RESUMO
OBJECTIVE: To provide an approach to facial contrast, analysing CIELAB colour differences (ΔEab,10∗) and its components in women's faces from two different ethnic groups, illuminated by modern white light-emitting diodes (LEDs) or traditional illuminants recommended by the International Commission on Illumination (CIE). METHODS: We performed spectrophotometric measurements of spectral reflectance factors on forehead and cheek of 87 young healthy women (50 Caucasians and 37 Orientals), plus five commercial red lipsticks. We considered a set of 10 white LED illuminants, representative of technologies currently available on the market, plus eight main illuminants currently recommended by the CIE, representative of conventional incandescent, daylight and fluorescent light sources. Under each of these 18 illuminants, we analysed the magnitude and components of ΔEab,10∗ between Caucasian and Oriental women (considering cheek and forehead), as well as for cheek-forehead and cheek-lipsticks in Caucasian and Oriental women. Colour-inconstancy indices for cheek, forehead and lipsticks were computed, assuming D65 and A as reference illuminants. RESULTS: ΔEab,10∗ between forehead and cheek were quantitatively and qualitatively different in Orientals and Caucasians, but discrepancies with respect to average values for 18 illuminants were small (1.5% and 5.0% for Orientals and Caucasians, respectively). ΔEab,10∗ between Caucasians and Orientals were also quantitatively and qualitatively different both for forehead and cheek, and discrepancies with respect to average values were again small (1.0% and 3.9% for forehead and cheek, respectively). ΔEab,10∗ between lipsticks and cheek were at least two times higher than those between forehead and cheek. Regarding ΔEab,10∗ between lipsticks and cheeks, discrepancies with respect to average values were in the range 1.5-12.3%, although higher values of up to 54.2% were found for a white RGB LED. This white RGB LED provided the highest average colour-inconstancy indices: 17.1 and 11.5 CIELAB units, under reference illuminants D65 and A, respectively. CONCLUSION: Colour contrasts in women's faces under CIE standard illuminants for outdoor and indoor conditions may be strongly altered using specific white LEDs. More research needs to be performed on the impact of spectral power distribution of light sources with high colour rendering indices on visual colour appearance of cosmetic products.
RESUMO
Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by intrahepatic cholestasis and abnormalities of heart, eye and vertebrae, as well as a characteristic facial appearance. Identification of rare AGS patients with cytogenetic deletions has allowed mapping of the gene of 20p12. We have generated a cloned contig of the critical region and used fluorescent in situ hybridization on cells from patients with submicroscopic deletions to narrow the candidate region to only 250 kb. Within this region we identified JAG1, the human homologue of rat Jagged1, which encodes a ligand for the Notch receptor. Cell-cell Jagged/Notch interactions are known to be critical for determination of cell fates in early development, making this an attractive candidate gene for a developmental disorder in humans. Determining the complete exon-intron structure of JAG1 allowed detailed mutational analysis of DNA samples from non-deletion AGS patients, revealing three frame-shift mutations, two splice donor mutations and one mutation abolishing RNA expression from the altered allele. We conclude that AGS is caused by haploinsufficiency of JAG1.
Assuntos
Síndrome de Alagille/genética , Proteínas de Membrana/genética , Receptores de Superfície Celular , Fatores de Transcrição , Proteínas de Ligação ao Cálcio , Linhagem Celular , Mapeamento Cromossômico , Cromossomos Humanos Par 20/genética , Clonagem Molecular , Análise Mutacional de DNA , Primers do DNA , Éxons/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Hibridização in Situ Fluorescente , Peptídeos e Proteínas de Sinalização Intercelular , Íntrons/genética , Proteína Jagged-1 , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Mutação , Polimorfismo Conformacional de Fita Simples , Splicing de RNA/genética , Receptor Notch1 , Análise de Sequência de DNA , Deleção de Sequência/genética , Proteínas Serrate-JaggedRESUMO
Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by microcephaly, psychomotor regression, seizures and stereotypical hand movements. Recently, deletions and inactivating mutations in FOXG1, encoding a brain-specific transcription factor that is critical for forebrain development, have been found to be associated with the congenital variant of RTT. Here we report the clinical features and molecular characteristics of two cases of the congenital variant of RTT. We conducted mutation screenings of FOXG1 in a cohort of 15 Japanese patients with a clinical diagnosis of atypical RTT but without MECP2 and CDKL5 mutations. Two unrelated female patients had heterozygous mutations (c.256dupC, p.Gln86ProfsX35 and c.689G>A, pArg230His). Both showed neurological symptoms from the neonatal period, including hypotonia, irritability and severe microcephaly. Further, their psychomotor development was severely impaired, as indicated by their inability to sit unaided or acquire speech sounds, and they had a hyperkinetic movement disorder, because both displayed hand stereotypies and jerky movements of the upper limbs. Brain magnetic resonance imaging scans revealed delayed myelination with hypoplasia of the corpus callosum and frontal lobe. These cases confirm the involvement of FOXG1 in the molecular etiology of the congenital variant of RTT and show the characteristic features of FOXG1-related disorder.
Assuntos
Fatores de Transcrição Forkhead/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Síndrome de Rett/genética , Povo Asiático/genética , Sequência de Bases , Encéfalo/patologia , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Imageamento por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Bainha de Mielina/patologia , Reação em Cadeia da Polimerase , Síndrome de Rett/patologiaRESUMO
Concomitant administration of calcium channel blockers (CCBs) and angiotensin-converting enzyme inhibitors (ACEIs) to hypertensive patients at high risk for cardiovascular disease can prevent cardiovascular disease occurrence, but the effects of this treatment on renal and vascular function in low-risk hypertensive patients are unknown. The current study was an open-label prospective study. Hypertensive patients with no history of cardiovascular disease who had not met their blood pressure (BP) goals with CCB treatment were administered perindopril and followed for 6 months. Both home and office BP were significantly lowered by perindopril administration. The morning/evening (M/E) ratios calculated from home BP were 1.31 and 1.05 for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. When the patients were divided into two groups based on the presence or absence of an anti-hypertensive response, urinary albumin excretion, and cardio ankle vascular index were significantly reduced by perindopril administration in all the subjects, irrespective of the presence or absence of anti-hypertensive reaction. In low-risk hypertensive patients, perindopril improves renal and vascular function probably via its persistent anti-hypertensive effects and the concomitant effects of CCB.
Assuntos
Albuminúria/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminúria/urina , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Bloqueadores dos Canais de Cálcio/farmacologia , Quimioterapia Combinada , Seguimentos , Humanos , Hipertensão/fisiopatologia , Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Perindopril/farmacologia , Perindopril/uso terapêutico , Estudos Prospectivos , Resultado do TratamentoRESUMO
Pyruvate dehydrogenase complex (PDC) deficiencies are a major cause of primary lactic acidosis. Most cases result from mutations of the gene for the pyruvate dehydrogenase E1alpha subunit (PDHA1), with fewer cases resulting from mutations in genes for E3, E3-binding protein, E2, and the E1beta subunit (PDHB). We have found four cases of PDHB mutations among 83 analyzed cases of PDC deficiency. In this series, PDHB mutations were found to be about 10% as frequent as PDHA1 mutations. All cases were diagnosed by low PDC activity, with normal E2 and E3 activities. These included a 6.5-year-old male (consanguineous, homozygous R36C); a neonatal female who died soon after birth, (compound heterozygous C306R/D319V), a 26-year-old female (heterozygous I142M/W165S), and a 13month old female (consanguineous, homozygous Y132C) who is a sibling of a previously published case. Their ethnic background is diverse (Caucasian, Arab, and African American descent). All cases had lactic acidosis and developmental delay. Three cases had agenesis of the corpus callosum, seizures, and hypotonia; one died within the first year of life. These clinical findings are similar to those of PDHA1 deficiency, except that ataxia was more frequent in PDHA1 cases and consanguinity was found only in PDHB families. PDC activity in lymphocytes from six parents is normal, who all are heterozygous carriers for the respective mutations. Immunoreactivity of E1beta was markedly reduced in one case and showed a slightly larger form of E1beta in one case. Computer analysis predicts that: R36C affects the interaction of several amino acids resulting in conformational change, C306R affects interaction of the two beta subunits, D319 is in the interface of E1 and E2, I142M affects conformation around a K ion affecting stability of the beta subunit, W165S affects hydrophobic interaction between the beta subunits, and Y132C affects interaction between the beta subunits. All of these residues are conserved in E1beta across species, and Y132 is also conserved in other TPP-requiring enzymes. These observations support the conclusion that these are pathogenic mutations.
Assuntos
Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Acidose Láctica/genética , Adulto , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Consanguinidade , Análise Mutacional de DNA , Evolução Fatal , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Modelos MolecularesRESUMO
Only limited therapeutic measures are currently available for the treatment of spinal cord injury. This review describes the pathologic mechanisms of trauma-induced spinal cord injury in rats, which will contribute to new understanding of the pathologic process leading to spinal cord injury and to further development of new therapeutic strategies. Spinal cord injury induced by trauma is a consequence of an initial physical insult and a subsequent progressive injury process that involves various pathochemical events leading to tissue destruction; the latter process should therefore be a target of pharmacological treatment. Recently, activated neutrophils have been shown to be implicated in the latter process of the spinal cord injury in rats. Activated neutrophils damage the endothelial cells by releasing inflammatory mediators such as neutrophil elastase and oxygen free radicals. Adhesion of activated neutrophils to the endothelial cell could also play a role in endothelial cell injury. This endothelial cell injury could in turn induce microcirculatory disturbances leading to spinal cord ischemia. We have found that some therapeutic agents that inhibit neutrophil activation alleviate the motor disturbances observed in the rat model of spinal cord injury. Methylprednisolone (MPS) and GM1 ganglioside, which are the only two pharmacological agents currently clinically available for treatment of acute spinal cord injury, do not inhibit neutrophil activation in this rat model. Taken together, these observations raise a possibility that other pharmacological agents that inhibit neutrophil activation used in conjunction with MPS or GM1 ganglioside may have a synergistic effect in the treatment of traumatic spinal cord injury in humans.
Assuntos
Traumatismos da Medula Espinal/patologia , Animais , Modelos Animais de Doenças , Gangliosídeo G(M1)/uso terapêutico , Glucocorticoides/uso terapêutico , Leucócitos/fisiologia , Metilprednisolona/uso terapêutico , RatosRESUMO
Potential difference across the cell membrane and intracellular activity of the potassium ion in rat liver cells were measured simultaneously using double-barreled potassium ion-selective microelectrodes. Both potential difference across the membrane and K+ activity in liver cells were depressed after treatment with the antineoplastic agents mitomycin C and 5-Flourouracil Dry Syrup, suggesting that these drugs would induce disturbances of cellular energy metabolism in liver cells. When the antineoplastic agents were used in combination with coenzyme Q10, the depression of potential difference across the membrane and K+ activity and the hypofunction of liver cells in energy metabolism were significantly prevented.
Assuntos
Fluoruracila/farmacologia , Fígado/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Mitomicinas/farmacologia , Potássio/metabolismo , Ubiquinona/farmacologia , Animais , Antineoplásicos/antagonistas & inibidores , Metabolismo Energético/efeitos dos fármacos , Ratos , Sarcoma Experimental/fisiopatologiaRESUMO
The partial pressure of oxygen (pO2) of FSaII tumors grown in the leg of C3H mice significantly improved when the tumors were heated by immersing the tumor-bearing legs in a water bath at 41.5 degrees C for 60 min. The tumor pO2 also substantially increased when the tumor-bearing mice breathed carbogen (95% O2:5% CO2). Additionally, mild hyperthermia followed by carbogen breathing further increased the tumor pO2 and increased radiation cytotoxicity as assessed by the in vivo/in vitro excision assay for surviving FSaII cells. It was concluded that mild hyperthermia in combination with carbogen breathing is potentially useful to reoxygenate radioresistant hypoxic cells and improve the radiotherapy of human tumors.
Assuntos
Dióxido de Carbono/administração & dosagem , Hipóxia Celular , Hipertermia Induzida , Neoplasias/metabolismo , Neoplasias/radioterapia , Oxigênio/administração & dosagem , Oxigênio/metabolismo , Radiossensibilizantes/administração & dosagem , Animais , Fibrossarcoma/metabolismo , Fibrossarcoma/radioterapia , Humanos , Camundongos , Pressão Parcial , Células Tumorais CultivadasRESUMO
When S-benzyl-N-acetyl-L-[U-14C]cysteine, a mercapturic acid, was administered to rats intravenously, the plasma level of radioactivity decreased very rapidly with a concomitant increase in the renal level of radioactivity. The renal radioactivity reached its maximum within 2 min and then decreased rapidly with concomitant appearance of the radioactive mercapturic acid in the urine. Bilateral ligation of the ureters resulted in only a slight decrease in the rate of disappearance of mercapturic acid from the plasma, while bilateral nephrectomy caused a marked retardation of its clearance from the plasma. Intravenous administration of probenecid, a well known inhibitor of a renal transtubular transport system for organic acids, caused a significant retardation of mercapturate clearance from the plasma in both of the control and ureter-ligated animals. The renal accumulation of this mercapturic acid as well as its excretion into urine was inhibited by probenecid. All these data suggested that a mercapturic acid in the plasma was preferentially taken up by renal tubule cells from the basolateral side of plasma membranes via the probenecid-sensitive transtubular transport system and then excreted rapidly into the lumenal space. This transtubular transport of a mercapturic acid seems to constitute an important process in the hepato-renal cooperation in the mercapturic acid biosynthesis in vivo.
Assuntos
Acetilcisteína/metabolismo , Túbulos Renais/metabolismo , Acetilcisteína/análogos & derivados , Acetilcisteína/sangue , Animais , Transporte Biológico/efeitos dos fármacos , Cinética , Fígado/metabolismo , Masculino , Probenecid/farmacologia , RatosRESUMO
Topological features and some properties of the membrane-bound peptidase(s) participating in the metabolism of a glutathione S-conjugate in the kidney were studied. S-Carbamidomethyl glutathione, a model compound for glutathione S-conjugate, was demonstrated to be sequentially hydrolyzed by gamma-glutamyltransferase (5-glutamyl)-peptide:amino-acid 5-glutamyltransferase; EC 2.3.2.2) and peptidase(s) bound to rat renal brush border membrane vesicles. Hydrolysis of S-carbamidomethyl cysteinylglycine was found to be inhibited by 1,10-o-phenanthroline, suggesting a participation of a metal-requiring peptidase in this process. The hydrolytic activity of the membranous peptidase was markedly depressed by cysteinylglycine S-acetyldextran polymer (molecular weight, 500 000), a nonpermeating derivative for cysteinylglycine. Papain treatment of brush border membrane vesicles resulted in the solubilization of most hydrolytic activity toward S-carbamidomethyl cysteinylglycine. Amino-peptidase M was also solubilized from the membrane and the increase in the specific activity of this enzyme in the papain-soluble fraction was in parallel within that of the peptidase activity for hydrolysis of S-carbamidomethyl cysteinylglycine. The hydrolytic activity of purified brush border membrane vesicles toward S-carbamidomethyl glutathione was fully reconstituted by the combined use of purified gamma-glutamyltransferase and aminopeptidase M. These findings indicated that, as in the case of the cleavage of gamma-glutamyl linkage of glutathione and related compounds, hydrolysis of the S-substituted cysteinylglycine occurred exclusively on the lumenal surface of renal brush border membrane as catalyzed mainly by aminopeptidase M.
Assuntos
Glutationa/análogos & derivados , Rim/enzimologia , Peptídeo Hidrolases/metabolismo , Aminopeptidases/metabolismo , Antígenos CD13 , Fracionamento Celular , Diazo-Oxo-Norleucina/farmacologia , Dipeptidases/metabolismo , Glutationa/metabolismo , Membranas/enzimologia , Microssomos/enzimologia , Microvilosidades/enzimologia , Fenantrolinas/farmacologia , gama-Glutamiltransferase/metabolismoRESUMO
The effect of concanavalin A and its succinylated derivative on cell agglutination and potassium compartmentation of mature and immature erythrocytes was observed. The binding of tetravalent concanavalin A to the surface glycoproteins of rabbit erythrocytes leads to a change in the properties of the surface membrane, which results in an induction of cell agglutination and concomitant release of potassium from the cells. Both of the phenomena induced by concanavalin A are temperature dependent, and observed at above 15 degrees C. Divalent succinylated concanavalin A, lacking the inducing activity of surface glycoprotein cross-linking into patches and caps, caused neither cell agglutination nor change in the potassium compartmentation of erythrocytes and reticulocytes. In the case of immature reticulocytes, however, remarkable agglutination of the cells was induced without a change in the potassium compartmentation after treatment with tetravalent concanavalin A. It is suggested that changes in the molecular organization of the surface membrane occur in which potassium compartmentation of the reticulocytes becomes more susceptible to surface glycoprotein cross-linking during cellular maturation.
Assuntos
Concanavalina A/farmacologia , Membrana Eritrocítica , Eritrócitos , Animais , Membrana Eritrocítica/fisiologia , Eritrócitos/fisiologia , Glicoproteínas/metabolismo , Hemaglutinação , Potássio/metabolismo , Ligação Proteica , Coelhos , Reticulócitos/metabolismo , Succinatos/farmacologia , TemperaturaRESUMO
BACKGROUND: Excessive production of nitric oxide (NO) by the inducible isoform of NO synthase (iNOS) is critically involved in endotoxin (ET)-induced hypotension. Tumor necrosis factor-alpha (TNF-alpha) plays an important role in induction of iNOS. Because activated protein C (APC), a physiological anticoagulant, inhibits TNF-alpha production, it might prevent hypotension by inhibiting excessive production of NO. In this study, we examined this possibility using a rat model of septic shock. METHODS AND RESULTS: Intravenous administration of APC prevented both ET-induced hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-). The hypotension was also inhibited when APC was administered 30 minutes after ET administration. APC inhibited the increases in lung levels of iNOS activity by inhibiting expression of iNOS mRNA in animals given ET. APC significantly inhibited the increases in lung tissue levels of TNF-alpha and expression of TNF-alpha mRNA in animals given ET. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor DIP-APC, an active site-blocked APC, showed any effect on these ET-induced changes. Both inhibition of TNF-alpha production by leukocytopenia and treatment with anti-rat TNF-alpha antibody produced effects similar to those induced by APC. Aminoguanidine, a selective inhibitor of iNOS, inhibited both the hypotension and the increases in plasma levels of NO(2)(-)/NO(3)(-) in this animal model. CONCLUSIONS: These observations strongly suggest that APC inhibits iNOS induction by decreasing TNF-alpha production, leading to the prevention of ET-induced hypotension. Furthermore, such effects of APC were not dependent on its anticoagulant effects but rather on its serine protease activity.
Assuntos
Endotoxinas/administração & dosagem , Hipotensão/prevenção & controle , Óxido Nítrico/metabolismo , Proteína C/farmacologia , Clorometilcetonas de Aminoácidos/química , Animais , Anticorpos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Compostos de Dansil/química , Fator Xa/química , Fator Xa/farmacologia , Hipotensão/induzido quimicamente , Hipotensão/metabolismo , Injeções Intravenosas , Isoflurofato/química , Leucopenia/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Nitratos/sangue , Óxido Nítrico Sintase/efeitos dos fármacos , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Nitritos/sangue , Proteína C/química , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Organismos Livres de Patógenos Específicos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alagille syndrome (AGS) is an autosomal dominant, developmental disorder affecting multiple organ systems including liver, heart, vertebrae, eye and face. Recurrent deletions of the 20p12 region led to the localization, and ultimately to the identification of mutations in the Jagged1 gene (JAG1) in AGS patients. A translocation t(3;20)(q13.3;p12.2) in an AGS patient was characterized using fluorescent in situ hybridization (FISH). The involvement of 3q and 20p in this translocation was demonstrated using probes for 3q and 20p. Three overlapping YAC clones, 940D11, 953A2, and 675G11 extending to nearly 4 Mb including the JAG1 were used as probes for FISH analysis to define the translocation breakpoint. The translocated chromosome was found to have a deletion of more than 3 Mb including the entire JAG1 gene. The observation of an accompanying large deletion, revealed by molecular characterization of the t(3;20) translocation, is similar to the only other translocation reported in an AGS patient; a t(2;20) translocation was also found to have a large deletion of the JAG1 region at 20p12.
Assuntos
Síndrome de Alagille/genética , Deleção Cromossômica , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 3/genética , Proteínas/genética , Translocação Genética/genética , Síndrome de Alagille/diagnóstico , Proteínas de Ligação ao Cálcio , Humanos , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular , Proteína Jagged-1 , Masculino , Proteínas de Membrana , Proteínas Serrate-JaggedRESUMO
BACKGROUND AND OBJECTIVE: Activated protein C (APC) is a natural anticoagulant with anti-inflammatory activity. APC inhibits neutrophil activation through inhibition of tumor necrosis factor (TNF)-alpha production. Such anti-inflammatory activity of APC has recently been shown to be critical in the treatment of patients with severe sepsis. We previously demonstrated that activated neutrophils play a crucial role in the development of stress-induced gastric mucosal injury. Thus, inhibition of neutrophil activation by APC should reduce endothelial cell damage, maintain gastric blood flow, and lessen gastric mucosal injury. In the present study, we examined this possibility by using a rat model of water-immersion restraint stress (WIRS)-induced gastric mucosal injury. METHODS AND RESULTS: Gastric mucosal injury was observed 4 h after WIRS, without increases in gastric mucosal levels of either myeloperoxidase activity or TNF-alpha, but with significant increases in plasma levels of TNF-alpha 1 h after WIRS. Intravenous administration of APC (100 micro g kg-1) significantly reduced WIRS-induced gastric mucosal injury by inhibiting decrease in gastric mucosal blood flow. Administration of APC also inhibited both the decrease in gastric tissue levels of 6-keto-prostaglandin F1alpha and the increase in gastric mucosal micorvascular permeability in animals subjected to WIRS. Furthermore, APC inhibited WIRS-induced increases in plasma levels of TNF-alpha. Neither active site-blocked factor Xa, which is a selective inhibitor of thrombin generation, nor active site-blocked APC had any effect on these events. Intraperitoneal administration of anti-rat TNF-alpha antibody produced effects similar to those of APC. CONCLUSIONS: The observations in the present study strongly suggest that APC reduces stress-induced gastric mucosal injury by inhibiting the decrease in gastric mucosal blood flow through attenuation of the activated neutrophil-induced endothelial cell injury via inhibition of TNF-alpha production. In addition, we show that serine protease activity of APC, rather than its anticoagulant activity, is critical for the protective mechanism(s) by which TNF-alpha production could be inhibited.
Assuntos
Células Endoteliais/efeitos dos fármacos , Proteína C/farmacologia , Úlcera Gástrica/prevenção & controle , Estresse Fisiológico/patologia , Animais , Permeabilidade Capilar/efeitos dos fármacos , Células Endoteliais/patologia , Mucosa Gástrica/patologia , Masculino , Ativação de Neutrófilo , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Proteína C/administração & dosagem , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The effects of mild temperature hyperthermia (MTH) on the oxygenation and radioresponse in rodent tumors were investigated. FSall tumors grown in the legs of C3H mice and R3230 AC tumors grown in the legs of Fischer rats were heated with a water bath and the partial pressure of oxygen (pO2) was determined using the microelectrode method. In FSall tumors, the pO2 measured immediately after heating at 41.5 degrees C for 1 hour was markedly higher than that in the control tumors, whereas heating at higher temperatures for 1 hour decreased the tumor oxygenation. In R3230 AC tumors, heating at 41.5 degrees C for 1 hour caused a moderate increase in the pO2 and heating at 42.5 degrees or 43.5 degrees C for 30 minutes markedly increased the pO2. However, heating at 42.5 degrees C or higher temperatures for 1 hour decreased the pO2 in the R3230 AC tumors. The improvement of oxygenation in FSall tumors by heating at 41.5 degrees C for 1 hour increased the radiation-induced cell death in these tumors. The combination of carbogen breathing with MTH was far more potent than carbogen breathing or MTH alone in increasing tumor oxygenation and potentiating the radiation effect in FSall tumors.
Assuntos
Dióxido de Carbono/uso terapêutico , Hipertermia Induzida , Neoplasias Experimentais/terapia , Oxigênio/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adenocarcinoma/radioterapia , Adenocarcinoma/terapia , Animais , Sobrevivência Celular , Terapia Combinada , Relação Dose-Resposta à Radiação , Fibrossarcoma/radioterapia , Fibrossarcoma/terapia , Camundongos , Camundongos Endogâmicos C3H , Transplante de Neoplasias , Neoplasias Experimentais/patologia , Neoplasias Experimentais/radioterapia , Consumo de Oxigênio , Ratos , Ratos Endogâmicos F344 , Termodinâmica , Células Tumorais CultivadasRESUMO
PURPOSE: To determine the most effective combination of carbogen breathing with mild temperature hyperthermia (MTH) to increase the oxygenation and radiation response in murine tumors. METHODS AND MATERIALS: MTH at 41.5 degrees C for 60 min was applied by immersion of the tumor in a precisely controlled water bath. The tumor pO2 was measured with a polarographic microelectrode. The radiation response of the tumor was determined using the in vivo/in vitro assay for surviving tumor cells. RESULTS: In the FSaII fibrosarcoma the median pO2 increased from a control value of 6.5 +/- 0.5 mm Hg to 16.6 +/- 1.1 mm Hg immediately after MTH and was 10.9 +/- 1.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the FSaII pO2 to 19.9 +/- 2.1 mm Hg. Carbogen breathing for 5 min beginning immediately after MTH increased the median pO2 more than 5 times to 35.4 +/- 3.8 mm Hg. This combined treatment also substantially increased the response of the tumors to a radiation exposure of 20 Gy. In another tumor model, the SCK mammary carcinoma, MTH treatment increased the median pO2 from the control level of 4.4 +/- 0.2 mm Hg to 12.6 +/- 1.2 mm Hg, and it returned to 4.3 +/- 0.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the SCK tumor pO2 to 17.1 +/- 1.4 mm Hg. The median SCK pO2 was increased about 7 times to 31.2 +/- 4.2 mm Hg when MTH was followed immediately with carbogen breathing for 5 min. The radiation response was also markedly increased by this combination. When the animals breathed carbogen for 15 or 30 min, the pO2 and radiosensitivity in both tumor types either remained the same or was lower than that after 5 min of breathing. In addition, both FSaII and SCK tumors were radiosensitized 24 h after MTH treatment alone or with 5 min of carbogen breathing. CONCLUSIONS: A shorter carbogen breathing time immediately after MTH causes the most tumor radiosensitization. The results of this study also demonstrate that MTH increases radiosensitivity with and without carbogen breathing up to 24 h after the mild hyperthermia treatment.
Assuntos
Dióxido de Carbono/administração & dosagem , Hipertermia Induzida , Neoplasias Experimentais/irrigação sanguínea , Neoplasias Experimentais/radioterapia , Consumo de Oxigênio , Oxigênio/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Sobrevivência Celular , Fibrossarcoma/irrigação sanguínea , Fibrossarcoma/metabolismo , Fibrossarcoma/radioterapia , Neoplasias Mamárias Experimentais/irrigação sanguínea , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/radioterapia , Camundongos , Camundongos Endogâmicos C3H , Neoplasias Experimentais/metabolismo , Pressão ParcialRESUMO
PURPOSE: Local control rate and survival rate of esophageal cancer treated with radical radiation therapy (RT) were analyzed with special respect to total treatment time and fractionation. METHODS AND MATERIALS: Between 1979 and 1992, 88 patients with Stages I-III esophageal cancer were treated radically with RT at Kyoto University Hospital and Wakayama Red Cross Hospital. Of the 88 patients, 52 patients were treated with conventional fractionation (1.7-2.0 Gy/day, five times/week), and the remaining 36 patients were treated with accelerated hyperfractionation (AHF). In 1989, we started AHF regimen for esophageal cancer. Daily fractionations were 2.0 Gy and 1.2 Gy (field-in-field), or 1.5 Gy and 1.5 Gy at 5- to 6-h interval. Most of the patients treated with AHF received the total radiation dose of 64-68 Gy. Twenty-seven patients were treated with intraluminal brachytherapy (IBT) as boost therapy following external RT. Fourteen patients were treated with IBT following AHF. RESULTS: The median of treatment time of AHF was approximately 2 weeks shorter than that of conventional fractionation. Local control rate at 1 year were 47% for AHF, which was significantly higher than that for conventional fractionation (22%, p < 0.05). The improvement of local control by AHF was responsible for a trend to an improved cause-specific survival (p = 0.07). Local control rates at 1 year were plotted as a function of total treatment time. The slope of the linear regression line was -2.3 +/- 0.5% per day (p < 0.025) for patients treated with external RT alone, indicating a 2.3% per day loss in local control. Pretreatment and treatment parameters were evaluated in a multivariate analysis for the end point of local control. T stage (T1, 2 vs. T3, 4; p = 0.003) and fractionation schedule (p = 0.03) were independent of prognostic significance. Patients could tolerate the AHF well, although esophageal stenosis was noted frequently as a late toxicity. CONCLUSION: Accelerated hyperfractionation was the most important treatment-related variable in this patient population. Total treatment time may have a significant impact on the treatment outcome for esophageal cancer.
Assuntos
Carcinoma/radioterapia , Neoplasias Esofágicas/radioterapia , Radioterapia/métodos , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Idoso , Idoso de 80 Anos ou mais , Braquiterapia/métodos , Carcinoma/mortalidade , Carcinoma/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia/efeitos adversos , Dosagem Radioterapêutica , Taxa de Sobrevida , Fatores de TempoRESUMO
PURPOSE: The results of three-dimensional treatment planning using a computed tomography simulator were evaluated in patients with maxillary cancer. METHODS AND MATERIALS: Treatment planning was done in 25 patients using an x-ray simulator and plain x-ray films (1979-1982, group 1) in 34 patients using an x-ray simulator and computed tomography films (1983-1987, group 2), in 24 patients using a computed tomography simulator (1988-1992, group 3). The number of patients with Stage IV disease increased in the order of group 1 to group 3. RESULTS: The average radiation field was smallest in group 3 (66.5 cm2) followed by group 2 (67.4 cm2) and group 1 (72.9 cm2). A radiation dose of more than 30 Gy to the lens of the effected side was delivered to 13% of group 3, 44% of group 2, and 44% of group 1. The dose to the lens on the uneffected side was zero in 56% of group 1, 74% of group 2, and 96% of group 3. A long-term decrease in visual activity on the effected side occurred in 11% of group 3, 32% of group 2, and 44% of group 1. However, a significant increase in survival was only noted between groups 1 and 2, because the three population of patients were different. CONCLUSION: The three-dimensional treatment planning results in a better treatment than two-dimensional treatment planning as measured by complication rates and field sizes.
Assuntos
Neoplasias Maxilares/radioterapia , Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Análise de SobrevidaRESUMO
We have performed radiotherapy treatment planning (RTP) with a new system called CT simulator in 72 patients. With the system, RTP is performed with the patient lying on the CT couch within a short period of time. All the CT images scanned were immediately transported to the multi-image monitors and to the treatment planning device. Radiotherapy treatment planning could be performed not only at the beam center but also at any CT slice. Using a laser-beam field projector, field outlines were drawn over the patient's skin. In clinical use, the system was useful for cases in which a target lies adjacent to dose limiting organs, cases with a complicated target shape, cases with complicated dose distribution curves, and cases treated with tangential fields. This system enables us to make optimum use of CT information and to make accurate 3-dimensional treatment planning programs.
Assuntos
Simulação por Computador , Sistemas Computacionais , Neoplasias/radioterapia , Planejamento da Radioterapia Assistida por Computador , Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X , Humanos , Neoplasias/diagnóstico por imagemRESUMO
PURPOSE: To introduce the process of developing an integrated radiotherapy network. METHODS AND MATERIALS: We developed a new radiotherapy treatment-planning system in 1987 that we named the Computer Tomography (CT) simulator. CT images were immediately transported to multiimage monitors and to a planning computer, and treatment planning could be performed with the patient lying on the CT couch. The results of planning were used to guide a laser projector, and radiation fields were projected onto the skin of the patient. Since 1991, an integrated radiotherapy network system has been developed, which consists of a picture archiving and communicating system (PACS), a radiotherapy information database, a CT simulator, and a linear accelerator with a multileaf collimator. RESULTS: Clinical experience has been accumulated in more than 1,000 patients. Based on our 7 years of experience, we have modified several components of our original CT simulator and have developed a second generation CT simulator. A standard protocol has been developed for communication between the CT scanner, treatment planning computer, and radiotherapy apparatus using the Ethernet network. As a result, treatment planning data can be transported to the linear accelerator within 1 min after completion of treatment planning. CONCLUSION: This system enables us to make optimal use of CT information and to devise accurate three-dimensional (3D) treatment-planning programs. Our network also allows for the performance of fully computer-controlled dynamic arc conformal therapy.