, and 15% for 60min of incubation at 4°C; (2) evaluate cooling rates from 5 to 25°C/min for freezing and their interaction with cryoprotectants, and (3) test fertility of thawed sperm cryopreserved with selected cryoprotectants and associated cooling rates. Evaluation of cryoprotectant toxicity showed that methanol and ME (5% and 10%) did not change the sperm motility after 30min; Me(2)SO, DMA, and DMF (10% and 15%) and glycerol (5%, 10% and 15%) significantly decreased the motility of sperm within 1min after mixing. Based on these results, methanol and ME were selected as cryoprotectants (10%) to evaluate with different cooling rates (from 5 to 25°C/min) and were compared to Me(2)SO and DMF (10%) (based on their use as cryoprotectants in previous publications). Post-thaw motility was affected by cryoprotectant, cooling rate, and their interaction (P⩽0.000). The highest post-thaw motility (50±10%) was observed at a cooling rate of 10°C/min with methanol as cryoprotectant. Comparable post-thaw motility (37±12%) was obtained at a cooling rate of 15°C/min with ME as cryoprotectant. With DMF, post-thaw motility at all cooling rates was ⩽10% which was significantly lower than that of methanol and ME. With Me(2)SO, post-thaw motilities were less than 1% at all cooling rates, and significantly lower compared to the other three cryoprotectants (P⩽0.000). When sperm from individual males were cryopreserved with 10% methanol at a cooling rate of 10°C/min and 10% ME with a rate of 15°C/min, no difference was found in post-thaw motility. Fertility testing of thawed sperm cryopreserved with 10% methanol at a rate of 10°C/min showed average hatching of 70±30% which was comparable to that of fresh sperm (86±15%). Overall, this study established a baseline for high-throughput sperm cryopreservation of medaka provides an outline for protocol standardization and use of automated processing equipment in the future.


Assuntos
Criopreservação/veterinária , Crioprotetores/farmacologia , Crioprotetores/toxicidade , Oryzias , Preservação do Sêmen/veterinária , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Acetamidas/farmacologia , Acetamidas/toxicidade , Animais , Temperatura Baixa , Criopreservação/métodos , Dimetil Sulfóxido/farmacologia , Dimetil Sulfóxido/toxicidade , Dimetilformamida/farmacologia , Dimetilformamida/toxicidade , Etilenoglicóis/farmacologia , Etilenoglicóis/toxicidade , Congelamento , Masculino , Metanol/farmacologia , Metanol/toxicidade , Preservação do Sêmen/métodos , Motilidade Espermática/efeitos dos fármacos , Temperatura Ambiente
14.
J Virol ; 84(19): 10121-30, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20668083

RESUMO

We examined properties of the innate immune response against the tumor-specific antigen simian virus 40 (SV40) large tumor antigen (Tag) following experimental pulmonary metastasis in naive mice. Approximately 14 days after mKSA tumor cell challenge, expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin-2 (IL-2), and RANTES was upregulated in splenocytes harvested from mice, as assessed by flow cytometry and antibody array assays. This response was hypothesized to activate and induce tumor-directed NK cell lysis since IL-2-stimulated NK cells mediated tumor cell destruction in vitro. The necessary function of NK cells was further validated in vivo through selected antibody depletion of NK cells, which resulted in an overwhelming lung tumor burden relative to that in animals receiving a control rabbit IgG depletion regimen. Interestingly, mice achieved increased protection from experimental pulmonary metastasis when NK cells were further activated indirectly through in vivo administration of poly(I:C), a Toll-like receptor 3 (TLR3) agonist. In a separate study, mice receiving treatments of poly(I:C) and recombinant SV40 Tag protein immunization mounted effective tumor immunity in an established experimental pulmonary metastasis setting. Initiating broad-based immunity with poly(I:C) was observed to induce a Th1 bias in the SV40 Tag antibody response that led to successful antitumor responses not observed in animals treated only with poly(I:C) or SV40 Tag. These data have direct implications for immunotherapeutic strategies incorporating methods to elicit inflammatory reactions, particularly NK cell-driven lysis, against malignant cell types that express a tumor-specific antigen such as SV40 Tag.


Assuntos
Antígenos Transformantes de Poliomavirus/imunologia , Imunidade Inata , Neoplasias Pulmonares/imunologia , Animais , Anticorpos Antineoplásicos/biossíntese , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Imunoterapia , Técnicas In Vitro , Interleucina-2/farmacologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Camundongos , Camundongos Endogâmicos BALB C , Poli I-C/farmacologia , Coelhos , Células Th1/imunologia , Receptores Toll-Like/metabolismo
15.
Mutat Res ; 688(1-2): 36-40, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20193694

RESUMO

Spermatozoa comprise a large and homogeneous population of cells that may serve as an alternative to resource-intensive assays of transmissible mutations based on progeny. To evaluate mutagenic responses in spermatozoa derived from germ cells exposed to a mutagen at different stages of spermatogenesis, we compared cII mutant frequencies (MFs) in spermatozoa collected from male lambda transgenic medaka exposed to ethylnitrosourea (ENU) as either post-meiotic or pre-meiotic germ cells. cII MFs in spermatozoa exposed to ENU as spermatogonial stem cells were induced significantly, 9-fold, compared to controls, whereas, cII MFs in spermatozoa exposed as spermatozoa/late spermatids were not elevated. To directly compare responses in spermatozoa with those in progeny, we analyzed cII MFs directly in spermatozoa and in the offspring produced from identical sperm samples of ENU-exposed males. cII MFs in isolated spermatozoa exposed to ENU as post-meiotic germ cells were not significantly elevated, whereas 11-30% of the progeny derived from the identically exposed germ cells exhibited significantly elevated cII MFs, approximately 2-fold to >130-fold, compared to controls. The contradictory responses between spermatozoa and progeny analyses can be attributed to induced pre-mutational lesions that remain intact in spermatozoa but were not detected as mutations. Progeny analyses, by contrast, revealed mutant individuals with elevated cII mutant frequencies because persistent DNA damage in the spermatozoa was fixed as mutations in cells of the early stage embryo. Spermatozoa exposed to a mutagen as spermatogonial stem cells can provide an efficient means to detect the portion of transmissible mutations that were fixed as mutations in spermatozoa. The caveat is that direct analyses of mutations in spermatozoa excludes the contribution of mutations that arise from post-fertilization processes in cells of early stage embryos, and therefore may underestimate the actual frequency of mutant offspring.


Assuntos
Análise Mutacional de DNA/métodos , Mutação em Linhagem Germinativa , Espermatozoides/ultraestrutura , Fatores de Transcrição/genética , Proteínas Virais/genética , Animais , Animais Geneticamente Modificados , Etilnitrosoureia , Estudos de Viabilidade , Masculino , Mutagênicos , Oryzias , Espermatogênese
17.
Comp Biochem Physiol C Toxicol Pharmacol ; 149(2): 152-60, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18929684

RESUMO

An accumulating body of research indicates there is an increased cancer risk associated with chronic infections. The genus Mycobacterium contains a number of species, including M. tuberculosis, which mount chronic infections and have been implicated in higher cancer risk. Several non-tuberculosis mycobacterial species, including M. marinum, are known to cause chronic infections in fish and like human tuberculosis, often go undetected. The elevated carcinogenic potential for fish colonies infected with Mycobacterium spp. could have far reaching implications because fish models are widely used to study human diseases. Japanese medaka (Oryzias latipes) is an established laboratory fish model for toxicology, mutagenesis, and carcinogenesis; and produces a chronic tuberculosis-like disease when infected by M. marinum. We examined the role that chronic mycobacterial infections play in cancer risk for medaka. Experimental M. marinum infections of medaka alone did not increase the mutational loads or proliferative lesion incidence in all tissues examined. However, we showed that chronic M. marinum infections increased hepatocellular proliferative lesions in fish also exposed to low doses of the mutagen benzo[a]pyrene. These results indicate that chronic mycobacterial infections of medaka are acting as tumor promoters and thereby suggest increased human risks for cancer promotion in human populations burdened with chronic tuberculosis infections.


Assuntos
Carcinoma Hepatocelular/microbiologia , Neoplasias Hepáticas Experimentais/microbiologia , Infecções por Micobactéria não Tuberculosa/microbiologia , Mycobacterium marinum/metabolismo , Oryzias , Adenoma/induzido quimicamente , Adenoma/microbiologia , Adenoma/patologia , Animais , Animais Geneticamente Modificados , Benzo(a)pireno/toxicidade , Carcinógenos/toxicidade , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Doença Crônica , Relação Dose-Resposta a Droga , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Testes de Mutagenicidade , Oryzias/genética , Oryzias/microbiologia
18.
Comp Biochem Physiol C Toxicol Pharmacol ; 149(2): 141-51, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18722551

RESUMO

Recent changes in the risk assessment landscape underscore the need to be able to compare the results of toxicity and dose-response testing between a growing list of animal models and, quite possibly, an array of in vitro screening assays. How do we compare test results for a given compound between vastly different species? For example, what dose level in the ambient water of a small fish model would be equivalent to 10 ppm of a given compound in the rat's drinking water? Where do we begin? To initially address these questions, and in order to compare dose-response tests in a standard rodent model with a fish model, we used the concept of molecular dose. Assays that quantify types of DNA damage that are directly relevant to carcinogenesis integrate the factors such as chemical exposure, uptake, distribution, metabolism, etc. that tend to vary so widely between different phyletic levels. We performed parallel exposures in F344 rats and Japanese medaka (Oryzias latipes) to the alkylating hepatocarcinogen, dimethylnitrosamine (DMN). In both models, we measured the DNA adducts 8-hydroxyguanine, N(7)-methylguanine and O(6)-methylguanine in the liver; mutation frequency using lambda cII transgenic medaka and lambda cII transgenic (Big Blue(R)) rats; and early morphological changes in the livers of both models using histopathology and immunohistochemistry. Pulse dose levels in fish were 0, 10, 25, 50, or 100 ppm DMN in the ambient water for 14 days. Since rats are reported to be especially sensitive to DMN, they received 0, 0.1, 1, 5, 10, or 25 ppm DMN in the drinking water for the same time period. While liver DNA adduct concentrations were similar in magnitude, mutant frequencies in the DMN-exposed medaka were up to 20 times higher than in the Big Blue rats. Future work with other compounds will generate a more complete picture of comparative dose response between different phyletic levels and will help guide risk assessors using "alternative" models.


Assuntos
Carcinógenos/toxicidade , Dimetilnitrosamina/toxicidade , Modelos Biológicos , Oryzias/genética , Animais , Animais Geneticamente Modificados , Carcinógenos/metabolismo , Carcinógenos/farmacologia , DNA/genética , DNA/isolamento & purificação , Adutos de DNA/análise , Adutos de DNA/metabolismo , Dimetilnitrosamina/metabolismo , Dimetilnitrosamina/farmacologia , Relação Dose-Resposta a Droga , Guanina/análogos & derivados , Guanina/análise , Guanina/metabolismo , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Testes de Mutagenicidade , Mutação , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos , Medição de Risco , Abastecimento de Água
19.
Exp Biol Med (Maywood) ; 233(8): 958-67, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18480423

RESUMO

Telomerase plays a primary role in the maintenance of telomeres in immortal, germ, and tumor cells in humans but is lacking in most somatic cells and tissues. However, many species, including fish and inbred mice, express telomerase in most cells and tissues. Little is known about the expression of telomerase in aquatic species, although the importance of telomerase for longevity has been suggested. We compared telomerase activity and telomere lengths among a broad range of tissues from aquatic species and found telomerase at significant levels in both long- and short-lived aquatic species, suggesting constitutive telomerase expression has an alternative function. Telomere lengths in these aquatic species were comparable to those observed in normal human tissues and cell strains. Given that a host of aquatic species with short life spans have telomerase and a tremendous capacity to regenerate, we tested the hypothesis that telomerase upregulation is important for tissue regeneration. During regeneration, telomerase activity was upregulated and telomere lengths are maintained with the shortest telomeres being elongated, indicating the importance for maintaining telomere length and integrity during tissue regeneration. Thus, the expression of telomerase in aquatic animals is likely not related to longevity but to their ability to regenerate injured tissue.


Assuntos
Peixes/fisiologia , Regeneração/fisiologia , Telomerase/metabolismo , Animais , Sequência de Bases , Feminino , Peixes/genética , Fundulidae/genética , Fundulidae/fisiologia , Longevidade/genética , Longevidade/fisiologia , Masculino , Oryzias/genética , Oryzias/fisiologia , Regeneração/genética , Telômero/genética , Telômero/metabolismo , Distribuição Tecidual , Regulação para Cima , Peixe-Zebra/genética , Peixe-Zebra/fisiologia
20.
Aquat Toxicol ; 87(1): 60-7, 2008 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-18313153

RESUMO

Chromium is an increasing health concern for aquatic environments, however, the mechanism of chromium toxicity in aquatic species is yet unknown. We used a medaka (Oryzias latipes) fin cell line to investigate the cytotoxicity and genotoxicity of sodium chromate, a soluble form of hexavalent chromium. We used a clonogenic cytotoxicity assay to measure sodium chromate cytotoxicity, gamma-H2A.X immunofluoresence to measure DNA double-strand breaks, and chromosome damage to measure clastogenicity. We found that sodium chromate is cytotoxic to medaka fin cells, with toxicity increasing in a concentration-dependent manner. Treatments of 0.5, 1, 5, 10, 25, 50 and 100 microM sodium chromate caused 100, 103.5, 87.8, 77.5, 40.9, 15 and 2.7% survival, respectively, relative to the control. We visualized DNA double-strand breaks in medaka cells through the formation of gamma-H2A.X foci. Breaks could be detected at concentrations as low as 1 microM. We also found that sodium chromate induces chromosomal aberrations, causing chromatid lesions and exchanges that increase with concentration. Treatments of 0, 1, 5, 10 and 25 microM sodium chromate damaged 10.3, 17, 32.3, 43 and 51.6% of metaphases and induced 13, 23, 44, 69 and 118 total aberrations in 100 metaphases, respectively. These data show that hexavalent chromium is both cytotoxic and genotoxic to fish cells. Our results set the context for future work in the medaka cell culture model and provide important tools for investigating mechanisms of toxicity in aquatic organisms.


Assuntos
Cromatos/toxicidade , Oryzias/fisiologia , Compostos de Sódio/toxicidade , Ensaio Tumoral de Célula-Tronco , Poluentes Químicos da Água/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Relação Dose-Resposta a Droga
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