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1.
Clin Radiol ; 77(3): 188-194, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34916046

RESUMO

AIM: To evaluate utilisation of a medical imaging call centre (MICC) at a multi-site, academic radiology department, focusing on communication of critical, urgent, or significant unexpected findings. MATERIALS AND METHODS: Institutional research ethics board approval was obtained. All calls made to MICC from 1 January to 31 December 2019 were reviewed retrospectively. The total number of calls, date, and reason of each call, level of report alert, and turnaround time (TAT) were recorded. Level 1, 2, and 3 alerts were defined as "potentially life-threatening new/unexpected findings", "could result in morbidity/mortality", or "not immediately life-threatening or urgent", respectively. TAT was defined as the time from alert request received by the MICC until acknowledgement of receipt by the referring physician, with a desired TAT of 60 min, 3 h, and 3 days for each level, respectively. RESULTS: The MICC received 29,799 calls in 2019, on average 2,483 (range 1,989-3,098) calls per month. The most common indications for contacting the MICC were to request imaging reports to be expedited (14,916 calls, 50%) and issuing report alerts to communicate unexpected or urgent findings (7,060 calls, 24%). Average number and range of calls for Level 1, 2, and 3 alerts were 57 (39-80), 345 (307-388), and 187 (127-215) per month, respectively. Average TAT for Level 1, 2, and 3 report alerts were 59 min, 2 h 26 min, and 19 h 39 min, respectively. CONCLUSION: The MICC received a large volume of calls and was a successful method for timely communication of unexpected or urgent imaging findings using a three-tiered alert system.


Assuntos
Call Centers/estatística & dados numéricos , Comunicação , Diagnóstico por Imagem/estatística & dados numéricos , Radiologia/estatística & dados numéricos , Diagnóstico por Imagem/classificação , Emergências/classificação , Emergências/epidemiologia , Humanos , Enfermeiras e Enfermeiros/estatística & dados numéricos , Ontário , Radiologistas/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Tempo
2.
Orthopade ; 50(4): 326-332, 2021 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-32350550

RESUMO

A Thymic carcinoma in adults is rare. We present the case of a 47-year-old man, who was treated conservatively for spondylolisthesis L5/S1 in our institution for several years. In the further course, the patient complained about pain exacerbation with acute lower back pain. Cross-sectional scanning showed a tumor of the lumbar vertebral body three. A biopsy of this mass revealed a metastatic thymic carcinoma of the squamous cells. After palliative therapy, the patient died 9 months after initial diagnosis.


Assuntos
Fusão Vertebral , Espondilolistese , Timoma , Neoplasias do Timo , Adulto , Estudos Transversais , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Timoma/diagnóstico por imagem , Neoplasias do Timo/diagnóstico por imagem , Neoplasias do Timo/terapia
3.
J Virol ; 91(2)2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27807226

RESUMO

The retinoic acid-inducible gene 1 (RIG-I) signaling pathway is essential for the recognition of viruses and the initiation of host interferon (IFN)-mediated antiviral responses. Once activated, RIG-I interacts with polyubiquitin chains generated by TRIM25 and binds mitochondrial antiviral signaling protein (MAVS), leading to the production of type I IFN. We now show specific interactions among these key partners in the RLR pathway through the use of bimolecular fluorescence complementation (BiFC) and super-resolution microscopy. Dimers of RIG-I, TRIM25, and MAVS localize into different compartments. Upon activation, we show that TRIM25 is redistributed into cytoplasmic dots associated with stress granules, while RIG-I associates with TRIM25/stress granules and with mitochondrial MAVS. In addition, MAVS competes with TRIM25 for RIG-I binding, and this suggests that upon TRIM25-mediated activation of RIG-I, RIG-I moves away from TRIM25 to interact with MAVS at the mitochondria. For the first time, the distribution of these three proteins was analyzed at the same time in virus-infected cells. We also investigated how specific viral proteins modify some of the protein complexes in the pathway. The protease NS3/4A from hepatitis C virus redistributes the complexes RIG-I/MAVS and MAVS/MAVS but not RIG-I/TRIM25. In contrast, the influenza A virus NS1 protein interacts with RIG-I and TRIM25 in specific areas in the cell cytoplasm and inhibits the formation of TRIM25 homocomplexes but not the formation of RIG-I/TRIM25 heterocomplexes, preventing the formation of RIG-I/MAVS complexes. Thus, we have localized spatially in the cell different complexes formed between RIG-I, TRIM25, and MAVS, in the presence or absence of two viral IFN antagonistic proteins. IMPORTANCE: The first line of defense against viral infections is the innate immune response. Viruses are recognized by pathogen recognition receptors, such as the RIG-I like receptor family, that activate a signaling cascade that induces IFN production. In the present study, we visualized, for the first time in cells, both in overexpression and endogenous levels, complexes formed among key proteins involved in this innate immune signaling pathway. Through different techniques we were able to analyze how these proteins are distributed and reorganized spatially within the cell in order to transmit the signal, leading to an efficient antiviral state. In addition, this work presents a new means by how, when, and where viral proteins can target these pathways and act against the host immune system in order to counteract the activation of the immune response.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteína DEAD-box 58/metabolismo , Complexos Multiproteicos/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Linhagem Celular , Proteína DEAD-box 58/química , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Espaço Intracelular , Ligação Proteica , Multimerização Proteica , Transporte Proteico , Transdução de Sinais , Fatores de Transcrição/química , Proteínas com Motivo Tripartido/química , Ubiquitina-Proteína Ligases/química , Proteínas não Estruturais Virais/metabolismo
5.
Euro Surveill ; 18(8)2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23449231

RESUMO

On 24 October 2012, a patient with acute respiratory distress syndrome of unknown origin and symptom onset on 5 October was transferred from Qatar to a specialist lung clinic in Germany. Late diagnosis on 20 November of an infection with the novel Coronavirus (NCoV) resulted in potential exposure of a considerable number of healthcare workers. Using a questionnaire we asked 123 identified contacts (120 hospital and three out-of-hospital contacts) about exposure to the patient. Eighty-five contacts provided blood for a serological test using a two-stage approach with an initial immunofluorescence assay as screening test, followed by recombinant immunofluorescence assays and a NCoV-specific serum neutralisation test. Of 123 identified contacts nine had performed aerosol-generating procedures within the third or fourth week of illness, using personal protective equipment rarely or never, and two of these developed acute respiratory illness. Serology was negative for all nine. Further 76 hospital contacts also tested negative, including two sera initially reactive in the screening test. The contact investigation ruled out transmission to contacts after illness day 20. Our two-stage approach for serological testing may be used as a template for similar situations.


Assuntos
Busca de Comunicante , Infecções por Coronavirus/diagnóstico , Coronavirus/isolamento & purificação , Transmissão de Doença Infecciosa do Paciente para o Profissional/prevenção & controle , Síndrome do Desconforto Respiratório/etiologia , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Diagnóstico Tardio , Notificação de Doenças , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Alemanha , Pessoal de Saúde/estatística & dados numéricos , Humanos , Transmissão de Doença Infecciosa do Paciente para o Profissional/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Exposição Ocupacional , Catar , Reação em Cadeia da Polimerase em Tempo Real , Síndrome do Desconforto Respiratório/epidemiologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Inquéritos e Questionários , Viagem , Resultado do Tratamento
6.
Euro Surveill ; 17(49)2012 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-23231891

RESUMO

We present a rigorously validated and highly sensitive confirmatory real-time RT-PCR assay (1A assay) that can be used in combination with the previously reported upE assay. Two additional RT-PCR assays for sequencing are described, targeting the RdRp gene (RdRpSeq assay) and N gene (NSeq assay), where an insertion/deletion polymorphism might exist among different hCoV-EMC strains. Finally, a simplified and biologically safe protocol for detection of antibody response by immunofluorescence microscopy was developed using convalescent patient serum.


Assuntos
Infecções por Coronavirus/diagnóstico , Coronavirus/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Coronavirus/classificação , Coronavirus/genética , Infecções por Coronavirus/virologia , Imunofluorescência , Alemanha , Humanos , Laboratórios/normas , Polimorfismo de Fragmento de Restrição , RNA Viral/sangue , RNA Viral/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Virologia/métodos
7.
Nat Cell Biol ; 3(3): 301-5, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11231581

RESUMO

Influenza A viruses are important worldwide pathogens in humans and different animal species. The functions of most of the ten different viral proteins of this negative-strand RNA virus have been well elucidated. However, little is known about the virus-induced intracellular signalling events that support viral replication. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation and survival. Investigation of the function of this pathway has been facilitated by the identification of specific inhibitors such as U0126, which blocks the cascade at the level of MAPK/ERK kinase (MEK). Here we show that infection of cells with influenza A virus leads to biphasic activation of the Raf/MEK/ERK cascade. Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production. Thus, signalling through the mitogenic cascade seems to be essential for virus production and RNP export from the nucleus during the viral life cycle.


Assuntos
Butadienos/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A/fisiologia , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Nitrilas/farmacologia , Transporte Ativo do Núcleo Celular , Animais , Western Blotting , Linhagem Celular , Genes Reporter , Humanos , Imuno-Histoquímica , Vírus da Influenza A/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Microscopia Confocal , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Fosforilação , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Ribonucleoproteínas/metabolismo , Transfecção , Proteínas Virais/metabolismo , Replicação Viral
8.
Forensic Sci Int ; 320: 110713, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33578178

RESUMO

People will deposit, redistribute and remove biological traces when they interact with their environment. Understanding the dynamics of trace DNA is crucial to assess both the optimal sampling strategy to recover traces and the relevance of DNA evidence in the context of a case. This paper addresses the prevalence of DNA of drivers, passengers, and unknown individuals in vehicles. Five vehicles with a regular driver only, and five vehicles with a regular driver and regular passenger have each been sampled at twenty locations. Based on the findings, we propose a sampling strategy for investigative purposes as well as for evaluative purposes when evaluating the findings given scenarios that propose the person-of-interest as either the driver or passenger in a vehicle.


Assuntos
DNA/análise , Veículos Automotores , Condução de Veículo , Impressões Digitais de DNA , Humanos , Prevalência , Manejo de Espécimes
9.
Psychopharmacology (Berl) ; 237(10): 3161-3171, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32700023

RESUMO

Ayahuasca is a psychoactive plant brew containing dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). It originates from the Amazon basin, where it is used primarily for ceremonial purposes. Ayahuasca tourists are now entering certain communities seeking alternative physical or psychological healing, as well as spiritual growth. RATIONALE: Recent evidence has shown that the similar acting psychedelic compound, psilocybin, facilitated long-term increases in trait openness following a single administration. OBJECTIVES: This paper assesses the impact of ayahuasca on personality in a traditional framework catering for ayahuasca tourists. METHOD: Within a mixed design, we examined the effect of ayahuasca on participants' personality (measured by the NEO Personality Inventory 3 questionnaire) across time (pre- to post-ayahuasca administration, and 6-month follow-up), relative to a comparison group (who did not ingest ayahuasca). RESULTS: The results demonstrated significant increases in agreeableness pre- and post-ayahuasca administration and significant reductions in neuroticism in 24 participants, relative to the comparison group. Both of these changes were sustained at 6-month follow-up, and trait level increases were also observed in openness at this stage. Additionally, greater perceived mystical experience (measured using the Mystical Experience Questionnaire 30) was associated with increased reductions in neuroticism. CONCLUSIONS: These findings, which indicate a positive mediating effect of ayahuasca on personality, support the growing literature suggesting potential therapeutic avenues for serotonergic psychedelics.


Assuntos
Banisteriopsis , Alucinógenos/farmacologia , Turismo Médico/psicologia , Neuroticismo/efeitos dos fármacos , Personalidade/efeitos dos fármacos , Extratos Vegetais/farmacologia , Adulto , Banisteriopsis/química , Feminino , Seguimentos , Alucinógenos/isolamento & purificação , Humanos , Masculino , Turismo Médico/tendências , Inibidores da Monoaminoxidase/isolamento & purificação , Inibidores da Monoaminoxidase/farmacologia , Misticismo/psicologia , N,N-Dimetiltriptamina/isolamento & purificação , N,N-Dimetiltriptamina/farmacologia , Neuroticismo/fisiologia , Personalidade/fisiologia , Peru/epidemiologia , Extratos Vegetais/isolamento & purificação , Psilocibina/isolamento & purificação , Psilocibina/farmacologia , Inquéritos e Questionários
10.
Vasa ; 38(2): 190-2, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19588310

RESUMO

INTRODUCTION: Percutaneous left ventricular assist devices are an important tool in the management of patients with severe cardiogenic shock. Limited experiences concerning vascular complications after long term implantation of these devices exist. We report on a large arteriovenous fistula after placement of a left ventricular assist device, which has not been described in the literature. The arteriovenous fistula was of clinical relevance because it represented a supplementary cardiac burden in a patient with impaired left ventricular function after a severe myocardial infarction.


Assuntos
Fístula Arteriovenosa/cirurgia , Artéria Femoral/cirurgia , Virilha/irrigação sanguínea , Coração Auxiliar , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Complicações Pós-Operatórias/cirurgia , Choque Cardiogênico/cirurgia , Angioplastia Coronária com Balão , Fístula Arteriovenosa/diagnóstico por imagem , Velocidade do Fluxo Sanguíneo/fisiologia , Remoção de Dispositivo , Feminino , Artéria Femoral/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Complicações Pós-Operatórias/diagnóstico por imagem , Reoperação , Choque Cardiogênico/diagnóstico por imagem , Stents , Ultrassonografia Doppler Dupla , Veias/diagnóstico por imagem , Veias/cirurgia
11.
Parasit Vectors ; 12(1): 369, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349867

RESUMO

BACKGROUND: The efficacy of an extended-release injectable moxidectin (0.5 mg/kg) suspension (ProHeart® 12) (PH 12) in preventing the development of Dirofilaria immitis in dogs for 12 months was investigated in laboratory and field studies in the USA. METHODS: In each of two laboratory studies, 20 dogs ≥ 12 months of age were randomly allocated to receive a subcutaneous injection of saline or PH 12 on Day 0 and were then inoculated with 50 D. immitis third-stage larvae (L3) on Day 365. All dogs were necropsied ~ 5 months post-inoculation for adult worm counts. The field efficacy study included dogs ≥ 10 months of age from 19 veterinary clinics in the USA treated with either 20 monthly doses of Heartgard® Plus (HG Plus) (296 dogs) or two doses of PH 12 (297 dogs) on Days 0 and 365. Efficacy was determined on Days 365, 480 and 605 using adult HW antigen and microfilaria testing to assess adult HW infection. RESULTS: PH 12 was 100% effective in preventing HW disease in all three of these studies. In the laboratory studies, no PH 12-treated dogs had any adult HWs, whereas all control dogs in both studies had adult HWs [geometric mean, 30.2 (range, 22-37) for Study 1 and 32.6 (22-44) for Study 2]. In the field study, all dogs treated with PH 12 tested negative for adult HW infection on all test days (Days, 365, 480 and 605), whereas four dogs receiving HG Plus (positive control) tested positive for HWs during the study (three dogs on Day 365 and one dog on Day 480). All four dogs treated with HG Plus that subsequently tested positive for HWs during the field study were from the lower Mississippi River Valley region, where HW resistance to macrocyclic lactone preventives has been confirmed to occur. PH 12 was significantly better than HG Plus in preventing heartworm disease in the field study (P = 0.0367). PH 12 was well-tolerated in both laboratory and field studies. CONCLUSIONS: A single dose of ProHeart® 12 was 100% effective in preventing heartworm disease in dogs for a full year in both laboratory and field studies.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Filaricidas/administração & dosagem , Macrolídeos/administração & dosagem , Animais , Preparações de Ação Retardada/administração & dosagem , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Feminino , Hospitais Veterinários/estatística & dados numéricos , Injeções Subcutâneas , Masculino , Distribuição Aleatória , Estados Unidos
12.
J Bone Joint Surg Am ; 100(17): 1448-1454, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30180052

RESUMO

BACKGROUND: Guidelines recommend both histological analysis and culture for definite diagnosis of osteomyelitis. It is not clear if histological and culture criteria can be used interchangeably in the clinical scenario of toe amputation. We therefore prospectively compared the results of intraoperative culture and those of histological examination in this setting. METHODS: Consecutive patients requiring toe or forefoot amputation at the University Hospital Basel during a 2-year period were included in the study. Biopsy specimens from the residual bone were cultured according to microbiological standards. Histological analysis was performed using standardized criteria for osteomyelitis. Clinical outcomes were assessed retrospectively via chart review. RESULTS: Of 51 patients included in the study, 33 (65%) had a positive culture of residual bone and 14 (27%) showed histological signs of osteomyelitis. A negative histological result but a positive culture was found for 21 (41%) of the patients, suggesting that culture has a high false-positive rate if histological analysis is used as the reference to rule out osteomyelitis. The recommended criteria of both positive histological findings and positive culture were fulfilled by 12 (24%) of the 51 patients. CONCLUSIONS: Positive cultures of residual bone after forefoot or toe amputation overestimate the true rate of osteomyelitis as defined by histological analysis, presumably because of contamination from soft tissue at the time of surgery. Additional studies are needed to evaluate the indications for, and the duration of, antibiotic treatment according to these findings. CLINICAL RELEVANCE: Our results cast doubt on the strategy of relying solely on culture of bone biopsy specimens when deciding whether antibiotic treatment for osteomyelitis is necessary after toe or forefoot amputation.


Assuntos
Amputação Cirúrgica , Antepé Humano/patologia , Osteomielite/patologia , Idoso , Antibacterianos/uso terapêutico , Infecções Bacterianas/patologia , Células Cultivadas , Feminino , Ossos do Pé/patologia , Ossos do Pé/cirurgia , Antepé Humano/cirurgia , Humanos , Masculino , Cuidados Pós-Operatórios , Estudos Prospectivos , Infecção da Ferida Cirúrgica/patologia , Dedos do Pé/patologia , Dedos do Pé/cirurgia
13.
Mol Cell Biol ; 11(4): 2026-34, 1991 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1826044

RESUMO

Spliceosomal U6 small nuclear RNA (snRNA) plays a central role in the pre-mRNA splicing mechanism and is highly conserved throughout evolution. Previously, a sequence element essential for both capping and cytoplasmic-nuclear transport of U6 snRNA was mapped in the 5'-terminal domain of U6 snRNA. We have identified a protein in cytoplasmic extracts of mammalian and Trypanosoma brucei cells that binds specifically to this U6 snRNA element. Competition studies with mutant and heterologous RNAs demonstrated the conserved binding specificity of the mammalian and trypanosomal proteins. The in vitro capping analysis of mutant U6 snRNAs indicated that protein binding is required but not sufficient for capping of U6 snRNA by a gamma-monomethyl phosphate. Through RNA affinity purification of mammalian small nuclear ribonucleoproteins (snRNPs), we detected this protein also in nuclear extract as a new specific component of the U6 snRNP but surprisingly not of the U4/U6 or the U4/U5/U6 multi-snRNP. These results suggest that the U6-specific protein is involved in U6 snRNA maturation and transport and may therefore be functionally related to the Sm proteins of the other spliceosomal snRNPs.


Assuntos
Splicing de RNA , RNA Nuclear Pequeno/metabolismo , Ribonucleoproteínas/genética , Animais , Sequência de Bases , Ligação Competitiva , Células HeLa , Humanos , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Ligação Proteica , Capuzes de RNA/metabolismo , RNA Nuclear Pequeno/genética , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas Nucleares Pequenas , Especificidade por Substrato , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/metabolismo
14.
Transplant Proc ; 39(5): 1381-5, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17580144

RESUMO

UNLABELLED: We retrospectively compared perioperative donor outcomes and early complication rate of right- and left-sided retroperitoneoscopic living donor nephrectomy (RLDN). METHODS: From November 2001 to April 2006, we performed 118 RLDN. Including 24% (n = 28) right-sided RLDN and 76% (n = 90) left-sided RLDN. Perioperative results and the rate of adverse events were compared for both sides. RESULTS: We observed no significant difference in operation time, blood loss, warm ischemia time, or postoperative creatinine levels between right- and left-sided kidney donors. RLDN was successfully performed in 116 of 118 donors. One donor in each group had to be converted to an open approach. We observed one graft loss due to renal artery kinking in one recipient after left-sided RLDN. Two right donations needed a saphenous venous patch due to a short right renal vein (<2 cm). Overall, intraoperative and postoperative complications were comparable between the two donor groups. CONCLUSION: Right-sided RLDN provides comparable perioperative and postoperative results to those of left-sided RLDN. Our results demonstrated that groups with significant experience in RLDN can perform right living donor nephrectomy safely and efficiently with minimal invasiveness.


Assuntos
Doadores Vivos , Nefrectomia/métodos , Espaço Retroperitoneal/cirurgia , Adulto , Idoso , Perda Sanguínea Cirúrgica , Feminino , Lateralidade Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Nefrectomia/efeitos adversos , Nefrectomia/psicologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Coleta de Tecidos e Órgãos/efeitos adversos , Coleta de Tecidos e Órgãos/métodos
15.
Mutat Res ; 595(1-2): 167-73, 2006 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-16375931

RESUMO

In an attempt to examine the interaction of man-made mineral fibres with benzo[a]pyrene (B[a]P), homozygous X-lacI transgenic F344 rats were intratracheally treated with rock (stone) wool RWI and glass wool MMVF 10 fibres together with B[a]P. To analyze the induction of gene mutations by fibres and B[a]P in lung, single doses of 1 and 2 mg fibres/animal or multiple doses of 2 mg fibres/animal were administered weekly on 4 consecutive weeks (total dose 8 mg/animal). B[a]P (10 mg/animal) was administered either simultaneously with fibres (for single dose treatment with fibres) or together with the last fiber treatment (for multiple dose treatment with fibres). Animals were scarified 4 weeks after the last treatment. Benzo[a]pyrene administered simultaneously with RW1 fibres exhibited a strong synergistic effect on mutagenicity, the observed mutant frequency (MF) being more than three-fold higher than the net sum of the MF induced after separate administration of both agents. Our data suggest that DNA adducts induced by simultaneous B[a]P and fiber treatment lead to a strong increase in mutatant frequencies.


Assuntos
Bacteriófago lambda/genética , Benzo(a)pireno/farmacologia , Óperon Lac/genética , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Fibras Minerais/efeitos adversos , Mutagênese/efeitos dos fármacos , Animais , Animais Geneticamente Modificados , Amianto/toxicidade , Adutos de DNA/genética , Malondialdeído/metabolismo , Mutagênese/genética , Mutação/genética , Estresse Oxidativo , Ratos , Ratos Endogâmicos F344
16.
Mutat Res ; 595(1-2): 174-83, 2006 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-16364376

RESUMO

The potential of two asbestos substitute mineral fibres--rock (stone) wool RW1 and glass wool MMVF10--to induce gene mutations, DNA strand breaks, inflammation and oxidative stress has been studied in rats. Male homozygous lamda-lacI transgenic F344 rats were intratracheally instilled with single doses of 1 and 2 mg/animal of fibres or with multiple doses of 2 mg/animal administered weekly on four consecutive weeks (8 mg in total). Exposure to RW1 fibres for 16 weeks significantly increased mutant frequency (MF) in the lung in a dose-dependent manner, while MMVF10 fibres did not exhibit any increase of MF at any dose. RW1 fibres gave a significant increase of MF at a dose of 1 mg. Four weeks after instillation, neither the single nor the multiple doses significantly increased MF for both fibre types. To investigate mechanisms for induction of mutations, other genotoxicity markers and parameters of inflammatory and oxidative damage were determined in relation to MF. A weak correlation of mutagenicity data with other genotoxicity parameters studied was observed. DNA strand breaks as measured by comet assay were increased in alveolar macrophages and lung epithelial cells of RW1 and MMVF10 treated rats. RWl fibres caused more extensive lung inflammation as measured by release of neutrophils into broncho-alveolar lavage fluid than MMVF10 fibres. The effects were observed 16 weeks post-exposure, indicating a persistence of the pathogenic process during the exposure period. Only minor differences in the extent of inflammatory processes were observed between the doses of 2 mg and 4 x 2 mg, suggesting that any threshold for inflammation lies below the dose of 2 mg. With the exception of the highest dose of MMVF10 fibres after 16 weeks of exposure, no significant increase of oxidative damage as measured by levels of malondialdehyde in lung tissue was observed. MMVF10 fibres caused weaker inflammation in the lung of rats and did not exhibit any mutagenic effect. We conclude that a weak but chronic inflammation (more likely than acute inflammation or direct oxidative damage) in the lung tissue of fibre treated rats characterized by moderate influx of inflammatory cells into BAL is probably responsible for the observed mutagenic effect of RW1 fibres.


Assuntos
Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Fibras Minerais/efeitos adversos , Mutagênese/efeitos dos fármacos , Animais , Amianto/farmacologia , Amianto/toxicidade , Biomarcadores , Lavagem Broncoalveolar , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Malondialdeído/metabolismo , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo , Ratos , Ratos Endogâmicos F344 , Fator de Necrose Tumoral alfa/metabolismo
17.
Cancer Res ; 56(19): 4391-7, 1996 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-8813132

RESUMO

The antiandrogenic and gestagenic steroid cyproterone acetate (CPA) has been widely used in human therapy. There is currently a debate about the safety of CPA, since it proved to be genotoxic in rat liver and human hepatocytes [I. Neumann et al., Carcinogenesis (Lond.), 13: 373-378, 1992, J. Topinka et al., Carcinogenesis (Lond.), 14: 423-427, 1993, L. R. Schwarz et al., Biological Reactive Intermediates: V. Basic Mechanistic Research in Toxicology and Human Risk Assessment. pp. 243-251, 1996; A. Martelli et al., Carcinogenesis (Lond.), 16: 1265-1269, 1995]. Little is known about the metabolic pathways of activation of CPA to genotoxic metabolites. Using rat hepatocytes and subcellular fractions of female rat liver, we have examined whether sulfoconjugation plays an essential role in the activation of CPA to DNA-binding metabolites which are detectable with 32P-postlabeling. Incubation of hepatocyte cultures with 30 microM CPA for 6 h caused the formation of several DNA adducts; the total adduct level amounted to about 12,400 adducts/10(9) nucleotides. When the cells were incubated in sulfate-free medium to prevent the synthesis of the cosubstrate of sulfonation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), formation of all CPA-DNA adducts was greatly reduced, amounting to only 5% of that determined in the presence of sulfate (810 microM). Activation of CPA is likely to be catalyzed by hydroxysteroid sulfotransferase(s), because the specific substrate dehydroepiandrosterone almost completely inhibited DNA-binding of CPA. Our assumption that sulfonation plays a decisive role in the bioactivation of CPA is further supported by the results obtained with an in vitro system consisting of calf thymus DNA, various subcellular liver fractions, and the cofactor PAPS, NADPH, or NADH. Significant DNA binding only occurred when cytosol and both PAPS and the reduced pyridine nucleotides were present. The DNA adduct spot obtained was chromatographically identical to the adduct spot A detected in isolated liver cells, suggesting that the CPA-DNA adduct formed in vivo and in vitro is identical. Cytosol is known to contain not only sulfotransferases but also reductases. Thus, the requirement for NADPH or NADH suggests that in addition to sulfotransferase(s), reductases are involved in the activation of CPA. We propose that bioactivation of CPA involves reduction of the keto group at C-3 followed by sulfonation of the hydroxysteroid. The resulting sulfoconjugate is most likely unstable and supposed to generate a reactive carbonium ion.


Assuntos
Acetato de Ciproterona/farmacocinética , Adutos de DNA/análise , DNA/metabolismo , Pró-Fármacos/farmacocinética , Animais , Biotransformação , Acetato de Ciproterona/toxicidade , Citosol/metabolismo , Feminino , Fígado/metabolismo , Masculino , NAD/metabolismo , NADP/metabolismo , Oxirredutases/metabolismo , Pró-Fármacos/toxicidade , Ratos , Ratos Wistar , Sulfotransferases/metabolismo
18.
Cancer Res ; 45(5): 2116-22, 1985 May.
Artigo em Inglês | MEDLINE | ID: mdl-3921236

RESUMO

A significant population of humans (5 to 10%) are phenotypic poor metabolizers of debrisoquine. We have isolated the cytochrome P-450 isozyme from rat liver responsible for this activity and have shown that antibodies raised against the protein are able to inhibit this catalytic activity in human liver microsomes (Distlerath, L. M., and Guengerich, F. P., Proc. Natl. Acad. Sci. USA, 81: 7348-7352, 1984). These antibodies were utilized to determine which metabolic transformations are linked to debrisoquine 4-hydroxylation in human liver microsomes using techniques of immunochemical inhibition. The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1'-hydroxylation in microsomes prepared from several different human livers. The oxidation of the pyrrolizidine alkaloids lasiocarpine and monocrotaline were inhibited by roughly one-third. The antibodies did not inhibit N,N-dimethylnitrosamine N-demethylation, oxidation of vinylidene chloride to 2,2-chloroacetaldehyde, oxidation of trichloroethylene to chloral, N-oxidation of azoprocarbazine, morphine N-demethylation, diazepam N-demethylation, oxidation of benzo(a)pyrene to alkali-soluble metabolites, oxidation of benzo(a)pyrene 7,8-dihydrodiol to products covalently bound to DNA, the N- and ring-oxidation of 1- and 2-naphthylamine and 2-aminofluorene, or the conversion of aflatoxin B1 to DNA adducts or aflatoxin Q1. Studies with space-filling models of the drugs the metabolism of which is associated with debrisoquine 4-hydroxylase in the literature indicated that all can be fitted to a general structure in which a basic nitrogen is about 5 A away from the site of carbon hydroxylation and a hydrophobic domain is near the site of hydroxylation. These results may be useful in predicting which chemicals may or may not be metabolized in an atypical manner by a segment of the human population.


Assuntos
Sistema Enzimático do Citocromo P-450/análise , Fígado/enzimologia , Oxigenases de Função Mista/análise , Aflatoxina B1 , Aflatoxinas/metabolismo , Citocromo P-450 CYP2D6 , Sistema Enzimático do Citocromo P-450/imunologia , Debrisoquina/metabolismo , Humanos , Hidroxilação , Imunoquímica , Microssomos Hepáticos/enzimologia , Especificidade por Substrato
19.
Biochim Biophys Acta ; 1263(1): 39-44, 1995 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-7632731

RESUMO

U6 RNA undergoes several conformational transitions during the spliceosome cycle: after the interaction with U4, the singular form of U6 is converted into the U4-U6 base-paired form, and within the spliceosome, the U4-U6 duplex isomerizes into the active U6-U2 conformation. The secondary structure of the singular form contains an extended 3' stem-loop, the upper part of which (intramolecular helix) most likely reforms in the spliceosome. We have previously shown in the mammalian splicing complementation system that the loop and the three adjacent, highly conserved base pairs of the intramolecular helix function during both the U4-U6 interaction and the first step of splicing. Here we demonstrate that the balanced stability of the lower, less conserved part of the 3' stem-loop is also critical for U4-U6 interaction; however, no specific splicing function could be detected in this region. The analysis of the heterologous interaction between mammalian U4 snRNP and yeast U6 RNA derivatives suggests that there are--in addition to the 3' loop and the stability of the intramolecular helix--specific sequence determinants in the 3' terminal domain of U6 that are important for efficient U4/U6 snRNP assembly.


Assuntos
RNA Nuclear Pequeno/genética , Spliceossomos/genética , Composição de Bases , Sequência de Bases , Humanos , Dados de Sequência Molecular , Mutação Puntual , Reação em Cadeia da Polimerase , Splicing de RNA , RNA Nuclear Pequeno/metabolismo , Ribonucleoproteína Nuclear Pequena U4-U6/biossíntese , Saccharomyces cerevisiae/genética
20.
Transplant Proc ; 37(2): 609-12, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15848473

RESUMO

INTRODUCTION: We retrospectively compared perioperative donor outcomes and early postoperative pain control after retroperitoneoscopic (RLDN) and standard open (OLDN) living donor nephrectomy. METHODS: One hundred donors included fifty after RLDN (37 women/13 men) and 50 after OLDN (35 women/15 men) were retrospectively analyzed for basic analgesics, for opioid consumption, and for visual analog scale (VAS) to verify the experienced pain. The donors were questioned in the morning and evening of the first through fifth postoperative days. RESULTS: The mean age of both groups was equal. The mean operating time was 149.7 +/- 48.2 minutes (60 to 270) for RLDN and 164.1 +/- 30.3 minutes (60 to 240) for OLDN (P = NS). The mean warm ischemia time was 120 +/- 36 seconds (50 to 240) and 114 +/- 31 seconds (60 to 190) for the RLDN and OLDN groups, respectively (P = NS). The mean evening VAS for RLDN versus OLDN on postoperative days 1 to 5 was: 2.1 versus 2.2 (P = NS), 0.9 versus 1.8 (P = .009), 0.5 versus 1.3 (P = .016), 0.1 versus 0.7 (P = .013), and 0.1 versus 0.7 (P = .013), respectively. In both groups there was a tendency toward a higher VAS score in the morning than in the evening. RLDN donors showed significantly earlier period free of pain (VAS = 0) than those after OLDN. There was a significant difference of being free from any opiate between both groups after surgery. CONCLUSIONS: After RLDN donors experienced less postoperative pain than after OLDN over the early postoperative days. Therefore, postoperative regional anesthesia is not necessary for donors operated by a retroperitoneoscopic approach.


Assuntos
Doadores Vivos , Nefrectomia/métodos , Coleta de Tecidos e Órgãos/métodos , Adulto , Idoso , Analgésicos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Espaço Retroperitoneal , Estudos Retrospectivos
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