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PURPOSE: Most of the existing literature reports no association or a slight negative association between coffee consumption and the risk of developing breast cancer. However, the level of risk differs when considering various subgroups, such as menopausal status, hormonal status of the tumor or genetic mutations. The present review based on a literature search sets the point on the potential influence of a common daily drink, coffee, on the risk of developing breast cancer in the general population, in different subgroups of women and the consequences of drinking coffee after breast cancer has been diagnosed and treated. RESULTS: This review confirms that in the general population, there is no association between coffee intake and breast cancer risk or a slight protective effect, even at high dosages. Coffee is inversely associated with breast cancer risk in postmenopausal women and in women carrying a BRCA1 mutation. Possible risk differences exist between slow and fast caffeine metabolizers and with weight. Coffee consumption after breast cancer diagnosis and surgery, associated with tamoxifen and/or radiotherapy, reduced the occurrence of early events. The effects of coffee intake are less clear in other subgroups, mainly premenopausal women, women carrying a BRCA2 mutation and tumors with variable hormonal status (positive or negative for ER/PR) and would need additional studies.
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Neoplasias da Mama , Café , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Cafeína , Feminino , Humanos , Pré-Menopausa , Fatores de Risco , TamoxifenoRESUMO
Our previous studies consistently showed that MDMA-induced locomotor hyperactivity is dramatically increased by coadministration of ethanol (EtOH) in rats, indicating possible potentiation of MDMA abuse liability. Thus, we aimed to identify the brain region(s) and neuropharmacological substrates involved in the pharmacodynamics of this potentiation. We first showed that potentiation of locomotor activity by the combination of ip administration of EtOH (1.5 g/kg) and MDMA (6.6 mg/kg) is delay sensitive and maximal when both drugs are injected simultaneously. Then, we used the 2-deoxyglucose quantitative autoradiography technique to assess the impact of EtOH, MDMA, or their combination on local cerebral metabolic rates for glucose (CMRglcs). We showed a specific metabolic activation in the ventral striatum (VS) under MDMA + EtOH versus MDMA or EtOH alone. We next tested if reversible (tetrodotoxin, TTX) or permanent (6-hydrodoxyopamine, 6-OHDA) lesion of the VS could affect locomotor response to MDMA and MDMA + EtOH. Finally, we blocked dopamine D1 or glutamate NMDA receptors in the VS and measured the effects of MDMA and MDMA + EtOH on locomotor activity. We showed that bilateral reversible inactivation (TTX) or permanent lesion (6-OHDA) of the VS prevented the potentiation by EtOH of MDMA-induced locomotor hyperactivity. Likewise, blockade of D1 or NMDA receptors in the VS also reduced the potentiation of MDMA locomotor activity by EtOH. These data indicate that dopamine D1 and glutamate NMDA receptor-driven mechanisms in the VS play a key role in the pharmacodynamics of EtOH-induced potentiation of the locomotor effects of MDMA.
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Etanol/farmacologia , N-Metil-3,4-Metilenodioxianfetamina/farmacologia , Estriado Ventral/efeitos dos fármacos , Animais , Combinação de Medicamentos , Sinergismo Farmacológico , Etanol/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Oxidopamina/farmacologia , Ratos , Ratos Long-Evans , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Tetrodotoxina/farmacologiaRESUMO
Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, N-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.
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Variação Biológica Individual , Cafeína/metabolismo , Café/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Polimorfismo Genético , Animais , Cafeína/farmacocinética , Café/genética , Sistema Enzimático do Citocromo P-450/genética , Interações Medicamentosas , Humanos , Preparações Farmacêuticas/metabolismo , Distribuição TecidualRESUMO
OBJECTIVE: Within a complex systems biology perspective, we wished to assess whether hippocampi with established neuropathological features have distinct metabolome. Apparently normal hippocampi with no signs of sclerosis (noHS), were compared to hippocampal sclerosis (HS) type 1 (HS1) and/or type 2 (HS2). Hippocampus metabolome from patients with epilepsy-associated neuroepithelial tumors (EANTs), namely, gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs), was also compared to noHS epileptiform tissue. METHODS: All patients underwent standardized temporal lobectomy. We applied 1 H high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy to 48 resected human hippocampi. NMR spectra allowed quantification of 21 metabolites. Data were analyzed using multivariate analysis based on mutual information. RESULTS: Clear distinct metabolomic profiles were observed between all studied groups. Sixteen and 18 expected metabolite levels out of 21 were significantly different for HS1 and HS2, respectively, when compared to noHS. Distinct concentration variations for glutamine, glutamate, and N-acetylaspartate (NAA) were observed between HS1 and HS2. Hippocampi from GG and DNT patients showed 7 and 11 significant differences in metabolite concentrations when compared to the same group, respectively. GG and DNT had a clear distinct metabolomic profile, notably regarding choline compounds, glutamine, glutamate, aspartate, and taurine. Lactate and acetate underwent similar variations in both groups. SIGNIFICANCE: HRMAS NMR metabolomic analysis was able to disentangle metabolic profiles between HS, noHS, and epileptic hippocampi associated with EANT. HRMAS NMR metabolomic analysis may contribute to a better identification of abnormal biochemical processes and neuropathogenic combinations underlying mesial temporal lobe epilepsy.
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Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Metabolômica/métodos , Adolescente , Adulto , Criança , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/cirurgia , Feminino , Hipocampo/cirurgia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Lobo Temporal/cirurgia , Adulto JovemRESUMO
There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilepsy (PWE). Commonalities between autism, depression, aging and dementia, psychosis, and epilepsy were the focus of the presentations and discussion. In the last session, additional experts commented on new conceptualization of translational epilepsy research efforts. Here, the presentations are reviewed, and salient points are highlighted.
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Demência/complicações , Epilepsia/complicações , Esquizofrenia , Pesquisa Translacional Biomédica , Demência/psicologia , Epilepsia/psicologia , Humanos , Psicologia do EsquizofrênicoAssuntos
Distinções e Prêmios , Epilepsia , Epilepsia/genética , Epilepsia/terapia , Humanos , PesquisaRESUMO
Over the last decade, Food Regulation Authorities have concluded that coffee/caffeine consumption is not harmful if consumed at levels of 200â mg in one sitting (around 2½ cups of coffee) or 400â mg daily (around 5 cups of coffee). In addition, caffeine has many positive actions on the brain. It can increase alertness and well-being, help concentration, improve mood and limit depression. Caffeine may disturb sleep, but only in sensitive individuals. It may raise anxiety in a small subset of particularly sensitive people. Caffeine does not seem to lead to dependence, although a minority of people experience withdrawal symptoms. Caffeine can potentiate the effect of regular analgesic drugs in headache and migraine. Lifelong coffee/caffeine consumption has been associated with prevention of cognitive decline, and reduced risk of developing stroke, Parkinson's disease and Alzheimer's disease. Its consumption does not seem to influence seizure occurrence. Thus, daily coffee and caffeine intake can be part of a healthy balanced diet; its consumption does not need to be stopped in elderly people.
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Encéfalo/efeitos dos fármacos , Cafeína/farmacologia , Café , HumanosRESUMO
As reported previously, in the lithium-pilocarpine model of temporal lobe epilepsy (TLE), carisbamate (CRS) produces strong neuroprotection, leads to milder absence-like seizures, and prevents behavioral impairments in a subpopulation of rats. To understand the metabolic basis of these effects, here we injected 90 mg/kg CRS or vehicle twice daily for 7 days starting 1 h after status epilepticus (SE) induction in rats. Two months later, we injected [1-13 C]glucose and [1,2-13 C]acetate followed by head microwave fixation after 15 min. 13 C incorporation into metabolites was analyzed using 13 C magnetic resonance spectroscopy. We found that SE reduced neuronal mitochondrial metabolism in the absence but not in the presence of CRS. Reduction in glutamate level was prevented by CRS and aspartate levels were similar to controls only in rats displaying absence-like seizures after treatment [CRS-absence-like epilepsy (ALE)]. Glutamine levels in CRS-ALE rats were higher compared to controls in hippocampal formation and limbic structures while unchanged in rats displaying motor spontaneous recurrent seizures after treatment (CRS-TLE). Astrocytic mitochondrial metabolism was reduced in CRS-TLE, and either enhanced or unaffected in CRS-ALE rats, which did not affect the transfer of glutamine from astrocytes to neurons. In conclusion, CRS prevents reduction in neuronal mitochondrial metabolism but its effect on astrocytes is likely key in determining outcome of treatment in this model. To understand the metabolic basis of the strong neuroprotection and reduction in seizure severity caused by carisbamate (CRS) in the lithium-pilocarpine (Li-Pilo) model of temporal lobe epilepsy (TLE), we injected CRS for 7 days starting 1 h after status epilepticus and 2 months later [1-13 C]glucose and [1,2-13 C]acetate. 13 C Magnetic resonance spectroscopy analysis was performed on brain extracts and we found that CRS prevented reduction in neuronal mitochondrial metabolism but its effect on astrocytes was likely key in determining outcome of treatment in this model. ALE = absence like epilepsy; acetyl CoA = acetyl coenzyme A; GS = glutamine synthetase; PAG = phosphate activated glutaminase; PC = pyruvate carboxylase; OAA = oxaloacetate; TCA cycle = tricarboxylic acid cycle.
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Pentylenetetrazol, kainic acid, or pilocarpine can be used to induce seizures in animal models of epilepsy. The present Review describes disturbances in astrocyte-neuron interactions in the acute, latent, and chronic phases analyzed by magnetic resonance spectroscopy of brain tissue extracts from rats injected with [1-(13)C]glucose and [1,2-(13)C]acetate. The most consistent change after onset of seizures was the decrease in (13)C labeling of glutamate (GLU) from [1-(13) C]glucose regardless of brain area, severity, or duration of the period with seizures and toxin used. In most cases this decrease was accompanied by a reduction in glutamine (GLN) labeling from [1-(13)C]glucose, presumably as a direct consequence of the reduction in labeling of GLU and the GLU-GLN cycle. Amounts of GLN were never changed. Reduction in the content of N-acetyl aspartate (NAA) was first detectable some time after status epilepticus but before the occurrence of spontaneous seizures. This decrease can be an indication of neuronal death and/or mitochondrial impairment and might indicate beginning gliosis. It is known that gliosis occurs in the chronic phase of temporal lobe epilepsy in hippocampus, but astrocyte metabolism appears normal in this phase, indicating that the gliotic astrocytes have a somewhat reduced metabolism per volume. A decrease in (13)C labeling of GLU from [1-(13)C]glucose is a very sensitive measure for the onset of epileptogenesis, whereas reduction of NAA is first detectable later. In the chronic phases of the hippocampal formation, astrocyte metabolism is upregulated given that the number of neurons is reduced.
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Astrócitos/fisiologia , Comunicação Celular/fisiologia , Epilepsia/etiologia , Neurônios/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Convulsivantes/toxicidade , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Humanos , Neurônios/efeitos dos fármacosAssuntos
Distinções e Prêmios , Pesquisa Biomédica/métodos , Epilepsia/terapia , Neurologistas , Transtornos Psicofisiológicos/terapia , Pesquisa Biomédica/tendências , Epilepsia/diagnóstico , Epilepsia/psicologia , Humanos , Masculino , Neurologistas/tendências , Transtornos Psicofisiológicos/diagnóstico , Transtornos Psicofisiológicos/psicologiaRESUMO
OBJECTIVE: From May to September 2014, Epilepsia conducted an online survey seeking opinions on whether consciousness should be used in describing focal and generalized seizures, and what terms should be applied to describe focal seizures with loss of awareness and amnesia. This study reports the findings of that survey. METHODS: Two questions asked if consciousness should be used to classify seizures and what terms should be applied. Another four questions addressed demographic information. RESULTS: Of 209 individuals that started the poll, 147 (70.3%) completing it, and most that completed it were epileptologists (66%) from Europe (41%) and North America (27%). A majority (64%) indicated that the presence or absence of consciousness should be used to describe focal and generalized seizures, whereas 23% said it should not be used. When asked what term should be used to describe focal seizures with altered awareness and amnesia, 36% said focal impaired consciousness seizures (FICS), 30% selected complex partial seizures (CPS), and 16% answered focal dyscognitive seizures. SIGNIFICANCE: This survey indicates that most responders prefer that consciousness be considered in the description of focal and generalized seizures, despite the difficulty in determining awareness clinically. Furthermore, responders could not agree on a single term that could be used to define focal seizures with loss of awareness and amnesia.
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Atitude do Pessoal de Saúde , Estado de Consciência/fisiologia , Convulsões/classificação , Convulsões/fisiopatologia , Europa (Continente) , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , América do Norte , Sistemas On-LineRESUMO
OBJECTIVE: From May 20 to September 1 2014, Epilepsia conducted an online survey seeking opinions about the use of medical marijuana and cannabidiol (CBD) for people with epilepsy. This study reports the findings of that poll. METHODS: The survey consisted of eight questions. Four questions asked if there were sufficient safety and efficacy data, whether responders would advise trying medical marijuana in cases of severe refractory epilepsy, and if pharmacologic grade compounds containing CBD should be available. Four questions addressed occupation, geographic region of residence, if responders had read the paper, and if they were International League Against Epilepsy/International Bureau for Epilepsy (ILAE/IBE) members. RESULTS: Of 776 who started or completed the survey, 58% were patients from North America, and 22% were epileptologists and general neurologists from Europe and North America. A minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% would advise using medical marijuana in severe cases of epilepsy. By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, saying that there were sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public. SIGNIFICANCE: This survey indicates that there is a wide disparity in opinion on the use of medical marijuana and CBD in the treatment of people with epilepsy, which varied substantially, with fewer medical specialists supporting its use compared with general medical personal, and patients and the public.