RESUMO
Proliferation of smooth muscle cells of the arterial wall in response to local injury is an important aetiologic factor of vascular proliferative disorders such as atherosclerosis and restenosis after angioplasty. Ras proteins are key transducers of mitogenic signals from membrane to nucleus in many cell types. We investigated the role of ras proteins in the vascular response to arterial injury by inactivating cellular ras of rats in which the common carotid artery was subjected to balloon injury. DNA vectors expressing ras transdominant negative mutants, which interfere with ras function, reduced neointimal formation after injury. Our results indicate a key role for ras in smooth muscle cell proliferation and show that the local delivery of transdominant negative mutants of ras in vivo might prevent some of the acute vascular injury caused by balloon injury.
Assuntos
Genes ras , Terapia Genética , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Lesões das Artérias Carótidas , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/patologia , Cateterismo/efeitos adversos , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , DNA Recombinante/genética , DNA Recombinante/uso terapêutico , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-raf , Proteínas Proto-Oncogênicas p21(ras)/genética , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão , TransfecçãoRESUMO
Injury of the arterial wall induces the formation of the neointima. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.
Assuntos
Divisão Celular , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Músculo Liso Vascular/citologia , Transdução de Sinais , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Aminofilina/farmacologia , Amrinona/farmacologia , Animais , Artérias Carótidas , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Ativação Enzimática , Inibidores do Crescimento/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/lesões , Músculo Liso Vascular/metabolismo , Inibidores de Fosfodiesterase/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Here we describe the cloning and expression pattern of Ci-isl, a homologue of vertebrate genes, in the ascidian. Early in development, Ci-isl expression occurs in the primordia of palps and brain vesicle, then in the tailbud embryo it is transiently extended to the notochord cells. At larva stage, the expression is down-regulated in the notochord, and it persists predominantly in the compartments of the nervous system. These observations indicate that also in invertebrates, islet genes show an expression pattern during differentiation of the nervous system.
Assuntos
Ciona intestinalis/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Animais , Ciona intestinalis/embriologia , Ciona intestinalis/crescimento & desenvolvimento , Clonagem Molecular , Proteínas de Homeodomínio/biossíntese , Hibridização In Situ , Proteínas com Homeodomínio LIM , Larva , Mamíferos/genética , Proteínas do Tecido Nervoso/biossíntese , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Fatores de TranscriçãoRESUMO
BACKGROUND: Cancer-related breakthrough pain (BTP) is a common and quite challenging pain syndrome, with significant impact on quality of life. To date, no widely recognized and validated tool for the diagnosis and evaluation of BTP exists. The Alberta Breakthrough Pain Assessment Tool (ABPAT) underwent a validation process during its development, but no experience of its implementation in clinical practice has been reported. METHODS: ABPAT was tested in a cohort of cancer patients suffering from chronic severe cancer-related pain in order to assess its acceptability and efficacy as a tool for the characterization of BTP. RESULTS: A total of consecutive 249 patients from seven different centres were included in a 2-month study period and all completed the questionnaire; 231 out of the 249 (92.8%) stated that questions were easily understandable and 217 out of the 249 (87.1%) stated that the tool allowed to explain extensively the BTP problem. Physician-patient correlation tests about baseline BTP intensity and BTP relief by medication showed statistical significance at the level of p = 0.001 and p = 0.0001, respectively. Evaluation of the efficacy of BPT medication revealed a 78.2% of patients declaring a good relief from BTP, with a significant reduction of mean BTP numeric rating scale score (p = 0.0001), but only 55.9% of patients responded to be satisfied about time for onset of the relief. CONCLUSIONS: In this study, ABPAT resulted to be a well-accepted tool for BTP assessment and characterization in a relatively large cohort of cancer patients. It is effective in discovering the unmet needs of cancer patients and in exploring the outcomes of BTP treatment.
Assuntos
Dor Irruptiva/diagnóstico , Dor Irruptiva/etiologia , Neoplasias/complicações , Medição da Dor/instrumentação , Adulto , Idoso , Analgésicos Opioides/uso terapêutico , Dor Irruptiva/tratamento farmacológico , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Médicos , Qualidade de Vida , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Previous studies have tested multivariate models of bulimia pathology development, documenting that a confluence of perfectionism, body dissatisfaction, and low self-esteem is predictive of disordered eating. However, attempts to replicate these results have yielded controversial findings. The objective of the present study was to test an interactive model of perfectionism, weight and shape concerns, and self-esteem in a sample of patients affected by Eating Disorder (ED). One-hundred-sixty-seven ED patients received the Structured Clinical Interview for DSM-IV Axis I (SCID-I), and they completed the Eating Disorder Examination Questionnaire (EDE-Q), the Rosenberg Self-Esteem Scale (RSES), and the Multidimensional Perfectionism Scale (MPS-F). Several mediation analysis models were fit to test whether causal effects of concern over weight and shape on the frequency of bulimic episodes were mediated by perfectionism and moderated by low levels of self-esteem. Contrary to our hypotheses, we found no evidence that the causal relationship investigated was mediated by any of the dimensions of perfectionism. As a secondary finding, the dimensions of perfectionism, perceived criticism and parental expectations, were significantly correlated with the presence of bulimic symptoms. The validity of the interactive model remains controversial, and may be limited by an inadequate conceptualization of the perfectionism construct.
Assuntos
Imagem Corporal/psicologia , Bulimia/psicologia , Modelos Psicológicos , Personalidade , Autoimagem , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Satisfação Pessoal , Reprodutibilidade dos Testes , Adulto JovemRESUMO
UNLABELLED: We hypothesized that the assessment of kinetic alterations on two dimensional echocardiogram (2DE) would provide greater diagnostic information than clinical symptoms and ECG changes only. The study was aimed to determine sensitivity of 2DE in patients with cardiac ischemic events and to improve the indications to thrombolysis. Three-hundred ninety-one patients (87 F; 304 M) hospitalized for suspected acute myocardial infarction (AMI), first episode, within 4 h from the onset of symptoms, suitable for thrombolysis Killip class I-II and with unstable angina (UA), were admitted in the study. Patients had to show ECG changes and alterations of segmentary motion on 2DE performed at entry, or 2DE alterations without ECG changes. The 2DE variables analyzed included right ventricular function and left ventricular systolic function. Thrombolysis was performed when 2DE and ECG changes were evidenced at the same time and when 2DE alterations without ECG changes were observed. Patients with UA treated with heparin alone were also studied. The presence of segmentary motion alterations was mandatory. RESULTS: Inferior AMIs, 87 patients (60 +/- 13 years), anterior AMI, 169 patients (61 +/- 11 years); UA group subjected to thrombolysis, 87 patients (62 +/- 12 years); UA group treated with heparin, 48 patients (62 +/- 12 years). We noted only one patient false negative, and five patients false positive. Alterations of right ventricular function were observed in 24, 14 and nine patients with inferior, anterior AMI and UA, respectively. Normal ECG at entry was observed in seven, two and seven patients with inferior, anterior AMI and UA, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ecocardiografia , Isquemia Miocárdica/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Angina Instável/diagnóstico por imagem , Angina Instável/tratamento farmacológico , Angina Instável/fisiopatologia , Angioplastia Coronária com Balão , Ponte de Artéria Coronária , Creatina Quinase/sangue , Eletrocardiografia , Feminino , Fibrinolíticos/uso terapêutico , Heparina/uso terapêutico , Humanos , Isoenzimas , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/fisiopatologia , Sensibilidade e Especificidade , Taxa de Sobrevida , Sístole , Terapia Trombolítica , Função Ventricular Esquerda , Função Ventricular DireitaRESUMO
BACKGROUND: Breakthrough cancer pain (BTP) can place physical, psychological and economic burdens on patients and their productive life. By preventing instead of treating BTP after it occurs, the efficacy of analgesic treatment in cancer patients could be maximized. With this study, we investigated circadian variations in the occurrence of BTP events in cancer patients. METHODS: The circadian variation of BTP was assessed in two different series (group 1, n = 47; group 2, n = 76) of advanced cancer patients suffering from severe chronic pain and undergoing analgesic treatment with major opioids. RESULTS: BTP episodes showed a circadian pattern, with an acrophase occurring at 10:00 a.m. (p < 0.001) in all patients. When the two series of patients were considered separately, an acrophase was similarly observed, with 60% of BTP episodes recorded between 10:00 a.m. and 6:00 p.m. The circadian rhythm of BTP was maintained after stratifying the patients according to whether they had bone metastases or visceral metastases. BTP episodes negatively correlated with quality of life. CONCLUSIONS: BTP onset follows a circadian rhythm, with an acrophase occurring in the late morning.
Assuntos
Dor Irruptiva/etiologia , Dor Irruptiva/fisiopatologia , Ritmo Circadiano/fisiologia , Neoplasias/complicações , Neoplasias/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/uso terapêutico , Dor Irruptiva/tratamento farmacológico , Dor Crônica/tratamento farmacológico , Dor Crônica/etiologia , Feminino , Humanos , Hidrocortisona/metabolismo , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/fisiopatologia , Medição da Dor , Cuidados Paliativos , Estudos Prospectivos , Qualidade de Vida , Saliva/metabolismo , Inquéritos e Questionários , Resultado do TratamentoRESUMO
O presente estudo foi conduzido com o objetivo de determinar as causas de fotossensibilização em ruminantes e equídeos no Nordeste do Brasil, através da revisão dos laudos de exames arquivados no Laboratório de Patologia Veterinária da Universidade Federal da Paraíba. Durante os quatro anos do estudo foram diagnosticados 22 surtos de fotossensibilização, incluindo 11 surtos de fotossensibilização primária e oito surtos de fotossensibilização hepatógena. A intoxicação por Froelichia humboldtiana foi a principal causa de fotossensibilização e a única causa de fotossensibilização primária. As espécies mais gravemente afetadas por fotossensibilização primária foram os asininos, caprinos, bovinos e ovinos, mas os equinos e mulas também são afetados. A intoxicação por Brachiaria decumbens foi a principal causa de fotossensibilização hepatógena e afetou apenas os ovinos e bovinos. Outras plantas associadas com fotossensibilização hepatógena incluíram Enterolobium contortisiliquum e Lantana camara. Dermatite alérgica foi diagnosticada em dois rebanhos ovinos e em um cavalo. Os animais tinham lesões crônicas, caracterizadas por alopecia, crostas e hiperpigmentação no topo da cabeça, ao redor dos olhos (ovinos) e nos membros (equino). O prurido foi o principal sinal clínico observado nos casos de fotossensibilização primária e hipersensibilidade à picada de insetos.(AU)
The study was conducted to determine the causes of photosensitization in ruminants and equidae in northeastern Brazil through a review of the files at the Laboratório de Patologia Veterinária of Universidade Federal da Paraíba. During four years of the study 22 outbreaks of photosensitization were diagnosed, including 11 outbreaks of primary photosensitization and eight outbreaks of hepatogenous photosensitization. Poisoning by Froelichia humboldtiana was the main cause of photosensitization, and the only cause of primary photosensitization. The most severely affected animals by primary photosensitization are donkeys, goats, cattle and sheep, but horses and mules may also be affected. Poisoning by Brachiaria decumbens was the main cause of hepatogenous photosensitization, and affected only sheep and cattle. Other plants associated with hepatogenous photosensitization in cattle include Enterolobium contortisiliquum and Lantana camara. Allergic dermatitis was diagnosed in two flocks of sheep and in a horse. The animals had chronic lesions characterized by areas of alopecia, crusts and hyperpigmentation on the head, around the eyes (sheep) and at the legs (horse). Itching was the main clinical sign in cases of primary photosensitization and insect hypersensitivity.(AU)
Assuntos
Animais , Ruminantes/anormalidades , Fármacos Fotossensibilizantes/efeitos adversos , Dermatite/complicações , Cavalos/anormalidadesAssuntos
Doença de Crohn/cirurgia , Adolescente , Adulto , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Recidiva , ReoperaçãoRESUMO
In the hermaphrodite ascidian Ciona intestinalis, the egg vitelline coat (VC) controls gamete self-nonself discrimination. Oocytes, after germinal vesicle breakdown, can be fertilized by both self and nonself sperm. However, a barrier to fertilization by self sperm progressively develops in the VC in the 3 hours after germinal vesicle breakdown. During this period, follicle cells attached to the outer surface of the VC release self-sterility factors that bind to the VC. Within the follicle cells, these factors (possibly peptides) are thought to be shuttled to the cell membrane by an hsp70 homolog (Cihsp70). In fact, antibodies to hsp70 block the development of self-sterility. Proteasomes are central to the production of antigen peptides. Specific inhibition of proteasome activity with clasto-lactacystin beta-lactone (CLbetaL) prevented the onset of self-sterility, but had no effect once this process had started. CLbetaL did not block fertilization by nonself sperm. The self-sterility factors were removed from mature oocytes by exposure to acidified media, and their biological activity was transferred to immature oocytes treated with CLbetaL. The obvious high multiplicity of self-nonself recognition alleles involved in fertilization, and the involvement of an hsp70 and a proteasome in processing self-sterility factors, suggests that this system may be evolutionarily related to the vertebrate immune system.
Assuntos
Ciona intestinalis/fisiologia , Cisteína Endopeptidases/metabolismo , Complexos Multienzimáticos/metabolismo , Oócitos/fisiologia , Folículo Ovariano/enzimologia , Membrana Vitelina/metabolismo , Ácidos , Animais , Inibidores de Cisteína Proteinase/farmacologia , Feminino , Fertilização , Proteínas de Choque Térmico HSP70/metabolismo , Lactonas/farmacologia , Complexo de Endopeptidases do ProteassomaRESUMO
Differentiated thyroid cells expressing polyoma Middle-T became transformed and tumorigenic when injected into syngenic animals. The expression of thyroglobulin was greatly reduced and no longer responsive to thyrotropin (TSH) and to cAMP. Inhibition of endogenous c-ras by the expression of two transdominant negative mutant H-ras genes, Asn17 and Leu61-Ser186, reactivated thyroglobulin synthesis. Reactivation of thyroglobulin synthesis by c-ras inhibition was not observed in the absence of TSH. These findings indicate that MT elicits dedifferentiation of thyroid cells by activating endogenous c-ras and that c-ras interferes with TSH or cAMP signaling.
Assuntos
Antígenos Transformantes de Poliomavirus/fisiologia , Tireoglobulina/biossíntese , Glândula Tireoide/metabolismo , Proteínas ras/fisiologia , Animais , Diferenciação Celular , Linhagem Celular Transformada , Transformação Celular Viral , AMP Cíclico/biossíntese , Genes ras , Iodo/metabolismo , Mutação , RNA Mensageiro/biossíntese , Ratos , Receptores da Tireotropina/genética , Transdução de Sinais , Glândula Tireoide/citologia , Tireotropina/farmacologia , Tireotropina/fisiologia , Proteínas ras/biossíntese , Proteínas ras/genéticaRESUMO
Transcription of the H ferritin gene in vivo is stimulated by cAMP and repressed by the E1A oncoprotein. We report here the identification of the cis-element in the human promoter responsive to both cAMP- and E1A-mediated signals. This promoter region is included between positions -62 to -45 and binds a approximate 120-kDa transcription factor called Bbf. Bbf forms a complex in vivo with the coactivator molecules p300 and CBP. Recombinant E1A protein reduces the formation of these complexes. In vivo overexpression of p300 in HeLa cells reverses the E1A-mediated inhibition of the ferritin promoter transcription driven by Bbf. These data suggest the existence of a common mechanism for the cAMP activation and the E1A-mediated repression of H ferritin transcription.
Assuntos
Proteínas E1A de Adenovirus/fisiologia , AMP Cíclico/fisiologia , Ferritinas/genética , Transcrição Gênica , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Células HeLa , Humanos , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismoRESUMO
The v-Ki-Ras oncoprotein dedifferentiates thyroid cells and inhibits nuclear accumulation of the catalytic subunit of cAMP-dependent protein kinase. After activation of v-Ras or protein kinase C, the regulatory subunit of type II protein kinase A, RIIbeta, translocates from the membranes to the cytosol. RIIbeta mRNA and protein were eventually depleted. These effects were mimicked by expressing AKAP45, a truncated version of the RII anchor protein, AKAP75. Because AKAP45 lacks membrane targeting domains, it induces the translocation of PKAII to the cytoplasm. Expression of AKAP45 markedly decreased thyroglobulin mRNA levels and inhibited accumulation of C-PKA in the nucleus. Our results suggest that: 1) The localization of PKAII influences cAMP signaling to the nucleus; 2) Ras alters the localization and the expression of PKAII; 3) Translocation of PKAII to the cytoplasm reduces nuclear C-PKA accumulation, resulting in decreased expression of cAMP-dependent genes, including RIIbeta, TSH receptor, and thyroglobulin. The loss of RIIbeta permanently down-regulates thyroid-specific gene expression.