Differences in responsiveness of mediodorsal thalamic and medial prefrontal cortical neurons to social interaction and systemically administered phencyclidine in rats.

Phencyclidine (PCP) is a psychotomimetic drug that induces schizophrenia-like symptoms in healthy individuals and behavioral abnormalities with corresponding symptoms of schizophrenia in non-human animals. Our previous studies showed that systemically administered PCP produces tonic activation of neurons in the medial prefrontal cortex (mPFC) of rats and that this activation is mainly via excitatory inputs from regions outside the mPFC. Such long-lasting activation of PFC neurons is now considered to be a pivotal factor in PCP-induced behavioral abnormalities. Although our previous study identified the ventral hippocampus as a possible source of the excitatory inputs, it is not the only source innervating the mPFC. Several regions such as the thalamus also have monosynaptic projections to the mPFC. Recently, increased c-fos expression by systemic PCP administration was reported in the mediodorsal nucleus of the thalamus (MD) and the centromedial nucleus of the thalamus (CM), which have strong reciprocal innervations with the mPFC. However, few studies have reported effects of PCP on the firing activity of MD/CM neurons in unanesthetized animals. In the current study in freely moving rats, we examined effects of systemically administered PCP on the spontaneous firing activity of the MD/CM, after identifying the response properties of recorded neurons in social interaction with an unfamiliar partner. About 30% of MD/CM neurons recorded exhibited tonic excitation following systemic PCP administration, whereas only a few neurons (7%) were inhibited by PCP. The proportion of MD neurons activated by systemic PCP administration was about half of that in the mPFC. Although the proportion of neurons responsive to social interaction did not differ between the two regions (40%), neurons activated during social interaction in the mPFC (90%) were more likely to be affected by systemic PCP administration than those in the MD/CM (45%). These results suggest that neurons responsive to social interaction in the mPFC may be differently affected by PCP than those in the MD/CM.

A novel DISC1-interacting partner DISC1-Binding Zinc-finger protein: implication in the modulation of DISC1-dependent neurite outgrowth.

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C(2)H(2)-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC(1)) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.

Multiple pathways regulating DnaA function in Escherichia coli: distinct roles for DnaA titration by the datA locus and the regulatory inactivation of DnaA.

Escherichia coli DnaA protein forms a multimeric complex at the chromosomal origin of replication (oriC), where a series of initiation reactions occurs and DNA polymerase III holoenzyme is loaded. The ATP-bound form of DnaA, which is active for initiation, is converted to the inactive ADP-bound form through interaction with the sliding clamp, the beta subunit of DNA polymerase III holoenzyme loaded on DNA. This negative regulation, termed RIDA, is required for preventing untimely initiations. Here, we asked if RIDA is functionally related to another negative regulation, DnaA titration by the datA site. The datA site can harbor hundreds of DnaA molecules, and is also required for preventing untimely initiations. We reveal here that, in growing cells of the datA(+) and datA-deleted strains, the ATP-DnaA levels were both maintained in a limited range of about 20-30% of the total ATP- plus ADP-DnaA molecules. This indicates that RIDA functions in the absence of datA. In synchronized datA-deleted cells, the ATP-DnaA level fluctuated in a manner similar to that observed in datA(+) cells. This suggests that RIDA operates independent from DnaA titration to datA. We suggest that these two mechanisms may play complementary roles during the cell cycle to prevent untimely initiations and thus ensure the scheduled initiation.

Hypolipidemic action of phytic acid (IP6): prevention of fatty liver.

Until recently, most published reports on phytic acid (myo-inositol hexaphosphoric acid, IP6) have focused on the possible decreased mineral bioavailability. Because myo-inositol is known to function as a lipotropic factor, studies in my laboratory were conducted to investigate whether dietary IP6 also reduces excessive liver lipids. Male Wistar rats were fed sucrose or corn starch diets, supplemented with myo-inositol or IP6 for 12-14 days. Equimolar myo-inositol and IP6 similarly depressed the rises in hepatic levels of lipids and in hepatic activities of lipogenic enzymes due to sucrose feeding. However, dietary myo-inositol and phytate did not prevent orotic acid-induced hepatic lipid accumulation, which is known to be caused by severe inhibition of hepatic lipoprotein secretion. These results suggest that myo-inositol and phytate might both protect against fatty liver resulting from elevated hepatic lipogenesis.

Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil.

To elucidate the molecular mechanisms underlying neuronal death after transient forebrain ischemia, we cloned genes expressed after transient forebrain ischemia in the Mongolian gerbil by a differential display method. A gerbil homolog of rat zinc transporter, ZnT-1, which transports intracellular Zn2+ out of cells, was isolated. Its expression became detectable exclusively in pyramidal neurons of the CA1 region 12 hr after ischemia and reached a maximum from day 1 to day 2 as shown by in situ hybridization. By day 7, expression had disappeared entirely from the cells in the CA1 region, because the neurons had died. No other brain regions exhibited such a significant level of ZnT-1 mRNA expression during this period. Zn2+ was shown to accumulate in CA1 pyramidal neurons expressing ZnT-1 mRNA after the ischemia by using zinquin, a zinc-specific fluorescent dye. When primary hippocampal neurons were exposed to a high dose of Zn2+, ZnT-1 mRNA accumulated. These results suggest that the induction of ZnT-1 mRNA observed in CA1 neurons was caused by an increase in the intracellular Zn2+ concentration. It was reported recently that Zn2+ chelator blocked neuronal death after ischemia and that the influx of Zn2+ might be a key mechanism underlying neuronal death. The induction of ZnT-1 mRNA in CA1 pyramidal neurons fated to die after transient ischemia is of interest to the study of postischemic events and the molecular mechanisms underlying delayed neuronal death.

[Clinical efficacy of sairei-to in various urinary tract diseases centering on fibrosis].

A joint multi-institution study was conducted on the efficacy of Sairei-to, centering on urinary tract fibrosis. The subjects consisted of 18 patients with retroperitoneal fibrosis (including 3 women), 77 patients with plastic induration of penis, 5 patients with sclerotic lipogranuloma (all men), and 67 patients with hemorrhagic cystitis (including 6 men). As a rule, Sairei-to was administered in monotherapy for periods of 4 weeks or longer. Efficacy was most pronounced in the patients with sclerotic lipogranuloma and plastic induration of penis, with overall improvement rates (percentage of patients with ratings of effective or better) of 80% in the former and 77.9% in the latter group. The overall improvement rate in the patients with retroperitoneal fibrosis was 61.1%. In the above diseases, there were numerous patients concurrently administered drugs such as antiinflammatory enzyme preparations and corticoid preparations, and the improvement rates were somewhat higher in these patients treated concurrently with other drugs. Outstanding efficacy was also seen in hemorrhagic cystitis. Dividing the patients into irradiation and non-irradiation groups, respective overall improvement rates of 77.8% and 82.8% were obtained, with the non-irradiation group showing a slightly higher rate. The non-irradiation group showed slightly higher improvement rates in the subjects treated concurrently with drugs such as antibacterial drug. Conversely, the irradiation group showed significantly superior rates for monotherapy. Side effects such as mild gastrointestinal disturbances were seen in only 13 of 167 patients (7.8%), and the utility of this drug in treatment of the above diseases should be held in high regard.

On the stereoselective synthesis of (+)-pinoresinol in Forsythia suspensa from its achiral precursor, coniferyl alcohol.

The residue from Forsythia suspensa stems, upon removal of soluble enzymes, has provided the first evidence for a stereoselective coupling enzyme in lignan biosynthesis. This preparation catalyses the preferred formation (ca 65%) of (+)-[8,8'-14C]pinoresinol from [8-14C]coniferyl alcohol in the absence of exogenously provided cofactors; addition of H2O2 had little effect on enantiomeric composition. However, when NAD and malate were supplied, the stereoselectivity of the coupling reaction was significantly enhanced and pinoresinol consisting of ca 80% of the (+)-antipode was obtained. Clearly, the insoluble residue contains a specific coupling enzyme which catalyses (+)-pinoresinol formation from coniferyl alcohol. By contrast, when [8-14C]sinapyl alcohol was employed as substrate, only racemic syringaresinols were formed: this non-stereoselective peroxidase-catalysed coupling reaction presumably accounts for the low levels of (-)-pinoresinol encountered in this system when coniferyl alcohol is used as a substrate.

An extraordinary accumulation of (-)-pinoresinol in cell-free extracts of Forsythia intermedia: evidence for enantiospecific reduction of (+)-pinoresinol.

Stereoselective and enantiospecific transformation mechanisms in lignan biogenesis are only now yielding to scientific inquiry: it has been shown that soluble cell-free preparations from Forsythia intermedia catalyse the formation of the enantiomerically pure lignan, (-)-secoisolariciresinol, when incubated with coniferyl alcohol in the presence of NAD(P)H and H2O2. Surprisingly, (-)-pinoresinol also accumulates in this soluble cell-free assay mixture in > 96% enantiomeric excess, even though it is not the naturally occurring antipode present in Forsythia sp. But these soluble cell-free preparations do not engender stereoselective coupling; instead, racemic pinoresinols are first formed, catalysed by an H2O2-dependent peroxidase reaction. An enantiospecific NAD(P)H reductase then converts (+)-pinoresinol, and not the (-)-antipode, into (-)-secoisolariciresinol. Stereoselective synthesis [correction of syntheis] of (+)-pinoresinol from E-coniferyl alcohol is, however, catalysed by an insoluble enzyme preparation in F. suspensa, obtained following removal of readily soluble and ionically bound enzymes; no exogenously supplied cofactors were required other than oxygen, although the reaction was stimulated by NAD-malate addition. Thus, the overall biochemical pathway to enantiomerically pure (-)-secoisolariciresinol has been delineated.

Serum zinc concentration in acute myocardial infaction.

The serum zinc concentration was examined in 61 patients with acute myocardial infarction who were admitted within twenty-four hours after the onset. Forty-two of 61 patients were admitted within twelve hours. The zinc level fell sharply as early as within three hours after the onset. The minimum values were attained two or three days after infarction and then rose to normal values within five to ten days. There was a mild degree of change and early recovery in 9 patients who underwent major abdominal surgery. The pathologic factors that could influence these two conditions are discussed. In those patients whose serum zinc concentrations were remarkably lowered, clinically estimated severity was far graver, and prognosis seemed to be much worse. It should be asked whether zinc supplementation would be of therapeutic benefit to patients with acute infarction.

Clinical application of a static splitting agent for removing the denture from its cast after curing.

A very effective method for removing a denture from its cast after curing has been developed using a static expansive agent for hydration. Three filling hole designs for packing the expansive agent into a stone cast were examined to obtain the most effective method of splitting the cast for clinical application. The dynamic strain in the resin denture base was measured during static splitting one filling hole design was the safest for handling and the most effective for removing the denture. The upper tolerance limits for the maximum strain were estimated to be 2.9 x 10(-3) in the upper denture and 3.4 x 10(-3) in the lower denture. These values were lower than one-third of the critical strain corresponding to the proportional limit of the denture resin.

Vascular dilatory action of Artemisia capillaris bud extracts and their active constituent.

In perfusion experiments, the acetone extract of Artemisia capillaris buds significantly inhibited the response to norepinephrine of helical strips of rabbit thoracic aorta. The acetone extract was fractionated by column chromatography to identify the active constituent. Kinetic experiments using rabbit thoracic aorta showed that 6,7-dimethoxycoumarin (scoparone) has a marked inhibitory effect on the contractions induced by norepinephrine, 5-hydroxytryptamine, histamine and angiotensin II. Like nitroglycerin, scoparone appeared to be a competitive antagonist of norepinephrine.

[Remarkable pain relief in the treatment with high-dose medroxyprogesterone acetate in advanced prostatic carcinoma].

A 60-year-old man was admitted to our hospital because of lumbago due to a metastatic bone tumor that originated from the prostate. Previously, he had been treated with 500 mg/kg of diethylstilbestrol diphosphate and 75 mg/day of chlormadinone acetate. At our hospital, he was given 470.1 mg/day of estramustine sodium phosphate and a bilateral orchiectomy was performed. However, he felt increased lumbago. Thus, a dose of 1200 mg/day of medroxyprogesterone acetate was started. Although the histology of his prostate and bone scintigram did not change, the patient no longer felt lumbago from about 2 weeks after the start of this treatment. Six months later, he remains free of lumbago. In this report, we describe the effect of high-dose medroxyprogesterone acetate on the clinical course, and the plasma and urine levels of the hormones.

The effect of scoparone, a coumarin derivative isolated from the Chinese crude drug Artemisiae capillaris flos, on the heart.

In the present study, scoparone isolated from Artemisia Capillaris Flos has been investigated to determine its pharmacological properties on the heart. Scoparone was found to cause the increase in coronary flow and heart rate, but did not affect cardiac output, left ventricular pressure or left ventricular work in the isolated perfused heart. Scoparone at 25 mg/kg and 50 mg/kg, p.o. had a marked inhibitory effect on the ST wave depression. Consequently it is suggested that scoparone has antianginal action.

Effect of hyperbaric oxygen therapy on essential haematuria.

Forty-three patients with essential haematuria were studied for 35 days to determine the efficacy of hyperbaric oxygen (OHP) exposure on haemostatic ability. Out of 15 untreated patients, haematuria persisted for the study period in all but one patient (6.7%). Out of 11 patients who received 90 mg/day of carbazochrome sodium sulfate and 750 mg/day of tranexanic acid excellent haemostatic results had been obtained in 2 (18.2%). Results of exposure of 17 patients to 2 atm. pressure of OHP for 90 min daily were excellent in 10 (58.8%) and good in one (5.9%). No serious adverse effects had been noted following OHP treatment. These results indicate that OHP can be applied for the treatment of essential haematuria if routine haemostatic drugs fail to improve the condition.

A case of large intestinal malignant lymphoma.

Primary malignant lymphoma of gastrointestinal tract is relatively rare and the most of it are seen in stomach or small intestine, and in Japan only 130 cases of primary large intestinal malignant lymphoma were reported from the accumulating results of the postoperative cases in the 11th Congress of the Japanese Research Society for Cancer of the Colon and Rectum. This paper describes the case report of the primary malignant lymphoma originated from the cecum, and the review of the literature. The patient was 63 year-old female, who came to this hospital for slight fever and right lower abdominal pain that was gradually increasing. After the investigation by using barium enema and the intrapelvic CT, cecum tumor was detected. The ileocecal excision was performed, and revealed the 4 X 4.5 cm tumorous type lesion of which surface was slightly irregular. Histopathologically the tumor was follicular lymphoma (partial type), medium sized cell type by the Lymphoma-leukemia Study Group (LSG) classification. After discharge, cyclophosphamide was administered by 100 mg/day for six weeks, and the sign of the recurrence has not been observed.

Hyperbaric oxygenation for experimental bladder tumor. II. Hyperbaric oxygenation in combination with chemotherapy in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors.

Two series of experiments were conducted to ascertain whether hyperbaric oxygenation (HBO) treatment with or without antineoplastic chemotherapy can really suppress tumor development in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tumor in rats. HBO treatment of 2 ATA of air saturating with 30-35% of oxygen for 90 min daily plus 0.5 mg/100 g body weight of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) administration for 5 times suppressed the neoplastic spread of the bladder for 9 weeks and reduced the bladder weight in BBN-treated rats. Similar effects were also obtained in ACNU-treated rats, but to a lesser extent. HBO treatment associated with or without doxorubicin failed to suppress tumor growth in BBN-treated animals. Based on these findings combined with the previous study (part I), HBO treatment associated with ACNU might be available for the treatment of some cases of bladder tumors.

Central noradrenergic neurons and vascular non-collagen protein in the initial phase of two-kidney, one-clip renovascular hypertension.

Rats had been given intraventricular injection of 6-hydroxydopamine (6-OHDA) before clipping the unilateral renal artery (2K-1C) that caused selective ablation of the central noradrenergic neurons. Central catecholamines and the in vivo incorporation of 3H-proline into vascular non-collagen protein were determined in 2K-1C rats in the acute hypertensive stage. It is suggested that increased non-collagen protein synthesis in the mesenteric artery and the low level of hypothalamic norepinephrine concentration may participate in the development of 2K-1C hypertension in rats.

Inhibition of superoxide anion production in guinea pig polymorphonuclear leukocytes by a seleno-organic compound, ebselen.

Production of superoxide anion (O2-) induced by tetradecanoyl phorbol acetate (TPA) in intact guinea pig polymorphonuclear leukocytes (PMNL) was markedly inhibited by a seleno-organic compound, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (Ebselen), with glutathione peroxidase-like activity. The compound almost completely inhibited O2- production by a particulate fraction prepared from TPA-treated PMNL at a concentration as low as 250 nM.

[The clinical effects of Tsumura No. 111 Seishin-rensi-in on irregular complaints of the urinary tract].

We studied the effects of Tsumura No. 111. Seisin-rensi-in on irregular complaints accompanying urological and renal diseases. Of 105 patients who visited our medical facilities, 99 served as the subject of this study. In principle, Tsumura Seisin-rensi-in was administered at a dose of 2.5 g x 3 times/day before meals for 4 or more weeks. Of 99 cases, 8 showed excellent results (8.2%), and 42 showed positive effects (41.2%). Adverse effects were observed in 7 cases, and in 4 cases drug administration was discontinued. This drug was recognized to be effective against irregular complaints accompanying chronic cystitis and acute or chronic pyelonephritis.