Biomedical subjects

Hitoshi Yoshida

Publications and source records attributed to Hitoshi Yoshida.

At least 19 recordsLinked to original sources

PubMed2006

The ACC synthase TOE sequence is required for interaction with ETO1 family proteins and destabilization of target proteins.

The Arabidopsis ETO1 protein is a negative regulator of ethylene biosynthesis. It specifically inhibits the enzyme activity of type 2 1-aminocyclopropane-1-carboxylate synthases (ACC synthases or ACS) and promotes their degradation by a proteasome-dependent pathway. To further understand the function of the ETO1 family in the plant kingdom, we cloned a cDNA of LeEOL1 (Lycopersicon esculentum ETO 1- LIKE 1), an ETO1 homolog from tomato. LeEOL1 encodes a putative protein with domain architecture conserved in the Arabidopsis ETO1/EOL1/EOL2 proteins and in the predicted rice EOL proteins. LeEOL1 is expressed in leaf, stem, root, flower, and the full ripe stage of fruit, suggesting diverse regulatory roles in the development of tomato. Yeast two-hybrid analysis revealed specific interactions between LeEOL1 and type 2 ACC synthases. When the C-terminal 14 amino acids (TOE; target of ETO1) of LE-ACS3 specific to type 2 ACC synthases were fused to a type 1 ACS, LE-ACS2, at the corresponding position, it allowed LE-ACS2 to strongly interact with LeEOL1. A GFP-TOE(LE-ACS3) fusion protein expressed in rice calli and in the roots of wild-type Arabidopsis showed reduced stability compared to native GFP. However, the fluorescence of GFP-TOE(LE-ACS3) was comparable to that of the native GFP in Arabidopsis eto1-4 mutant. Furthermore, MG132 treatment significantly enhanced the fluorescence of GFP-TOE(LE-ACS3) in the roots of wild-type Arabidopsis. These results suggest that the ETO1-family-mediated ACS protein degradation pathway is conserved in both monocots and dicots, and that TOE acts as a protein destabilization signal recognized by the ETO1 protein family.

Amino Acid Sequence↗

PubMed2006

Catalytic inactivation of human phospholipase D2 by a naturally occurring Gly901Asp mutation.

BACKGROUND: We previously showed that the 1814C-->T (Thr577Ile) polymorphism of the human phospholipase D2 (PLD2) gene is associated with the prevalence of colorectal cancer, with the T allele representing a risk factor for this condition. However, we failed to detect a difference in PLD activity of cell lysates or membrane fractions between cells transfected with cDNAs encoding the Thr577 or Ile577 variants of PLD2. In the present study, we have examined the possible functional relevance of other naturally occurring polymorphisms (or mutations) of the human PLD2 gene that result in amino acid substitutions. METHODS: Human embryonic kidney cells were transfected with expression vectors for each PLD2 variant and assayed for enzyme activity in vitro and in vivo. RESULTS AND CONCLUSIONS: The G-->A (Gly901Asp) mutation of the human PLD2 gene was found to result in catalytic inactivation of the encoded protein.

Alleles↗

PubMed2006

Expression of CD27 on peripheral CD4+ T-lymphocytes correlates with the development of severe acute graft-versus-host disease after allogeneic bone marrow transplantation.

Allogeneic immune responses during hematopoietic reconstitution play central roles in beneficial and adverse effects after allogeneic bone marrow transplantation (allo-BMT). Appropriate regulation of the immune responses might improve the outcome of allo-BMT. However, a useful marker for monitoring allogeneic immune responses remains to be established. We enrolled 22 consecutive patients who underwent myeloablative allo-BMT between March 2002 and March 2006 and examined the relationship between CD27 expression on peripheral blood T-lymphocytes, a possible marker for naive/effector phenotypes, and clinical events, especially acute graft-versus-host disease (aGVHD). In 8 patients with aGVHD of grades II to IV, the CD27+/CD27- ratios of CD4+ (but not CD8+) T-lymphocytes were significantly higher after allo-BMT, even at day 21, than the ratios in patients with aGVHD of grade 0 or I and remained high after day 21. In contrast, the ratios were low after day 21 following allo-BMT in 14 patients with aGVHD of grade 0 or I. Moreover, the clinical analysis suggested a relationship between the ratio and aGVHD grade. Thus, we showed that the CD27+/CD27- ratio in CD4+ T-lymphocytes may have value in predicting the development of severe aGVHD and may correlate with clinical symptoms of aGVHD.

Acute Disease↗

PubMed2006

[Anesthetic management for patients with Brugada syndrome].

Brugada syndrome should not be neglected in terms of anesthetic management because its perioperative autonomic imbalance may cause ventricular fibrillation and sudden cardiac arrest. Diagnosis of Brugada syndrome is easily made by unique electrocardiographic pattern of right bundle branch block and ST segment elevation in the right precordial leads. Thus the number of patients with Brugada syndrome for anesthetic management tends to increase. We review current concept of anesthetic management for patients with Brugada syndrome including fourteen cases in our institution, two out of which developed VF during operation.

Adult↗

PubMed2006

[Safe management of anesthesia with total intravenous anesthesia using propofol, fentanyl and ketamine for a patient treated with intraoperative radiotherapy].

A 3-year-old girl with neuroblastoma was scheduled for intraoperative radiation therapy. Prior to surgery, meetings were held to ensure the safety during transfer between the operating room and the radiation unit because those units were placed on the different floors in our hospital. In the operating room the patient was anesthetized with propofol, fentanyl and ketamine (PFK). After the resection of the tumor, the patient was moved to the radiation unit. All personnel had to leave the treatment room while the radiation was administered, which required 3 minutes. During the transfer and treatment, the following apparatus were effective to ensure the patient's safety; mobile respiratory and cardiovascular monitors, closed-circuit television to observe the monitors and patient, and a portable gas powered ventilator. The total intravenous anesthesia with PFK was used throughout all scheduled procedures. For patients treated with intraoperative radiation therapy, the administration of inhalation anesthetics should be discontinued to supply 100% oxygen, which enhances the effect of irradiation, and to avoid the complexity of the transfer with an anesthetic machine. This discontinuation, however, may cause the cardiovascular instability. It seems that total intravenous anesthesia has advantages over inhalation anesthesia for patients who undergo intraoperative radiation therapy.

Adrenal Gland Neoplasms↗

PubMed2006

Human DEAD-box/RNA unwindase rck/p54 contributes to maintenance of cell growth by affecting cell cycle in cultured cells.

Understanding the control of gene expression in cancer cells requires defining the molecular and cellular basis of RNA metabolism compared with that in steady-state normal cells. Previously, we reported evidence that human RNA structure-modifying unwindase rck/p54, a member of the DEAD-box family, was highly expressed in most of the malignant cell lines tested and that this expression was linked to malignant transformation. Here, we show that rck/p54 positively affects cell growth, probably by modulating the gene expression at the translational level in cultured cells. In cell growth and differentiation induced by external stimuli, the level of rck/p54 expression was up-regulated during cell proliferation and down-regulated during differentiation. The down-regulation of rck/p54 in HeLa cells by RNAi induced cell growth inhibition through cell cycle arrest at S phase. Immunoprecipitation using anti-rck/p54 antibody in HeLa cells demonstrated the co-precipitation of rck/p54 with eIF4E, which is well-known to bind to the 5'cap-structure, resulting in initiation of translation. These data suggest that rck/p54 contributes to cell growth possibly by modulating translation-initiation control of the genes involved in the cell proliferation, which is a newly defined mechanism leading to carcinogenesis.

Amino Acid Sequence↗

PubMed2006

[Effect of amino acid infusion for prevention of intraoperative hypothermia during laparotomy].

BACKGROUND: Amino acid infusion prevents intraoperative hypothermia. The purpose of this study is to examine the effect of amino acid infusion on intraoperative core temperature of patients during laparotomy. METHODS: Forty-two patients (duration of surgery of 180 min or more) and 32 patients (duration of surgery less than 180 min) scheduled for open gastrectomy under sevoflurane anesthesia combined with epidural anesthesia were randomly allocated to receive either amino acid solution (A group) or electrolyte solution (S group) intravenously. Each solution was started at anesthesia induction. The levels of tympanic temperature were recorded after induction, during surgery and at extubation. RESULTS: Patients in each of the two groups (A group vs. S group) were comparable with their characteristics and anesthetic management. Amino acid infusion prevented intraoperative hypothermia for cases of 180 min or more. The number of patients with temperature of less than 35.5 degrees C in A group was less those that in S group for cases shorter than 180 min. CONCLUSIONS: Amino acid infusion has more preventive effect on intraoperative hypothermia than electrolyte solution.

Aged↗

PubMed2005

Lack of interaction between orexinergic and alpha2-adrenergic neuronal systems in rat cerebrocortical slices.

Orexinergic and norepinephrinergic alpha2-adrenoceptor expressing neurons contribute to the regulation of the sleep-wakefulness cycle. In the present study, we have examined a possible interaction between orexinergic and alpha2-adrenergic systems in orexin-A (100 nM)- and K+ (25 mM)-evoked norepinephrine release from slices of rat cerebrocortex. In this tissue norepinephrinergic neurons are predominantly innervated via the locus coeruleus. Clonidine concentration-dependently inhibited K+-evoked norepinephrine release with pIC50 (Imax) of 6.44+/-0.38 (48.8+/-6.9%). A selective orexin-1 receptor antagonist, SB-334867 was ineffective. SB-334867 concentration-dependently inhibited orexin A-evoked norepinephrine release with pIC50 (Imax) of 6.05+/-0.14 (86.4+/-5.4%); clonidine (alpha2-agonist) was ineffective. In contrast, yohimbine reversed the inhibitory effects of clonidine (1 microM) on K+-evoked norepinephrine release with pIC50 (Imax) of 6.50+/-0.34 (77.6+/-10.9%); orexin A was ineffective. The present data suggest a lack of interaction between orexinergic and alpha2-adrenergic neurons in rat cerebral cortex.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2005

Arabidopsis ETO1 specifically interacts with and negatively regulates type 2 1-aminocyclopropane-1-carboxylate synthases.

BACKGROUND: In Arabidopsis, ETO1 (ETHYLENE-OVERPRODUCER1) is a negative regulator of ethylene evolution by interacting with AtACS5, an isoform of the rate-limiting enzyme, 1-aminocyclopropane-1-carboxylate synthases (ACC synthase or ACS), in ethylene biosynthetic pathway. ETO1 directly inhibits the enzymatic activity of AtACS5. In addition, a specific interaction between ETO1 and AtCUL3, a constituent of a new type of E3 ubiquitin ligase complex, suggests the molecular mechanism in promoting AtACS5 degradation by the proteasome-dependent pathway. Because orthologous sequences to ETO1 are found in many plant species including tomato, we transformed tomato with Arabidopsis ETO1 to evaluate its ability to suppress ethylene production in tomato fruits. RESULTS: Transgenic tomato lines that overexpress Arabidopsis ETO1 (ETO1-OE) did not show a significant delay of fruit ripening. So, we performed yeast two-hybrid assays to investigate potential heterologous interaction between ETO1 and three isozymes of ACC synthases from tomato. In the yeast two-hybrid system, ETO1 interacts with LE-ACS3 as well as AtACS5 but not with LE-ACS2 or LE-ACS4, two major isozymes whose gene expression is induced markedly in ripening fruits. According to the classification of ACC synthases, which is based on the C-terminal amino acid sequences, both LE-ACS3 and AtACS5 are categorized as type 2 isozymes and possess a consensus C-terminal sequence. In contrast, LE-ACS2 and LE-ACS4 are type 1 and type 3 isozymes, respectively, both of which do not possess this specific C-terminal sequence. Yeast two-hybrid analysis using chimeric constructs between LE-ACS2 and LE-ACS3 revealed that the type-2-ACS-specific C-terminal tail is required for interaction with ETO1. When treated with auxin to induce LE-ACS3, seedlings of ETO1-OE produced less ethylene than the wild type, despite comparable expression of the LE-ACS3 gene in the wild type. CONCLUSION: These results suggest that ETO1 family proteins specifically interact with and negatively regulate type 2 ACC synthases. Our data also show that Arabidopsis ETO1 can regulate type 2 ACS in a heterologous plant, tomato.

Amino Acid Motifs↗

PubMed2005

Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2.

PURPOSE: Substantial evidence indicates that supraoligomerization of the death receptors for Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is necessary for efficient activation of the apoptotic pathway. Bivalent IgG antibodies can induce the efficient apoptosis by mimicking the natural ligands but only after these antibodies are further oligomerized by cross-linking. In this study, we generated a novel agonist antibody to TRAIL receptor 2 (TRAIL-R2) capable of inducing apoptosis without cross-linking and elucidated its mode of action and efficacy. EXPERIMENTAL DESIGN: A fully human antibody to TRAIL-R2, KMTR2, was generated from KM Mouse immunized with TRAIL-R2 ectodomain. Apoptosis-inducing activities of unfractionated or purified monomeric IgG of KMTR2 was evaluated in the presence or absence of cross-linkers, secondary antibodies or Fc receptor-expressing effector cells, against human colorectal adenocarcinoma Colo205. Oligomerization of TRAIL-R2 was analyzed by size exclusion chromatography and confocal microscopy, and in vivo efficacy was examined in Colo205 xenograft model. RESULTS: KMTR2 specifically recognized TRAIL-R2 and induced apoptosis with or without cross-linking. Size exclusion chromatography showed that the apoptosis activity coeluted with monomeric IgG and was effective independent of secondary antibody or Fc receptor-expressing effector cells. The antibody formed supracomplexes with soluble recombinant and membrane-anchored TRAIL-R2 and enhanced clustering of TRAIL-R2 on cell surface without cross-linking. KMTR2 was dramatically efficacious in reducing established human tumor. CONCLUSION: Our findings indicate that novel agonist antibody KMTR2 can direct antibody-dependent oligomerization of TRAIL-R2 and initiates efficient apoptotic signaling and tumor regression independent of host effector function. Thus, the direct agonist would be a lead candidate for cancer therapeutics.

Animals↗

PubMed2005

Differential effects of a novel IFN-zeta/limitin and IFN-alpha on signals for Daxx induction and Crk phosphorylation that couple with growth control of megakaryocytes.

OBJECTIVE: Although a novel IFN-zeta/limitin uses IFN-alpha/beta receptor, it lacks some common activities of type I IFNs. We compared effects on megakaryocyte proliferation and differentiation as well as signals for their biological activities. MATERIALS AND METHODS: Recombinant IFN-zeta/limitin and IFN-alpha titrated with a cytopathic effect dye binding assay, were used in this study. Colony assays and serum-free suspension cultures for megakaryocytes were performed to compare their growth inhibitory effects. To analyze signals, megakaryocytes cultured in serum-free suspension cultures were stimulated and Western blotted with the indicated antibody. RESULTS: Both IFN-zeta/limitin and IFN-alpha suppressed the proliferation of megakaryocyte progenitors without influencing their differentiation. However, much higher concentrations of IFN-zeta/limitin were required for the growth inhibition than IFN-alpha. The growth inhibition by IFN-zeta/limitin and IFN-alpha was significantly reduced when either Tyk2 or STAT1 was disrupted. In addition, the antisense oligonucleotides against Crk and Daxx, downstream molecules of Tyk2, greatly rescued the IFN-zeta/limitin- and IFN-alpha-induced reduction of megakaryocyte colony numbers. In cultured megakaryocytes, IFN-zeta/limitin induced the expression of SOCS-1 as strongly as IFN-alpha. However, IFN-zeta/limitin induced weaker phosphorylation of Crk and lower induction of Daxx than IFN-alpha. CONCLUSIONS: Weaker signals for Crk and Daxx may participate in less megakaryocyte suppressive activity of IFN-zeta/limitin and may distinguish IFN-zeta/limitin from IFN-alpha in megakaryocytes. Our results extend the understanding about thrombocytopenia in patients with IFN-alpha treatment as well as the possibility for the clinical application of human homologue of IFN-zeta/limitin or an engineered cytokine with useful features of the IFN-zeta/limitin structure.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Interleukin-1beta has a role in cerebral cortical state-dependent electroencephalographic slow-wave activity.

STUDY OBJECTIVES: To investigate the hypothesis that interleukin (IL)-1beta is involved in mediating localized electroencephalogram synchronization. DESIGN: We evaluated bilateral cortical electroencephalograms after unilateral local application of IL-1beta onto the somatosensory cortex of rats. Furthermore, we investigated the effects of unilateral application of an IL-1beta inhibitor, the IL-1 soluble receptor, on spontaneous sleep and sleep rebound after sleep deprivation. SETTING: University research laboratory. INTERVENTIONS: N/A. PARTICIPANTS: Rats. MEASUREMENTS AND RESULTS: Neither dose of IL-1beta or the IL-1 soluble receptor affected the duration of non-rapid eye movement sleep or rapid eye movement sleep. Unilateral application of IL-1beta induced state- and frequency-dependent electroencephalogram asymmetries. During non-rapid eye movement sleep, but not during other states, electroencephalographic slow-wave activity was greater on the side that received IL-1beta (10- and 50-ng doses). Electroencephalographic power in the higher frequencies was not affected by IL-1beta in any state. Unilateral application of the IL-1 soluble receptor (0.1, 1.0 and 5.0 microg) had no effect on the spontaneous sleep electroencephalogram. In contrast, unilateral application of the IL-1 soluble receptor (5.0 microg) attenuated sleep deprivation-enhanced electroencephalographic slow-wave power ipsilaterally during non-rapid eye movement sleep. CONCLUSIONS: Results suggest that IL-1beta can induce state-dependent localized increases of electroencephalographic delta wave power, suggesting an enhancement of sleep intensity within the cortex.

Animals↗

PubMed2005

SHPS-1 negatively regulates integrin alphaIIbbeta3 function through CD47 without disturbing FAK phosphorylation.

CD47 (integrin-associated protein) serves as a receptor for thrombospondin-1 (TSP-1) and Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), and the TSP-1/CD47 interaction has been believed to augment integrin-mediated platelet function. Here, employing SHPS-1-immunoglobulin (Ig) as a ligand, we have newly demonstrated that CD47 acts as an inhibitory receptor for platelet function. The binding of SHPS-1-Ig was solely mediated by CD47, because CD47-deficient platelets failed to bind murine SHPS-1-Ig. The human SHPS-1/CD47 interaction inhibited the platelet aggregation induced by several kinds of agonists at a low concentration. Moreover, human SHPS-1 expressed on the cell surface as well as soluble SHPS-1-Ig markedly inhibited the platelet spreading on, but not initial adhesion to, immobilized fibrinogen. Again, neither murine SHPS-1 expressed on the cell surface nor murine SHPS-1-Ig inhibited the spreading of CD47-deficient platelets. We further investigated the tyrosine phosphorylation of signaling proteins during platelet spreading on immobilized fibrinogen. Unexpectedly, SHPS-1 inhibited alpha(IIb)beta(3)-mediated platelet spreading without disturbing focal adhesion kinase (FAK) tyrosine phosphorylation. Further examination revealed that SHPS-1 inhibited the tyrosine phosphorylation of alpha-actinin, a downstream effector of FAK, but not of cortactin. Thus, it is likely that the SHPS-1/CD47 interaction inhibits alpha(IIb)beta(3)-mediated outside-in signaling by interfering with the downstream pathway of FAK. Taken together, our data suggest that SHPS-1 negatively regulates platelet function via CD47, especially alpha(IIb)beta(3)-mediated outside-in signaling.

Actinin↗

PubMed2005

[Changes in core temperature associated with lower extremity tourniquet--the influence of ambient temperature and warming equipments].

BACKGROUND: We investigated changes in core temperature associated with lower extremity tourniquet (TQ) under two different ambient temperatures (1) and two different warming equipments (2) under general anesthesia combined with lumbar epidural anesthesia. METHODS: (1) The values of core temperature at ambient temperature of either 22 degrees C (n = 15) or 20 degrees C (n=15) were recorded after induction of anesthesia, at start of TQ application, at the termination of TQ application, and 14 minute after TQ release. (2) The values of core temperature using either air-forced warming or active heated i.v. at ambient temperature 20 degrees C were recorded at four points as mentioned above. RESULTS: (1) Changes in core temperature were not observed during TQ application at ambient temperature both 20 degrees C and 22 degrees C. Core temperatures in both groups decreased significantly after TQ release, and core temperatures at termination of TQ application and after TQ release at ambient temperature 20 degrees C were significantly lower than those at ambient temperature 22 degrees C. (2) Significant increases in core temperatures using two different warming equipments were observed at termination of TQ application and after TQ release at ambient temperature 20 degrees C. Core temperatures using air-forced warming were maintained during the investigation, though significant decrease in core temperature using active heated i.v. was recorded after TQ release. CONCLUSIONS: Air-forced warming maintains core temperature efficiently associated with lower extremity tourniquet.

Aged↗

PubMed2005

[Effect of amino acid solution on intraoperative core temperature the influence of anesthetics].

BACKGROUND: Propofol anesthesia has more thermogenic effect than isoflurane when combined with amino acid solutions. The purpose of this study is to compare the effects of intraoperative administration of amino acid solutions on intraoperative core temperature under propofol anesthesia with those under sevoflurane anesthesia. METHODS: Thirty patients scheduled for total hip arthroplasty were randomly allocated to undergo either propofol anesthesia or sevoflurane anesthesia. i.v. amino acid infusion started at anesthesia induction in all patients. The values of tympanic temperature were recorded after induction, during surgery and at extubation. RESULTS: Patients in the two groups were comparable with their characteristics and anesthetic managements. The temperatures under sevoflurane anesthesia were unchanged during study, whereas those under propofol anesthesia decreased significantly. CONCLUSIONS: Sevoflurane anesthesia has more preventive effect on intraoperative hypothermia than propofol anesthesia when combined with amino acid solutions.

Aged↗

PubMed2004

Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias.

CREB-binding protein (CBP) and highly related p300 protein are transcriptional co-activators that play an essential role in chromatin remodeling through histone acetyltransferase activity and interaction with other transcriptional regulators. In this study, various hematological malignancies, including nine cell lines and 45 clinical samples (32 acute myeloid leukemias (AML), nine acute lymphoblastic leukemias (ALL), two cases of myelodysplastic syndrome (MDS), one multiple myeloma, and one chronic myelogenous leukemia in blast crisis), were examined to ask whether mutation of the CBP and p300 genes could be involved in leukemogenesis. The answer was approached by employing the reverse transcription-polymerase chain reaction and single-strand conformation polymorphism (RT-PCR/SSCP) technique and subsequent sequence analysis. A T-lymphoblastic cell line, CEM had an in-frame 21-base-pair deletion within the bromodomain of its p300 cDNA. Genomic DNA analysis revealed aberrant splicing caused by mutation of the acceptor site of intron 17 from ag to gg, which should interfere with catalytic step II of the pre-mRNA splicing reaction. In 1 MDS patient, a missense mutation was detected, which caused a replacement from Ser to Gly at codon 507 of p300. This is the first report of CBP/p300 mutations in leukemias, which might be relatively rare but nonetheless contribute to pathogenesis in some fraction of cases.

Acetyltransferases↗

PubMed2004

CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells.

CD9, a member of the tetraspanin family, has been shown to be involved in a range of cellular activities, including migration, proliferation and adhesion, but the molecular mechanisms by which it mediates such events is unclear. Here, we found that anti-CD9 monoclonal antibody ALB6 inhibited cell proliferation, reduced cell viability and induced not only morphological changes specific to apoptosis but also molecular changes, as evidenced by TUNEL and annexin-V staining. For the possible mechanism of ALB6-induced apoptosis, ALB6 activated the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 mitogen-activated-protein kinase (MAPK) within 5-15 minutes, as well as caspase-3 within 24-48 hours. It is noteworthy that ALB6 induced tyrosine phosphorylation of the p46 Shc isoform specifically and that the overexpression of its dominant-negative form completely suppressed the ALB6-induced activation of JNK/SAPK, p38 MAPK and caspase-3, resulting in the inhibition of apoptotic cell death. These results suggest that CD9 might regulate apoptosis through the specialized signals in human cancer cell lines.

Adaptor Proteins, Signal Transducing↗

PubMed2004

State-specific asymmetries in EEG slow wave activity induced by local application of TNFalpha.

Sleep is posited to be a fundamental property of groups of highly interconnected neurons and regulated in part by activity-dependent sleep regulatory substances such as tumor necrosis factor alpha (TNFalpha). We show that the unilateral local application of TNFalpha onto the somatosensory cortex of rats induced state- and frequency-dependent EEG asymmetries. In contrast, the unilateral injection of a TNFalpha inhibitor, a TNFalpha soluble receptor, attenuated sleep deprivation-enhanced EEG slow wave power ipsilaterally during non-rapid eye movement sleep (NREMS) but not during REMS or waking. Results are consistent with the notion that sleep begins with state changes occurring within small groups of highly interconnected neurons and is driven in part by the local production of sleep regulating substances.

Analysis of Variance↗