Oral histidine intake improves working memory through the activation of histaminergic nervous system in mice.

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.

Histamine N-Methyltransferase in the Brain.

Brain histamine is a neurotransmitter and regulates diverse physiological functions. Previous studies have shown the involvement of histamine depletion in several neurological disorders, indicating the importance of drug development targeting the brain histamine system. Histamine N-methyltransferase (HNMT) is a histamine-metabolising enzyme expressed in the brain. Although pharmacological studies using HNMT inhibitors have been conducted to reveal the direct involvement of HNMT in brain functions, HNMT inhibitors with high specificity and sufficient blood⁻brain barrier permeability have not been available until now. Recently, we have phenotyped Hnmt-deficient mice to elucidate the importance of HNMT in the central nervous system. Hnmt disruption resulted in a robust increase in brain histamine concentration, demonstrating the essential role of HNMT in the brain histamine system. Clinical studies have suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders such as Parkinson's disease and attention deficit hyperactivity disorder. Postmortem studies also have indicated that HNMT expression is altered in human brain diseases. These findings emphasise that an increase in brain histamine levels by novel HNMT inhibitors could contribute to the improvement of brain disorders.

Intraoperative hemorrhage in revision total hip arthroplasty: a retrospective single-center study.

PURPOSE: The amount of intraoperative hemorrhages and factors associated with hemorrhages and transfusions during revision total hip arthroplasty (reTHA) have not been identified for Japanese patients. We aimed to clarify the amount of intraoperative hemorrhages, and to elucidate the factors associated with hemorrhages and transfusions during reTHA in Japanese patients. METHODS: We retrospectively reviewed patients who underwent reTHA (n = 48) and primary total hip arthroplasty (pTHA) (n = 615) in a single hospital and extracted data regarding hemorrhage, transfusion, patient comorbidities, and surgical anesthesia. We defined massive blood loss (MBL) as a hemorrhage comprising more than half of the circulating blood volume within 3 h. The odds ratio (OR) and 95% confidence interval (CI) were estimated using a multivariate logistic regression analysis. RESULTS: There was a significant difference in hemorrhages between reTHA and pTHA patients (1790 g versus 625 g; p < 0.001). Among patients with reTHA, MBL was significantly associated with younger age (OR 0.91; 95% CI 0.84-1.00; p = 0.04) and lower body mass index (BMI) (OR 0.69; 95% CI 0.53-0.91; p = 0.01). Although not significant, the incidence of MBL tended to be higher for patients with hyperlipidemia (OR 4.88; 95% CI 0.99-24.1; p = 0.051). Furthermore, the need for allogeneic transfusion was significantly associated with the number of prepared autologous blood packs (OR 0.15; 95% CI 0.07-0.55; p = 0.002). CONCLUSION: Although this study was limited by its small population and a possibility of underestimating the hemorrhage, hemorrhages in reTHA patients was two times greater than that in pTHA patients. Younger age and lower BMI increased the risk of MBL in reTHA. Preparing autologous blood decreased the risk of intraoperative allogeneic transfusion.

Heparan sulfate in pancreatic ß-cells contributes to normal glucose homeostasis by regulating insulin secretion.

Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic ß-cells and may be involved in ß-cell functions. However, the importance of HS for ß-cell function remains unknown. Here, we generated mice with ß-cell-specific deletion of Ext1 (ßExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in ß-cell function. ßExt1CKO mice decreased body weights compared with control mice, despite increased food intake. Additionally, ßExt1CKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge. Glucose-induced insulin secretion (GIIS) from isolated ßExt1CKO islets was also significantly reduced, highlighting the contribution of HS to insulin secretion and glucose homeostasis. The gene expression essential for GIIS was decreased in ßExt1CKO islets. Pdx1 and MafA were downregulated in ßExt1CKO islets, indicating that HS promoted ß-cell development and maturation. BrdU- or Ki67-positive ß-cells were reduced in ßExt1CKO pancreatic sections, suggesting the involvement of HS in the proliferation of ß-cells. Moreover, insufficient vascularization in ßExt1CKO islets may contribute to central distribution of α-cells. These data demonstrate HS plays diverse roles in ß-cells, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis.

Histamine elicits glutamate release from cultured astrocytes.

Astrocytes play key roles in regulating brain homeostasis and neuronal activity. This is, in part, accomplished by the ability of neurotransmitters in the synaptic cleft to bind astrocyte membrane receptors, activating signalling cascades that regulate concentration of intracellular Ca2+ ([Ca2+]i) and gliotransmitter release, including ATP and glutamate. Gliotransmitters contribute to dendrite formation and synaptic plasticity, and in some cases, exacerbate neurodegeneration. The neurotransmitter histamine participates in several physiological processes, such as the sleep-wake cycle and learning and memory. Previous studies have demonstrated the expression of histamine receptors on astrocytes, but until now, only a few studies have examined the effects of histamine on astrocyte intracellular signalling and gliotransmitter release. Here, we used the human astrocytoma cell line 1321N1 to study the role of histamine in astrocyte intracellular signalling and gliotransmitter release. We found that histamine activated astrocyte signalling through histamine H1 and H2 receptors, leading to distinct cellular responses. Activation of histamine H1 receptors caused concentration-dependent release of [Ca2+]i from internal stores and concentration-dependent increase in glutamate release. Histamine H2 receptor activation increased cyclic adenosine monophosphate (cAMP) levels and phosphorylation of transcription factor cAMP response-element binding protein. Taken together, these data emphasize a role for histamine in neuron-glia communication.

Suppression of IFN-γ Production in Murine Splenocytes by Histamine Receptor Antagonists.

Accumulating evidence suggests that histamine synthesis induced in several types of tumor tissues modulates tumor immunity. We found that a transient histamine synthesis was induced in CD11b⁺Gr-1⁺ splenocytes derived from BALB/c mice transplanted with a syngeneic colon carcinoma, CT-26, when they were co-cultured with CT-26 cells. Significant levels of IFN-γ were produced under this co-culture condition. We explored the modulatory roles of histamine on IFN-γ production and found that several histamine receptor antagonists, such as pyrilamine, diphenhydramine, JNJ7777120, and thioperamide, could significantly suppress IFN-γ production. However, suppression of IFN-γ production by these antagonists was also found when splenocytes were derived from the Hdc-/- BALB/c mice. Suppressive effects of these antagonists were found on IFN-γ production induced by concanavalin A or the combination of an anti-CD3 antibody and an anti-CD28 antibody in a histamine-independent manner. Murine splenocytes were found to express H1 and H2 receptors, but not H3 and H4 receptors. IFN-γ production in the Hh1r-/- splenocytes induced by the combination of an anti-CD3 antibody and an anti-CD28 antibody was significantly suppressed by these antagonists. These findings suggest that pyrilamine, diphenhydramine, JNJ7777120, and thioperamide can suppress IFN-γ production in activated splenocytes in a histamine-independent manner.

JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice.

Brain histamine acts as a neurotransmitter and regulates various physiological functions, such as learning and memory, sleep-wake cycles, and appetite regulation. We have recently shown that histamine H3 receptor (H3R) is expressed in primary mouse microglia and has a strong influence on critical functions in microglia, including chemotaxis, phagocytosis, and cytokine secretion in vitro. However, the importance of H3R in microglial activity in vivo remains unknown. Here, we examined the effects of JNJ10181457 (JNJ), a selective and potent H3R inverse agonist, on microglial functions ex vivo and in vivo. First, we injected ATP, which is a typical chemoattractant, into hippocampal slices to investigate the effect of JNJ on chemotaxis. ATP-induced microglial migration toward the injected site was significantly suppressed by JNJ treatment. Next, we examined whether JNJ affected microglial phagocytosis in hippocampal slices and in the prefrontal cortex. Microglial engulfment of dead neurons induced by N-methyl-d-aspartate was inhibited in the presence of JNJ. The increase in zymosan particle uptake by activated microglia in the prefrontal cortex was prevented by JNJ administration. Finally, we determined the importance of JNJ in a lipopolysaccharide (LPS)-induced depression model. JNJ reduced the LPS-induced upregulation of microglial pro-inflammatory cytokines and improved depression-like behaviour in the tail-suspension test. These results demonstrate the inhibitory effects of JNJ on chemotaxis, phagocytosis, and cytokine production in microglia inside the brain, and highlight the importance of microglial H3R for brain homeostasis.

Histamine H3 receptor in primary mouse microglia inhibits chemotaxis, phagocytosis, and cytokine secretion.

Histamine is a physiological amine which initiates a multitude of physiological responses by binding to four known G-protein coupled histamine receptor subtypes as follows: histamine H1 receptor (H1 R), H2 R, H3 R, and H4 R. Brain histamine elicits neuronal excitation and regulates a variety of physiological processes such as learning and memory, sleep-awake cycle and appetite regulation. Microglia, the resident macrophages in the brain, express histamine receptors; however, the effects of histamine on critical microglial functions such as chemotaxis, phagocytosis, and cytokine secretion have not been examined in primary cells. We demonstrated that mouse primary microglia express H2 R, H3 R, histidine decarboxylase, a histamine synthase, and histamine N-methyltransferase, a histamine metabolizing enzyme. Both forskolin-induced cAMP accumulation and ATP-induced intracellular Ca(2+) transients were reduced by the H3 R agonist imetit but not the H2 R agonist amthamine. H3 R activation on two ubiquitous second messenger signalling pathways suggests that H3 R can regulate various microglial functions. In fact, histamine and imetit dose-dependently inhibited microglial chemotaxis, phagocytosis, and lipopolysaccharide (LPS)-induced cytokine production. Furthermore, we confirmed that microglia produced histamine in the presence of LPS, suggesting that H3 R activation regulate microglial function by autocrine and/or paracrine signalling. In conclusion, we demonstrate the involvement of histamine in primary microglial functions, providing the novel insight into physiological roles of brain histamine.

Involvement of the histamine H1 receptor in the regulation of sympathetic nerve activity.

The histamine system is involved in the regulation of the autonomic nervous system. We used gene-targeted mice to investigate the role of histamine receptors in the regulation of the sympathetic nervous system. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed histamine H1, H2, and H3 receptor expression in the superior cervical ganglion, which contains sympathetic nerve cell bodies. We measured the heart rate variability (HRV), the changes in the beat-to-beat heart rate, which is widely used to assess autonomic activity in the heart. H1 blockade attenuated the baroreflex-mediated changes in heart rate in wild-type (WT) mice, whereas the heart rate response to H2- and H3-specific blockers was unaffected. l-Histidine decarboxylase (HDC) expression in the superior cervical ganglion of H1R-null mice was higher than that in WT controls, whereas the enzyme levels in H2R- and H3R-null mice were not significantly different from those in the WT. All mutant mice (H1R-, H2R-, and H3R-null mice) showed normal electrocardiogram (ECG) patterns with little modification in ECG parameters and the expected response to the ß-adrenergic blocker propranolol. Similar to our findings in WT mice, H1 blockade attenuated the baroreflex-mediated heart rate change in H1R-null mice, whereas the heart rate response was unaffected in H2R- and H3R-null mice. The HRV analysis revealed relatively unstable RR intervals, an increased standard deviation of the interbeat interval (SDNN), and low-frequency (LF) component in H1R-null mice compared with the other groups, suggesting that sympathetic nerve activity was altered in H1R-null mice. Taken together, our findings indicate that H1 receptors play a major role in the regulation of sympathetic nerve activity.

G-cell hyperplasia of the stomach induces ECL-cell proliferation in the pyloric glands in a paracrinal manner.

An inhibitory mechanism toward gastrin hypersecretion is significantly different between G-cell hyperplasia and gastrinoma despite the common clinical manifestations; hypergastrinemia and its related persistent gastric ulcers. We recenlty studied the G-cell, d-cell and ECL-cell density in a case of G-cell hyperplasia. The 70-year-old patient has been treated for persistent gastric ulcers with a markedly increased plasma gastrin (5600 pg/mL). The stomach was surgically resected because of the obstruction associated with ulcer scars. The number of G-cells in the pyloric glands was quantified on the surgical specimens and G-cell hyperplasia was histolopathologically identified. Immunostainig of histidine decarboxylate revealed the presence of ECL-cell hyperplasia in the pyloric glands and its density was significantly and positively correlated with G-cell density. Somatostatin immunoreactive cells (D-cells) increased in their number in the oxyntic glands. These results all indicated that hypersecretion of gastrin in G-cell hyperplasia could induce ECL-cell proliferation in a paracrinal manner. In addition, relatively non-prominent endocrinological features in the G-cell hyperplasia compared to gastrinoma could be also related to the paracrinal somatostatin inhibitory effects upon ECL-cells in the pyloric glands.

Predominant role of plasma membrane monoamine transporters in monoamine transport in 1321N1, a human astrocytoma-derived cell line.

Monoamine neurotransmitters should be immediately removed from the synaptic cleft to avoid excessive neuronal activity. Recent studies have shown that astrocytes and neurons are involved in monoamine removal. However, the mechanism of monoamine transport by astrocytes is not entirely clear. We aimed to elucidate the transporters responsible for monoamine transport in 1321N1, a human astrocytoma-derived cell line. First, we confirmed that 1321N1 cells transported dopamine, serotonin, norepinephrine, and histamine in a time- and dose-dependent manner. Kinetics analysis suggested the involvement of low-affinity monoamine transporters, such as organic cation transporter (OCT) 2 and 3 and plasma membrane monoamine transporter (PMAT). Monoamine transport in 1321N1 cells was not Na(+) /Cl(-) dependent but was inhibited by decynium-22, an inhibitor of low-affinity monoamine transporters, which supported the importance of low-affinity transporters. RT-PCR assays revealed that 1321N1 cells expressed OCT3 and PMAT but no other neurotransmitter transporters. Another human astrocytoma-derived cell line, U251MG, and primary human astrocytes also exhibited the same gene expression pattern. Gene-knockdown assays revealed that 1321N1 and primary human astrocytes could transport monoamines predominantly through PMAT and partly through OCT3. These results might indicate that PMAT and OCT3 in human astrocytes are involved in monoamine clearance.

Insufficient intake of L-histidine reduces brain histamine and causes anxiety-like behaviors in male mice.

L-histidine is one of the essential amino acids for humans, and it plays a critical role as a component of proteins. L-histidine is also important as a precursor of histamine. Brain histamine is synthesized from L-histidine in the presence of histidine decarboxylase, which is expressed in histamine neurons. In the present study, we aimed to elucidate the importance of dietary L-histidine as a precursor of brain histamine and the histaminergic nervous system. C57BL/6J male mice at 8 wk of age were assigned to 2 different diets for at least 2 wk: the control (Con) diet (5.08 g L-histidine/kg diet) or the low L-histidine diet (LHD) (1.28 g L-histidine/kg diet). We measured the histamine concentration in the brain areas of Con diet-fed mice (Con group) and LHD-fed mice (LHD group). The histamine concentration was significantly lower in the LHD group [Con group vs. LHD group: histamine in cortex (means ± SEs): 13.9 ± 1.25 vs. 9.36 ± 0.549 ng/g tissue; P = 0.002]. Our in vivo microdialysis assays revealed that histamine release stimulated by high K(+) from the hypothalamus in the LHD group was 60% of that in the Con group (P = 0.012). However, the concentrations of other monoamines and their metabolites were not changed by the LHD. The open-field tests showed that the LHD group spent a shorter amount of time in the central zone (87.6 ± 14.1 vs. 50.0 ± 6.03 s/10 min; P = 0.019), and the light/dark box tests demonstrated that the LHD group spent a shorter amount of time in the light box (198 ± 8.19 vs. 162 ± 14.1 s/10 min; P = 0.048), suggesting that the LHD induced anxiety-like behaviors. However, locomotor activity, memory functions, and social interaction did not differ between the 2 groups. The results of the present study demonstrated that insufficient intake of histidine reduced the brain histamine content, leading to anxiety-like behaviors in the mice.

Molecular mechanism of histamine clearance by primary human astrocytes.

Histamine clearance is an essential process for avoiding excessive histaminergic neuronal activity. Previous studies using rodents revealed the predominant role of astrocytes in brain histamine clearance. However, the molecular mechanism of histamine clearance has remained unclear. We detected histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, in primary human astrocytes and the astrocytes of human brain specimens. Immunocytochemical analysis and subcellular fractionation assays revealed that active HNMT localized to the cytosol, suggesting that histamine transport into the cytosol is crucial for histamine inactivation. We showed that primary human astrocytes transported histamine in a time-dependent manner. Kinetics analysis showed that two low-affinity transporters were involved in histamine transport. Histamine uptake by primary human astrocytes was not dependent on the extracellular Na(+) /Cl(-) concentration. Histamine is reported to be a substrate for three low-affinity and Na(+) /Cl(-) -independent transporters: organic cation transporter 2 (OCT2), OCT3, and plasma membrane monoamine transporter (PMAT). RT-PCR analysis revealed that OCT3 and PMAT were expressed in primary human astrocytes. Immunohistochemistry confirmed OCT3 and PMAT expression in the astrocytes of human brain specimens. Drug inhibition assays and gene knockdown assays revealed the major contribution of PMAT and the minor contribution of OCT3 to histamine transport. The present study demonstrates for the first time that the molecular mechanism of histamine clearance is by primary human astrocytes. These findings might indicate that PMAT, OCT3 and HNMT in human astrocytes play a role in the regulation of extraneuronal histamine concentration and the activities of histaminergic neurons.

A Novel Near-Infrared Fluorescence Probe THK-565 Enables In Vivo Detection of Amyloid Deposits in Alzheimer's Disease Mouse Model.

PURPOSE: Noninvasive imaging of protein aggregates in the brain is critical for the early diagnosis, disease monitoring, and evaluation of the effectiveness of novel therapies for Alzheimer's disease (AD). Near-infrared fluorescence (NIRF) imaging with specific probes is a promising technique for the in vivo detection of protein deposits without radiation exposure. Comprehensive screening of fluorescent compounds identified a novel compound, THK-565, for the in vivo imaging of amyloid-ß (Aß) deposits in the mouse brain. This study assessed whether THK-565 could detect amyloid-ß deposits in vivo in the AD mouse model. PROCEDURES: The fluorescent properties of THK-565 were evaluated in the presence and absence of Aß fibrils. APP knock-in (APP-KI) mice were used as an animal model of AD. In vivo NIRF images were acquired after the intravenous administration of THK-565 and THK-265 in mice. The binding selectivity of THK-565 to Aß was evaluated using brain slices obtained from these mouse models. RESULTS: The fluorescence intensity of the THK-565 solution substantially increased by mixing with Aß fibrils. The maximum emission wavelength of the complex of THK-565 and Aß fibrils was 704 nm, which was within the optical window range. THK-565 selectively bound to amyloid deposits in brain sections of APP-KI mice After the intravenous administration of THK-565, the fluorescence signal in the head of APP-KI mice was significantly higher than that of wild-type mice and higher than that after administration of THK-265. Ex vivo analysis confirmed that the THK-565 signal corresponded to Aß immunostaining in the brain sections of these mice. CONCLUSIONS: A novel NIRF probe, THK-565, enabled the in vivo detection of Aß deposits in the brains of the AD mouse model, suggesting that NIRF imaging with THK-565 could non-invasively assess disease-specific pathology in AD.

In vivo [18F]THK-5351 imaging detected reactive astrogliosis in argyrophilic grain disease with comorbid pathology: A clinicopathological study.

Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.

Contribution of astrocytic histamine N-methyltransferase to histamine clearance and brain function in mice.

Brain histamine acts as a neurotransmitter in the regulation of various brain activities. Previous studies have shown that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, controls brain histamine concentration and brain function. However, the relative contribution of astrocytic or neuronal HNMT to the regulation of the histaminergic system is still inconclusive. Here, we phenotyped astrocytes-specific HNMT knockout (cKO) mice to clarify the involvement of astrocytic HNMT in histamine clearance and brain function. First, we performed histological examinations using HNMT reporter mice and showed a wide distribution of HNMT in the brain and astrocytic HNMT expression. Then, we created cKO mice by Cre-loxP system and confirmed that HNMT expression in cKO primary astrocytes was robustly decreased. Although total HNMT level in the cortex was not substantially different between control and cKO brains, histamine concentration after histamine release was elevated in cKO cortex. In behavioral tests, impaired motor coordination and lower locomotor activity were observed in the cKO mice. However, anxiety-like behaviors, depression-like behaviors, and memory functions were not altered by astrocytic HNMT disruption. Although sleep analysis demonstrated that the quantity of wakefulness and sleep did not change, the increased power density of delta frequency during wakefulness indicated lower cortical activation in cKO mice. These results demonstrate that astrocytic HNMT contributes to histamine clearance after histamine release in the cortex and plays a role in the regulation of motor coordination, locomotor activity, and vigilance state.

[Eighty cases of monitored anesthesia care (MAC) for inguinal hernia repairs using tumescent local anesthesia (TLA)].

BACKGROUND: This paper discusses the efficacy and difficulty of the management of monitored anesthesia care (MAC) for inguinal hernia repairs using tumescent local anesthesia(TLA). METHODS: Eighty patients were retrospectively divided into four groups (all n = 20) according to the drugs used; group P (propofol), group PF (propofol and fentanyl), group PFM (propofol, fentanyl and midazolam), group PR (propofol and remifentanyl). The four groups were analyzed in terms of the applied dose, airway use, wake-up test to determine whether hernia was repaired, postoperative pain and nausea. RESULTS: More propofol was administered in group P than in group PFM and PR. Although, airway was used for nine patients, there was no difference between the four groups. Postoperative pain and nausea also do not differ between the groups. One patient in group P showed unsuccessful repair with wake-up test. CONCLUSIONS: MAC shows a beneficial effect on inguinal hernia repairs under TLA. The rate of airway use was as high as eleven percent, and maintenance of the patients' airway requires attention. In terms of wake-up test, propofol combined with opioid administration may be more effective than propofol administration alone. There was no significant difference between the groups in pain and nausea, regardless at the use of fentanyl or remifentanil.

Histaminergic neurons in the tuberomammillary nucleus as a control centre for wakefulness.

Histamine plays pleiotropic roles as a neurotransmitter in the physiology of brain function, this includes the maintenance of wakefulness, appetite regulation and memory retrieval. Since numerous studies have revealed an association between histaminergic dysfunction and diverse neuropsychiatric disorders, such as Alzheimer's disease and schizophrenia, a large number of compounds acting on the brain histamine system have been developed to treat neurological disorders. In 2016, pitolisant, which was developed as a histamine H3 receptor inverse agonist by Schwartz and colleagues, was launched for the treatment of narcolepsy, emphasising the prominent role of brain histamine on wakefulness. Recent advances in neuroscientific techniques such as chemogenetic and optogenetic approaches have led to remarkable progress in the understanding of histaminergic neural circuits essential for the control of wakefulness. In this review article, we summarise the basic knowledge about the histaminergic nervous system and the mechanisms underlying sleep/wake regulation that are controlled by the brain histamine system. LINKED ARTICLES: This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.4/issuetoc.

Gata2 heterozygous mutant mice exhibit reduced inflammatory responses and impaired bacterial clearance.

Infectious diseases continually pose global medical challenges. The transcription factor GATA2 establishes gene networks and defines cellular identity in hematopoietic stem/progenitor cells and in progeny committed to specific lineages. GATA2-haploinsufficient patients exhibit a spectrum of immunodeficiencies associated with bacterial, viral, and fungal infections. Despite accumulating clinical knowledge of the consequences of GATA2 haploinsufficiency in humans, it is unclear how GATA2 haploinsufficiency compromises host anti-infectious defenses. To address this issue, we examined Gata2-heterozygous mutant (G2 Het) mice as a model for human GATA2 haploinsufficiency. In vivo inflammation imaging and cytokine multiplex analysis demonstrated that G2 Het mice had attenuated inflammatory responses with reduced levels of inflammatory cytokines, particularly IFN-γ, IL-12p40, and IL-17A, during lipopolysaccharide-induced acute inflammation. Consequently, bacterial clearance was significantly impaired in G2 Het mice after cecal ligation and puncture-induced polymicrobial peritonitis. These results provide direct molecular insights into GATA2-directed host defenses and the pathogenic mechanisms underlying observed immunodeficiencies in GATA2-haploinsufficient patients.

[The development of online role-play for pharmacological education].

The role-play for pharmacological education has been developed by Yanagita et al. since 2010 and incorporated into the curriculum of more than 20 medical or pharmaceutical universities in Japan. This case and communication based active learning course provides the practice to acqire fundamental competences for drug therapy, through role playing of medical professionals and patients in simulated clinical settings. The online pharmacological role-play for the first time was performed at Tohoku Medical and Pharmaceutical University Faculty of Medicine during the state of emergency in Japan. We found that the online role-play was as useful as face-to-face role-plays to train appropriate drug prescriptions and communication skills in medical students. In this review, we described the course design, preparation, and operation of online role-play for pharmacological education. We also explained the differences, advantages, and disadvantages between online and face-to-face setting. Finally, we gave examples on-going challenges to the effective use of the online role-play as a core curricular model of pharmacological and pharmacotherapeutic education.