Carbamazepine treatment of corticosteroid-induced mood disorder.
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Biomedical subjects
Publications and source records attributed to K Wada.
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We found that proadrenomedullin N-terminal 20 peptide (PAMP) decreased dose-dependently (3-30 nmol/mouse) food intake after intra-third cerebroventricular administration in fasted ddY mice. Gastric emptying also was delayed after central injection of PAMP. In our previous study, PAMP was demonstrated to elicit hyperglycemia via bombesin (BN) receptor. Then, we examined whether the effects of PAMP on feeding and gastric emptying were induced through BN receptor. Surprisingly, PAMP-induced reductions in feeding and gastric emptying rate were not blocked by a BN antagonist, [D-Phe(6), Leu-NHEt(13), des-Met(14)]-BN (6-14). PAMP suppressed feeding in mice lacking gastrin-releasing peptide receptor or BN receptor subtype-3. These results indicate that centrally administered PAMP inhibits food intake, involving the delayed gastric emptying, not through BN receptors but through selective PAMP receptor.
Seven species (eight populations) of sentinel crabs (genus Macrophthalmus) from the Japan coast and Uca vocans and Ocypode ceratophthalma, were examined electrophoretically for genetic variations in 13 enzymatic and one non-enzymatic protein comprising 17 loci. Most species were highly differentiated from each other (Nei's genetic distance, 0.29-1.63). The least genetic distance was found between M. japonicus and M. banzai, the genetic distinctiveness of the two taxa being supported by three divergent loci with no common allele. The genetic relationships among Macrophthalmus species differed greatly from those inferred from morphological features, with a UPGMA tree suggesting that the sub-genus Macrophthalmus is polyphyletic.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that is known to play a central role in adipocyte differentiation and insulin sensitivity. Through work in several animal models of intestinal inflammation, it is now recognized that PPARgamma also inhibits tissue injury associated with immune activation. These studies point to PPARgamma as a novel anti-inflammatory mediator with broad therapeutic potential.
Glycinebetaine is an important osmoprotectant in bacteria, plants, and animals, but only little information is available on the synthesis of glycinebetaine in tree plants. Among four mangrove species, glycinebetaine could be detected only in Avicennia marina. Pinitol was the main osmoprotectant in the other three species. The level of glycinebetaine in A. marina increased under high salinity. Betaine-aldehyde dehydrogenase (BADH) was detected in all four species, but choline monooxygenase could not be detected. A cDNA library was constructed from the leaves of A. marina. Two kinds of BADH cDNAs were isolated, one homologous to the spinach chloroplast BADH, and the other with unique residues SKL at the end of C-terminus. The BADH transcription levels of the former were higher than those of the latter. The levels of the former BADH increased at high salinity whereas those of the latter were independent of salinity. BADHs were expressed in Escherichia coli and purified. Two kinds of A. marina BADHs exhibited similar kinetic and stability properties, but were significantly different from those of spinach BADH. A. marina BADHs efficiently catalyzed the oxidation of betainealdehyde, but not the oxidation of omega-aminoaldehydes and were more stable at high temperature than the spinach BADH.
Anti-inflammatory effects of cyclic AMP elevating agents were examined in a mouse model of lipopolysaccharide (LPS)-induced microvascular permeability change. Vascular permeability on the back skin was measured by the local accumulation of Pontamine sky blue (PSB) after subcutaneous injection of LPS (400 microg site-1) from Salmonella typhimurium. Dye leakage in the skin was significantly increased 2 h after injection of LPS. This LPS-induced dye leakage was suppressed by phosphodiesterase inhibitors, including pentoxifylline (160 mg kg-1), milrinone (5 - 10 mg kg-1), rolipram (0.5 - 10 mg kg-1) and zaprinast (5 - 10 mg kg-1). The dye leakage was also inhibited by beta-adrenoceptor agonists, including isoproterenol (0.5 - 5 mg kg-1) and salbutamol (0.05 - 5 mg kg-1), an adenylate cyclase activator, forskolin (5 mg kg-1), and a cell permeable cyclic AMP analogue, 8-bromo-cyclic AMP (8-Br-cAMP, 10 mg kg-1). LPS caused a transient increase in serum TNF-alpha level peaking at 1 h after the injection. This increase in serum TNF-alpha was completely blocked by a pretreatment with pentoxifylline (160 mg kg-1), milrinone (5 mg kg-1), rolipram (1 mg kg-1), zaprinast (10 mg kg-1), salbutamol (0.5 mg kg-1), forskolin (1 mg kg-1) and 8-Br-cAMP (10 mg kg-1). LPS caused an increase in serum IL-1alpha level peaking at 3 h after injection. This increase in serum IL-1alpha was not significantly suppressed by the cyclic AMP elevating agents. Our study suggests that cyclic AMP elevating agents attenuate LPS-induced microvascular permeability change by suppressing TNF-alpha up regulation.
BACKGROUND AND AIMS: The classification of gastritis by using the revised Sydney system suggests that there are two types of Helicobacter pylori-related gastritis. The aim of the present study was to examine the risk factors that might be involved in the presence of either atrophic gastritis or intestinal metaplasia of the gastric corpus of Japanese patients. METHODS: Biopsy samples were obtained from the gastric corpus in 154 patients with dyspepsia, and the degree of atrophy or intestinal metaplasia was determined histologically. The correlation between several variables and presence of atrophy or intestinal metaplasia was evaluated by using multivariate analysis. RESULTS: Among the 11 variables, which included age, peptic ulcer diseases and H. pylori infection, H. pylori infection was the major risk factor associated with the presence of atrophic gastritis or intestinal metaplasia of the gastric corpus. In contrast, duodenal ulcer (DU) disease reduced the risk of contracting both conditions. Age was an independent risk factor only for intestinal metaplasia of the gastric corpus. When 128 H. pylori-positive subjects were analyzed, DU and age were similarly associated with the presence of both conditions. CONCLUSIONS: These results suggest that DU reduces the risk for contracting atrophic gastritis and intestinal metaplasia, and age is an independent risk factor for intestinal metaplasia of the gastric corpus in dyspeptic Japanese patients.
We examined the employment and marital status of adult patients with epilepsy who did not have mental retardation and who had been treated at Hirosaki University Hospital, Hirosaki, Japan, for more than 5 years. The present study included 278 patients (142 males and 136 females) ranging from 20 to 60 years of age. We investigated the occupational status of the subjects and found that 168 had permanent jobs, but 41 patients were unemployed at the time of this survey. The proportion of the patients whose seizures were controlled at the time of this survey was 68% (114/168) in the group having permanent jobs, and 22% (9/41) in the unemployed group. Forty cases answered that they had resigned from their jobs due to occurrence of epileptic seizures. Of these patients, 13 were dismissed and 27 resigned voluntarily due to the potential for seizures. As to relationship between jobs and neuropsychiatric complications, the incidence of a past history of psychotic states in the unemployed group was significantly higher than that in the employed group. As to marital status, 13 males and 16 females (n = 29) had experienced divorce. Seven cases (two males and five females) had answered that epilepsy had been the reason for their divorce. We conclude that epilepsy or epileptic seizures have various negative effects on the patient's social life.
We investigated the characteristics of patients with hypnotic-related psychiatric disorders. Subjects were 90 patients reported in the nationwide Mental Hospital Survey in 1998, who were divided into three groups according to their history of substances use. Group A (patients without history of any illicit substance use) was estimated to be the most common and core group with iatrogenic characteristics. Hypnotic use in Group B (patients with history of any illicit substance use) was recognized as one of behavioral disorders in the psychosocial context. Patients in Group C (patients with multiple-substance use and without history of any illicit substance use) showed the most serious disorders in the context of addiction. More specified treatment programs would be required considering patients' characteristics.
Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) act on various neurons of the CNS as neurotrophic factors promoting neuronal differentiation and survival. We examined the survival-promoting effects of BDNF and IGF-1 on serum deprivation-induced death in cultured cerebral cortical neurons, and compared the intracellular signaling pathways stimulated by BDNF and IGF-1 in the neurons. We found that the survival-promoting effect of BDNF was much weaker than that of IGF-1 in serum deprivation-induced death of cultured cortical neurons. We found no differences in the levels of phosphatidylinositol 3-kinase (PtdIns3-K) activity or Akt (also called PKB) phosphorylation induced by BDNF and IGF-1 in the cultured cortical neurons, although many reports suggest that PtdIns3-K and Akt are involved in survival promotion. In addition, phosphorylation signals of mitogen-activated protein kinase (MAPK) and cAMP responsive element-binding protein (CREB), which have also been reported to be involved in survival promotion, were stimulated by BDNF much more potently than by IGF-1. These results show that there may be, as yet unidentified, intracellular signaling pathways other than the PtdIns3-K-Akt, MAPK and CREB signaling, to regulate survival promotion. These unidentified signaling pathways may be responsible for the distinct strengths of the survival-promoting effects of BDNF and IGF-1.
BACKGROUND & AIMS: Complement activation plays an important role in the local pathogenesis of ischemia/reperfusion (I/R) injury. We investigated the action of anti-C5 monoclonal antibody (mAb) on local and remote organ injuries after intestinal I/R in the rat. METHODS: Under anesthesia, functional anti-rat C5 mAb (18A), an isotype-matched control anti-C5 mAb (16C), or vehicle (phosphate-buffered saline) was administered 60 minutes before the superior mesenteric artery was occluded for 90 minutes and reperfused for 60 minutes. Tissue injury was assessed by lactate dehydrogenase release, myeloperoxidase activity, and microvessel relaxation. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, and intercellular adhesion molecule (ICAM)-1 expression was assessed by reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: The loss of endothelium-dependent relaxation of microvessels from the superior mesenteric artery after I/R was significantly attenuated by 18A but not by 16C. Intestinal lactate dehydrogenase release after I/R was significantly reversed by 18A treatment. Anti-C5 treatment significantly inhibited the increased myeloperoxidase activity in the lung and intestine after intestinal I/R. Furthermore, increased intestinal TNF-alpha, IL-1alpha, and vascular ICAM-1 expression after I/R were significantly inhibited by anti-C5 mAb. CONCLUSIONS: Anti-C5 therapy significantly improved intestinal I/R tissue injury as well as lung injury.
BACKGROUND & AIMS: Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been linked to several physiologic pathways including those related to the regulation of intestinal inflammation. We sought to determine whether PPAR gamma could function as an endogenous anti-inflammatory pathway in a murine model of intestinal ischemia-reperfusion (I/R) injury. METHODS: PPAR gamma-deficient and wild-type mice were examined for their response to I/R procedure. Treatment with a PPAR gamma-specific ligand was also performed. RESULTS: In a murine model of intestinal I/R injury, we observed more severe injury in PPAR gamma-deficient mice and protection against local and remote tissue injury in mice treated with a PPAR gamma-activating ligand, BRL-49653. Activation of PPAR gamma resulted in down-regulation of intercellular adhesion molecule 1 expression by intestinal endothelium and tissue tumor necrosis factor alpha messenger RNA levels most likely by inhibition of the NF-kappa B pathway. CONCLUSIONS: These data strongly suggest that an endogenous PPAR gamma pathway exists in tissues that may be amenable to therapeutic manipulation in I/R-related injuries.
PURPOSE: To detect cell specific apoptosis factors, Fas and Fas ligand, and the common intracellular apoptosis modulators, interleukin-1 beta converting enzyme (ICE)-like protease (caspase 1), Bcl-2, Bcl-xL and Bax in lens epithelial cells (LEC) of human cataracts. To study the effects of Fas-stimulating monoclonal antibody on inhibition of LEC proliferation. METHODS: Reverse-transcriptase-polymerase chain reaction (RT-PCR) was used to detect Fas, Fas ligand, caspase 1, Bcl-2, Bcl-xL and Bax, after cDNA was synthesized from the total RNA isolated from human cataractous LEC obtained by capsulotomy during cataract surgery. Fas-stimulating monoclonal antibody was added at the concentrations of 10, 30, 100, 300 and 1000 ng/ml to the incubation medium of human cataractous LEC; and the specimens were incubated for 24 h at 37 degrees C with 5% CO(2) circulation and 100% humidity. The specimens were then stained with Hoechst 33342, and the number of apoptotic cells was counted. RESULTS: Fas, caspase 1, Bcl-2, Bcl-xL and Bax mRNA were detected by RT-PCR. Fas ligand mRNA was not detected by RT-PCR. At each concentration, Fas-stimulating monoclonal antibody significantly inhibited LEC proliferation. CONCLUSIONS: Human cataractous LEC expressed mRNA of Fas and various modulators of apoptosis pathways. Fas-stimulating monoclonal antibody may have the potential to prevent posterior capsule opacification after cataract surgery by inhibiting LEC proliferation.
Regulation of neutrophil (PMN) trafficking by soluble mediators is a critical component in the outcome of host defense, inflammation resolution, and neutrophil-mediated tissue injury. Elucidation of the endogenous mediators that protect tissues from excess leukocyte traffic and aberrant PMN activation that can lead to tissue damage and chronic inflammation is of considerable interest, especially the endogenous mechanisms of anti-inflammation. To this end, we recently uncovered two new classes of mediators: inosine monophosphate (IMP) and aspirin-triggered 15(R)-epimers of native lipoxin A(4). Here, we examined the combined actions of both classes of compounds in regulating key events in neutrophil trafficking. Neutrophil rolling in mouse microvessels was inhibited by both IMP or 5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) in a concentration-dependent fashion. When combined, IMP (300 nM) and 15-epi-LX (10 nM) demonstrated additive inhibition of neutrophil rolling in microvessels. IMP and 15-epi-LX also significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil accumulation into the mouse air pouch in a dose-dependent manner. Again, the combination of low dose IMP (10 microg) and LX analog (5 microg) gave additive inhibition of neutrophil accumulation in this model. These results demonstrate the inhibition of neutrophil trafficking in two separate models by two different classes of small endogenous molecules. The additive inhibition by IMP and aspirin-triggered LX may represent key pathways that protect and resolve inflammatory responses that could be harnessed for treatment.
The modifying effects of dietary administration of the citrus limonoids obacunone and limonin on azoxymethane (AOM)-induced colon tumorigenesis were investigated in two experiments in male F344 rats. In a pilot study, we examined the modifying effects of obacunone and limonin on AOM-induced (20 mg/kg body wt, once a week for 2 weeks) formation of aberrant crypt foci (ACF). Dietary feeding of both compounds at dose levels of 200 and 500 p.p.m. during AOM exposure for 4 weeks ('initiation' feeding) or after AOM treatment for 4 weeks ('post-initiation' feeding) significantly inhibited ACF formation (55-65% reduction by 'initiation' feeding, P < 0.001; 28-42% reduction by 'post-initiation' feeding, P < 0.05-0.002). In a long-term study designed to confirm the protective effects of obacunone and limonin on ACF development, one group was treated with AOM alone and another four groups received the carcinogen treatment plus diets containing 500 p.p.m. test compounds for 3 weeks (initiation phase) or 29 weeks (post-initiation phase). Two groups were treated with obacunone or limonin alone (500 p.p.m. in diet) and one group was maintained on the basal diet. At the termination of the study, dietary exposure to obacunone or limonin during the initiation phase was found to have significantly reduced the incidence of colonic adenocarcinoma (72 versus 25 or 6%, P = 0.004 or 0.00003). Obacunone or limonin feeding during the post-initiation phase also reduced the frequency of colonic adenocarcinoma (72 versus 13%, P = 0.0002). Our results suggest that the citrus limonoids obacunone and limonin might be useful for the prevention of human colon cancers.
BACKGROUND: After completing basic research on the anti-tumor effects and neurotoxicity of 5-fluoro-2'-deoxyuridine (FdUrd) and the balance of thymidine kinase and thymidine phosphorylase activities and confirming the safety of intrathecal FdUrd administration in a previous clinical study of meningeal carcinomatosis, intracavitary administration of FdUrd was performed as a second trial in patients with malignant glioma and metastatic brain tumors. METHODS: The study population consisted of 13 patients, six with glioblastoma, one with anaplastic astrocytoma and six with metastatic brain tumors. This treatment was applied for cystic, small-volume residual or recurrent tumors. FdUrd (1-10 microg) was administered every day at least 25 times through an Ommaya device placed in the cyst or closed postoperative cavity reconstructed with a patch of galea aponeurotica. Intracavitary chemotherapy with FdUrd was preceded by radiation therapy in two patients but no other adjuvant therapy was performed. RESULTS: No side effects such as headache, nuchal pain, convulsive attack, bone marrow suppression or liver dysfunction were observed during the course of chemotherapy. Seven of the 13 patients showed responses: complete response six, minor response one, no change two and progressive disease four after the twenty-fifth intracavitary administration of FdUrd when tumor sizes on CT scans and MRI before and after intracavitary chemotherapy were compared. CONCLUSIONS: Intracavitary FdUrd chemotherapy may be useful for the treatment of small-volume tumors.
Delta(1)-Pyrroline-5-carboxylate reductase (P5CR) (EC 1.5.1.2. L-proline: NAD(P)-5-oxidoreductase), the second enzyme in the proline biosynthetic pathway, was purified from spinach (Spinacia oleracea L.) leaves. Following ammonium sulfate fractionation, purification was performed by several chromatographic methods: Blue Cellulofine, DEAE-TOYOPEARL, Sephacryl S-300 HR, and POROS QE/M. Two isoenzymes resolved by anion exchange chromatography were designated P5CR-1 and P5CR-2. Only P5CR-2 was purified from the intact chloroplasts, indicating differential distribution of the isoenzymes. P5CR isoenzymes, P5CR-1 and P5CR-2, are a homopolymer with an apparent molecular mass of 310 kDa, consisting of 10 to 12 subunits of about 28.5 kDa. P5CR-1 and P5CR-2 showed K(m) values of 9 and 19 microM for NADPH and values of 0.122 and 0.162 mM for Delta(1)-pyrroline-5-carboxylate (P5C), respectively. We decided partial amino acid sequences of P5CR-1 which showed the 70 to 80% homology to the deduced amino acid sequences of several plant P5CR cDNAs. Both isoenzymes had much lower affinity for NADH than for NADPH and were inhibited by free ATP and Mg(2+) ion. The inhibition was partially mitigated when ATP and Mg(2+) were added simultaneously to the reaction mixture. Cations at high concentration were inhibitory to P5CR activity. Interestingly, P5CR-2 was more stable to heat treatment at 40 degrees C than P5CR-1.
OBJECTIVE: Chronic cerebral vasospasm is resistant to conventional treatments despite recent advances in treatment modalities. We studied the preventive effect of ultraviolet (UV) irradiation on development of vasospasm and its mechanism in a rat femoral artery model. METHODS: The rat femoral artery model for vasospasm was used in this investigation (n = 108). The femoral arteries were divided into four groups: empty and no irradiation (control), UV irradiation (UV group), blood placement (VS group), and blood placement after UV irradiation (VS + UV group). Luminal area was measured, and smooth muscle cell counts in the medial layer of the vessel wall were obtained. An immunohistochemical study was performed with cross sections of fixed femoral arteries at 12 hours and 1, 3, 5, 7, and 49 days after blood placement. The rings of femoral arteries on Day 7 were subjected to pharmacological study. RESULTS: Pretreatment with UV irradiation (VS + UV group) resulted not only in significant inhibition of chronic vasospasm but also in a significant decrease in smooth muscle cells compared with the VS group on Days 5 and 7. The UV-treated arteries (UV and VS + UV groups) exhibited a significant number of Bax- and Bcl-2-positive cells on Days 5 and 7, but few CPP-32 positive cells were observed at the same time points. In the pharmacological study, contractile response to KCI or phenylephrine was reduced significantly in the UV-treated arteries. CONCLUSION: These results imply that UV irradiation prevents chronic vasospasm and suggest that UV-induced cell death plays an important role in the preventive effect without causing complications during the chronic period.