RESUMO
PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE]⯱â¯SEâ¯=â¯0.72⯱â¯0.02 vs 0.53⯱â¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPEâ¯=â¯0.79 vs 0.79, pâ¯=â¯0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76⯱â¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.
Assuntos
Neoplasias Orofaríngeas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , PrognósticoRESUMO
Papillary transitional cell tumors were found in the urinary bladders in 8 rats out of 80 that received 2600 milligrams per kilogram of body weight per day of a mixture of sodium cyclamate and sodium saccharin (10:1) for up to 105 weeks. From week 79 on, several of these rats received cyclohexylamine hydrochloride (125 milligrams per kilogram per day, the molecular equivalent of the conversion of about 10 percent of the cyclamate dosage to cyclohexylamine) in addition to the sodium cyclamate and sodium saccharin. In another study in which 50 rats were fed daily 15 milligrams of cyclohexylamine sulfate per kilogram of body weight for 2 years, eight males and nine females survived. One of the eight males had a tumor of the urinary bladder. In neither study were bladder tumors found in the control rats or in rats treated with lower doses of the compounds.
Assuntos
Aminas , Carcinoma Papilar/induzido quimicamente , Carcinoma de Células de Transição/induzido quimicamente , Cicloexanos , Edulcorantes , Neoplasias da Bexiga Urinária/induzido quimicamente , Ração Animal , Animais , Peso Corporal , Legislação de Medicamentos , Ratos , Edulcorantes/metabolismo , Estados UnidosRESUMO
BACKGROUND: Synbiotics often are prescribed to limit antibiotic-associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking. OBJECTIVE: To determine whether synbiotic co-administration mitigates AAGS in healthy research cats treated with clindamycin. ANIMALS: 16 healthy research cats. METHODS: A randomized, double-blinded, placebo-controlled, 2-way, 2-period, crossover study with a 6-week washout was performed. Each study period consisted of a 1-week baseline and a 3-week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant. RESULTS: Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F-value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F-value = 31.1, P < 0.01) despite period effects (F-value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F-value = 17.9, P < 0.01). CONCLUSIONS AND CLINICAL IMPORTANCE: Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic-associated diarrhea.
Assuntos
Antibacterianos/efeitos adversos , Doenças do Gato/induzido quimicamente , Clindamicina/efeitos adversos , Gastroenteropatias/veterinária , Simbióticos , Animais , Doenças do Gato/prevenção & controle , Gatos , Estudos Cross-Over , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/prevenção & controle , Masculino , Simbióticos/administração & dosagem , Vômito/induzido quimicamente , Vômito/prevenção & controle , Vômito/veterináriaRESUMO
Sertoli cells from rats aged 16 days were cultured in defined medium for 2 days and then treated by addition of fresh medium containing various hormones (treated) or saline (control). The concentration of lactate in the medium was measured as a function of time. The production of lactate measured under these conditions was increased by addition of FSH to the medium. For NIH FSH (13 and 14), ED50 for stimulation of lactate production was approximately 0.05 micrograms/ml. Stimulation was also seen with LH and TSH (ED50, 0.8 micrograms/ml for both hormones). Reasons are given for believing that TSH may possess the inherent capacity to stimulate production of lactate in contrast to LH, which appears to act only by way of contaminating traces of FSH. Dibutyryl cAMP also stimulates lactate production by Sertoli cells. Other hormones tested, including androgens, were without effect. When production of lactate by Sertoli cells was compared with the maximal consumption by spermatids in vitro, it became apparent that Sertoli cells may provide the major source of metabolic substrate for spermatids in the form of lactate. Stimulation of lactate production by FSH was inhibited by puromycin, cycloheximide, and actinomycin D. Evidently this response requires synthesis of new protein and RNA. This effect of FSH may be important in the regulation of spermatogenesis.
Assuntos
Hormônio Foliculoestimulante/farmacologia , Lactatos/biossíntese , Células de Sertoli/metabolismo , Animais , Bucladesina/farmacologia , Células Cultivadas , Glucose/farmacologia , Cinética , Ácido Láctico , Hormônio Luteinizante/farmacologia , Masculino , Prolactina/farmacologia , Puromicina/farmacologia , Ratos , Células de Sertoli/efeitos dos fármacos , Testosterona/farmacologia , Tireotropina/farmacologiaRESUMO
Insulin stimulates the synthesis of lactate by cultured Sertoli cells prepared from rats aged 13 days, to a much greater extent if glucose is present in the incubation medium than when it is absent. Insulin also stimulates the transport of 3-O-methyl-D-[14 C]glucose into cultured Sertoli cells. This increased transport results from a decrease in the Michaelis-Menten constant (Km) of methylglucose for the transport system without change in maximum velocity (Vmax). Moreover, insulin stimulates influx of the glucose analog and is without effect on efflux. Insulin does not alter transport of methylglucose in peritubular fibroblasts or in mixed populations of germ cells. It was observed that whereas insulin stimulates transport of methylglucose at micromolar concentrations, insulin-like growth factor I (IGF I) exerts the same effect at nanomolar (physiological) concentrations. Moreover, the response to insulin plus IGF I is the same as the maximal responses to either hormone alone. In view of the effects of insulin and IGF I on glucose transport by Sertoli cells and in view of the importance of lactate as a substrate for germ cells, it is suggested that IGF I may be important for the development of normal germinal epithelium in rat testes.
Assuntos
Hexoses/metabolismo , Insulina/farmacologia , Peptídeos/farmacologia , Células de Sertoli/metabolismo , Somatomedinas/farmacologia , 3-O-Metilglucose , Animais , Células Cultivadas , Lactatos/biossíntese , Masculino , Metilglucosídeos/metabolismo , Ratos , Testículo/citologia , Testículo/metabolismoRESUMO
PIP: This is an extension of work recently reported by Rose regarding young women using a combination of progesterone and estrogen for ovulation control. The 10 subjects studied had an abnormal xanthurenic acid excretion after a loading dose of tryptophan. After treatment with 2.5 mg norethynodrel and .1 mg mestranol (Enovid-E) from Days 5 to 24 of the the cycle, 24-hour urine specimens were collected before and after administration of 2 gm of L-tryptophan. They were then given 25 mg of pyridoxine hydrochloride 4 times a day during the 48 hours required to repeat the tryptophan loading test. Controls were 18 healthy women not taking drugs. Metabolites of trytophan determined were indican, anthranilic acid glucuronide, 0-aminohippuric acid, kynurenic acid, acetylkynurenine, kynurenine, 3-hydroxykynurenine, xanthurenic acid, and N-methyl-2-pyridone-5-carboxamide. Urine specimines were analyzed for these and for 4-pyridoxic acid taking usual precautions to avoid dietary factors or drugs which might vitiate the results. At first the ingestion of the steroid had no significant effect on the basal excretion of urinary tryptophan metabolites. However, after the loading dose of tryptophan, the subjects taking Enovid E- excreted a mean level of 697 micro-moles of xanthurenic acid compared with a mean level of 29.8 micro-moles in controls. Some of the other metabolites were also excreted in increased quantities: 3-hydroxykynurenine, kynurenine, kynurenic acid, and acetylkynurenine. The others were excreted in normal quantities. When experimental subjects were given 100 mg/day of supplemental pyridoxine hydrochloride, tryptophan metabolism was essentially normal. These results should be considered in human metabolic studies of pyridoxine-requiring enzyme systems.^ieng
Assuntos
Mestranol/metabolismo , Noretinodrel/metabolismo , Ovulação/efeitos dos fármacos , Piridoxina/metabolismo , Triptofano/metabolismo , Feminino , HumanosRESUMO
The role of calcium-activated potassium (KCa) channels in the in vivo relaxation of arterioles was investigated before endotoxin shock (Pre-ENDT) and during endotoxin shock at 180 min (Post-ENDT). Diameters of 2nd and 3rd order (A2 and A3) arterioles in the left cremaster muscle of male Sprague-Dawley rats anesthetized with pentobarbital sodium were measured using videomicroscopy. Adenosine (ADO) at 534 micrograms intraarterially, topical ADO at 10(-3) M, and the endothelium-dependent agonist topical acetylcholine (ACH) at 10(-4) M significantly dilated both A2 and A3 arterioles Pre-ENDT and Post-ENDT. Topical tetraethylammonium chloride (TEA) at 1 mM blocked ADO (intraarterially and topical)-induced A2 and A3 arteriolar dilations Pre-ENDT and Post-ENDT. Arteriolar dilation to ACH was maintained Pre-ENDT, but was blocked by TEA in A2 and A3 arterioles Post-ENDT. The endothelium-independent agonist sodium nitroprusside (10(-5) M), when topically applied, caused maximal arteriolar dilation Pre-ENDT and Post-ENDT in the presence of TEA. The data show that vascular smooth muscle KCa channels are a significant factor in ADO-induced relaxation of cremaster microvessels and are not significantly affected by ENDT. The results also suggest that the mechanism for endothelium-dependent ACH vasodilation changes from a non-KCa channel-mediated mechanism Pre-ENDT to a KCa-mediated mechanism Post-ENDT.
Assuntos
Arteríolas/fisiologia , Cálcio/metabolismo , Canais de Potássio/metabolismo , Choque Séptico/metabolismo , Vasodilatação/efeitos dos fármacos , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Adenosina/metabolismo , Adenosina/farmacologia , Administração Tópica , Animais , Arteríolas/anatomia & histologia , Arteríolas/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Endotoxinas/toxicidade , Masculino , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Nitroprussiato/farmacologia , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Choque Séptico/tratamento farmacológico , Tetraetilamônio , Compostos de Tetraetilamônio/farmacologia , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
Adrenergic and endothelium-dependent arteriolar reactivity are greatly reduced in hemorrhagic shock. However, development of tolerance to endotoxin may prevent the decrease. The reactivity of cremaster muscle arterioles was tested in pentobarbital-anesthetized endotoxin-tolerant (ENDT-T) and nontolerant control rats. Tolerance was developed by sublethal intraperitoneal injections of Escherichia coli endotoxin for 4 days (n = 9). Controls received saline (n = 9). Mean arterial pressure (MAP), arteriolar diameter-response curves to topical norepinephrine (NE) (10-9M to 10-3M) and responses to 10-3M acetylcholine (ACh) were obtained as follows 1) at control, 2) following hemorrhage to 40 mmHg. 3) after uptake of 25% of bled volume with the remainder infused, and 4) at 240 min post-hemorrhage. The A1, A2, and A3 arterioles were constricted following hemorrhage in the ENDT-T group and in the saline group. After reinfusion and in late shock, vessel diameters remained constricted. MAP increased to control levels (106 +/- 5 and 101 +/- 4 mmHg, respectively) following re-infusion in both groups but in late shock it decreased until death in the nontolerant group and decreased only minimally (96 +/- 4 mmHg) in the ENDT-T group. The nontolerant group NE ED50 increased from pre-hemorrhage to late shock (p < .05). The ENDT-T group ED50 was unchanged. The bleeding volumes of the two groups were not different. The survival time of the nontolerant group was 234 +/- 36 min, whereas the ENDT-T group all survived and were sacrificed at 427 +/- 30 min. The response to endothelium-dependent ACH vasodilation in late shock was significantly reduced in the saline group but was unchanged in the ENDT-T group. Alpha 1 receptor activity was maintained in both groups. Alpha 2 receptor activity was attenuated pre-hemorrhage and at 240 min post-hemorrhage in ENDT-T rats. In late shock, alpha 2 receptor activity was attenuated in nontolerant rats. The development of endotoxin tolerance prevents the loss of arteriolar responsiveness to NE and ACh. ENDT-T rats have attenuated alpha 2 receptor activity but not alpha 1 receptor activity.
Assuntos
Acetilcolina/fisiologia , Arteríolas/fisiopatologia , Endotélio Vascular/fisiologia , Lipopolissacarídeos/toxicidade , Norepinefrina/fisiologia , Choque Hemorrágico/fisiopatologia , Animais , Hemodinâmica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
A prospective study of 104 patients was undertaken to determine the frequency of severe heparin-induced thrombocytopenia in patients receiving either bovine lung or porcine mucosal heparin. One of 54 patients randomized to receive bovine heparin and two of 50 patients randomized to receive porcine heparin developed heparin-induced thrombocytopenia (platelet count less than 100,000/microliters). Although three previous studies suggest a remarkably high frequency of bovine heparin-induced thrombocytopenia, or a high frequency compared to porcine heparin, our study supports other evidence that clinically important, severe heparin-induced thrombocytopenia (platelet count less than 100,000/microliters) occurs in 10 percent of patients or less receiving heparin, and that there is no significant difference of occurrence between bovine and porcine heparin.
Assuntos
Heparina/efeitos adversos , Trombocitopenia/induzido quimicamente , Doença Aguda , Adolescente , Feminino , Humanos , Masculino , Massachusetts , Estudos Prospectivos , Distribuição Aleatória , Trombocitopenia/epidemiologia , Fatores de TempoRESUMO
In the legal context, junk science is defined as evidence that is outside of mainstream scientific or medical views. Junk science does not have indicia of reliability and is not generally accepted. Despite the lack of scientific reliability, US courts, expert witnesses and juries are increasingly reliant on junk science in making causation decisions in complex medical liability cases. Courts have accepted junk science even where reliable scientific evidence is available. The United States silicone gel breast implant litigation is a prime example of this phenomenon. The issue of whether silicone breast implants are associated with disease has been a controversial subject for scientists and physicians, an emotional issue for women who have breast implants, and a lucrative business for the lawyers and expert witnesses who are the proponents of junk science. Junk science has provided to juries a quick and convenient explanation for claimed diseases or syndromes which have required years for reliable scientists to conclude are not related to breast implants. The breast implant litigation highlights the often dramatic difference between decisions based upon junk science and decisions grounded in scientific method, fact and reality. Recently, judges involved in the breast implant litigation have become concerned about the use of junk science in light of the growing body of legitimate scientific evidence that breast implants do not cause disease. Several judges have been motivated to take the unique and novel approach of convening scientific panels of independent experts to study the scientific issues and make findings to the court. Through the use of independent scientific experts, several judges have meaningfully assessed the evidence that the litigants present and have prevented or strictly limited the use of junk science in the courtroom. Using this procedure, other judges are weighing the evidence for future cases. This paper will briefly explore the background of mass tort medical products litigation and the development of junk science. The paper will then focus on the history of the breast implant litigation and the steps that the courts have already taken to combat junk science, including the use of scientific panels.
Assuntos
Equipamentos e Provisões , Prova Pericial/normas , Jurisprudência , Próteses e Implantes , Materiais Biocompatíveis , Feminino , Humanos , Comitê de Profissionais/normas , Estados UnidosRESUMO
Complementary data acquired with different microscopy techniques provide a basis for establishing a more comprehensive understanding of health and disease at a cellular level, particularly when data acquired with different methodologies can be correlated in both time and space. In this Communication, a brief description of a novel instrument capable of simultaneously performing confocal optical and magnetic resonance microscopy is presented, and the first combined images of live Xenopus laevis oocytes are shown. Also, the potential benefits of combined microscopy are discussed, and it is shown that the a priori knowledge of the high-resolution optical images can be used to enhance the boundary resolution and contrast of the MR images.
Assuntos
Imageamento por Ressonância Magnética , Microscopia Confocal , Oócitos/ultraestrutura , Animais , Desenho de Equipamento , Microscopia de Fluorescência , XenopusRESUMO
There is increasing evidence that the cerebrovasculture may be involved in the pathology of Alzheimer's disease. Here, we report that potassium channel openers (KCOs) inhibit dose and time dependent necrosis induced by beta-amyloid (Abeta) in cultured vascular endothelial cells. Cell proliferation rate was assayed by a colorimetric method. Abeta cytotoxicity and inhibition by the K(ATP) channel opener diazoxide and the K(Ca) channel opener NS1619 was correlated with changes in nitric oxide (NO) production. The protective effects were partly blocked by potassium channel blockers. Toxicity of Abeta and KCO protection was verified by histological examination of endothelial cells with scanning electron microscopy. eNOS levels in endothelial cells were not changed by any of the treatments. The results suggest that disruption of K(+) channels function may be a critical step in Abeta-induced cytotoxicity in endothelial cells by alteration of NO release.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/toxicidade , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Canais de Potássio/fisiologia , Animais , Benzimidazóis/farmacologia , Encéfalo/irrigação sanguínea , Bovinos , Células Cultivadas , Diazóxido/farmacologia , Endotélio Vascular/ultraestrutura , Glibureto/farmacologia , Tetraetilamônio/farmacologiaRESUMO
Adolescent boys (N = 128) from a maximum security prison for juvenile offenders were administered a task to assess hostile attributional biases. As hypothesized, these biases were positively correlated with undersocialized aggressive conduct disorder (as indicated by high scores on standardized scales and by psychiatric diagnoses), with reactive-aggressive behavior, and with the number of interpersonally violent crimes committed. Hostile attributional biases were found not to relate to nonviolent crimes or to socialized aggressive behavior disorder. These findings held even when race and estimates of intelligence and socioeconomic status were controlled. These findings suggest that within a population of juvenile offenders, attributional biases are implicated specifically in interpersonal reactive aggression that involves anger and not in socialized delinquency.
Assuntos
Agressão/psicologia , Hostilidade , Delinquência Juvenil/psicologia , Desenvolvimento da Personalidade , Adolescente , Humanos , Masculino , Testes de Personalidade , Meio SocialRESUMO
The functional importance of Ca++ activated K+ (K(Ca)) channels in cGMP mediated relaxation of pressurized septal arteries (internal basal diameter 213 +/- 4 microm) was investigated. Vascular tone was increased by the thromboxane A2 analogue, U-46619 and internal pressure was maintained at 60 mmHg. Vessels were tested with an endothelium independent agonist (nitroprusside) and endothelium dependent agonist (acetylcholine) of nitric oxide which activates soluble guanylate cyclase. Receptor activation of particulate guanylate cyclase was tested by atrial natriuretic peptide. Direct changes in intracellular cGMP concentration were done with the cell permeable analog, 8-Bromo-cGMP. Tetraethylammonium ion (TEA+), 1 mM, significantly inhibited relaxation to nitroprusside from 10(-7) to 10(-3) M with a maximal inhibition of 53 +/- 8% at 10(-3) M. Relaxation to acetylcholine from 10(-9) M to 10(-5) M was significantly inhibited by TEA+ with a maximal inhibition of 52 +/- 13% at 10(-7) M. TEA+ significantly inhibited relaxation to 8-Bromo-cGMP from 10(-6) M to 10(-3) M with a maximal inhibition of 59 +/- 14% at 10(-4) M. The relaxation response to atrial natriuretic peptide from 10(-12) M to 10(-7) M was significantly inhibited by TEA+ with a maximal inhibition of 84 +/- 5% at 10(-11) M. The large conductance K(Ca) channel blocker, iberiotoxin, eliminated the relaxation response to 8-Bromo-cGMP (10(-3) M). The results suggest that a large portion of the dilator action of cGMP is mediated by effects on K+ membrane channels.
Assuntos
Cálcio/farmacologia , Vasos Coronários/fisiologia , GMP Cíclico/análogos & derivados , GMP Cíclico/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Canais de Potássio/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Acetilcolina/farmacologia , Animais , Fator Natriurético Atrial/farmacologia , Vasos Coronários/efeitos dos fármacos , GMP Cíclico/farmacologia , Técnicas In Vitro , Músculo Liso Vascular/efeitos dos fármacos , Nitroprussiato/farmacologia , Peptídeos/farmacologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Ratos , Venenos de Escorpião/farmacologia , Tetraetilamônio , Compostos de Tetraetilamônio/farmacologia , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacologia , Vasoconstritores/farmacologiaRESUMO
The hypothesis for this study is that block of calcium activated potassium (KCa) channels inhibits cAMP induced relaxation in pressurized rat coronary resistance arteries. Pressure-diameter experiments with septal arteries (200-270 microns internal diameter at 60 mmHg and maximum dilation) showed significant basal tone over a range of pressure from 40-120 mmHg. The level of tone was increased with the thromboxane A2 analogue 9,11-dideoxy-11 alpha, 9 alpha-epoxy-methanoprostaglandin F2 alpha (U46619) in all experiments. Receptor activation of the cAMP pathway was done with adenosine (ADO) and isoproterenol (ISO). Tetraethylammonium ion (TEA+), 1mM, significantly inhibited relaxation to ADO (10(-6)-10(-3)M) with a maximal inhibition of 75 +/- 7% (as a % of maximum diameter change with the vasodilator alone) at 10(-3)M ADO. TEA+ inhibited ISO (10(-6)M) relaxation by 63 +/- 9%. Direct activation of the cAMP pathway was done with forskolin and 8-bromo-cAMP. TEA+ significantly inhibited forskolin (10(-6)-10(-4)M) induced relaxation with a maximal inhibition of 81.3 +/- 1.2% at 10(-4)M forskolin. TEA+ and iberiotoxin (10(-7)M) significantly inhibited 8- bromo-cAMP (10(-3)M) induced relaxation by 72 +/- 5% and 56 +/- 3% respectively. The effect of TEA+ on relaxation induced by nitroprusside (a cGMP dependent vasodilator) was not significant. The results show that rat coronary resistance arteries possess significant myogenic tone and modulation of Kca channels plays a major role in cAMP mediated relaxation.
Assuntos
Cálcio/metabolismo , Vasos Coronários/efeitos dos fármacos , AMP Cíclico/metabolismo , Bloqueadores dos Canais de Potássio , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Adenosina/farmacologia , Animais , Vasos Coronários/metabolismo , Vasos Coronários/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Nitroprussiato/farmacologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Ratos , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacologia , Resistência Vascular/efeitos dos fármacosRESUMO
The hypothesis for this study is that the decreased arterial response to catecholamines may be due to the effect of endotoxemia on vessel tone. One control ring was taken from one femoral artery of a Wistar rat and after endotoxin (ENDT) infusion (i.v. 6 mg/kg-1 hr.), one ring was removed from the contralateral artery. The post-ENDT rings were tested in four groups which were determined by the mean arterial pressure (MAP) levels at the time of dissection: 100 mmHg (120 min), 80 mmHg (270 min), 60 mmHg (300 min) or 40 mmHg (330 min). KCl, phenylephrine (PHE) and arginine-vasopressin (AVP) dose-response curves (DR) were obtained at a preload of 500 mg which allowed the maximum response in control rings. When compared at 500 mg preload the maximal active response to all agonists post-ENDT was decreased by about 50%. By increasing the preload on the ENDT rings to 800 mg, the active tension became 2.49 times the active tension of the control rings. Length-tension experiments also showed a greater response for post-ENDT rings and a greater preload at maximum response but the ring circumference was the same. In contrast the in vivo femoral artery diameters at 90 min post-ENDT (100 mmHg) were 82.6% of control. Endothelium-dependent relaxation by acetylcholine (ACh) was abolished by ENDT but endothelium-independent relaxation to nitroprusside (NP) was not affected. It is concluded that the resting tone and active tension of femoral artery smooth muscle is increased by ENDT and the decreased in vivo responsiveness to vasoconstrictor agonists may be the result of vessel constriction due to loss of endothelium. The results also suggest that in vitro comparison of vessels in studies of endotoxin shock be done at the same muscle length rather than at the same preload.
Assuntos
Artéria Femoral/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Choque Séptico/fisiopatologia , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Acetilcolina/farmacologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Arginina Vasopressina/farmacologia , Bradicinina/farmacologia , Artéria Femoral/fisiopatologia , Técnicas In Vitro , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico/antagonistas & inibidores , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , ômega-N-MetilargininaRESUMO
Several series of experiments are reported that investigate learning in the Africanized honey bee. In the first series, classical conditioning of proboscis extension was studied by confining bees to small metal tubes where they received pairings of an odor with a 3-s feeding of sucrose. After a number of odor-sucrose pairings, the bees began to extend their proboscis to the odor. Controls include Unpaired, Discrimination, and Pseudoconditioning Groups. This technique was used to look at conditioning to a light CS, and to the odors of beeswax, geraniol, citral, and hexanal. The results indicate that acquisition was best when sucrose was paired with the odor of beeswax. Conditioning to the remaining odors was roughly similar, but acquisition did not occur using a light. In a second series of experiments, odors were no longer followed by sucrose feedings and the conditioned response slowly disappeared. With the exception of geraniol as a CS, this extinction effect did not occur if the animals continued to be fed on an unpaired schedule. In a third series of experiments, conditioned inhibition was demonstrated when geraniol was used as conditioned stimuli, but no effect was found when the odors of hexanal, citral and wax were used. In a fourth series of experiments, unrestrained bees flew back and forth from the laboratory to the hive, where they were taught to distinguish targets based on color and odor. With this technique, color and odor discrimination in the Africanized bees was demonstrated. In addition, it was found that more intruder bees visited the experimental station when the stimuli used were olfactory rather than visual.
Assuntos
Abelhas/fisiologia , Comportamento Animal/fisiologia , Aprendizagem/fisiologia , AnimaisRESUMO
beta-amyloid (A beta), the major component of senile plaques in Alzheimer's disease (AD), normally circulates in the blood at nanomolar levels but is elevated in AD. Previous studies have found that high concentrations (10(-5)-10(-4) M) of A beta result in neuronal cell death. Here we show that physiological levels of soluble A beta can induce dysfunction in perfused rat cerebral vessels and in cultured endothelial cells. At concentrations of 10(-9)-10(-6) M, A beta induced a significant concentration-dependent reduction of NO production in endothelial cells. At 10(-8) M, A beta significantly decreased the sensitivity of cerebral vessels to acetylcholine (ACh), an endothelium dependent vasodilator. At 10(-7) M and higher concentrations, A beta significantly reduced the maximum response of vessels to ACh, and induced significant endothelial cell death. A beta (10(-9)-10(-5) M) did not cause any detectable change in nitric oxide synthase levels. The results suggest that a modest increase in the concentration of A beta above its normal physiological level in the circulation, as found in the early stages of AD, results in decreased NO production and vessel sensitivity to endothelium-dependent vasodilation that could lead to constricted blood vessels and ischemia in the surrounding tissue. Further increases in A beta concentration, which may occur in the later stages of AD, result in cell death and decreased maximum vasodilator response of cerebral vessels.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Morte Celular/fisiologia , Artérias Cerebrais/metabolismo , Transtornos Cerebrovasculares/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico/biossíntese , Acetilcolina/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Morte Celular/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Artérias Cerebrais/efeitos dos fármacos , Artérias Cerebrais/fisiopatologia , Circulação Cerebrovascular/fisiologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
beta-Amyloid toxicity plays a central role in the pathology of Alzheimer's disease. Contraction and relaxation responses of pressurized rat posterior cerebral artery were studied before and after in vitro exposure to beta-amyloid. The peptide-induced characteristic features of endothelial dysfunction including enhanced vasoconstriction with serotonin and diminished relaxation to endothelium-dependent vasodilators acetylcholine and bradykinin. Response to the endothelium-independent vasodilator nitroprusside was not affected by beta-Amyloid. beta-amyloid inhibition of acetylcholine-induced vasodilation was prevented by the oxygen radical scavenging enzyme superoxide dismutase. Endothelial destruction and the protective effect of superoxide dismutase was verified by electron microscopy. The results suggest that beta-amyloid peptide produces endothelial dysfunction in cerebral microvessels through reactive oxygen species.