RESUMO
BACKGROUND: Severe chemotherapy-related toxicities are frequent among older patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) and the Cancer and Aging Research Group Study (CARG) score were both developed to predict these events. PATIENTS AND METHODS: The objective of this study was to evaluate the scores' predictive performance in a prospective cohort, which included patients aged 70 years and older referred for a geriatric assessment prior to chemotherapy for a solid tumor. The main endpoints were grades 3/4/5 toxicities for the CARG score and grades 4/5 hematologic toxicities and grades 3/4/5 non-hematologic toxicities for the CRASH score. RESULTS: A total of 248 patients were included, of which 150 (61%) and 126 (51%) experienced at least one severe adverse event as defined respectively in CARG and CRASH studies. The incidence of adverse events was not significantly greater in the intermediate and high-risk CARG groups than in the low-risk group (odds ratio (OR) [95% CI] = 0.3 [0.1-1.4] (P = .1) and 0.4 [0.1-1.7], respectively). The area under curve (AUC) was 0.55. Similarly, the incidence of severe toxicities was no greater in the intermediate-low, intermediate-high, and high-risk CRASH groups than in the low-risk CRASH group (OR [95%CI] = 1 [0.3-3.6], 1 [0.3-3.4], and 1.5 [0.3-8.1], respectively). The AUC was 0.52. The type of cancer, performance status, comorbidities, body mass index, and MAX2 index were independently associated with grades 3/4/5 toxicities. CONCLUSION: In an external cohort of older patients referred for a pretherapeutic GA, the CARG and CRASH scores were poor predictors of the risk of chemotherapy severe toxicities.
Assuntos
Antineoplásicos , Neoplasias , Idoso , Humanos , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Estudos Prospectivos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Avaliação Geriátrica , Fatores de RiscoRESUMO
A remarkable feature of early neuronal networks is their endogenous ability to generate spontaneous rhythmic electrical activity independently of any external stimuli. In the mouse embryonic SC, this activity starts at an embryonic age of â¼ 12 d and is characterized by bursts of action potentials recurring every 2-3 min. Although these bursts have been extensively studied using extracellular recordings and are known to play an important role in motoneuron (MN) maturation, the mechanisms driving MN activity at the onset of synaptogenesis are still poorly understood. Because only cholinergic antagonists are known to abolish early spontaneous activity, it has long been assumed that spinal cord (SC) activity relies on a core network of MNs synchronized via direct cholinergic collaterals. Using a combination of whole-cell patch-clamp recordings and extracellular recordings in E12.5 isolated mouse SC preparations, we found that spontaneous MN activity is driven by recurrent giant depolarizing potentials. Our analysis reveals that these giant depolarizing potentials are mediated by the activation of GABA, glutamate, and glycine receptors. We did not detect direct nAChR activation evoked by ACh application on MNs, indicating that cholinergic inputs between MNs are not functional at this age. However, we obtained evidence that the cholinergic dependency of early SC activity reflects a presynaptic facilitation of GABA and glutamate synaptic release via nicotinic AChRs. Our study demonstrates that, even in its earliest form, the activity of spinal MNs relies on a refined poly-synaptic network and involves a tight presynaptic cholinergic regulation of both GABAergic and glutamatergic inputs.
Assuntos
Acetilcolina/metabolismo , Potenciais de Ação/fisiologia , Junções Comunicantes/fisiologia , Ácido Glutâmico/metabolismo , Glicina/metabolismo , Neurônios Motores/fisiologia , Rede Nervosa/fisiologia , Medula Espinal/citologia , Ácido gama-Aminobutírico/metabolismo , Acetilcolina/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Colinérgicos/farmacologia , Embrião de Mamíferos , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Feminino , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Ácido Glutâmico/farmacologia , Glicina/farmacologia , Proteínas de Homeodomínio/genética , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Neurônios Motores/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Gravidez , Tetrodotoxina/farmacologia , Fatores de Transcrição/genética , Ácido gama-Aminobutírico/farmacologiaRESUMO
Rhythmic electrical activity is a hallmark of the developing embryonic CNS and is required for proper development in addition to genetic programs. Neurotransmitter release contributes to the genesis of this activity. In the mouse spinal cord, this rhythmic activity occurs after embryonic day 11.5 (E11.5) as waves spreading along the entire cord. At E12.5, blocking glycine receptors alters the propagation of the rhythmic activity, but the cellular source of the glycine receptor agonist, the release mechanisms, and its function remain obscure. At this early stage, the presence of synaptic activity even remains unexplored. Using isolated embryonic spinal cord preparations and whole-cell patch-clamp recordings of identified motoneurons, we find that the first synaptic activity develops at E12.5 and is mainly GABAergic. Using a multiple approach including direct measurement of neurotransmitter release (i.e., outside-out sniffer technique), we also show that, between E12.5 and E14.5, the main source of glycine in the embryonic spinal cord is radial cell progenitors, also known to be involved in neuronal migration. We then demonstrate that radial cells can release glycine during synaptogenesis. This spontaneous non-neuronal glycine release can also be evoked by mechanical stimuli and occurs through volume-sensitive chloride channels. Finally, we find that basal glycine release upregulates the propagating spontaneous rhythmic activity by depolarizing immature neurons and by increasing membrane potential fluctuations. Our data raise the question of a new role of radial cells as secretory cells involved in the modulation of the spontaneous electrical activity of embryonic neuronal networks.
Assuntos
Glicina/metabolismo , Periodicidade , Medula Espinal/embriologia , Medula Espinal/metabolismo , Potenciais Sinápticos/fisiologia , Animais , Células CHO , Células Cultivadas , Cricetinae , Cricetulus , Feminino , Camundongos , Neurônios Motores/citologia , Neurônios Motores/metabolismo , Gravidez , Medula Espinal/citologiaRESUMO
In the hypoglossal nucleus of wild-type mice, early mixed glycinergic-GABAergic inhibitory transmission becomes mainly glycinergic during postnatal maturation. In spastic mice (SPA), a model of human hyperekplexic syndrome, an insertion into the gene of the glycine receptor (GlyR) beta subunit results in a decreased accumulation of GlyRs at postsynaptic sites and an impaired glycinergic neurotransmission. In SPA mice displaying a mild phenotype (B6C3Fe strain), a compensatory process involving an increased aggregation of GABA(A) receptors (GABA(A)Rs) at postsynaptic sites was proposed to explain survival of mutant animals until adulthood. However, C57BL/6J strain SPA mice which express a lower amount of GlyR beta subunit die 2-3 weeks after birth, suggesting that GABAergic compensation does not necessarily take place. We performed a morphofunctional study of inhibitory synapses in the developing hypoglossal nucleus of C57BL/6J SPA mice. In this mutant, the inhibitory synaptic activity was mainly GABAergic. Accordingly, we observed a developmental loss of glycinergic presynaptic terminals and an increase in the density of GABAergic presynaptic terminals during the first two postnatal weeks. In addition, while C57BL/6J SPA mice displayed a strong impairment in GlyR aggregation at postsynaptic loci, the proportion of inhibitory presynaptic terminals facing diffuse GABA(A)Rs significantly increased during development. Our results suggest crosstalk between postsynaptic and presynaptic elements, leading to the developmental regulation of the presynaptic terminal neurotransmitter content according to the level of postsynaptic GlyR aggregation. They also indicate that GABAergic neurotransmission does not compensate for defects in GlyR postsynaptic aggregation leading to spastic syndrome in C57BL/6J SPA mice.