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1.
Br J Biomed Sci ; 73(4): 163-167, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27922431

RESUMO

BACKGROUND: Five key factors enabling a good surgical grossing technique include a flat uniformly perpendicular specimen cutting face, appropriate immobilisation of the tissue specimen during grossing, good visualisation of the cutting tissue face, sharp cutting knives and the grossing knife action. TruSlice and TruSlice Digital are new innovative tools based on a guillotine configuration. The TruSlice has plastic inserts whilst the TruSlice Digital has an electronic micrometre attached: both features enable these dissection factors to be controlled. The devices were assessed in five hospitals in the UK. MATERIAL AND METHODS: A total of 267 fixed tissue samples from 23 tissue types were analysed, principally the breast (n = 32) skin (30), rectum (28), colon (27) and cervix (17). Precision and accuracy were evaluated by measuring the defined thickness, and the consistency of achieving the defined thickness of tissue samples taken respectively. Both parameters were expressed as a total percentage of compliance for the cohort of samples accessed. RESULTS: Overall, the mean (standard deviation) score for precision was 81 (11) % whilst the accuracy score was 82 (11) % (both p < 0.05, chi-squared test), although this varied with type of tissue. Accuracy and precision were strongly correlated (rp = 0.83, p < 0.001). CONCLUSION: The TruSlice Digital devices offer an assured precision and accuracy performance which is reproducible across an assortment of tissue types. The use of a micrometre to set tissue slice thickness is innovative and should comply with laboratory accreditation requirements, alleviating concerns of how to tackle issues such as the 'measurement of uncertainty' at the grossing bench.


Assuntos
Desenho de Equipamento , Microdissecção/instrumentação , Microtomia/instrumentação , Especificidade de Órgãos , Equipamentos e Provisões/normas , Feminino , Humanos , Masculino , Microdissecção/métodos , Microtomia/métodos , Reprodutibilidade dos Testes
2.
J Clin Oncol ; 17(7): 2144-52, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10561270

RESUMO

PURPOSE: To describe quality-of-life considerations in post-remission therapies for children with acute myelogenous leukemia. PATIENTS AND METHODS: A quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) method, was applied to Pediatric Oncology Group Trial 8821, which compared randomized assignment with intensive consolidation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). Nonrandomized assignment to allogeneic bone marrow transplantation (allo BMT) on the basis of availability of a matched related donor was also evaluated. A 25-patient cohort provided data for modeling chronic graft-versus-host disease. The Q-TWiST analysis was performed based on the intent-to-treat principle. RESULTS: As previously reported, the 3-year event-free survival was not significantly different between the randomized arms (CC v ABMT). At a median follow-up of 5 years (of the censoring distribution), the CC group had less time in toxicity (TOX) and more time without symptoms or toxicity (TWiST), relapse-free time, and alive time than patients assigned to ABMT (none of these were statistically significant). Compared with the CC group, allo BMT patients spent more time in TOX (P <.001), more time in TWiST (P =.06), and had more relapse-free time (P =.03) and time alive (P =.07). Allo BMT was superior to ABMT with greater time in TWiST (P =.02), relapse-free time (P =.01), and time alive P =.002). CONCLUSION: The Q-TWiST analysis is a powerful decision aid in choosing among alternative therapies. Prospective information on patient preferences will facilitate future trials evaluating treatment outcomes. Refinements in the Q-TWiST method could be included to further enhance the power of this patient care decision-making tool.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Medula Óssea , Técnicas de Apoio para a Decisão , Leucemia Mieloide/terapia , Qualidade de Vida , Doença Aguda , Transplante de Medula Óssea/efeitos adversos , Criança , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Leucemia Mieloide/mortalidade , Análise de Sobrevida , Estados Unidos/epidemiologia
3.
J Bone Joint Surg Br ; 87(11): 1502-6, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16260667

RESUMO

We analysed at a mean follow-up of 7.25 years the clinical and radiological outcome of 117 patients (125 knees) who had undergone a primary, cemented, modular Freeman-Samuelson total knee replacement. While the tibial and femoral components were cemented, the patellar component was uncemented. A surface-cementing technique was used to secure the tibial components. A total of 82 knees was available for radiological assessment. Radiolucent lines were seen in 41 knees (50%) and osteolytic lesions were seen in 13 knees (16%). Asymptomatic, rotational loosening of the patellar implant was seen in four patients and osteolysis was more common in patients with a patellar resurfacing. Functional outcome scores were available for 41 patients (41 knees, 35%) and the mean Western Ontario McMasters Universities score was 77.5 (sd 19.5) and the cumulative survival was 93.4% at ten years with revision for aseptic loosening as an endpoint. Increased polyethylene wear from modular components, a rotationally-loose patella, and the surface-cementing technique may have contributed to the high rate of osteolysis seen in our study.


Assuntos
Artroplastia do Joelho/efeitos adversos , Cimentos Ósseos , Osteólise/etiologia , Idoso , Artroplastia do Joelho/métodos , Feminino , Seguimentos , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/fisiopatologia , Prótese do Joelho , Masculino , Pessoa de Meia-Idade , Osteólise/diagnóstico por imagem , Polietileno , Falha de Prótese , Infecções Relacionadas à Prótese/cirurgia , Radiografia , Reoperação , Análise de Sobrevida , Resultado do Tratamento
4.
Br Dent J ; 219(12): 583-7, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26679138

RESUMO

INTRODUCTION: Molar-incisor-hypomineralisation (MIH) has been identified in recent years as a condition affecting the first permanent molars and, in some cases, the permanent incisors. Many factors have been suggested as to its aetiology. Examples of MIH have also been reported in skeletal remains in the past. These historical examples have, however, been for unknown individuals. CASE REPORT: A skull that has become available for dental examination that is uncertainly attributed to be that of Lady Eleanor Talbot (c.1436-1468) who ended her life as a Carmelite nun in Norwich (England). The dental findings of the examination showed enamel defects of molar teeth 36 and 46, as well as small areas on other molars, and striations of the enamel of permanent anterior teeth consistent with MIH. There is exposure of the roots of some maxillary teeth with resultant root caries. The presence of areas of enamel decalcification commensurate with 'Turner teeth' on 43 and 44 indicates that there were likely to have been periapical abscesses secondary to dental caries of the primary teeth. In addition, there is occlusal wear of all of teeth with extensive calculus and periodontal exposure of the roots of the mandibular incisors. Failed development or very early ante-mortem loss of premolars 15 and 25 is evident, as well as evidence in the same region of a large abscess cavity with extensive maxillary bone destruction. Healing cribra orbitalia, porosity, which is considered to be an indicator of nutritional stress, is visible on the superior aspect of the left orbit. CONCLUSION: A case of MIH is reported in a skull dating from the mid-15th century.


Assuntos
Hipoplasia do Esmalte Dentário , Feminino , História Medieval , Humanos
5.
J Clin Endocrinol Metab ; 80(10): 2869-72, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7559867

RESUMO

The combination of neurodevelopmental regression and adrenal insufficiency should alert practitioners or emergency room physicians about ALD. Although still unproven, early medical intervention with either gene therapy or bone marrow transplantation may offer more promise to these patients.


Assuntos
Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/psicologia , Transplante de Medula Óssea , Ácidos Erúcicos/uso terapêutico , Deficiências da Aprendizagem/etiologia , Trioleína/uso terapêutico , Adrenoleucodistrofia/terapia , Encéfalo/patologia , Criança , Diagnóstico Diferencial , Gorduras Insaturadas na Dieta/uso terapêutico , Combinação de Medicamentos , Humanos , Aprendizagem , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Exame Físico
6.
Curr Pharm Des ; 8(10): 873-85, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11945137

RESUMO

Interest in kainate receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant kainate receptors have been used to identify and distinguish kainate receptors in neurons. Furthermore, the development of selective antagonists for kainate receptor subtypes has increased our understanding of the functional roles of kainate receptors in neurons and synaptic transmission. In this review we described the activity of agonists and antagonists at kainate receptors and their selectivity profiles at NMDA and non-NMDA receptors.


Assuntos
Agonistas de Aminoácidos Excitatórios/química , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Ácido Caínico/agonistas , Receptores de Ácido Caínico/antagonistas & inibidores , Regulação Alostérica , Animais , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Receptores de Ácido Caínico/genética , Receptores de Ácido Caínico/metabolismo , Receptores de N-Metil-D-Aspartato/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Relação Estrutura-Atividade , Especificidade por Substrato
7.
Neuropharmacology ; 40(8): 984-91, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11406189

RESUMO

The present study describes the pharmacological activity of two novel positive allosteric modulators at AMPA receptors in acutely isolated rat cerebellar Purkinje neurons and cultured rat hippocampal neurons. Currents elicited by application of glutamate (100 microM) to isolated cerebellar Purkinje neurons were potentiated by LY392098, LY404187, cyclothiazide, CX516 and aniracetam. The rank order of potency was LY404187> LY392098> cyclothiazide > CX516> aniracetam. LY392098 displayed a higher maximal efficacy than the other compounds examined. AMPA-activated inward currents in cultured rat hippocampal neurons were potentiated by LY392098, LY404187 and cyclothiazide in a reversible and concentration-dependent manner although considerable heterogeneity in the magnitude of response from cell to cell was observed. LY392098 was ineffective in potentiating AMPA receptor responses when dialyzed via the intracellular solution. The selectivity profiles of the two novel AMPA receptor potentiators were examined. LY392098 or LY404187 had minimal activity on NMDA receptor responses, on voltage-gated calcium channel currents in cultured hippocampal neurons and on GluR5 kainate receptor currents in acutely isolated rat dorsal root ganglion neurons.


Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Células de Purkinje/efeitos dos fármacos , Receptores de AMPA/fisiologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Anti-Hipertensivos/farmacologia , Benzotiadiazinas/farmacologia , Células Cultivadas , Sinergismo Farmacológico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Células de Purkinje/fisiologia , Ratos , Receptores de Ácido Caínico/fisiologia
8.
Neuropharmacology ; 37(10-11): 1261-7, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9849663

RESUMO

The activity of a gamma-substituted glutamate analogue, (2S, 4R, 6E)-2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid (LY339434) and (2S,4R)-4-methylglutamic acid at ionotropic glutamate receptors has been examined. Ligand binding studies were performed using [3H] AMPA binding to membranes expressing either homomeric recombinant GluR1, GluR2, GluR4 receptors, and [3H] kainate binding to GluR5 and GluR6 kainate receptors. LY339434 and (2S,4R)-4-methylglutamic acid showed selectivity in ligand binding studies for kainate receptors over AMPA receptors. Within the kainate class of glutamate receptors, LY339434 showed selectivity for GluR5 over GluR6 whereas (2S,4R)-4-methylglutamic acid showed high affinity for both GluR5 and GluR6 kainate receptors. Examination of the functional activity of LY339434 and (2S,4R)-4-methylglutamic acid showed that both compounds evoked inward currents in dorsal root ganglion neurons (DRG) with estimated EC50 values of 0.8 +/- 0.2 microM and 0.17 +/- 0.04 microM, respectively. In GluR5 expressing HEK 293 cells, LY339434 evoked inward currents with an estimated EC50 value of 2.5 +/- 0.9 microM but had little effect on GluR6 expressing cells at concentrations less than 100 microM. LY339434 was a weak AMPA receptor agonist (EC50 values > 300 microM) as determined by activity in acutely isolated cerebellar Purkinje neurons. LY339434 and (2S,4R)-4-methylglutamic acid had agonist activity at NMDA receptors studied in cultured hippocampal neurons with EC50s of 2.5 microM and 11.7 microM, respectively. These results indicate that both LY339434 and (2S,4R)-4-methyl glutamic acid may be useful pharmacological tools for the examination of kainate receptors.


Assuntos
Aminoácidos/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Glutamatos/farmacologia , Glutaratos/farmacologia , Hipocampo/efeitos dos fármacos , Receptores de AMPA/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Células Cultivadas , Glutaratos/metabolismo , Hipocampo/metabolismo , Potenciais da Membrana/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/metabolismo
9.
Neuropharmacology ; 46(6): 793-806, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15033339

RESUMO

An increasing body of evidence suggests that native kainate receptors form ion channels from homomeric and heteromeric combinations of five receptor subunits: GluR5, GluR6, GluR7, KA1 and KA2. We have examined the activity of agonists and antagonists at recombinant human kainate receptors expressed in HEK293 cells, using both whole-cell electrophysiological recording and 96-well plate fluo-3 based calcium microfluorimetry (FLIPR). Both homomeric (GluR5 and GluR6) and heteromeric (GluR5/6, GluR5/KA2 and GluR6/KA2) receptors were examined. Heteromeric receptor assemblies showed electrophysiological and pharmacological profiles which were distinct from homomeric channels. Several agonists, including AMPA, ATPA and (S)-5-iodowillardiine, and antagonists, including gamma-D-glutamylaminomethylsulphonic acid (GAMS) and the decahydroisoquinoline compounds LY293558, LY377770 and LY382884, were found to act at GluR5-containing channels while having no effect at GluR6 homomers. AMPA, ATPA and (S)-5-iodowillardiine did activate GluR6/KA2 heteromers, but only as partial agonists. Additionally, ATPA was shown to act as an antagonist at homomeric GluR6 receptors at high concentrations (IC50 approximately 2 mM). Kynurenic acid was also found to differentiate between GluR6 and GluR6/KA2 receptors, antagonizing glutamate at GluR6 (IC50 = 0.4 mM), while having no effect at GluR6/KA2 channels. The results of the current study provide a broad pharmacological characterization of both homomeric and heteromeric recombinant human kainate receptors, and identify which compounds are likely to be useful tools for studying these various receptor subtypes.


Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Ácido Caínico/agonistas , Receptores de Ácido Caínico/antagonistas & inibidores , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Receptores de Glutamato/fisiologia , Receptores de Ácido Caínico/fisiologia , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inibidores
10.
Neuropharmacology ; 40(8): 976-83, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11406188

RESUMO

The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.


Assuntos
Cálcio/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Receptores de AMPA/fisiologia , Proteínas Recombinantes/metabolismo , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Anti-Hipertensivos/farmacologia , Benzotiadiazinas/farmacologia , Linhagem Celular , Dioxóis/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Eletrofisiologia , Humanos , Piperidinas/farmacologia , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Glutamato/metabolismo , Receptores de Glutamato/fisiologia
11.
J Med Chem ; 35(17): 3263-9, 1992 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-1507211

RESUMO

Two modes of tethering a chiral (phenylisopropyl)amino substituent in pyrazolo[3,4-d]pyrimidines and purines have been explored. One mode gave (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5- propoxy-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (12a) and its corresponding R-enantiomer 12b, which were selective for A2 and A1 adenosine receptors, respectively. The corresponding diimidazo[1,2-c:4',5'-e]pyrimidines 12e and 12f were analogously selective. This is the first example where a single chiral recognition unit provides enantiomers with opposite selectivities for adenosine receptors. The second mode gave (2S-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5- propoxy-3H-imidazo[1,2-c]-pyrazolo[4,3-e]pyrimidine (12c) and its corresponding R-enantiomer 12d. Compounds 12c and 12d were significantly less potent than 12a and 12b at A1 receptors, and were nonselective.


Assuntos
Purinas/síntese química , Pirazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Purinérgicos/metabolismo , Animais , Córtex Cerebral/metabolismo , Conformação Molecular , Estrutura Molecular , Purinas/metabolismo , Purinas/farmacologia , Pirazóis/síntese química , Pirazóis/metabolismo , Pirimidinas/metabolismo , Ratos , Receptores Purinérgicos/efeitos dos fármacos , Estereoisomerismo
12.
J Med Chem ; 36(25): 4015-20, 1993 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-8258823

RESUMO

Several 8-substituted 1,3-dipropylxanthines were synthesized, and their receptor binding affinities at adenosine A1 and A2 receptors were measured. When enantiomeric pairs of compounds were examined, the R enantiomers were significantly more potent than the corresponding S enantiomers. The most potent compound at the A1 receptor was (R)-3,7-dihydro-8-(1-methyl-2-phenylethyl)-1,3-dipropyl-1H-purine-2,6-di one (5a; MDL 102,503), whose Ki value at the A1 receptor was 6.9 nM. However, a more selective compound was (R)-3,7-dihydro-8-(1-phenylpropyl)-1,3-dipropyl-1H-purine-2,6-dione (5d; MDL 102,234), which had a Ki value of 23.2 nM at the A1 receptor and an A2/A1 ratio of 153.


Assuntos
Antagonistas de Receptores Purinérgicos P1 , Xantinas/síntese química , Sítios de Ligação/efeitos dos fármacos , Receptores Purinérgicos P1/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Xantinas/química , Xantinas/farmacologia
13.
J Med Chem ; 37(1): 125-32, 1994 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-8289185

RESUMO

Selected examples from three series of isomeric (alkylthio)-1,2,4-triazoles were prepared and examined for anticonvulsant activity versus strychnine-, maximal-electroshock-, pentylenetetrazole-, and 3-mercaptopropionic-acid-induced seizures in mice. A number of 5-aryl-3-(alkylthio)-4H-1,2,4-triazoles were selective antagonists of strychnine-induced convulsions. The isomeric 3-aryl-5-(alkylthio)- and 5-aryl-3-(alkylthio)-1H-1,2,4-triazoles were essentially inactive as anticonvulsants. The most potent antagonist of strychnine-induced convulsions was 5-(2-fluorophenyl)-4-methyl-3-(methylthio)-4H-1,2,4-triazole (3s), while the most selective antagonist was 5-(3-fluorophenyl)-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3aa). The anticonvulsant profiles of these 4H-1,2,4-triazoles suggested that they were acting functionally like glycine receptor agonists. Since it has recently been postulated that compounds possessing glycine-agonist-like properties might be useful in the treatment of spasticity, we examined 5-phenyl-4-methyl-3-(methylsulfonyl)-4H-1,2,4-triazole (3c) in an in vivo model of spasticity. In this regard, 3c reduced the occurrence of hyperreflexia in rats that had received spinal transections 5-10 weeks previously. While triazole 3c appeared to possess glycine-agonist-like properties in vivo, it did not displace [3H]strychnine binding from rat brain stem/spinal cord membranes in vitro. On the other hand, 3c enhanced muscimol-stimulated 36Cl influx in a rat cerebellar membrane preparation, indicating a possible interaction of these triazoles with the GABAA receptor.


Assuntos
Anticonvulsivantes/uso terapêutico , Espasticidade Muscular/tratamento farmacológico , Paralisia , Convulsões/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Anticonvulsivantes/química , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cloretos/metabolismo , Eletrochoque , Flumazenil/metabolismo , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/etiologia , Relação Estrutura-Atividade , Estricnina , Triazóis/química , Triazóis/farmacologia
14.
Br J Pharmacol ; 106(4): 910-6, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1327393

RESUMO

1. Strychnine-sensitive glycine receptors are primarily localized in the brainstem and spinal cord where they are the major mediators of postsynaptic inhibition. A compound which acts functionally like a glycine receptor agonist would be potentially useful as a pharmacological tool and as a therapeutic agent for treating disorders of glycinergic transmission. 2. MDL 27,531 (4-methyl-3-methylsulphonyl-5-phenyl-4H-1,2,4-triazole) blocked strychnine-induced tonic extensor seizures in mice following either intraperitoneal (ED50 = 12.8 mg kg-1; 30 min) or oral (ED50 = 7.3 mg kg-1; 30 min) administration. Time course studies revealed a maximal effect at 30-60 min, though significant activity was still seen after 24 h. 3. MDL 27,531 was selective in antagonizing strychnine seizures and little or no activity was seen against seizures produced by other chemical convulsants (bicuculline; quinolinic acid; mercaptopropionic acid); by electrical stimuli (maximal electroshock); or by sensory stimuli (audiogenic seizure susceptible mice). MDL 27,531 blocked pentylenetetrazol-induced seizures with an ED50 = 55 mg kg-1. This profile differed from those of the anticonvulsants diazepam, valproic acid, and diphenylhydantoin. 4. The antagonism of strychnine seizures by MDL 27,531 occurred at doses that did not produce signs of sedation (suppression of spontaneous motor activity), motor ataxia (disruption of rotarod performance), muscle relaxation (inhibition of morphine-induced Straub tail), or CNS depression (potentiation of hexobarbitone sleep time). MDL 27,531 had less side effect potential (as derived from ratios obtained from the above measures) relative to those of the known muscle relaxants diazepam and baclofen. 5. Although MDL 27,531 behaved functionally like a selective agonist at the strychnine-sensitive glycine receptor, the compound did not alter the in vitro binding of [3H]-strychnine to mice brainstem/spinal cord membranes at concentrations of up to 100 microM. In further in vitro binding assays, MDL 27,531 at concentrations of up to 100 microM, did not displace the binding of [3H]-muscimol, [3H]-flunitrazepam, or["S]-t-butylbicyclophosphorthionate to rat cortical membranes. These ligands bind to the 7y-aminobutyric acid (GABA), benzodiazepine, and picrotoxin-convulsant binding sites, respectively.6. MDL 27,531 (10-100mgkg-', i.p.) enhanced binding of the benzodiazepine antagonist [3H]-Ro15-1788 to mouse cerebral cortex in vivo without directly affecting GABA levels.7. Ro 15-1788 (16, 32 mg kg-') significantly blocked the MDL 27,531 antagonism of strychnineinduced seizures, though this antagonism was not competitive. The same doses of Ro 15-1788 produced parallel rightward shifts in the dose-response curves for diazepam inhibition of pentylenetetrazol-induced seizures, consistent with a competitive antagonism.8. Thus, MDL 27,531 acts functionally like an agonist at the strychnine-sensitive glycine receptor in its capacity to reverse selectively strychnine-induced seizures. Though the precise mechanism of action of MDL 27,531 is unknown, MDL 27,531 may act at an allosteric site on the strychnine-sensitive receptor which produces agonist-like activity.


Assuntos
Receptores de Glicina , Convulsões/induzido quimicamente , Estricnina/antagonistas & inibidores , Triazóis/farmacologia , Administração Oral , Animais , Estimulação Elétrica , Hipnóticos e Sedativos/farmacologia , Injeções Intraperitoneais , Masculino , Camundongos , Receptores de Neurotransmissores/efeitos dos fármacos , Estricnina/farmacologia , Triazóis/administração & dosagem , Triazóis/efeitos adversos
15.
Bone Marrow Transplant ; 15(6): 997-8, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7581105

RESUMO

We describe a 7-year-old boy who developed acute, airway-threatening, non-infectious epiglottitis following high-dose cytosine arabinoside and total body irradiation preparative regimen for allogeneic BMT. Unlike gastrointestinal symptoms and oropharyngeal mucositis, acute epiglottitis is a previously unreported early complication following allogeneic BMT preparation. The pathogenesis of epiglottitis in our patient was presumably multifactorial, resulting from the combination of chemotherapy and irradiation. We recommend that this diagnosis be considered in the differential diagnosis of patients with significant upper airway symptoms following BMT preparation.


Assuntos
Transplante de Medula Óssea , Citarabina/efeitos adversos , Epiglotite/etiologia , Lesões por Radiação/etiologia , Irradiação Corporal Total/efeitos adversos , Doença Aguda , Criança , Terapia Combinada/efeitos adversos , Epiglote/efeitos dos fármacos , Epiglote/efeitos da radiação , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia
16.
J Am Geriatr Soc ; 49(6): 798-802, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11454121

RESUMO

OBJECTIVE: To test the efficacy of a mailed health survey, which included the Clock Completion Test (CCT), to screen previously undiagnosed older adults for dementia of the Alzheimer's type (DAT) in a community-dwelling population, and to determine whether the addition of selected risk factors for Alzheimer's disease (AD) would enhance the screening instrument's operating characteristics. DESIGN: Comparison of the results of a self-administered screen for DAT with the diagnosis of DAT by clinician evaluation or telephone interviews. SETTING: A geriatric assessment clinic. PARTICIPANTS: Three hundred and five women age 65 and older from St. Louis, Missouri. MEASUREMENTS: The sensitivity and specificity of the CCT and the CCT plus risk factors for AD were evaluated using two standards: The Short Blessed Test (SBT) and the physician diagnosis of probable AD using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. RESULTS: Sensitivity and specificity for the CCT by SBT criteria were 63% and 79%, respectively. Using the physician's assessment as a criterion, the CCT had better sensitivity (67%) but poorer specificity (69%). Adding two or more risk factors for AD improved sensitivity and specificity to 71% and 89% and, in the physician assessment subgroup, to 75% and 87%, primarily by halving the false-positive rate. CONCLUSION: The combination of the simple, self-administered CCT and two or more AD risk factors is a more effective screening instrument for DAT and potentially preclinical DAT than the CCT alone. However, the instrument may be better suited for use in an office setting because of a poor response rate by subjects with dementia.


Assuntos
Doença de Alzheimer/diagnóstico , Avaliação Geriátrica , Programas de Rastreamento/métodos , Testes Neuropsicológicos/normas , Inquéritos e Questionários/normas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Estatura , Correspondência como Assunto , Escolaridade , Terapia de Reposição de Estrogênios/estatística & dados numéricos , Reações Falso-Positivas , Feminino , Humanos , Programas de Rastreamento/psicologia , Programas de Rastreamento/normas , Anamnese/normas , Missouri/epidemiologia , Visita a Consultório Médico , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricos , Exame Físico/normas , Vigilância da População/métodos , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Método Simples-Cego
17.
Eur J Pharmacol ; 378(3): 331-7, 1999 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-10493110

RESUMO

We have examined the pharmacology of kainate receptors in cultured hippocampal neurons (6-8 days in vitro (DIV)) from embryonic rats (E17). Cultured neurons were pre-treated with concanavalin A to remove kainate receptor desensitization and whole-cell voltage clamp electrophysiology employed to record inward currents in response to glutamatergic agonists and antagonists. N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor responses were blocked using MK801 (3 microM) and the 2,3-benzodiazepine, LY300168 (GYKI53655, 50 microM), respectively. Inward currents were recorded in hippocampal neurons upon application of kainate and the 2S,4R isomer of 4-methyl glutamic acid (SYM2081) with EC50 values of 3.4 +/- 0.4 microM and 1.6 +/- 0.5 microM, respectively (n = 6 cells). The GluR5 selective agonists, LY339434 (100 microM) and (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl) propionic acid (ATPA) (100 microM), did not evoke detectable inward currents in any cell responding to kainate. LY293558 and the selective GluR5 antagonist, LY382884, had weak antagonist effects on responses evoked by either kainate or (2S,4R)-4-methyl glutamate (IC50 > 300 microM). The quinoxalinedione, 2,3-dihyro-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), blocked both kainate and (2S,4R)-4-methyl glutamate-activated currents at much lower concentrations (IC50 approximately 10 microM). These results provide pharmacological evidence that ion channels comprised of GluR6 kainate receptor subunits mediate kainate receptor responses in hippocampal neurons cultured 6-8 DIV.


Assuntos
Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Receptores de Ácido Caínico/efeitos dos fármacos , Animais , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Expressão Gênica , Glutamatos/farmacologia , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Ácido Caínico/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Neurônios/citologia , Neurônios/fisiologia , Técnicas de Patch-Clamp , Quinoxalinas/metabolismo , Quinoxalinas/farmacologia , Ensaio Radioligante , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de Ácido Caínico/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tetrazóis/metabolismo , Tetrazóis/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Receptor de GluK2 Cainato
18.
Eur J Pharmacol ; 154(2): 125-34, 1988 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-2465908

RESUMO

Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.


Assuntos
Desipramina/farmacologia , Fluoxetina/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , AMP Cíclico/metabolismo , Di-Hidroalprenolol , Ácido Hidroxi-Indolacético/metabolismo , Técnicas In Vitro , Masculino , Ratos , Ratos Endogâmicos , Serotonina/metabolismo
19.
Crit Rev Biomed Eng ; 28(3 - 4): 445-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11108213

RESUMO

We reported the effect of carbon coating on the changes in properties of the ultra-high-molecular-weight polyethylene standard material (Hospital for Special Surgery) alter gamma irradiation in air and storage for 2 years. The coating showed a slight improvement in crystallinity (X-ray) and tensile properties (under cyclic loading) over the uncoated and irradiated control group. The oxidation level as measured by Fourier- transform infrared spectroscopy was unaffected by coating.


Assuntos
Carbono/química , Materiais Revestidos Biocompatíveis , Raios gama , Teste de Materiais , Polietilenos/química , Polietilenos/efeitos da radiação , Ar , Radicais Livres/química , Oxirredução , Espectroscopia de Infravermelho com Transformada de Fourier , Resistência à Tração , Suporte de Carga
20.
J Orthop Trauma ; 13(7): 483-9, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10513970

RESUMO

OBJECTIVE: The purpose of the present study was to compare the biomechanical stability of C1 and C2 vertebrae after treatment of ligamentous instability by either modified Brooks posterior wiring (MB) or transarticular screw (TAS) techniques. We hypothesized that the TAS technique would be more stable because of direct fixation through the facet joints. STUDY DESIGN: We studied the in vitro stability (arthrodesis) of TAS fixation of C1 and C2 versus that of MB. TAS fixation involves placing screws across the facets from posteriorly at C2 to the anterior surface of C1, plus a bone graft and posterior wiring of C1 and C2. METHODS: Cervical spines from nine individuals with an average age of sixty-two years (range 51 to 71 years) were harvested from cadavers (six male, three female). C1 and the segment from C2 to C5 were potted to allow motion only at the C1-C2 articulation. The specimens were destabilized by cutting the transverse ligament on both sides of the odontoid and the tectorial membrane between C1 and C2. The MB and TAS techniques were performed by methods similar to those described in the literature. The stiffness of the C1-C2 articulation of each specimen was tested under rotation, lateral bending, flexion, and anterior translation in random order. Intact and destabilized specimens fixed with either MB or TAS were tested in sequence. RESULTS: Significantly higher stiffness values in the elastic zone were obtained with the TAS technique than with the MB technique for all modes of testing (p < 0.002, t test). Values for the neutral zone (the region where minimal loads produce displacement) were not significantly different between the MB and TAS techniques (p > 0.1, t test). CONCLUSION: We conclude that stability is significantly enhanced by use of the TAS construct for treatment of ligamentous instability at the atlantoaxial joint for all motions tested in the present study.


Assuntos
Artroplastia de Substituição/métodos , Articulação Atlantoaxial/cirurgia , Parafusos Ósseos , Fios Ortopédicos , Instabilidade Articular/cirurgia , Idoso , Articulação Atlantoaxial/fisiopatologia , Fenômenos Biomecânicos , Densidade Óssea , Feminino , Humanos , Instabilidade Articular/fisiopatologia , Masculino , Pessoa de Meia-Idade
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