[Carcinoma of the Ascending Colon Showing Rapid Progression of Disseminated Carcinomatosis of the Bone Marrow-Report of a Case].

A 72-year-old man with ascending colon cancer was admitted to our hospital. Right hemicolectomy and lymph node dissection(D3)were performed. The pathological diagnosis was signet-ring cell carcinoma, T4a(SE), N2b, M1a(LYM), Stage Ⅳ, R0, Cur B. Capecitabine was administered after surgery. Subcutaneous bleeding, thrombocytopenia, and a rapid increase in tumor marker levels occurred 9 months after surgery. He had already developed disseminated intravascular coagulation and was admitted to our hospital immediately. CT scan revealed metastasis in the thoracic vertebrae. Bone scintigraphy demonstrated multiple abnormal areas of uptake in the costal bones and the thoracic and lumber vertebrae. We made a final diagnosis of disseminated carcinomatosis of the bone marrow by histopathological examination. Unfortunately, before starting chemotherapy, his general condition deteriorated, and he died 14 days after hospitalization. We present here a case of colon cancer with disseminated carcinomatosis of the bone marrow.

[Super-Elderly Recurrent Rectal Cancer Effectively Treated with Chemotherapy for Three Years - Report of a Case].

The safety and feasibility of the chemotherapy for super-elderly patients over 85 years old have not been clarified yet. We report an extremely aged patient with recurrent rectal cancer that was successfully treated with chemotherapy. A 85-year-old woman underwent Hartmann procedure for rectal cancer. Nine months after surgery, CT scan revealed liver metastases in S5 and S7. We administered capecitabine plus bevacizumab chemotherapy. Liver metastases were disappeared after 6 courses. Although grade 2 hypertension was appeared, no other adverse event occurred. However, due to lung metastases, we attempted irinotecan plus bevacizumab as second line treatment. After 10 courses, general fatigue was gradually developed, so we changed the frequency of chemotherapy from biweekly to triweekly administration. The patient's performance status score has been kept 0, and she has been under treatment as an outpatient for 3 years. The chemotherapy for extremely aged patients with recurrent colorectal cancer was suggested to be safe and feasible under the adequate dose reduction and interval adjustment.

Action of modafinil through histaminergic and orexinergic neurons.

Modafinil is a wake-promoting drug used for the treatment of excessive daytime sleepiness due to narcolepsy as well as excessive sleepiness associated with obstructive sleep apnea and shift work disorder. Although the wake-promoting effect of modafinil is expressed through the dopaminergic and the norepinephrinergic systems similar to that of classical psychostimulants, the mechanism of action is distinct from those compounds in terms of the involvement of the histaminergic and the orexinergic systems. Modafinil activates the histaminergic system in an indirect manner, presumably via attenuation of the inhibitory GABAergic input to the histaminergic neurons. The orexinergic system controls arousal through the histaminergic system, and the modafinil-induced increment of histamine release is abolished in orexin neuron-ablated mice, suggesting that modafinil increases histaminergic tone via orexinergic neurons. Clinical and experimental investigations have suggested less importance of the orexinergic system in the wake-promoting effect of modafinil, but the orexinergic system is considered to be involved in modafinil-induced alertness or synaptic plasticity.

Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages.

Macrophages play a pivotal role in innate immune responses to pathogens via toll-like receptors. We previously demonstrated that aryl hydrocarbon receptor (Ahr) in combination with signal transducer and activator of transcription 1 (Stat1) negatively regulates pro-inflammatory cytokine production by inhibiting nuclear factor-κB activation in macrophages after LPS stimulation. Here, we show that Ahr also negatively regulates production of the pro-inflammatory cytokine IL-6 by suppressing histamine production in macrophages stimulated by LPS. We found that Ahr-Sp1 complex, independent of Stat1, represses histidine decarboxylase expression by inhibiting LPS-induced Sp1 phosphorylation on Ser residues in macrophages; this leads to suppression of histamine production. Moreover, we found that loratadine and chlorpromazine, histamine 1 receptor (H1R) antagonists, more effectively impair the production of LPS-induced IL-6 than that of other inflammatory cytokines in Ahr(-/-) macrophages. Collectively, these results demonstrate that Ahr negatively regulates IL-6 production via H1R signaling through the suppression of histamine production in macrophages following LPS stimulation.

Possible involvement of serotonin 5-HT2 receptor in the regulation of feeding behavior through the histaminergic system.

The central histaminergic system has been proven to be involved in several physiological functions including feeding behavior. Some atypical antipsychotics like risperidone and aripiprazole are known to affect feeding behavior and to antagonize the serotonin (5-HT) receptor subtypes. To examine the possible neural relationship between the serotonergic and histaminergic systems in the anorectic effect of the antipsychotics, we studied the effect of a single administration of these drugs on food intake and hypothalamic histamine release in mice using in vivo microdialysis. Single injection of risperidone (0.5mg/kg, i.p.) or aripiprazole (1mg/kg, i.p.), which have binding affinities to 5-HT(1A, 2A, 2B) and (2C) receptors decreased food intake in C57BL/6N mice with concomitant increase of hypothalamic histamine release. However, a selective D(2)-antagonist, haloperidol (0.5mg/kg, i.p.), did not have effects on food intake or histamine release. Furthermore, in histamine H(1) receptor-deficient mice, there was no reduction of food intake induced by atypical antipsychotics, although histamine release was increased. Moreover, selective 5-HT(2A)-antagonists, volinanserin (0.5, 1mg/kg, i.p.) and ketanserin (5, 10mg/kg, i.p.), significantly increased histamine release and 5-HT(2B/2C) -antagonist, SB206553 (2.5, 5mg/kg, i.p.), slightly increased it. On the contrary, 5-HT(1A) -selective antagonist, WAY100635 (1, 2mg/kg), did not affect the histaminergic tone. These findings suggest that serotonin tonically inhibits histamine release via 5-HT(2) receptors and that antipsychotics enhance the release of hypothalamic histamine by blockade of 5-HT(2) receptors resulting in anorexia via the H(1) receptor.

Modanifil activates the histaminergic system through the orexinergic neurons.

Modafinil is a drug used to treat hypersomnolence of narcolepsy. We previously reported that modafinil increases hypothalamic histamine release in rats but did not increase locomotor activity in histamine-depleted mice, suggesting that modafinil-induced locomotor activity involves the histaminergic system. Modafinil is also thought to express its effect through the orexinergic neurons, and orexin increases hypothalamic histamine release. These findings led us to investigate whether modafinil activates the histaminergic system via the orexinergic system. In the present study, we performed in vivo microdialysis and c-Fos immunohistochemistry to investigate whether the orexinergic system mediates the activation of the histaminergic system by modafinil using orexin neuron-deficient mice. Two hours after the injection, modafinil (150 mg/kg) caused a significant increase of histamine release compared to the basal release in wild type mice. However, modafinil had no effect on the histamine release in orexin neuron-deficient mice. By immunohistochemical study, we found that there was no neuronal activation in the tuberomammillary nucleus where the cell bodies of the histaminergic neurons exclusively exist in orexin neuron-deficient mice. These findings indicate that modafinil-induced increment of histamine release requires intact orexinergic neurons.

The effect of hardness of food on amygdalar histamine release in rats.

When animals eat food, the oral cavity receives a variety of sensory information from food. The hardness of food, which elicits somatic sensation, is thought to affect feeding behavior, however, the details of neuronal mechanism are unclear. The histaminergic system is known to be involved in feeding behavior, and our previous studies indicated that gustatory information activates the histaminergic system, and that palatability of tastants influences its activity. From these findings, we hypothesized that the hardness of food may affect the histaminergic system. Thus, in the present study, we examined the effect of the hardness of food on histamine release in the central nucleus of amygdala when rats consumed either of two types of pellets composed of similar ingredients but having different degrees of hardness: hard and soft pellets. Histamine release was significantly increased in the rat fed with hard pellets. By contrast, histamine release was not enhanced in soft pellets-fed rats. There were no significant differences between the hard and soft pellet intakes during the experimental period. When rats acquired a conditioned aversion to soft pellets, histamine release was increased during feeding, in sharp contrast to no change of histamine release pattern seen during unconditioned soft pellet intake. These observations indicate that the amygdalar histaminergic system is modulated by oral somatic sensation from food, and by palatability of food texture.

Possible involvement of histamine, dopamine, and noradrenalin in the periaqueductal gray in electroacupuncture pain relief.

Acupuncture and electroacupuncture are used in pain relief; however, the mechanism underlying the analgesic effect of acupuncture is unclear. Several lines of evidence propose that the periaqueductal gray (PAG), which is one of the regions that contributes to the endogenous pain inhibitory system, is involved in the analgesic effect of acupuncture, and the region receives several neural projections such as histamine and noradrenalin and contains the dopamine cell bodies. The current study examined the effects of electroacupuncture at Zusanli (ST36) and Shangjuxu (ST37) acupoints, which are used for clinical pain control, on the release of neurotransmitters in the PAG in rats. Histamine and dopamine release was increased after pain stimulus, while the changes were completely abolished by electroacupuncture. Pain stimulus had no effect on noradrenalin release, but electroacupuncture increased its release. These findings indicate that acupuncture at Zusanli and Shangjuxu exerts an antinociceptive effect via the activation of neurons in the PAG and that the histaminergic, dopaminergic, and noradrenalinergic systems in the PAG are related to electroacupuncture-induced pain relief.

Behavioral abnormalities and dopamine reductions in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia.

Genetic susceptibility plays an important role in the pathogenesis of schizophrenia. Genetic evidence for an association between the dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) and schizophrenia has been repeatedly reported in various populations worldwide. Thus, we performed behavioral analyses on homozygous sandy (sdy) mice, which lack dysbindin-1 owing to a deletion in the Dtnbp1 gene. Our results showed that sdy mice were less active and spent less time in the center of an open field apparatus. Consistent with the latter observation, sdy mice also displayed evidence of heightened anxiety-like response and deficits in social interaction. Compared to wild-type mice, sdy mice displayed lower levels of dopamine, but not glutamate, in the cerebral cortex, hippocampus, and hypothalamus. These findings indicate that sdy mice display a number of behavioral abnormalities associated with schizophrenia and suggest that these abnormalities may be mediated by reductions in forebrain dopamine transmission.

Comparison of the effect of an H(3)-inverse agonist on energy intake and hypothalamic histamine release in normal mice and leptin resistant mice with high fat diet-induced obesity.

Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H(3)-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H(3)-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance.

Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation.

Friend of GATA-1 (FOG-1) is a binding partner of GATA-1, a zinc finger transcription factor with crucial roles in erythroid, megakaryocytic, and mast-cell differentiation. FOG-1 is indispensable for the function of GATA-1 during erythro/megakaryopoiesis, but FOG-1 is not expressed in mast cells. Here, we analyzed the role of FOG-1 in mast-cell differentiation using a combined experimental system with conditional gene expression and in vitro hematopoietic induction of mouse embryonic stem cells. Expression of FOG-1 during the progenitor period inhibited the differentiation of mast cells and enhanced the differentiation of neutrophils. Analysis using a mutant of PU.1, a transcription factor that positively or negatively cooperates with GATA-1, revealed that this lineage skewing was caused by disrupted binding between GATA-1 and PU.1, which is a prerequisite for mast-cell differentiation. However, FOG-1 expression in mature mast cells brought approximately a reversible loss of the mast-cell phenotype. In contrast to the lineage skewing, the loss of the mast-cell phenotype was caused by down-regulation of MITF, a basic helix-loop-helix transcription factor required for mast-cell differentiation and maturation. These results indicate that FOG-1 inhibits mast-cell differentiation in a differentiation stage-dependent manner, and its effects are produced via different molecular mechanisms.

High dopamine turnover in the brains of Sandy mice.

Schizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.