RESUMO
We have no definitive treatment for dementia characterized by prolonged neuronal death due to the enormous accumulation of foreign matter, such as ß-amyloid. Since Alzheimer's type dementia develops slowly, we may be able to delay the onset and improve neuronal dysfunction by enhancing the energy metabolism of individual neurons. TND1128, a derivative of 5-deazaflavin, is a chemical known to have an efficient self-redox ability. We expected TND1128 as an activator for mitochondrial energy synthesis. We used brain slices prepared from mice 22 ± 2 h pretreated with TND1128 or ß-NMN. We measured Ca2+ concentrations in the cytoplasm ([Ca2+]cyt) and mitochondria ([Ca2+]mit) by using fluorescence Ca2+ indicators, Fura-4F, and X-Rhod-1, respectively, and examined the protective effects of drugs on [Ca2+]cyt and [Ca2+]mit overloading by repeating 80K exposure. TND1128 (0.01, 0.1, and 1 mg/kg s.c.) mitigates the dynamics of both [Ca2+]cyt and [Ca2+]mit in a dose-dependent manner. ß-NMN (10, 30, and 100 mg/kg s.c.) also showed significant dose-dependent mitigating effects on [Ca2+]cyt, but the effect on the [Ca2+]mit dynamics was insignificant. We confirmed the mitochondria-activating potential of TND1128 in the present study. We expect TND1128 as a drug that rescues deteriorating neurons with aging or disease.
Assuntos
Doença de Alzheimer , Mitocôndrias , Camundongos , Animais , Mitocôndrias/metabolismo , Encéfalo/metabolismo , Doença de Alzheimer/metabolismo , OxirreduçãoRESUMO
PURPOSE: Cerebrospinal fluid drainage (CSFD) is recommended during open or endovascular thoracic aortic repair. However, the incidence of CSFD complications is still high. Recently, CSF pressure has been kept high to avoid complications, but the efficacy of CSFD at higher pressures has not been confirmed. We hypothesize that CSFD at higher pressures is effective for preventing motor deficits. METHODS: This prospective observational study included 14 hospitals that are members of the Japanese Society of Cardiovascular Anesthesiologists. Patients who underwent thoracic and thoracoabdominal aortic repair were divided into four groups: Group 1, CSF pressure around 10 mmHg; Group 2, CSF pressure around 15 mmHg; Group 3, CSFD initiated when motor evoked potential amplitudes decreased; and Group 4, no CSFD. We assessed the association between the CSFD group and motor deficits using mixed-effects logistic regression with a random intercept for the institution. RESULTS: Of 1072 patients in the study, 84 patients (open surgery, 51; thoracic endovascular aortic repair, 33) had motor deficits at discharge. Groups 1 and 2 were not associated with motor deficits (Group 1, odds ratio (OR): 1.53, 95% confidence interval (95% CI): 0.71-3.29, p = 0.276; Group 2, OR: 1.73, 95% CI: 0.62-4.82) when compared with Group 4. Group 3 was significantly more prone to motor deficits than Group 4 (OR: 2.56, 95% CI: 1.27-5.17, p = 0.009). CONCLUSION: CSFD is not associated with motor deficits in thoracic and thoracoabdominal aortic repair with CSF pressure around 10 or 15 mmHg.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma da Aorta Torácica , Humanos , Aneurisma da Aorta Torácica/cirurgia , Aneurisma da Aorta Abdominal/cirurgia , Estudos Prospectivos , Vazamento de Líquido Cefalorraquidiano , Drenagem , Líquido Cefalorraquidiano , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Microglia are key cells of the immune system in the central nervous system and are suggested to be deeply involved in the development of neurodegenerative diseases. It is well known that microglia have functional plasticity, with an inflammatory M1 phenotype and an anti-inflammatory M2 phenotype. Inhibition of choline transport in macrophages has been reported to suppress the secretion of inflammatory cytokines. However, the role of the choline transport system in regulating microglial M1/M2 polarization has not been fully elucidated to date. In this study, we investigated the mechanism of choline uptake in microglia, and its association with microglial M1/M2 polarization. METHODS: The immortalized mouse microglial cell line SIM-A9 was used for [3H]choline uptake and expression analysis of choline transporters. The association between the choline uptake system and the M1/M2 polarization of microglia was also analyzed. RESULTS: Choline transporter-like protein (CTL) 1 and CTL2 were highly expressed in SIM-A9 cells, and CTL1 and CTL2 were localized in the plasma membrane and mitochondria, respectively. Functional analysis of choline uptake demonstrated the existence of Na+-independent, pH-dependent, and intermediate-affinity choline transport systems. Choline uptake was concentration-dependently inhibited by hemicholinium-3 (HC-3), an inhibitor of choline uptake, and increased by lipopolysaccharide (LPS) and interleukin-4 (IL-4). Expression of the mRNA of M1 microglia markers IL-1ß and IL-6 was increased by LPS, and their effects were suppressed by choline deprivation and HC-3. In contrast, mRNA expression of the M2 microglial marker arginase-1 (Arg-1) was increased by IL-4, and the effect was enhanced by choline deprivation and HC-3. CONCLUSIONS: Our results suggest that inhibition of CTL1-mediated choline uptake in microglia preferentially induces M2 microglia polarization, which is a potential therapeutic approach for inflammatory brain diseases.
Assuntos
Lipopolissacarídeos , Microglia , Animais , Polaridade Celular , Colina/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Proteínas de Membrana Transportadoras , Camundongos , Microglia/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , RNA Mensageiro/metabolismoRESUMO
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.
Assuntos
Encéfalo/metabolismo , Metabolômica/métodos , Mitocôndrias/metabolismo , Peptidil-Prolil Isomerase F/genética , Sepse/metabolismo , Animais , Temperatura Corporal , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Masculino , Camundongos , Poro de Transição de Permeabilidade Mitocondrial , Espécies Reativas de Oxigênio/metabolismo , Sepse/etiologia , Sepse/genética , Sepse/mortalidadeRESUMO
In the perioperative period, hypoxemia and hyperoxia are crucial factors that require attention, because they greatly affect patient prognoses. The pulse oximeter has been the only noninvasive monitor that can be used as a reference of oxygenation in current anesthetic management; however, in recent years, a new monitoring method that uses the oxygen reserve index (ORi™) has been developed by Masimo Corp. ORi is an index that reflects the state of moderate hyperoxia (partial pressure of arterial oxygen [PaO2] between 100 and 200 mmHg) using a non-unit scale between 0.00 and 1.00. ORi monitoring performed together with percutaneous oxygen saturation (SpO2) measurements may become an important technique in the field of anesthetic management, for measuring oxygenation reserve capacity. By measuring ORi, it is possible to predict hypoxemia and to detect hyperoxia at an early stage. In this review, we summarize the method of ORi, cautions for its use, and suitable cases for its use. In the near future, the monitoring of oxygen concentrations using ORi may become increasingly common for the management of respiratory function before, after, and during surgery.
Assuntos
Oximetria , Oxigênio , Gasometria , Humanos , Hipóxia , Pressão ParcialRESUMO
BACKGROUND: Cerebrospinal fluid drainage (CSFD) is recommended as a spinal cord protective strategy in open and endovascular thoracic aortic repair. Although small studies support the use of CSFD, systematic reviews have not suggested definite conclusion and a large-scale study is needed. Therefore, we reviewed medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open and endovascular repair) at multiple institutions to assess the association between CSFD and postoperative motor deficits. METHODS: Patients included in this study underwent descending or thoracoabdominal aortic repair between 2000 and 2013 at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery. We conducted a retrospective study to investigate whether motor-evoked potential monitoring is effective in reducing motor deficits in thoracic aortic aneurysm repair. We use the same dataset to examine whether CSFD reduces motor deficits after propensity score matching. RESULTS: We reviewed data from 1214 patients [open surgery, 601 (49.5%); endovascular repair, 613 (50.5%)]. CSFD was performed in 417 patients and not performed in the remaining 797 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. After propensity score matching (n = 700), mixed-effects logistic regression performed revealed that CSFD is associated with postoperative motor deficits at discharge [adjusted odds ratio (OR), 3.87; 95% confidence interval (CI), 2.30-6.51]. CONCLUSION: CSFD may not be effective for postoperative motor deficits at discharge.
Assuntos
Aneurisma da Aorta Abdominal , Aneurisma da Aorta Torácica , Traumatismos da Medula Espinal , Isquemia do Cordão Espinal , Aneurisma da Aorta Torácica/cirurgia , Líquido Cefalorraquidiano , Vazamento de Líquido Cefalorraquidiano , Drenagem , Humanos , Estudos Retrospectivos , Medula Espinal , Traumatismos da Medula Espinal/prevenção & controle , Isquemia do Cordão Espinal/etiologia , Isquemia do Cordão Espinal/prevenção & controleRESUMO
Obesity is a major global public health problem, and understanding its pathogenesis is critical for identifying a cure. In this study, a gene knockout strategy was used in post-neonatal mice to delete synoviolin (Syvn)1/Hrd1/Der3, an ER-resident E3 ubiquitin ligase with known roles in homeostasis maintenance. Syvn1 deficiency resulted in weight loss and lower accumulation of white adipose tissue in otherwise wild-type animals as well as in genetically obese (ob/ob and db/db) and adipose tissue-specific knockout mice as compared to control animals. SYVN1 interacted with and ubiquitinated the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1ß, and Syvn1 mutants showed upregulation of PGC-1ß target genes and increase in mitochondrion number, respiration, and basal energy expenditure in adipose tissue relative to control animals. Moreover, the selective SYVN1 inhibitor LS-102 abolished the negative regulation of PGC-1ß by SYVN1 and prevented weight gain in mice. Thus, SYVN1 is a novel post-translational regulator of PGC-1ß and a potential therapeutic target in obesity treatment.
Assuntos
Peso Corporal/genética , Mitocôndrias/fisiologia , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Células 3T3-L1 , Animais , Células Cultivadas , Regulação para Baixo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genéticaRESUMO
Cerebral Oximetry by Near-infrared Spectroscopy (NIRS) has been used in cardiovascular anesthesia, but there was no guideline of regional cerebral oxygen saturation measured by cerebral oximetry by NIRS. This guideline provides recommendations applicable to patients at a risk of developing cerebral ischemia in cardiovascular surgery. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment. The Japanese Society of Cardiovascular Anesthesiologists (JSCVA) Task Force on Guidelines make an effort to ensure that the guideline writing committee contains broad views in using cerebral oximetry. Adherence to recommendations could be enhanced by shared decision making between healthcare providers and patients. This guideline was focused on cerebral oximetry of pediatric and adult cardiovascular disease. We hope this guideline would play an important role in using cerebral oximetry by measured NIRS.
Assuntos
Anestesia em Procedimentos Cardíacos/métodos , Oximetria/métodos , Oxigênio/análise , Adulto , Anestesiologistas , Encéfalo/irrigação sanguínea , Circulação Cerebrovascular , Criança , Humanos , Japão , Espectroscopia de Luz Próxima ao Infravermelho/métodosRESUMO
The mechanism of brain edema is complex and still remains unclear. Our aim was to investigate the regional differences of cell volume and intracellular Ca2+ concentration ([Ca2+ ]i ) dynamics during hypotonic stress in male mouse hemi-brain slices. Brain slices were loaded with the fluorescence Ca2+ indicator fura-2, and cell volume and [Ca2+ ]i in the lateral cerebral cortex (LCC) and hippocampal CA1 (CA1) region were measured simultaneously during exposure to hypotonic stress using Ca2+ insensitive (F360) and Ca2+ sensitive fluorescence (F380), respectively. Brain cell swelling induced by hypotonic stress was followed by a regulatory volume change that coincided with an increase in [Ca2+ ]i . The degrees of change in cell volume and [Ca2+ ]i were significantly different between the LCC and CA1. The increase in cell volume and [Ca2+ ]i in the LCC, but not in the CA1, was decreased by the transient receptor potential channel blockers LaCl3 and GdCl3 . The increase in [Ca2+ ]i in both the LCC and CA1, was significantly decreased by the intracellular Ca2+ modulators thapsigargin and xestospongin C. The K+ channel activator isoflurane and Cl- channel blocker NPPB significantly decreased [Ca2+ ]i in the LCC. This study demonstrated that, between cells located in the LCC and in the CA1, the characteristics of brain edema induced by hypotonic stress are different. This can be ascribed to the different contribution of volume sensitive G-protein coupled receptor and stretch sensitive Ca2+ channels.
Assuntos
Região CA1 Hipocampal/metabolismo , Cálcio/metabolismo , Tamanho Celular , Córtex Cerebral/metabolismo , Espaço Intracelular/metabolismo , Pressão Osmótica/fisiologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Isoflurano/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrobenzoatos/farmacologia , Técnicas de Cultura de Órgãos , Pressão Osmótica/efeitos dos fármacosRESUMO
BACKGROUND: Spinal cord ischemic injury is the most devastating sequela of descending and thoracoabdominal aortic surgery. Motor-evoked potentials (MEPs) have been used to intraoperatively assess motor tract function, but it remains unclear whether MEP monitoring can decrease the incidence of postoperative motor deficits. Therefore, we reviewed multicenter medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open surgery and endovascular repair) to assess the association of MEP monitoring with postoperative motor deficits. METHODS: Patients included in the study underwent descending or thoracoabdominal aortic repair at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery between 2000 and 2013. Using multivariable mixed-effects logistic regression analysis, we investigated whether intraoperative MEP monitoring was associated with postoperative motor deficits at discharge after open and endovascular aortic repair. RESULTS: We reviewed data from 1214 patients (open surgery, 601 [49.5%]; endovascular repair, 613 [50.5%]). MEP monitoring was performed in 631 patients and not performed in the remaining 583 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. Multivariable logistic regression analysis revealed that postoperative motor deficits at discharge did not have a significant association with MEP monitoring (adjusted odds ratio [OR], 1.13; 95% confidence interval [CI], 0.69-1.88; P = .624), but with other factors: history of neural deficits (adjusted OR, 6.08; 95% CI, 3.10-11.91; P < .001), spinal drainage (adjusted OR, 2.14; 95% CI, 1.32-3.47; P = .002), and endovascular procedure (adjusted OR, 0.45; 95% CI, 0.27-0.76; P = .003). The sensitivity and specificity of MEP <25% of control value for motor deficits at discharge were 37.8% (95% CI, 26.5%-49.5%) and 95.5% (95% CI, 94.7%-96.4%), respectively. CONCLUSIONS: MEP monitoring was not significantly associated with motor deficits at discharge.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Torácica/cirurgia , Auditoria Clínica/métodos , Potencial Evocado Motor/fisiologia , Monitorização Intraoperatória/métodos , Complicações Pós-Operatórias/prevenção & controle , Traumatismos da Medula Espinal/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/epidemiologia , Aneurisma da Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Torácica/epidemiologia , Aneurisma da Aorta Torácica/fisiopatologia , Bases de Dados Factuais , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/fisiopatologia , Estudos Retrospectivos , Traumatismos da Medula Espinal/epidemiologia , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
We examined the functional characteristics of choline uptake in human tongue carcinoma using the cell line HSC-3. Furthermore, we explored the possible correlation between the inhibition of choline uptake and apoptotic cell death. Both choline transporter-like protein 1 (CTL1) and CTL2 mRNAs and proteins were expressed, and were located in plasma membrane and mitochondria, respectively. Choline uptake was saturable and mediated by a single transport system, which is pH-dependent. Several cationic drugs inhibited cell viability and [(3)H]choline uptake. Choline uptake inhibitors and choline deficiency inhibited cell viability and increased caspase-3/7 activity. We conclude that extracellular choline is mainly transported via a CTL1 that relies on a directed H(+) gradient as a driving force. The functional inhibition of CTL1 by cationic drugs could promote apoptotic cell death. Furthermore, CTL2 may be the major site for the control of choline oxidation in mitochondria and hence for the supply of endogenous betaine and S-adenosyl methionine, which serves as a major methyl donor. Identification of this CTL1- and CTL2-mediated choline transport system provides a potential new target for tongue cancer therapy.
Assuntos
Antígenos CD/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Neoplasias da Língua/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Colina/metabolismo , Humanos , RNA Mensageiro/metabolismoRESUMO
A 54-year-old woman was admitted for mitral valvular repair. After folding plasty to A3, a 30 mm Cosgrove-Edwards ring was placed. There was no mitral regurgitation jet observed by transesophageal echocardiography (TEE) during the operation. However, high blood pressure was monitored and treated in the intensive care unit, hemolytic anemia developed, and the serum lactate dehydrogenase level was elevated. Two weeks after the operation, serum lactate dehydrogenase was again elevated. TEE showed mild mitral regurgitation and the regurgitation jet colliding with the annuloplasty ring. Multiple transfusions of red blood cells were required. Repeat surgery was therefore undertaken. Lam and associates previously studying patients on hemolysis after mitral valvular repair noted high grade mitral regurgitation jets fragmented or accelerated. In the present case, mitral regurgitation was mild, but the high velocity and manner of regurgitation (collision with the annuloplasty ring) could cause hemolytic anemia. In the present case, high blood pressure might have caused chordae rupture. Furthermore, a flexible ring, such as the Cosgrove-Edwards ring, is likely to cause hemolytic anemia. As contributing factors to hemolysis after mitral valvular repair, perioperative blood pressure management and type of ring are significant.
Assuntos
Anemia Hemolítica/etiologia , Valva Mitral/cirurgia , Complicações Pós-Operatórias , Feminino , Humanos , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/cirurgia , ReoperaçãoRESUMO
Humanin is a secreted bioactive peptide that suppresses cell toxicity caused by a variety of insults. The neuroprotective effect of Humanin against Alzheimer disease (AD)-related death is mediated by the binding of Humanin to its heterotrimeric Humanin receptor composed of ciliary neurotrophic receptor α, WSX-1, and gp130, as well as the activation of intracellular signaling pathways including a JAK2 and STAT3 signaling axis. Despite the elucidation of the signaling pathways by which Humanin mediates its neuroprotection, the transcriptional targets of Humanin that behaves as effectors of Humanin remains undefined. In the present study, Humanin increased the mRNA and protein expression of SH3 domain-binding protein 5 (SH3BP5), which has been known to be a JNK interactor, in neuronal cells. Similar to Humanin treatment, overexpression of SH3BP5 inhibited AD-related neuronal death, while siRNA-mediated knockdown of endogenous SH3BP5 expression attenuated the neuroprotective effect of Humanin. These results indicate that SH3BP5 is a downstream effector of Humanin. Furthermore, biochemical analysis has revealed that SH3BP5 binds to JNK and directly inhibits JNK through its two putative mitogen-activated protein kinase interaction motifs (KIMs).
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Motivos de Aminoácidos , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Células Cultivadas , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Proteínas de Membrana/genética , Camundongos , Proteínas Mitocondriais/genética , Estrutura Terciária de ProteínaRESUMO
Humanin, a short bioactive peptide, inhibits a variety of cell deaths. Humanin-mediated inhibition of neuronal cell death, caused by an Alzheimer's disease (AD)-linked mutant gene occurs via binding of Humanin to its heterotrimeric Humanin receptor (htHNR), which results in the activation of the Janus-associated kinases (JAKs) and signal transducer and activator and transcription 3 (STAT3) signaling pathway. A previous study demonstrated that the Humanin-induced activation of the htHNR/JAK2/STAT3 signaling pathway leads to increased expression of SH3 domain-binding protein 5 (SH3BP5), which is an essential effector of Humanin's anti-cell death activity in some cultured neuronal cells. However, it remains unknown whether SH3BP5 is the sole effector of the Humanin signaling pathway via htHNR/JAKs/STAT3. Here we show that the Humanin signaling pathway via htHNR/JAKs/STAT3 increased the expression levels of mRNA and protein of Apollon/Bruce, an unusual member of the inhibitors of apoptosis proteins, and that overexpression of Apollon/Bruce inhibits neuronal death, caused by a London-type familial AD-linked mutant (V642I) of amyloid ß precursor protein. Overall, the results indicate that expression of Apollon/Bruce is upregulated by Humanin, and Apollon/Bruce could be an effector of Humanin in a context-dependent manner.
Assuntos
Doença de Alzheimer/metabolismo , Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/genética , Animais , Apoptose/genética , Células Cultivadas , Humanos , Proteínas Inibidoras de Apoptose/genética , Janus Quinases/genética , Janus Quinases/metabolismo , Camundongos , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genéticaRESUMO
Postoperative cognitive impairment is a recognized clinical phenomenon. Previously, such clinical findings were called "adverse cerebral effects of anesthesia on old people". POCD is transient disturbance that can affect patients of any age but is more common in elderly people. Its relevance with the immediate post-operative phase was made clear. The aging of the population and new developments in medicine both lead to the increasing number of elderly patietnts undergoing extensive surgery. Mechanism of POCD is considered to be due to the inflammatory response and Ca2+ dysregulation of the brain. For the diagnosis of POCD, pscychometric tests are applied. Risk factors for POCD are aging, extensive invasive operations, intra and postoperative complications, and anesthetics. To reduce POCD, it is necessary to provide preoperative screening and cognitive training, minimally invasive surgery, the use of short-acting agents, meticulous anesthetic technique to prevent perioperative disturbances of homeostasis and organ ischemia, tight volume balance, and EEG monitoring.
Assuntos
Transtornos Cognitivos/fisiopatologia , Complicações Pós-Operatórias/fisiopatologia , Anestesia/efeitos adversos , Cálcio/metabolismo , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/terapia , Humanos , Testes Neuropsicológicos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/terapia , Fatores de RiscoRESUMO
In recent years, the aging population has been growing, and the operative techniques and anesthetic methods have advanced. With these developments and medical support, the number of operations on very elderly patients has been increasing. We report the perioperative management of off-pump CABG for a 93-year-old man. When the heart was displaced during the operation, hypotension was induced and a marked reduction of his bispectral index (BIS) to "1" appeared. During the perioperative period, the patient developed delirium that was difficult to manage, but he was discharged from the hospital without any complications on POD 21. As part of the perioperative management, intraoperative cerebral circulatory management with attention to cerebral perfusion and prevention of postoperative delirium is crucial.
Assuntos
Anestesia , Ponte de Artéria Coronária sem Circulação Extracorpórea , Doença das Coronárias/cirurgia , Delírio/prevenção & controle , Assistência Perioperatória , Complicações Pós-Operatórias/prevenção & controle , Idoso de 80 Anos ou mais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Circulação Cerebrovascular , Monitores de Consciência , Delírio/tratamento farmacológico , Delírio/etiologia , Flunitrazepam/administração & dosagem , Haloperidol/administração & dosagem , Humanos , Cuidados Intraoperatórios , Masculino , Monitorização Intraoperatória , Consumo de Oxigênio , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Resultado do TratamentoRESUMO
We developed a conventional imaging method to measure Ca(2+) concentration in cytosol (using FuraRed as an indicator) and mitochondria (using Rhod-2 as an indicator), simultaneously, by alternative excitation with specific wave length. After confirming the availability of the method in Hela cells, we applied it to mouse whole-brain slice -preparation, which was exposed to oxygen- and glucose-deprived artificial cerebrospinal fluid (ischemic ACSF) for 12 min. The fluorescence (>570 nm) at the cerebral cortex and hippocampus due to FuraRed (excited by 480 ± 10 nm) decreased (indicating the increase in cytosolic Ca(2+)-concentration), while the fluorescence due to Rhod-2 (excited by 560 ± 10 nm) increased (indicating the increase in mitochondrial Ca(2+) concentration) during exposure to ischemic conditions. We found the characteristic protective effects of cyclosporine A (10(-6) M), a known blocker for mitochondrial permeability transition, and SEA0400 (10(-6) M), a blocker for Na(+)/Ca(2+) exchanger, on the abnormal Ca(2+) increase in cytosol. We confirmed that the present method will be useful for future pathological and pharmacological studies on ischemia-induced brain damage.
Assuntos
Cálcio/metabolismo , Citosol/metabolismo , Isquemia/patologia , Mitocôndrias/metabolismo , Neurônios/ultraestrutura , Compostos de Anilina/farmacologia , Animais , Benzofuranos , Citosol/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Compostos Heterocíclicos com 3 Anéis , Humanos , Imidazóis , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Fatores de TempoRESUMO
Traumatic brain injury and ischemia can result in marked neuronal degeneration and residual impairment of cerebral function. However, no effective pharmacological treatment directed at tissues of the central nervous system (CNS) for acute intervention has been developed. The detailed pathophysiological cascade leading to -neurodegeneration in these conditions has not been elucidated, but cellular calcium overload and mitochondrial dysfunction have been implicated in a wide range of animal models involving degeneration of the CNS. In particular, activation of the calcium-induced mitochondrial permeability transition (mPT) is considered to be a major cause of cell death inferred by the broad and potent neuroprotective effects of -pharmacological inhibitors of mPT, especially modulators of cyclophilin activity and, more specifically, genetic inactivation of the mitochondrial cyclophilin, cyclophilin D. Reviewed are evidence and challenges that could bring on the dawning of mitochondrial medicine aimed at safeguarding energy supply following acute injury to the CNS.
Assuntos
Ciclofilinas/metabolismo , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores , Animais , Arsenicais/farmacologia , Arsenicais/uso terapêutico , Lesões Encefálicas/tratamento farmacológico , Cálcio/metabolismo , Peptidil-Prolil Isomerase F , Ciclosporina/farmacologia , Ciclosporina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Isquemia/tratamento farmacológicoRESUMO
BACKGROUND: Recently, various sets of protein -biomarkers have been discovered in important diseases such as cancers, brain stroke and heart attack. However, clinical validation is difficult and time-consuming by individual assays or because of very low concentrations at early stages of the diseases. We have developed assay technology through an innovative modification of the immuno-PCR method for the super-sensitive and multiplex detection of target biomarkers. METHODS: In the assay technology, each different oligo-tag simultaneously detects multiplex protein targets with extremely high-level sensitivity in a dose-dependent manner by qRT-PCR (maximum: three plexes). In this study, we measured specific secreted protein concentrations in the culture supernatant of a 24-h culture of transfected SH-SY5Y cells with MUSTag. RESULTS: There was a significant increase in the protein level of tumor necrosis factor (TNF)-α measured with extremely high-level sensitivity (≥10 pg/mL). Compared with negative controls, the levels of TNF-α increased from 16.9 to 28.1 pg/mL (p = 0.011). CONCLUSION: We suggest that our assay technology might be of clinical value in treating patients with cancer, cerebral ischemia, or patients who need a prompt and predictive diagnosis for adequate treatment.
Assuntos
Fator de Iniciação 3 em Eucariotos/metabolismo , Fator de Necrose Tumoral alfa/análise , Angiopoietina-1/genética , Angiopoietina-1/metabolismo , Linhagem Celular Tumoral , Fator de Iniciação 3 em Eucariotos/genética , Proteínas de Fluorescência Verde/genética , Humanos , Neuroblastoma , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transfecção , Fator de Crescimento Transformador betaRESUMO
In Japan, the number of patients with chronic kidney disease (CKD) has increased. Hence, the opportunities for intensive care management of patients with CKD have also increased. Acute kidney injury (AKI) easily develops following CKD, and conversely, it can be a risk factor for CKD. At the time when CKD patients require ICU admission, their disease is already very severe, and the mortality rate tends to be high due to a number of associated complications. During the hemodynamic management of these patients, not only static indices such as CVP, but also dynamic indices such as stroke volume variation (SVV) should be used, since their circulation is very precariously balanced. While "goal-directed" hemodynamic management, which targets particular hemodynamic variables, might be useful in CKD patients, there is no evidence to prove its efficacy. Renal Replacement Therapy (RRT) is usually started after metabolic acidosis, hyperkalemia, ingestion of dialyzable toxin, volume overload and uremia have occurred. However, it is not clear whether continuous or intermittent RRT is beneficial in these patients.