Age-dependent regulation of depression-like behaviors through modulation of adrenergic receptor α1A subtype expression revealed by the analysis of interleukin-1 receptor antagonist knockout mice.

Interleukin-1 (IL-1) plays a crucial role in stress responses and its mRNA is induced in the brain by stress load; however, the precise role of IL-1 in higher brain functions and their abnormalities is largely unknown. Here, we report that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lack IL-1Ra molecules that antagonize the IL-1 receptor, displayed anti-depression-like phenotypes in the tail suspension test (TST) and forced-swim test (FST) only at a young stage (8 weeks), whereas the phenotypes disappeared at later stages (20 and 32 weeks). These anti-depression-like phenotypes were reversed by administration of adrenergic receptor (AR) antagonists against the ARα(1), ARα(2), and ARß subtypes. Although the contents of 5-HT, norepinephrine (NE), and dopamine (DA), which are known to be associated with major symptoms of psychiatric disorders, were not significantly different in the hippocampus or cerebral cortex between IL-1Ra KO and their wild-type (WT) littermate mice, the mRNA expression level of the ARα(1A) subtype was significantly changed in the cerebral cortex. Interestingly, the change in expression of the ARα(1A) subtype was correlated with an age-dependent alteration in the TST and FST in IL-1Ra KO mice. Furthermore, mild immobilization stress loaded on C57BL/6J male mice caused similar anti-depression-like phenotypes in the TST and FST to those observed in mutant mice. These results suggest that sustained activation of IL-1 signaling induced by gene manipulation in mutant mice affects the expression of the ARα(1A) subtype and that modification of adrenergic signaling by the IL-1 system may ultimately cause significant psychiatric abnormalities such as depression, and this mutant mouse could be regarded as a model animal of depression that specifically appears in children and adolescents.

Sexual activities and social relationships of people with HIV in Japan.

Sixty-one Japanese with sexually transmitted HIV were investigated to clarify the state of, and difficulties in, their sexual activities and social relationships. The study revealed the following difficulties in social relationships due to HIV infection. Thirty-one per cent had experienced discrimination or breach of confidentiality. Self-restriction due to anxiety over discrimination was observed in approximately 90%, and the self-restriction score tended to be higher in those who were not employed, those with economic problems, those who were in a relatively poor state of health, those who had developed AIDS and those who had previously experienced discrimination or breach of confidentiality. The experience of discrimination or breach of confidentiality, and the experience of receiving negative support tended to increase as the respondents had a wider emotional support network. About 60% were dissatisfied with their sex lives, and the degree of satisfaction was significantly lower in those who had fewer sexual contacts and those who had a suppressive attitude toward sexual contacts. A low degree of satisfaction with sex life was found to be an important factor that escalates the level of depression or anxiety.

How HIV infected haemophiliacs in Japan were informed of their HIV-positive status.

The purpose of this study is to find out how HIV-infected haemophiliacs were informed and notified of their HIV infection. Self-reporting questionnaires were mailed to approximately 500 patients, about one half of the haemophiliac patients with HIV in Japan. The response rate was about 57% (n=283); and 270 (male=269) patients, apart from secondary and tertiary infected patients, were eligible as subjects for the study. The mean age was 31.2 +/- 9.9 years. Of these subjects, approximately 60% did not receive explanation regarding the risk of HIV infection via unheated blood products. More than 60% did not receive notification until 1990, or five years after the test became available in Japan. Contents of the explanations being given at the time of notifications were poor. In this paper, some problems of notifications of medically induced HIV are discussed, and the lack or delay of explanation/notification is concluded to be a consequence of the paternalistic attitudes of Japanese physicians and the iatrogenic nature of HIV infection.

SHP-1 requires inhibitory co-receptors to down-modulate B cell antigen receptor-mediated phosphorylation of cellular substrates.

Signaling through the B cell antigen receptor (BCR) is negatively regulated by the SH2 domain-containing protein-tyrosine phosphatase SHP-1, which requires association with tyrosine-phosphorylated proteins for activation. Upon BCR ligation, SHP-1 has been shown to associate with the BCR, the cytoplasmic protein-tyrosine kinases Lyn and Syk, and the inhibitory co-receptors CD22 and CD72. How SHP-1 is activated by BCR ligation and regulates BCR signaling is, however, not fully understood. Here we demonstrate that, in the BCR-expressing myeloma line J558L mu 3, CD72 expression reduces the BCR ligation-induced phosphorylation of the BCR component Ig alpha/Ig beta and its cytoplasmic effectors Syk and SLP-65. Substrate phosphorylation was restored by expression of dominant negative mutants of SHP-1, whereas the SHP-1 mutants failed to enhance phosphorylation of the cellular substrates in the absence of CD72. This indicates that SHP-1 is efficiently activated by CD72 but not by other pathways in J558L mu m3 cells and that inhibition of SHP-1 specifically activated by CD72 reverses CD72-induced dephosphorylation of cellular substrates in these cells. Taken together, BCR-induced SHP-1 activation is likely to require inhibitory co-receptors such as CD72, and SHP-1 appears to mediate the negative regulatory effect of CD72 on BCR signaling by dephosphorylating Ig alpha/Ig beta and its downstream signaling molecules Syk and SLP-65.

CD72 negatively regulates signaling through the antigen receptor of B cells.

The immunoreceptor tyrosine-based inhibition motif (ITIM) is found in various membrane molecules such as CD22 and the low-affinity Fc receptor for IgG in B cells and the killer cell-inhibitory receptor and Ly-49 in NK cells. Upon tyrosine phosphorylation at the ITIMs, these molecules recruit SH2 domain-containing phosphatases such as SH2-containing tyrosine phosphatase-1 and negatively regulate cell activity. The B cell surface molecule CD72 carries an ITIM and an ITIM-like sequence. We have previously shown that CD72 is phosphorylated and recruits SH2-containing tyrosine phosphatase-1 upon cross-linking of the Ag receptor of B cells (BCR). However, whether CD72 modulates BCR signaling has not yet been elucidated. In this paper we demonstrate that expression of CD72 down-modulates both extracellular signal-related kinase (ERK) activation and Ca2+ mobilization induced by BCR ligation in the mouse B lymphoma line K46micromlambda, whereas BCR-mediated ERK activation was not reduced by the ITIM-mutated form of CD72. Moreover, coligation with CD72 with BCR reduces BCR-mediated ERK activation in spleen B cells of normal mice. These results indicate that CD72 negatively regulates BCR signaling. CD72 may play a regulatory role in B cell activation, probably by setting a threshold for BCR signaling.

Functional magnetic resonance imaging of auditory cortex: with special reference to the side of aural stimulation.

PURPOSE: To determine whether left- or right-side uniaural stimulation produces different fMRI activation patterns. METHODS: Subjects were 12 volunteers (8 right-handed, 4 left-handed) with normal hearing. Functional imaging using FE-type multishot echo planar imaging was obtained in the axial plane during pure-tone and pseudoword tasks. Auditory stimuli were presented to each ear individually. In pure-tone tasks, subjects heard clustered sequences at 2000 Hz. In pseudoword tasks, subjects heard spoken Japanese syllables. The numbers of activated pixels in the auditory cortex were counted and compared for pure-tone and pseudoword tasks, as was activation according to the side of aural stimulation. RESULTS: In right-handed subjects, prominent activation in pure-tone tasks was noted in the dominant hemisphere in 100% of cases and was unrelated to the side of the stimulation. In pseudoword tasks, prominent activation was noted on the side contralateral to the stimulus in 62.5-100% of cases. In left-handed subjects, prominent activation was noted on the side contralateral to the stimulus in both pure-tone and pseudoword tasks. CONCLUSION: Left- and right-side stimulation produced differences in fMRI responses, especially between pure-tone and pseudoword tasks. Moreover, right-handedness and left-handedness affected results. This type of auditory fMRI may be a noninvasive indicator of language lateralization.

An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells.

Our previous study demonstrated that the in vivo anti-metastatic effect induced by oral administration of ginseng protopanaxadiol saponins was mediated by their metabolic component M1, and that the growth, invasion and migration of tumor cells were inhibited by M1 but not by ginsenosides. Here we investigated the inhibitory mechanism of M1 on the growth of tumor cells. M1 inhibited the proliferation of B16-BL6 mouse melanoma cells in a time- and dose-dependent manner, with accompanying morphological changes at the concentration of 20 microM. In addition, at 40 microM M1 induced apoptotic cell death within 24 h. Fluorescence microscopy revealed that dansyl M1 entered the cytosol and quickly reached the nuclei (approximately 15 min). Western blot analysis revealed that M1 rapidly up-regulated the expression of p27Kip1, but down-regulated the expression of c-Myc and cyclin D1 in a time-dependent manner. Thus, the regulation of apoptosis-related proteins by M1 is responsible for the induction of apoptotic cell death, and this probably leads to the anti-metastatic activity in vivo.

Synthesis of a biologically active fluorescent derivative of GM1, a main Ginseng saponin metabolite formed by intestinal bacteria.

A fluorescent derivative of GM1 [20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol], a main Ginseng saponin metabolite formed by intestinal bacteria, was obtained from the condensation of its trisnor-aldehyde derivative with dansyl hydrazine. The dansylated GM1 fluoresced strongly and showed almost the same properties as its parent compound in lipophilicity and biological activities, so this fluorescent compound might provide an insight into the mechanism of pharmacological activities of GM1.

[Magnetic resonance imaging of brainstem lesions in a case of neuro-Behçet disease].

We reported a 28-year-old man with multiple lesions in the brainstem which were clearly identified and followed up with MRI. He had been treated for Behçet uveitis using cyclosporine and colchicine during the past 5 years, and he acutely presented with fever and headache, followed left hemiparesis, dysarthria and dysphagia. MRI on admission revealed multiple lesions in the ventral pontine region which showed mixed-intensity on T1WI, high-intensity on T2WI and enhancement with Gd-DTPA. His clinical symptoms spontaneously and gradually improved, but more rapidly improved due to additional administration of corticosteroid. The lesions in the brainstem became smaller and finally rudimentary during two months after the onset of neurological symptoms.

Unilateral megalencephaly in linear nevus sebaceous syndrome: a neuroradiological case report.

We report a case of linear nevus sebaceous syndrome with seizure, mental retardation, and hemiparesis. Magnetic resonance imaging (MRI) clearly demonstrated associated brain malformations of unilateral megalencephaly with cortical dysplasia and white matter change ipsilateral to the sebaceous nevi of the face and neck. Although magnetic resonance angiography (MRA) demonstrated only distortion of the main cerebral arteries without any occlusive or dysplastic findings, single photon emission computed tomography (SPECT) using [123I]N-Isopropyl-p-iodoamphetamine (IMP) revealed hypoperfusion in the affected cerebral hemisphere.

In vivo antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration.

The present study demonstrated in vivo and in vitro antimetastatic activities of a major intestinal bacterial metabolite M1 formed from protopanaxadiol saponins of ginseng (the root of Panax ginseng C. A. Meyer) in comparison with its whole standardized extract and ginsenosides Rb1, Rb2, and Rc. Although Ginseng extract (1 mg/mouse) and ginsenosides (0.5 mg/mouse) significantly inhibited lung metastasis produced by i.v. injection of B16-BL6 melanoma cells in syngeneic mice (27-61% of untreated control), they hardly inhibited the invasion and migration of B16-BL6 melanoma and HT1080 fibrosarcoma cells in vitro. However, the intestinal bacterial metabolite M1 inhibited lung metastasis of melanoma cells and in vitro tumor cell invasion and migration at nontoxic or marginally toxic concentrations. Additionally, pharmacokinetic studies of ginsenoside Rb1 and M1 after oral administration (2 mg/mouse) revealed that intact Rb1 was not detectable in serum for 24 h by HPLC analysis, whereas the level of M1 in the serum reached maximum at 8 h (8.5 +/- 0.4 micrograms/ml) after Rb1 administration and at 2 h (10.3 +/- 1.0 micrograms/ml) after M1 administration. These findings suggest that the in vivo antimetastatic effect by oral administration of ginsenosides is mediated by their metabolic component M1.

[Unilateral dissection of the cervical portion of the internal carotid artery and ipsilateral multiple cerebral infarctions caused by suicidal hanging: a case report].

This paper presents a case of traumatic dissection of the unilateral internal carotid artery of the cervical portion caused by hanging. A 63-year-old man attempted suicide by hanging and was rescued immediately after. No neurological deficits were detected for the first 4 hours. But then, right hemiplegia, aphasia and disturbed consciousness suddenly developed. On the 2nd day, MRI revealed multiple infarctions in the left cerebral hemisphere. MR angiography demonstrated severe stenosis at the cervical portion of the left internal carotid artery due to dissection. The left middle cerebral artery was not demonstrated. The patient was conservatively treated with fibrinolytic agents and regained consciousness gradually. But aphasia and right hemiplegia remained. During the next few weeks, the stenosis at the ICA slightly improved and the MCA was completely recanalized. Extracranial Doppler sonography revealed chronological hemodynamic changes of mean flow velocity and pulsatility index at the proximal and distal portion of the ICA stenosis.

Effect of diltiazem on hypoxic pulmonary vasoconstriction in dogs.

We have examined the effect of diltiazem upon the pulmonary vascular response to the left lower lobe (LLL) hypoxia in dogs. Without diltiazem, the fraction of cardiac output perfusing the LLL (QLLL/QT) measured by the ultrasonic doppler rheometer in the hypoxic phase was 21.0 +/- 11.7(%) of the ratio in the first normoxic phase. When diltiazem was given as a 0.48 mg/kg intravenous bolus followed by an intravenous infusion of 0.48 mg/kg/hr and 0.96 mg/kg intravenous bolus followed by an intravenous infusion of 0.96 mg/kg/hr, QLLL/QT in the hypoxic phase were 34.0 +/- 14.0, 48.6 +/- 16.1(%) of the ratio in the first normoxic phase respectively. Significant difference was observed at all diltiazem concentrations. With respect to PaO2, significant difference was not observed at all diltiazem concentrations in the ratio of the hypoxic phase to the first control phase. So we concluded that diltiazem obviously attenuated hypoxic pulmonary vasoconstriction (HPV) response but did not decrease PaO2 because of keeping myocardial oxygen balance and better ventilation/perfusing relationship.

Effect of nicorandil on exercise performance in patients with effort angina: a multicenter trial using a treadmill exercise test.

The effects of a single oral dose (20 mg) of a new vasodilator, nicorandil, on exercise performance were assessed in 29 patients with stable effort angina using a symptom-limited treadmill exercise test. A single-blind, placebo-controlled, randomized, crossover design was employed. Compared with placebo, 20 mg of nicorandil significantly increased maximal exercise duration and time to 1 mm of ST-segment depression at 1, 3, and 6 h after administration. Systolic blood pressure was reduced both at rest and during exercise. Heart rate increase during exercise did not differ significantly compared with control, though resting heart rate was increased. The maximal pressure-rate product at peak exercise was increased in association with increased exercise time in about half of the patients, while it was unchanged or decreased in the others. It was suggested that nicorandil may act by either reducing myocardial oxygen demand and/or increasing myocardial oxygen supply.

Studies on experimental coronary insufficiency. I. Effects of a physiological dose of adrenaline and noradrenaline on myocardial metabolism in dogs with graded coronary constriction.

To investigate the mechanism by which catecholamines produce myocardial ischemia, the effect of intracoronary-administered adrenaline and noradrenaline was studied in dogs with graded coronary constriction. A physiological dose of catecholamines was favorable for augmentation or improvement of myocardial metabolism and cardiac function in dogs without or with slight coronary constriction. However, in dogs with moderate or severe coronary constriction, similar doses of catecholamines produced myocardial ischemia and cardiac dysfunction.

Studies on experimental coronary insufficiency. II. Effects of beta-adrenergic blocking agent (propranolol) on metabolic response to adrenaline and noradrenaline in dogs with coronary constriction.

To obtain further information on the mechanism by which catecholamines produce myocardial ischemia, the effects of propranolol on metabolic and mechanical responses to adrenaline or noradrenaline were investigated in coronary-constricted dogs. Propranolol suppressed the myocardial ischemia produced by noradrenaline and adrenaline in dogs with moderate coronary constriction.