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In order to examine the construct validity of rats with excitotoxic damage of the left entorhinal cortex (EC) as an animal model of schizophrenia, we measured dopamine (DA)-related behaviors and methamphetamine (MAP)-induced DA release in the accumbens nucleus (NAC) in these animals. Quinolinic acid (lesion group) or phosphate buffer (sham group) was infused into the left EC of adolescent (postnatal 7 weeks) male Wistar rats. On the 14th and 28th postoperative day, spontaneous and MAP (1 mg/kg, i.p.)-induced locomotor activities, as well as MAP-induced stereotypy, were measured. The lesioned rats exhibited significantly greater spontaneous or MAP-induced locomotor activity on both of the postoperative days than did sham-operated animals, while EC lesions did not affect MAP-induced stereotypy on either occasion. MAP (1 mg/kg, i.p.)-induced DA release in NAC was measured by in vivo microdialysis on the 28th postoperative day. Lesioned rats did not show a significant change in MAP (1 mg/kg, i.p.)-induced DA release in NAC compared to sham-operated animals. These results suggest that excitotoxic damage of the left EC produces behavioral changes consistent with altered mesolimbic dopaminergic transmissions, possibly mediated by postsynaptic supersensitivity., (Copyright 2004 Elsevier Ireland Ltd.)

Our aim was to evaluate the effects of eradication and the incidence of secondary resistance by long-term low-dose daily 14-membered-ring macrolide therapy on Helicobacter pylori ( H. pylori) infection in patients with chronic lower respiratory tract inflammatory disease. In a retrospective analysis, we studied the seroprevalence of H. pylori IgG in 90 patients with inflammation of the lower respiratory tract (68 had been treated with macrolide and 22 served as controls). Then, in a prospective analysis, we evaluated the eradication effect of macrolide therapy by the decline of IgG values and the (13)C-urea breath test. Only long-term macrolide use significantly affected the seroprevalence of H. pylori IgG. However, macrolide therapy did not reduce the H. pylori IgG values in 24 patients and did not eradicate H. pylori in (13)C-urea breath tests. Chemosensitivity testing was performed on three H. pylori strains obtained by gastric biopsy from patients in whom the disease could not be eradicated. Only one strain demonstrated a resistant character. Daily long-term low-dose 14-membered-ring macrolide therapy for patients with lower respiratory inflammatory disease may not be sufficient to eradicate H. pylori, but some strains do not acquire a resistant nature.

NF (nuclear factor)-kappaB is known to be a critical transcription factor in inflammatory responses. We have reported that herbimycin A, a potent Src tyrosine kinase inhibitor, attenuates the NF-kappaB activation triggered by cytokines, bacterial endotoxin, and hydrogen peroxide. Accompanying the suppression by this agent, NF-kappaB-dependent gene expressions, such as cytokine, chemokine, and inducible-type nitric oxide, are specifically inhibited in glial cells. In the present study, we attempted to elucidate the possible target protein for herbimycin A on this pathway. We demonstrate here that herbimycin A preferentially inhibits IKK (IkappaB kinase)beta. Furthermore, substituting alanine for the cysteine at 59 (Cys59) in IKKbeta resulted in the insensitivity to herbimycin A, suggesting that this compound may interact with the Cys59 residue located near the catalytic ATP binding site. Taken together, these results indicate that herbimycin A can be considered a novel candidate for an anti-inflammatory drug agent through its specific inhibition of IKKbeta, which results in prevention of the expression of NF-kappaB-dependent genes implicated in the pathogenesis of inflammatory responses.

Mammalian cells acquire tolerance against multiple stressors through the high-level expression of stress-responsible genes. We have previously demonstrated that protein-disulfide isomerase (PDI) together with ubiquilin are up-regulated in response to hypoxia/brain ischemia, and play critical roles in resistance to these damages. We show here that ubiquilin interacts preferentially with poly-ubiquitin chains and 19S proteasome subunits. Taken together, these results suggest that ubiquitin could serve as an adaptor protein that both interacts with PDI and mediates the delivery of poly-ubiquitylated proteins to the proteasome in the cytosol in the vicinity of the endoplasmic reticulum membrane.

This study was performed to investigate the mechanisms underlying the augmentation of methamphetamine (MAP)-induced dopamine (DA) release in the entorhinal cortex-lesioned rats. Quinolinic acid or phosphate buffered saline was infused into the left entorhinal cortex of adolescent rats (postnatal day 7 weeks). After 4 weeks of lesioning, acute MAP (2 mg/kg, i.p.)-induced DA release in the amygdala was significantly enhanced in lesioned rats compared to sham operated rats. Inhibition of DA synthesis by alpha-methyl-p-tyrosine, an inhibitor of catecholamine synthesis, resulted in abolishment of the enhancement of MAP (2 or 5 mg/kg, i.p.)-induced DA release in the amygdala of lesioned rats. These results suggest that excessive DA pool in nerve terminals underlies the augmentation of MAP-induced DA release in the amygdala of the lesioned rats.

In the sham-operated rats, exposure to either footshock or psychological stress induced similar biphasic alterations of dopamine (DA) release (an initial increase followed by a decrease below baseline levels) in the amygdala 4 weeks after the surgery. On the other hand, the left entorhinal cortex lesions abolished the late decrement phase of DA release below baseline levels. These results suggest that entorhinal cortex lesions modulate stress-induced dopaminergic transmissions in the lateral amygdala.

Objective and Importance: Intradural-extradural dumbbell C2 schwannomas are rare. This report concerns two such cases with the intradural compartment located ventral to the spinal cord and involving both sensory and motor rootlets., Clinical Presentation: One patient was a 57-year-old woman with sensory disturbances in the right extremities and hyperreflexia in the left extremities. The other patient was a 73-year-old man who presented with tetraparesis, walking disability, atrophy of the nuchal and bilateral shoulder muscles, and pain in the right C2 dermatome., Intervention: The extradural component of the tumor was removed first; next, the intradural component was removed successfully via the posterior approach combined with a C1-C2 laminectomy. The patients experienced symptomatic improvement without further deficits except for sensory impairment of the C2 dermatome in one of the patients., Conclusion: Intradural-extradural dumbbell C2 schwannomas can be satisfactorily managed with a posterior approach. Removal of the extradural component and opening of the dural ring of the C2 nerve root are necessary for safe extraction of the intradural ventrally located component after debulking. These tumors may arise extradurally within the nerve sheath, extend intradurally and ventrally toward the spinal cord, and involve both sensory and motor rootlets.

Transient forebrain ischemia induces a delayed neuronal death in the CA1 area of the hippocampus. However, the mechanism leading to this phenomenon has yet to be established. The authors used an mRNA differential-display method to isolate genes for which mRNA levels change only in the hippocampus during ischemia/reperfusion. They succeeded in identifying the product of one down-regulated gene as phosphatidylinositol 4-kinase (PI 4-K). Compared with control levels, PI 4-K mRNA expression in the hippocampus, but not the cerebral cortex, was significantly decreased by 30% and about 80% 1 and 7 days after ischemia/reperfusion, respectively. Interestingly, PI 4-K and PI bisphosphate levels were selectively decreased in the CA1 region, but not other regions, whereas TUNEL-positive cells could be detected 3 days after ischemia. Consistent with these results, PI 4-K expression was suppressed by hypoxia in SK-N-MC neuroblastoma cells before loss of cell viability. Overexpression of wild-type PI 4-K, but not the kinase-negative mutant of PI 4-K (K1789A), recovered the loss of viability induced by hypoxia. These findings strongly suggest that a prior decrease in PI 4-K and PI bisphosphate levels caused by brain ischemia/hypoxia is partly involved in delayed neuronal cell death.

Using in vivo microdialysis technique, extracellular lactate levels were measured in the basolateral amygdaloid nucleus of the rat under immobilization stress. Immobilization stress (40 min) led to a tetrodotoxin-reversible increase in dialysate lactate levels. Diazepam (1.0 mg/kg, i.p.) reduced the ability of immobilization stress to increase lactate levels. Furthermore, the attenuation of the immobilization stress-induced increase of lactate levels by diazepam was antagonized by pretreatment with flumazenil (15 mg/kg, i.p.), a selective antagonist at benzodiazepine receptors. These findings suggest that immobilization stress increases lactate levels in rat basolateral amygdaloid nuclei, which is attenuated by stimulation of benzodiazepine receptors.

Up-regulation of several stress proteins such as heat-shock proteins and glucose-regulated proteins participate in tolerance against environmental stress. Previously, we found that protein-disulfide isomerase (PDI) is specifically up-regulated in response to hypoxia/brain ischemia in astrocytes. In addition, the overexpression of this gene into neurons protects against apoptotic cell death induced by hypoxia/brain ischemia. To address the detailed function of PDI, we screened for proteins that interact with PDI using the yeast two-hybrid system. We report here that PDI interacts with ubiquilin, which has a ubiquitin-like domain and a ubiquitin-associated domain. Interestingly, ubiquilin is also up-regulated in response to hypoxia in glial cells with a time course similar to that of PDI induction. In hypoxia-treated glial cells, the endogenous ubiquilin and PDI were almost completely co-localized, suggesting that ubiquilin is an endoplasmic reticulum-associated protein. Overexpression of this gene in neuronal cells resulted in significant inhibition of the DNA fragmentation triggered by hypoxia, but not that induced by nitric oxide or staurosporine. Moreover, ubiquilin has the ability to attenuate CHOP induction by hypoxia. These observations suggested that ubiquilin together with PDI have critical functions as regulatory proteins for CHOP-mediated cell death, and therefore up-regulation of these proteins may result in acquisition of tolerance against ischemic stress in glial cells.

In 1998, Prevention Committee of the Japanese Society for Tuberculosis announced guidelines for dealing with nosocomial tuberculosis infections. These guidelines recommended the two-step tuberculin tests (TST) as baseline data for each medical employee when they started to work. If accurate records of previous TSTs are available in addition to baseline data, they are useful to evaluate the presence of tuberculosis infection when they started to work. We therefore studied the frequency profile of size of TST among medical employees in INBA-HITEC Medical Center and discussed methods to improve investigative measures for tuberculosis infection, and prior to skin testing we asked self-reporting questionnaires regarding history of previous BCG vaccinations and TSTs. We expected that their records of previous TSTs were accurately preserved, however, records of previous TSTs reported by medical employees were found to be inaccurate. From two-step TSTs results, the magnitude of booster phenomenon was defined by diameter of erythema and induration. Results demonstrated that the increase of induration size was larger in subjects > or = 41-years-old than in subjects < 41-years-old. Regarding booster phenomenon, no statistically significant differences were detected according to type of duty post. Many subjects with size of TST erythema > or = 30 mm on the first test showed increase erythema > or = 10 mm on the second test. We therefore suggest that the second test be made for those showing reaction size > or = 30 mm on the first test.