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1.
Psychopharmacology (Berl) ; 240(1): 171-183, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538099

RESUMO

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.


Assuntos
Alcoolismo , Depressores do Sistema Nervoso Central , Humanos , Baclofeno/farmacologia , Baclofeno/uso terapêutico , Alcoolismo/diagnóstico por imagem , Alcoolismo/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Projetos Piloto , Etanol , Depressores do Sistema Nervoso Central/farmacologia , Poliésteres/farmacologia , Poliésteres/uso terapêutico , Recompensa , Antecipação Psicológica
2.
Int Rev Neurobiol ; 165: 17-34, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36208899

RESUMO

Coronavirus disease 2019 (Covid-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is primarily regarded as a respiratory disease; however, multisystemic involvement accompanied by a variety of clinical manifestations, including neurological symptoms, are commonly observed. There is, however, little evidence supporting SARS-CoV-2 infection of central nervous system cells, and neurological symptoms for the most part appear to be due to damage mediated by hypoxic/ischemic and/or inflammatory insults. In this chapter, we report evidence on candidate neuropathological mechanisms underlying neurological manifestations in Covid-19, suggesting that while there is mostly evidence against SARS-CoV-2 entry into brain parenchymal cells as a mechanism that may trigger Parkinson's disease and parkinsonism, that there are multiple means by which the virus may cause neurological symptoms.


Assuntos
COVID-19 , Depressores do Sistema Nervoso Central , Doenças do Sistema Nervoso , Doença de Parkinson , Sistema Nervoso Central , Humanos , SARS-CoV-2
3.
J Opioid Manag ; 18(4): 377-383, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36052934

RESUMO

A recent review suggests minimal respiratory depression (RD) after perioperative methadone, while another identified RD in up to 37 percent of patients. A meta-analysis is equivocal. At our institution, five of 75 opioid naive patients (6.6 percent) given perioperative methadone received naloxone. We report three of these cases in detail. Two others were discovered during an electronic medical record search for opioid naïve patients who received methadone plus naloxone during their anesthesia care. Our five patients indicate that RD owing to methadone can occur with excessive perioperative adjuvant medications and/or in patients who are taking home central nervous system depressants. We define perioperative adjuvant medications as medications given by the anesthesiologist prior to induction and intraoperatively. The risks and benefits of perioperative methadone administration, specifically in patients who received post-operative naloxone, deserve further investigation.


Assuntos
Depressores do Sistema Nervoso Central , Transtornos Relacionados ao Uso de Opioides , Insuficiência Respiratória , Analgésicos Opioides/efeitos adversos , Depressores do Sistema Nervoso Central/uso terapêutico , Humanos , Metadona/efeitos adversos , Naloxona/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/diagnóstico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/terapia
4.
Nat Commun ; 13(1): 5521, 2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130965

RESUMO

Assessing the neurological and behavioral effects of drugs is important in developing pharmacological treatments, as well as understanding the mechanisms associated with neurological disorders. Herein, we present a miniaturized, wireless neural probe system with the capability of delivering drugs for the real-time investigation of the effects of the drugs on both behavioral and neural activities in socially interacting mice. We demonstrate wireless drug delivery and simultaneous monitoring of the resulting neural, behavioral changes, as well as the dose-dependent and repeatable responses to drugs. Furthermore, in pairs of mice, we use a food competition assay in which social interaction was modulated by the delivery of the drug, and the resulting changes in their neural activities are analyzed. During modulated food competition by drug injection, we observe changes in neural activity in mPFC region of a participating mouse over time. Our system may provide new opportunities for the development of studying the effects of drugs on behaviour and neural activity.


Assuntos
Depressores do Sistema Nervoso Central , Neurofarmacologia , Animais , Encéfalo/fisiologia , Eletrofisiologia Cardíaca , Depressores do Sistema Nervoso Central/farmacologia , Camundongos , Neurônios/fisiologia
5.
Methods Mol Biol ; 2556: 287-302, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36175640

RESUMO

Three types of assays--colorimetric, fluorescent, and chemiluminescent--are used to determine the sialidase (neuraminidase: NA) activity of influenza viruses. The fluorescent assay is cost-effective and applicable for many laboratories and is, therefore, commonly used for global monitoring of the NA inhibitor susceptibility of influenza viruses. Here, I describe, in detail, protocols for the fluorescence-based NA activity assay and the NA inhibition assay, which are used to determine the NA activity and NA inhibitor susceptibility, respectively, of influenza viruses.


Assuntos
Depressores do Sistema Nervoso Central , Orthomyxoviridae , Antivirais/farmacologia , Bioensaio , Corantes , Inibidores Enzimáticos/farmacologia , Neuraminidase
6.
Drugs Aging ; 39(9): 729-738, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945484

RESUMO

BACKGROUND: Co-prescription of opioids with other central nervous system (CNS) depressants is common but the combination may increase the risk for adverse events such as falls and fractures, particularly among older adults. We explored the risk of fall- or fracture-related hospital visits after opioid initiation among older adults with varying degrees of concomitant CNS depressant burden. METHODS: We used population-based administrative health data from Ontario, Canada, to examine the relationship between hospital visits for falls or fractures at different levels of CNS burden among individuals aged 66 and older who started prescription opioids between March 1, 2008, and March 31, 2019. For comparison, we identified individuals starting prescription non-steroidal anti-inflammatory drugs (NSAIDs). The outcome was a hospital visit for falls or fractures within 14 days after starting analgesic therapy. We stratified the cohort according to additional CNS burden: none, low (one concurrent CNS depressant drug class) and high (≥ 2 concurrent CNS depressant classes) on the index date. We balanced opioid and NSAID recipients using inverse probability of treatment weighting and reported weighted hazard ratios from Cox proportional hazards models. We then used pairwise comparisons to determine differences between hazard ratios at different levels of CNS burden. RESULTS: The cohort included 1,066,692 older adults, with 562,692 new opioid recipients and 504,000 new NSAID recipients. Among opioid recipients, 83 % had no additional CNS burden, 13 % had low burden and 4 % had high burden. The short-term rate of falls or fractures for new opioid recipients increased by CNS burden from 97 per 1000 person-years (no burden) to 233 per 1000 person-years (high CNS burden). Opioid recipients had a similarly elevated hazard of falls or fractures within each CNS burden level compared to NSAID recipients (adjusted hazard ratio [aHR] 1.62, 95 % CI 1.50-1.76 for no burden; aHR 1.69, 95 % CI 1.45-1.97 for low burden; aHR 1.40, 95 % CI 1.08-1.82 for high burden). CONCLUSION: Among older adults, initiation of opioids is associated with an increased hazard of falls; however, this hazard is not modified by different levels of CNS depressant burden. This suggests that it remains important for physicians, patients, and caregivers to be vigilant when starting new opioid therapy regardless of other CNS medications taken concurrently.


Assuntos
Depressores do Sistema Nervoso Central , Fraturas Ósseas , Idoso , Analgésicos Opioides , Anti-Inflamatórios não Esteroides , Fármacos do Sistema Nervoso Central , Fraturas Ósseas/induzido quimicamente , Fraturas Ósseas/epidemiologia , Humanos , Ontário/epidemiologia
7.
J Psychopharmacol ; 36(9): 1020-1035, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35912873

RESUMO

BACKGROUND: The benzodiazepine drug alprazolam, a fast-acting tranquiliser, cannot be prescribed on the National Health Service in the United Kingdom. Illicit alprazolam supply and consumption have increased. Concern about increasing numbers of alprazolam-related fatalities started circulating in 2018. However, statistics on this issue are very limited. This study examined patterns in such mortality in Scotland. METHODS: Statistics on deaths where alprazolam was mentioned in the 'cause of death' were obtained from official mortality registers. Anonymised Scottish case-level data were obtained. Data were examined in respect of the characteristics of decedents and deaths using descriptive statistics. RESULTS: Scotland registered 370 deaths in 2004-2020; 366 of these occurred in 2015-2020: most involved males (77.1%); mean age 39.0 (SD 12.6) years. The principal underlying cause of death was accidental poisoning: opiates/opioids (77.9%); sedatives/hypnotics (15.0%). Two deaths involved alprazolam alone. Main drug groups implicated: opiates/opioids (94.8%), 'other benzodiazepines' (67.2%), gabapentinoids (42.9%), stimulants (30.1%), antidepressants (15.0%). Two-thirds (64.2%) involved combinations of central nervous system (CNS) depressants. DISCUSSION: Alprazolam-related deaths are likely due to an increasing illicit supply. The fall in deaths in 2019-2020 is partially due to increased use of designer benzodiazepines. Treatment for alprazolam dependence is growing. Clinicians need to be aware of continuing recreational alprazolam use. When such consumption occurs with CNS depressants, overdose and death risks increase. CONCLUSIONS: More awareness of alprazolam contributing to deaths, especially in conjunction with other CNS depressants, is needed by consumers and clinicians. Improved monitoring of illicit supplies could identify emerging issues of medicines' abuse.


Assuntos
Depressores do Sistema Nervoso Central , Alcaloides Opiáceos , Adulto , Alprazolam/efeitos adversos , Analgésicos Opioides , Benzodiazepinas/efeitos adversos , Humanos , Hipnóticos e Sedativos , Masculino , Escócia/epidemiologia , Medicina Estatal
8.
Cells ; 11(15)2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35954216

RESUMO

MicroRNAs (miRNAs) are small noncoding RNAs that play a prominent role in post-transcriptional gene regulation mechanisms in the brain tuning synaptic plasticity, memory formation, and cognitive functions in physiological and pathological conditions [...].


Assuntos
Depressores do Sistema Nervoso Central , MicroRNAs , Doenças do Sistema Nervoso , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Plasticidade Neuronal/fisiologia
9.
Adv Exp Med Biol ; 1370: 325-331, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35882807

RESUMO

This article briefly describes the trophic actions of taurine in the developing brain, contribution of taurine to the volume regulation of brain cells, and the interference of taurine with the synaptic amino acid receptors. Finally the possible use of taurine as a drug is discussed in various pathological states of the brain.When we searched material for this review, we got almost 4000 articles from the PubMed when using the terms "taurine and brain." It is impossible to review all these articles. We must only select some items from this plethora. A few years ago, several exhaustive reviews have appeared on this topic. The readers are referred to them and their references for more detailed information of the earlier studies (Oja and Kontro, Taurine. In: Lajtha A (ed) Handbook of neurochemistry, vol 3, 2nd edn. Plenum Press, New York, pp 501-533, 1983; Huxtable, Taurine and the oxidative metabolism of cysteine. Biochemistry of sulfur. Plenum Press, New York, pp 121-198, 1986; Prog Neurobiol 32:471-533, 1989; Physiol Rev 72:101-163, 1992; Sturman, Physiol Rev 73:119-147, 1993; Oja and Saransaari, Taurine. In: Lajtha A, Oja SS, Saransaari P, Schousboe A (eds) Handbook of neurochemistry and molecular neurobiology. Amino acids and peptides in the nervous system, vol 3, 3rd edn. Springer, Berlin, pp 155-206, 2007; Saransaari and Oja, Taurine in neurotransmission. In: Lajtha A, Vizi ES (eds) Handbook of neurochemistry and molecular neurobiology. Neurotransmitter systems, vol 6, 3rd edn. Springer, Berlin, pp 155-206, 2008). We now focus mainly on more recent articles published during the few last years.


Assuntos
Depressores do Sistema Nervoso Central , Taurina , Aminoácidos , Encéfalo/metabolismo , Cisteína , Taurina/metabolismo
10.
Int J Mol Sci ; 23(9)2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35562999

RESUMO

Glyphosate, a non-selective systemic biocide with broad-spectrum activity, is the most widely used herbicide in the world. It can persist in the environment for days or months, and its intensive and large-scale use can constitute a major environmental and health problem. In this systematic review, we investigate the current state of our knowledge related to the effects of this pesticide on the nervous system of various animal species and humans. The information provided indicates that exposure to glyphosate or its commercial formulations induces several neurotoxic effects. It has been shown that exposure to this pesticide during the early stages of life can seriously affect normal cell development by deregulating some of the signaling pathways involved in this process, leading to alterations in differentiation, neuronal growth, and myelination. Glyphosate also seems to exert a significant toxic effect on neurotransmission and to induce oxidative stress, neuroinflammation and mitochondrial dysfunction, processes that lead to neuronal death due to autophagy, necrosis, or apoptosis, as well as the appearance of behavioral and motor disorders. The doses of glyphosate that produce these neurotoxic effects vary widely but are lower than the limits set by regulatory agencies. Although there are important discrepancies between the analyzed findings, it is unequivocal that exposure to glyphosate produces important alterations in the structure and function of the nervous system of humans, rodents, fish, and invertebrates.


Assuntos
Depressores do Sistema Nervoso Central , Herbicidas , Síndromes Neurotóxicas , Animais , Glicina/análogos & derivados , Glicina/química , Glicina/toxicidade , Herbicidas/química , Herbicidas/toxicidade , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo
11.
Biochem Biophys Res Commun ; 609: 141-148, 2022 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-35429681

RESUMO

Histamine is synthesised from l-histidine through the catalysis of histidine decarboxylase (HDC). In the central nervous system (CNS), histamine is exclusively produced in histaminergic neurons located in the posterior hypothalamus and controls various CNS functions. Although histidine was known as a precursor of histamine, the impact of oral histidine intake on brain histamine concentration and brain function has not been fully elucidated. In the present study, we aimed to elucidate the importance of oral histidine supplementation in the histaminergic nervous system and working memory in stressful conditions. First, we confirmed that sleep deprivation by water-floor stress in male mice increased histamine consumption and resulted in histamine reduction and impaired working memory in the Y-maze test. This memory impairment was rescued by intracerebroventricular injection of histamine and histidine, indicating that oral histidine intake could also improve memory function. Next, we examined the impact of histidine intake on brain histamine concentration and neuronal activity. Histidine intake increased extracellular histamine concentration around the prefrontal cortex (PFC) and the basal forebrain (BF), leading to a robust increase in the number of c-fos-positive cells around these areas. Finally, we investigated the beneficial effects of histidine intake on working memory. Histidine supplementation alleviated impaired memory function induced by sleep deprivation. This beneficial effect of histidine on memory was cancelled by intracerebroventricular injection of the HDC inhibitor α-fluoromethylhistidine. These results demonstrate that oral histidine intake replenishes brain histamine and leads to the recovery of impaired working memory induced by sleep deprivation through histaminergic activation.


Assuntos
Depressores do Sistema Nervoso Central , Histidina , Animais , Histamina , Histidina/farmacologia , Histidina Descarboxilase , Masculino , Memória de Curto Prazo , Camundongos , Neurônios , Privação do Sono
12.
Neuron ; 110(8): 1275-1277, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35447095

RESUMO

Communication between the nervous system and immune system is important for regulating immunity in health and disease. Yu et al. (2022) show that neuropeptide Y and its homolog NPF serve as a "language" to facilitate crosstalk between these two systems across species, enabling neurons to downregulate harmful immune responses.


Assuntos
Depressores do Sistema Nervoso Central , Neuropeptídeos , Sistema Nervoso , Neurônios , Neuropeptídeo Y
13.
Mikrochim Acta ; 189(3): 100, 2022 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-35152330

RESUMO

Falsified medicines and healthcare supplements provide a major risk to public health and thus early identification is critical. Although a host of analytical approaches have been used to date, they are limited, as they require extensive sample preparation, are semi-quantitative and/or are inaccessible to low- and middle-income countries. Therefore, for the first time, we report a simple total analysis system which can rapidly and accurately detect falsified medicines and healthcare supplements. We fabricated a poly-lactic acid (PLA) pestle and mortar and using a commercial 3D printer, then made carbon black/PLA (CB/PLA) electrodes in the base of the mortar using a 3D printing pen to make an electrochemical cell. The pestle and mortar were able to crush and grind the tablets into a fine powder to the same consistency as a standard laboratory pestle and mortar. Using melatonin tablets to characterise the device, the 3D-printed pestle and mortar was able to detect the concentration of melatonin in the presence of insoluble excipients. The calibration plot showed a linear response from 37.5 to 300 µg/mL, where the limit of detection was 7 µg/mL. Electrochemical treatment was able to regenerate the CB/PLA working electrode allowing for repeated use of the device. In a blinded study, the device was able to accurately determine falsified melatonin tablets with recovery percentages between 101% and 105%. This was comparable to HPLC measurements. Overall, these findings highlight that our 3D-printed electrochemical pestle and mortar is an accessible and effective total analysis system that can have the ability to identify falsified medicines and healthcare supplements in remote locations.


Assuntos
Depressores do Sistema Nervoso Central/análise , Técnicas Eletroquímicas , Melatonina/análise , Poliésteres/química , Impressão Tridimensional , Eletrodos , Legislação de Medicamentos , Comprimidos
15.
Dig Dis Sci ; 67(2): 524-535, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33555515

RESUMO

OBJECTIVE: Alcohol consumption is always the main cause of acute pancreatitis (AP). It has been reported that alcohol exerts direct damage to the pancreas. However, the specific role of alcohol during AP needs to be investigated. This study aims to examine the effects of alcohol in cerulein-induced AP and the role of the AMPK pathway. METHODS: Human subjects from operations, cerulein-induced AP rat, and cerulein-stimulated AR42J cell line were enrolled in this study. Electron microscopy was employed for observation of cell morphology, immunohistochemistry for identification of cells, ELISA for detection of inflammation factors, Annexin V/PI double staining for evaluation of cell apoptosis, immunofluorescence for assessment of autophagic flux, oil red O staining for examination of lipid droplet accumulation, and Western blot for measurement of expressions of proteins related to autophagy, apoptosis, and AMPK signal pathway. PI3K inhibitor 3-MA and AMPK inhibitor BML-275 were utilized for investigation of the relationship between impaired autophagic flux and the AMPK pathway by inhibiting or stimulating the formation of autophagosome. RESULTS: Alcohol consumption caused lipid droplet accumulation in the pancreas, and it also activated AMPK signaling pathway, thus aggravating the autophagic flux during AP. Alcohol up-regulated the expressions of anti-apoptotic proteins during the induction of AP to inhibit cell apoptosis and enhance cell necrosis. Inhibition of autophagosome formation by AMPK inhibitor BML-275 ameliorated the decreased cell viability caused by alcohol and cerulein in vitro. CONCLUSION: Alcohol aggravates AP progression by impairing autophagic flux and enhancing cell autophagy through the AMPK signaling pathway.


Assuntos
Adenilato Quinase/metabolismo , Autofagia/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Pâncreas/efeitos dos fármacos , Pancreatite Alcoólica/metabolismo , Adenilato Quinase/antagonistas & inibidores , Adenilato Quinase/efeitos dos fármacos , Animais , Linhagem Celular , Ceruletídeo/toxicidade , Humanos , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Pancreatite/patologia , Pancreatite Alcoólica/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Transdução de Sinais
16.
Eur J Clin Pharmacol ; 78(2): 191-196, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34668986

RESUMO

PURPOSE: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment. METHODS: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis. RESULTS: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant. CONCLUSION: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed. CLINICAL TRIALS: NCT03782740 registered on 17 December 2018.


Assuntos
Depressores do Sistema Nervoso Central/uso terapêutico , Dismenorreia/tratamento farmacológico , Melatonina/uso terapêutico , Absenteísmo , Adulto , Analgésicos/administração & dosagem , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/efeitos adversos , Feminino , Hemorragia/patologia , Humanos , Melatonina/administração & dosagem , Melatonina/efeitos adversos , Adulto Jovem
17.
J Forensic Sci ; 67(1): 358-362, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34403143

RESUMO

Widmark calculations are the most commonly used alcohol calculations to estimate a) the amount of alcohol consumed based on blood alcohol concentration (BAC) and b) BACs at a set time after consumption of a known amount of alcohol. These calculations are vital in forensic casework. Previous work has demonstrated that using general error propagation-based equations the variability associated with alcohol calculations can be estimated, but these equations have only been determined for the volume of distribution version of the Widmark equation. However, recent investigations have shown that the total body water (TBW) version of the Widmark equation is more reliable than the version that utilizes the apparent volume of distribution of ethanol. To date, there is no general error propagation equation to determine the variability associated the TBW version of the Widmark equation. Using previously published studies of 185 individuals in which alcohol elimination rate (ß) and ethanol's volume of distribution were determined, we have shown that there is a negative correlation (-0.247) between the alcohol elimination rate (ß) and TBW. Using these data, we were able to produce equations allowing the estimation of the variability of the results calculated using the TBW version of the Widmark equation. This will allow forensic practitioners to give the best determination of the variability associated with Widmark calculations currently possible.


Assuntos
Concentração Alcoólica no Sangue , Depressores do Sistema Nervoso Central , Água Corporal , Etanol , Humanos , Incerteza
18.
Life Sci ; 288: 120180, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34843736

RESUMO

Alcoholic liver injury is a liver cell dysfunction disease caused by long-term or excessive alcohol consumption. Inhibiting the production of inflammatory factors is an important way to alleviate liver injury. Interleukin-9 (IL-9) is one of the members of IL-2Rγc family. It has multiple biological functions. Previous studies have shown that IL-9 is a cytokine that is closely related to inflammatory disease, allergic diseases, autoimmune diseases, and parasitic infections. However, no systematic studies have been performed to address the role of IL-9 in ALI. This project aims to investigate the effects of IL-9 on macrophage-related inflammatory response and hepatocyte apoptosis in alcohol-induced liver injury by injecting adeno-associated virus (AAV9) into tail vein. In the ALI model group, western blot and ELISA assays demonstrated that the expression of IL-9 was reduced. Overexpression of IL-9 relieved the injury and reduced the serum levels of IL-6, TNF-α in EtOH-induced ALI mouse model. Moreover, by using western blot, it was indicated that IL-9 can inhibit the expression of pro-apoptotic protein, such as cleaved caspase 3 and Bax. In vitro, mouse recombinant protein IL-9 inhibited the expression of IL-6, TNF-α in EtOH-induced RAW264.7 cells. Moreover, flow cytometry and western blot results displayed that macrophage-derived IL-9 inhibited hepatocyte apoptosis. After silencing STAT3 in AML-12 cells, the anti-apoptotic effect of macrophage-derived IL-9 was further enhanced. These results indicate that IL-9 reduces the production of pro-inflammatory factors in ALI. Furthermore, macrophage-derived IL-9 can reduce hepatocyte apoptosis by inhibiting the activation of the STAT3 pathway.


Assuntos
Apoptose , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Etanol/toxicidade , Hepatócitos/patologia , Interleucina-9/metabolismo , Macrófagos/imunologia , Fator de Transcrição STAT3/metabolismo , Animais , Depressores do Sistema Nervoso Central/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Interleucina-9/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/genética
19.
Hepatology ; 75(3): 610-622, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34716927

RESUMO

BACKGROUND AND AIMS: Liver fibrosis is the static and main (70%-80%) component of portal hypertension (PH). We investigated dynamic components of PH by a three-dimensional analysis based on correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or HVPG in patients. APPROACH AND RESULTS: Different animal models (bile duct ligation: n = 31, carbon tetrachloride: n = 12, thioacetamide: n = 12, choline-deficient high-fat diet: n = 12) and patients with a confirmed single etiology of cholestatic (primary biliary cholangitis/primary sclerosing cholangitis: n = 16), alcohol-associated (n = 22), and metabolic (NASH: n = 19) liver disease underwent CPA quantification on liver specimens/biopsies. Based on CPA-to-PP/HVPG correlation, potential dynamic components were identified in subgroups of animals/patients with lower-than-expected and higher-than-expected PP/HVPG. Dynamic PH components were validated in a patient cohort (n = 245) using liver stiffness measurement (LSM) instead of CPA. CPA significantly correlated with PP in animal models (Rho = 0.531; p < 0.001) and HVPG in patients (Rho = 0.439; p < 0.001). Correlation of CPA with PP/HVPG varied across different animal models and etiologies in patients. In models, severity of hyperdynamic circulation and specific fibrosis pattern (portal fibrosis: p = 0.02; septa width: p = 0.03) were associated with PH severity. In patients, hyperdynamic circulation (p = 0.04), vascular dysfunction/angiogenesis (VWF-Ag: p = 0.03; soluble vascular endothelial growth factor receptor 1: p = 0.03), and bile acids (p = 0.04) were dynamic modulators of PH. The LSM-HVPG validation cohort confirmed these and also indicated IL-6 (p = 0.008) and hyaluronic acid (HA: p < 0.001) as dynamic PH components. CONCLUSIONS: The relative contribution of "static" fibrosis on PH severity varies by type of liver injury. Next to hyperdynamic circulation, increased bile acids, VWF-Ag, IL-6, and HA seem to indicate a pronounced dynamic component of PH in patients.


Assuntos
Colágeno , Hipertensão Portal , Cirrose Hepática , Fígado , Pressão na Veia Porta/fisiologia , Animais , Biópsia/métodos , Depressores do Sistema Nervoso Central/farmacologia , Colestase/fisiopatologia , Colágeno/análise , Colágeno/metabolismo , Técnicas de Imagem por Elasticidade/métodos , Etanol/farmacologia , Hemodinâmica , Humanos , Hipertensão Portal/diagnóstico , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Fígado/diagnóstico por imagem , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Circulação Hepática , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Modelos Animais , Ratos
20.
Neurosci Biobehav Rev ; 132: 838-856, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34774900

RESUMO

Neurometabolic diseases (NMDs) are typically caused by genetic abnormalities affecting enzyme functions, which in turn interfere with normal development and activity of the nervous system. Although the individual disorders are rare, NMDs are collectively relatively common and often lead to lifelong difficulties and high societal costs. Neuropsychiatric manifestations, including ADHD symptoms, are prominent in many NMDs, also when the primary biochemical defect originates in cells and tissues outside the nervous system. ADHD symptoms have been described in phenylketonuria, tyrosinemias, alkaptonuria, succinic semialdehyde dehydrogenase deficiency, X-linked ichthyosis, maple syrup urine disease, and several mitochondrial disorders, but are probably present in many other NMDs and may pose diagnostic and therapeutic challenges. Here we review current literature linking NMDs with ADHD symptoms. We cite emerging evidence that many NMDs converge on common neurochemical mechanisms that interfere with monoamine neurotransmitter synthesis, transport, metabolism, or receptor functions, mechanisms that are also considered central in ADHD pathophysiology and treatment. Finally, we discuss the therapeutic implications of these findings and propose a path forward to increase our understanding of these relationships.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Depressores do Sistema Nervoso Central , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Humanos
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