RESUMO
BACKGROUND: Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism. METHODS: A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation. RESULTS: With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. CONCLUSION: Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.
Assuntos
Quimiorradioterapia/métodos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Melanoma/terapia , Oximas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Radiossensibilizantes/uso terapêutico , Radiocirurgia , Neoplasias Cutâneas/terapia , Sulfonamidas/uso terapêutico , Irradiação Corporal Total , Adulto , Idoso , Idoso de 80 Anos ou mais , Europa (Continente) , Estudos de Viabilidade , Feminino , Humanos , Imidazóis/efeitos adversos , Indóis/efeitos adversos , Masculino , Melanoma/enzimologia , Melanoma/patologia , Pessoa de Meia-Idade , Oximas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas B-raf/metabolismo , Tolerância a Radiação , Radiossensibilizantes/efeitos adversos , Radiodermite/etiologia , Radiodermite/prevenção & controle , Radiocirurgia/efeitos adversos , Estudos Retrospectivos , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/patologia , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vemurafenib , Irradiação Corporal Total/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: ABT-751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma. OBJECTIVE: Determine a maximum tolerated dose for ABT-751, and assess long-term tolerability and activity in canine lymphoma. ANIMALS: Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non-Hodgkin's lymphoma. METHODS: Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long-term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells. RESULTS: The maximum tolerated dose of ABT-751 was 350 mg/m(2) PO q24h. Dose-limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m(2) PO q48h. ABT-751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs). CONCLUSION: ABT-751 was well tolerated at 350 mg/m(2) PO q24h for 7 days and then q48h thereafter. Activity of ABT-751 suggested a rationale for additional studies of ABT-751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.
Assuntos
Antimitóticos/administração & dosagem , Antimitóticos/efeitos adversos , Doenças do Cão/tratamento farmacológico , Linfoma não Hodgkin/veterinária , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Administração Oral , Animais , Antimitóticos/sangue , Estudos de Coortes , Doenças do Cão/patologia , Cães , Relação Dose-Resposta a Droga , Feminino , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Masculino , Dose Máxima Tolerável , Sulfonamidas/sangueRESUMO
BACKGROUND AND PURPOSE: The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models. EXPERIMENTAL APPROACH: In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups. KEY RESULTS: In adult rats, [3H]-A-349821, 1.5 microg x kg(-1), penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response. CONCLUSIONS AND IMPLICATIONS: When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists.
Assuntos
Compostos de Bifenilo/farmacologia , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Autorradiografia , Aprendizagem da Esquiva/efeitos dos fármacos , Ligação Competitiva , Compostos de Bifenilo/farmacocinética , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Técnicas In Vitro , Masculino , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual , TrítioRESUMO
STUDY DESIGN: The effect of long-term (4 weeks) moderate locomotor exercise on segmental distribution of glutamate (Glu), aspartate, gamma-aminobutyric acid, glycine (Gly), serotonin and noradrenaline in the spinal cord of adult rats was investigated. OBJECTIVES: In light of the data showing modulation of some neurotransmitters in the low-lumbar segments of the rat due to physical exercise, our aim was to establish how segmentally specific is this effect with respect to neuroactive amino acids and monoamines. SETTING: Laboratory of Reinnervation Processes, Department of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland. METHODS: Amino acids and monoamines content was measured by means of HPLC in the whole tissue homogenate of the spinal cord in nonexercised and exercised rats. RESULTS: Glu and Gly homogenate concentration was the highest among all tested compounds. There was an intersegmental rostro-caudal gradient of concentration of neuroactive amino acids and monoamines, progressing caudally. Exercise modified this gradient exerting opposite effect on their concentration of amino acids and monoamines in the rostral and caudal lumbar segments. CONCLUSION: Locomotor exercise leads to neurochemical remodeling of the spinal cord, which is differently manifested in the rostral and caudal lumbar segments of the spinal cord.
Assuntos
Aminoácidos/metabolismo , Monoaminas Biogênicas/metabolismo , Atividade Motora/fisiologia , Condicionamento Físico Animal/métodos , Medula Espinal/metabolismo , Animais , Comportamento Animal , Cromatografia Líquida de Alta Pressão/métodos , Região Lombossacral , Masculino , Ratos , Ratos WistarRESUMO
Even experienced medical advisors need clear guidelines on the extent and form of expert opinions presented to courts of law. The importance of thorough document study, correctly organizing findings, and carefully weighing the various factors influencing an opinion cannot be stressed enough. Presented here is a sample opinion for German civil court trials at the state level. It illustrates how best to combine research and clinical results, personal professional experience, and citations from the literature to structure legally valid evidence in the form of an expert opinion. The importance of cogent response to examiners' and cross-examiners' questions is demonstrated, as are differences between civil and criminal proceedings. An appendix cites the appropriate passages from the German legal code concerning remuneration for expert opinions.
Assuntos
Certificação , Prova Pericial , Cirurgia Geral , Imperícia/legislação & jurisprudência , Prova Pericial/legislação & jurisprudência , Alemanha , HumanosRESUMO
During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
Assuntos
Antineoplásicos/síntese química , Oxazóis/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Cromatografia Líquida de Alta Pressão , Colchicina/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Oxazóis/química , Oxazóis/farmacologia , Relação Estrutura-Atividade , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Assuntos
Compostos de Bifenilo/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Antineoplásicos/sangue , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Área Sob a Curva , Disponibilidade Biológica , Compostos de Bifenilo/sangue , Compostos de Bifenilo/síntese química , Divisão Celular/efeitos dos fármacos , Cães , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Haplorrinos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/síntese química , Concentração Inibidora 50 , Injeções Intravenosas , Taxa de Depuração Metabólica , Neoplasias Experimentais/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
INTRODUCTION AND METHODS: Locomotor training leads to improvement of stepping ability in animals after spinal cord transection (1). Recent data point to neurotrophins as possible factors involved in this improvement. Motoneurones synthesising BDNF, NT-4 and NT-3 are a potent source of neurotrophins for the spinal network (2, 3). Physical exercise increases BDNF neurotrophin gene expression in the rat hippocampus (4). If exercise enhances BDNF expression also in the spinal cord, upregulation of its receptor Trk B may occur. To verify this hypothesis we tested whether exercise influences TrkB receptor system in the spinal cord. Six adult, male Wistar rats walked on the treadmill five days a week, 1,000 m daily with the speed of 20 to 25 cm/s. After 4 weeks of training animals were anaesthetised with pentobarbital sodium (80 mg/kg b.w.) and perfused with 0.01 M PBS followed by 2% paraformaldehyde and 0.2% parabenzoquinone in 0.1 M PB. Three non-trained animals were used as controls. Cryostat 40 microns sections were processed free-floating with TrkB polyclonal antibody (1:1,000, Santa Cruz) and ABC Vectastain detection system. Sections were examined under Nikon light microscope and analysed with Image-Pro Plus 4 software. RESULTS AND DISCUSSION: TrkB immunoreactivity (IR) was detected in number of spinal cells at the lumbar level in non-trained animals (Fig. 1A). The strongest IR appeared in the perikarya and processes of small diameter cells rarely scattered in the grey and white matter. The average area of these cells was 50 micron 2 (+/- 10). Exercise increased by over 50% the number of TrkB immunostained small cells (Fig. 1B). An enhancement of perikaryonal immunostaining of these cells was also observed (Fig. 1B, inset). Testing the identity of Trk B IR small diameter cells did not prove their astroglial (GFAP IR) and gabaergic (GAD IR) phenotype in the grey matter. Some of TrkB IR cells in the white matter were astrocytes. Our data point to physical exercise as a potent method to make spinal cells more receptive to neurotrophic stimuli.
Assuntos
Atividade Motora/fisiologia , Neurônios/metabolismo , Condicionamento Físico Animal/fisiologia , Receptor trkB/metabolismo , Medula Espinal/metabolismo , Animais , Tamanho Celular , Masculino , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Medula Espinal/citologiaRESUMO
A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
Assuntos
Quimiocinas CC , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares , Inibidores da Síntese de Proteínas/síntese química , Pirazóis/síntese química , Fatores de Transcrição/metabolismo , Animais , Asma/tratamento farmacológico , Divisão Celular , Quimiocina CCL11 , Técnicas de Química Combinatória , Ciclosporina/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Genes Reporter , Haplorrinos , Humanos , Imunossupressores/síntese química , Imunossupressores/química , Imunossupressores/farmacologia , Técnicas In Vitro , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Interleucina-4/antagonistas & inibidores , Interleucina-4/biossíntese , Interleucina-5/antagonistas & inibidores , Interleucina-5/biossíntese , Interleucina-8/antagonistas & inibidores , Interleucina-8/biossíntese , Células Jurkat , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Luciferases/genética , Fatores de Transcrição NFATC , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , RatosRESUMO
The entry of calcium and magnesium from external sources into mycorrhizal roots of 3-year-old Norway spruce trees (Picea abies [L.] Karst.) was monitored. Roots of intact plants were exposed for various periods of time, ranging from 2 min to 48 h, to nutrient solutions which contained the stable-isotope tracers 25Mg and 44Ca. After labelling, samples of roots were excised from the plants, shock-frozen, cryosubstituted and embedded. The resulting isotope composition in this material was analysed by a laser-microprobe-mass-analyser (LAMMA) at relevant positions within cross-sections of the roots. For both elements, we determined (i) the fractions of the isotopes originating from the plant prior to labelling, and (ii) the fraction of isotopes originating from the corresponding tracer that penetrated into the root. Both divalent cations rapidly penetrated across the cortical apoplast and reached the endodermis. After 2 min of exposure to the labelling solution, an initial transient gradient of the tracers could be observed within the root cortex. Subsequently, calcium as well as magnesium equilibrated between the apoplast of the entire cortex and the external tracer with a half-time, t1/2, of about 3 min. In contrast, the kinetics of radial movement into the vascular stele showed a delay with a t1/2 of 100-120 min. We take this as strong evidence that there exists a free apoplastic path for divalent cations in the cortex and that the endodermis is a major barrier to the further passage of Mg and Ca into the xylem. While 25Mg in the labelling solution exchanged rapidly with Mg in the cortical apoplast, the exchange across the plasma membrane with Mg present in the protoplasm of the same cortical cells was almost 2 orders of magnitude slower. The kinetics of Ca and Mg entry at + 6 degrees C were similar to those obtained at a root temperature of +22 degrees C.
Assuntos
Cálcio/metabolismo , Magnésio/metabolismo , Árvores/metabolismo , Isótopos de Cálcio , Isótopos , Cinética , Raízes de Plantas/metabolismoRESUMO
This essay discusses the effects of globalization on the German health care system. Globalization is regarded as a process to a "One-World-Society" without limits or borders to communication. Especially the economic effects of globalization are discussed, and the reduction of working places and wage levels in developed industrial societies, caused by globalization. Considering this development, it will not be possible to uphold present health care standards.
Assuntos
Saúde Global , Programas Nacionais de Saúde/economia , Garantia da Qualidade dos Cuidados de Saúde/economia , Controle de Custos/tendências , Previsões , Alemanha , HumanosRESUMO
The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Receptores do Fator de Necrose Tumoral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzilaminas/síntese química , Benzilaminas/farmacologia , Inibidores Enzimáticos/farmacologia , Éteres/síntese química , Éteres/farmacologia , Humanos , Camundongos , Camundongos Nus , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Receptor fasRESUMO
Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Compostos de Epóxi/síntese química , Células 3T3 , Animais , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/farmacocinética , Compostos de Epóxi/farmacologia , Genes ras/efeitos dos fármacos , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
To assess the duration of immunosuppression in FK506-dosed pigs, an undiluted whole blood assay was established to measure reactivities of T cells in their physiological milieu. PMA and ionomycin were shown to induce IL-2 production in swine blood. The IC50 of FK506 in inhibiting IL-2 production in whole blood and isolated PBMC stimulated with PMA and ionomycin measured 1.2 and 0.04 nM, respectively. These data underscore the influence of red blood cells and plasma proteins on drug potency. IL-2 levels were determined in blood drawn immediately before and 1, 24, 48, and 72 h after iv dosing. For pigs dosed with 0.05 mg/kg, 50% recovery of IL-2 production was observed at 16 h and 100% at 35 h after dosing. For pigs dosed with 0.15 mg/kg, 50% recovery was observed at 38 h and 100% at 72 h. Blood concentrations of FK506 at 50 and 100% recovery of IL-2 production measured 10.8 and 2.2 nM for pigs dosed with 0.05 mg/kg and 6.1 and 1.1 nM for pigs dosed with 0.15 mg/kg, respectively. These concentrations are severalfold higher than predicted from the IC50 of FK506 for inhibiting IL-2 production in the whole blood assay. These data suggest that the true potency of FK506 in blood after dosing is influenced by additional factors, which could include plasma protein binding, the presence of active or interfering metabolites, serum interfering factors, and sequestration of drug in blood cells. Our results demonstrate the utility of an undiluted whole blood assay for assessing the duration of immunosuppression in drug-dosed animals and emphasize the importance of assessing drug potency in the whole blood environment ex vivo.
Assuntos
Imunossupressores/sangue , Imunossupressores/farmacologia , Tacrolimo/sangue , Tacrolimo/farmacologia , Animais , Imunossupressores/farmacocinética , Interleucina-2/biossíntese , Interleucina-2/sangue , Interleucina-2/metabolismo , Ionomicina/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Suínos , Tacrolimo/farmacocinética , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
1. Extra- or intracellular recordings were made from seventy-six gamma-motoneurones of hindlimb muscles in chloralose anaesthetized cats to re-assess the coupling between secondary muscle spindle afferents (group II muscle afferents) and these neurones. The latencies of a number of responses evoked by group II muscle afferents in gamma-motoneurones were shorter than minimal latencies of responses induced disynaptically in other spinal neurones. These latencies are therefore compatible with monosynaptic coupling between muscle spindle secondaries and gamma-motoneurones. 2. Responses fulfilling criteria for monosynaptically evoked responses were seen in about one third of gamma-motoneurones with input from the group II muscle afferents tested (in 6 of 18 motoneurones recorded intracellularly and in 26 of 74 motoneurones recorded extracellularly). They were usually evoked from only one of the stimulated nerves, stimulation of group II afferents of other nerves being followed by responses at longer latencies. 3. Most gamma-motoneurones were excited by group II afferents from several muscles, both flexors and extensors. However, a comparison of group II input to gamma-motoneurones innervating medial gastrocnemius and four other hindlimb muscles revealed differences in both incidence and sources. 4. This study extends results of previous studies by providing evidence that some synaptic actions of group II afferents, including afferents from the same muscle, are evoked monosynaptically, and may assist in sustaining the activation of gamma-motoneurones by positive feedback.
Assuntos
Neurônios Motores gama/fisiologia , Músculo Esquelético/inervação , Neurônios Aferentes/fisiologia , Animais , Gatos , Estimulação Elétrica , Potenciais Evocados/fisiologia , Membro Posterior/inervação , Membro Posterior/fisiologia , Potenciais da Membrana/fisiologia , Músculo Esquelético/fisiologia , Técnicas de Patch-Clamp , Sinapses/fisiologiaRESUMO
1. Effects of noradrenaline (NA) and the alpha2 agonists tizanidine and clonidine were tested on extracellularly recorded responses of gamma-motoneurones in deeply anaesthetized cats. Two types of responses were used; firstly, short latency phasic responses evoked by electrical stimulation of group II afferents in a muscle nerve and, secondly, tonic background discharges. 2. Responses evoked by group II muscle afferents were depressed when NA and tizanidine were applied ionophoretically close to a gamma-motoneurone and when clonidine was applied systemically. The number of spike potentials evoked by stimulation of these afferents decreased and their latencies increased. Responses evoked by flexor or extensor afferents in gamma-motoneurones innervating flexors or extensors were similarly depressed. 3. Tonic discharges were inconsistently and/or insignificantly affected by locally applied NA and tizanidine but were depressed by systemically applied clonidine. 4. Control tests indicate specific effects of NA and tizanidine application since similarly ionophoresed H+ ions did not change responses of gamma-motoneurones to stimulation of group II afferents, or only weakly enhanced their background discharges. Furthermore, serotonin ejected from a solution with a similar pH facilitated rather than depressed responses of gamma-motoneurones. 5. The results indicate that some antispastic effects of clonidine and tizanidine may be due to the depression of group II-evoked responses of gamma-motoneurones, resulting in weaker responses of muscle spindles to muscle stretches.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Clonidina/análogos & derivados , Clonidina/farmacologia , Neurônios Motores gama/efeitos dos fármacos , Norepinefrina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 2 , Animais , Gatos , Estimulação Elétrica , Eletrofisiologia , Concentração de Íons de Hidrogênio , Iontoforese , Fusos Musculares/efeitos dos fármacos , Fusos Musculares/fisiologia , Condução Nervosa/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
In this essay the question is examined: Are there tendencies to "medicalisation" in the actual programmes of oral prevention? Medicalisation is interpreted as a subordination of the daily behaviour of clients under control of the medical system. Two possibilities of implementation of oral prophylaxis are discussed: Alternation of a concept of strict supervision and a concept of "oral self-care" emphasising more elements of behavioural self-control and empowerment.
Assuntos
Profilaxia Dentária/tendências , Humanos , Higiene Bucal/métodos , Higiene Bucal/tendências , Autocuidado/tendências , Controle Social Formal , Controles Informais da SociedadeRESUMO
This paper presents selected results of two recent representative cross sectional studies of oral health in the German population, conducted by the IDZ (Institute of German Dentists) for the old Federal States (the former Federal Republic of Germany) in 1989 (n= 1741) and the new Federal States (the former German Democratic Republic) in 1992 (n=1519). Each epidemiological study reported both clinical and sociological data. The following average DMFT values were determined: for the children aged 8/9 yr: 1.4; for the adolescents aged 13/14 yr: 4.9; for the adults aged 35-44 yr: 16.1; and for the adults aged 45-54 yr: 17.9. These are the overall averages for "Germany West" and "Germany East" combined. The overall results for periodontal health in adults were as follows: CPITN 0: 4.9%; CPITN 1:11.2%; CPITN 2: 24.6%; CPITN 3: 42.7%; and CPITN 4:16.6% for the adults aged 35-44 yr and CPITN 0: 2.4%; CPITN 1: 8.1%; CPITN 2: 20.4%; CPITN 3: 46.8%; and CPITN 4: 22.3% for the adults aged 45-54 yr. The following average tooth loss figures were calculated for Germany as a whole: age group 35-44 yr: 3.9 missing teeth; age group 45-54 yr: 7.7 missing teeth. In addition, all the morbidity data determined have been analysed for statistical significance in the comparison between "West" and "East" Germany. The prevalences presented are also differentiated according to the socioeconomic status (SES) of the subjects, with the lower social strata as a whole showing higher morbidity prevalences. Comparisons show that caries has declined significantly among children and adolescents in Germany in the last 10-15 yr. Finally, the authors recommend the inclusion of qualitative research techniques when studying the differential causation of the inverse correlation between oral morbidity and social status.