Inflammatory bone loss in experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in interleukin-1 receptor antagonist knockout mice.

The interleukin-1 receptor antagonist (IL-1Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is not clear whether IL-1Ra plays a protective role in periodontal disease. This study was undertaken to compare experimental periodontitis induced by Aggregatibacter actinomycetemcomitans in IL-1Ra knockout (KO) mice and wild-type (WT) mice. Computed tomography (CT) analysis and hematoxylin-and-eosin (H&E) and tartrate-resistant acid phosphatase (TRAP) staining were performed. In addition, osteoblasts were isolated; the mRNA expression of relevant genes was assessed by real-time quantitative PCR (qPCR); and calcification was detected by Alizarin Red staining. Infected IL-1Ra KO mice exhibited elevated (P, <0.05) levels of antibody against A. actinomycetemcomitans, bone loss in furcation areas, and alveolar fenestrations. Moreover, protein for tumor necrosis factor alpha (TNF-α) and IL-6, mRNA for macrophage colony-stimulating factor (M-CSF), and receptor activator of NF-κB ligand (RANKL) in IL-1Ra KO mouse osteoblasts stimulated with A. actinomycetemcomitans were increased (P, <0.05) compared to in WT mice. Alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OCN)/bone gla protein (BGP), and runt-related gene 2 (Runx2) mRNA levels were decreased (P, <0.05). IL-1α mRNA expression was increased, and calcification was not observed, in IL-1 Ra KO mouse osteoblasts. In brief, IL-1Ra deficiency promoted the expression of inflammatory cytokines beyond IL-1 and altered the expression of genes involved in bone resorption in A. actinomycetemcomitans-infected osteoblasts. Alterations consistent with rapid bone loss in infected IL-Ra KO mice were also observed for genes expressed in bone formation and calcification. In short, these data suggest that IL-1Ra may serve as a potential therapeutic drug for periodontal disease.

Living donor liver transplantation using a right liver graft with additional vein reconstructions for patient with situs inversus.

Living donor liver transplantation (LDLT) using a right liver graft with additional vein reconstructions has not been previously reported in a situs inversus (SI) patient. A 60-year-old man with SI was referred for LDLT for end-stage cirrhosis secondary to hepatitis B. The calculated regional volumes of the individual hepatic vein territories in the right liver graft suggested that the middle hepatic vein (MHV) tributaries and the inferior right hepatic veins (IRHVs) should be reconstructed in addition to the right hepatic vein (RHV). On the back-table, the recipient's recanalized umbilical vein graft was anastomosed to the V5 opening, and the other side of vein graft was anastomosed to the RHV and V8 opening to create a large single orifice. After total hepatectomy, the right liver graft was placed in the left subphrenic space at the reversed position. The common orifice of hepatic venous drainage from RHV, V8 and V5 was anastomosed to the anatomical RHV conduit of the recipient, followed by IRHV anastomosis to the inferior vena cava. Postoperative course was almost uneventful, and no vascular complications were experienced. Even for SI patients, LDLT using a right liver graft with reconstructions of the MHV tributaries and the IRHVs is feasible.

Lipopolysaccharide of Aggregatibacter actinomycetemcomitans up-regulates inflammatory cytokines, prostaglandin E2 synthesis and osteoclast formation in interleukin-1 receptor antagonist-deficient mice.

BACKGROUND AND OBJECTIVE: The interleukin (IL)-1 receptor antagonist (Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is unclear whether the IL-1Ra plays a protective role in periodontal disease. The purpose of this study was to compare IL-1Ra knockout (KO) and wild-type (WT) mice in regard to proinflammatory cytokine production, osteoclast formation and bone resorption in response to periodontal bacterial lipopolysaccharide (LPS). MATERIAL AND METHODS: Peritoneal macrophages (Mφs) were obtained from 13-wk-old IL-1Ra KO and WT mice. Peritoneal Mφs were cultured with or without 10 µg/mL of Aggregatibacter actinomycetemcomitans LPS for 24 h. The levels of IL-1alpha (IL-1α), IL-1beta (IL-1ß), tumor necrosis factor-α (TNF-α) and IL-6 were measured in periotoneal Mφs supernatant fluid (PM-SF) using an ELISA. Bone marrow cells were obtained from the mice and stimulated with PM-SF for 9 d, then stained with TRAP. The frequency of TRAP-positive multinucleated giant cell formation was calculated based on a fusion index. PM-SF-stimulated calvarial bone resorption was analyzed using micro-computed tomography, and calvarial histological analysis was performed using hematoxylin and eosin and TRAP staining. The expression of cyclooxygenase-2 (Cox2), prostanoid receptor EP4 (Ep4) and Rank mRNAs in bone marrow cells were measured using real-time quantitative PCR, while prostaglandin E2 (PGE2 ) production was determined by ELISA. RESULTS: The levels of IL-1α, IL-1ß, TNF-α and IL-6 in IL-1Ra KO mice PM-SF stimulated with A. actinomycetemcomitans LPS were significantly increased by approximately 4- (p < 0.05), 5- (p < 0.05), 1.3- (p < 0.05) and 6- (p < 0.05) fold, respectively, compared with the levels in WT mice. Moreover, osteoclast formation, expression of Rank, Ep4 and Cox2 mRNAs and production of PGE2 were significantly increased by approximately 2- (p < 0.05), 1.6- (p < 0.05), 2.5- (p < 0.05), 1.6- (p < 0.05) and 1.9- (p < 0.05) fold, respectively, in IL-1Ra KO mice stimulated with A. actinomycetemcomitans LPS compared with WT mice. CONCLUSION: IL-1Ra regulates IL-1 activity and appears to reduce the levels of other inflammatory cytokines, including TNF-α and IL-6, while it also reduces expression of the EP4 receptor related to prostanoid sensitivity and osteoclast formation. These results suggest that IL-1Ra is an important molecule for inhibition of inflammatory periodontal bone resorption.

Inducible transgenic expression in the short-lived fish Nothobranchius furzeri.

This study demonstrates inducible transgenic expression in the exceptionally short-lived turquoise killifish Nothobranchius furzeri, which is a useful vertebrate model for ageing research. Transgenic N. furzeri bearing a green fluorescent protein (Gfp) containing construct under the control of a heat shock protein 70 promoter were generated, heat shock-induced and reversible Gfp expression was demonstrated and germline transmission of the transgene to the F1 and F2 generations was achieved. The availability of this inducible transgenic expression system will make the study of ageing-related antagonistically pleiotropic genes possible using this unique vertebrate model organism.

Mild hepatic macrovesicular steatosis may be a risk factor for hyperbilirubinaemia in living liver donors following right hepatectomy.

BACKGROUND: The aim of this study was to evaluate the effects of mild macrovesicular steatosis on the outcome of living liver donors following right hepatectomy. METHODS: The medical records of 46 living liver donors who underwent right hepatectomy were studied. Ten donors had mild macrovesicular steatosis (5-10 per cent in seven and 11-20 per cent in three patients). Five donors with other liver pathology were excluded. Outcome in these ten donors (group 1) was compared with that in the remaining 31 donors with normal liver histology (group 2). RESULTS: The median duration until normalization of total bilirubin levels was 14 and 5 days in groups 1 and 2 respectively (P = 0.028). The peak total bilirubin level was significantly higher in group 1 than in group 2 (80.4 versus 49.6 micromol/l; P = 0.033). Multivariable analysis showed mild macrovesicular steatosis to be an independent risk factor for hyperbilirubinaemia (odds ratio 7.94 (95 per cent confidence interval 1.17 to 54.03); P = 0.034). CONCLUSION: Mild macrovesicular steatosis may be related to adverse outcome in living liver donors who undergo right hepatectomy and, in terms of donor safety, is of potential concern in donor selection.

Soluble interleukin-1 receptor type II levels in gingival crevicular fluid in aggressive and chronic periodontitis.

BACKGROUND: Interleukin (IL)-1 is closely related to the initiation and progression of periodontal disease. IL-1 levels in the gingival crevicular fluid (GCF) of subjects with periodontitis are higher than those in periodontally healthy controls, and the levels of IL-1 correlate with disease severity. However, soluble IL-1 receptor type II (sIL-1RII), which acts as a decoy receptor for IL-1s, has not been investigated in detail in periodontal disease. The purpose of this study was to measure sIL-1RII levels in the GCF of subjects with chronic or aggressive periodontitis; the correlation between the sIL-1RII levels in GCF and clinical parameters also was examined. METHODS: IL-1beta and sIL-1RII were measured in 64 GCF samples collected from 47 subjects with chronic periodontitis (CP) and 17 subjects with aggressive periodontitis (AgP). The clinical characteristics of each site were recorded at the time of GCF sampling. IL-1beta and sIL-1RII were measured by specific non-cross-reactive enzyme-linked immunosorbent assay. RESULTS: The disease severity was comparable in CP and AgP. IL-1beta was detected in 98% of CP GCF samples and 88% of AgP GCF samples. sIL-1RII was detected in 55% of CP GCF samples and 35% of AgP GCF samples. However, the concentrations of IL-beta and sIL-1RII detected in GCF from subjects with CP or AgP were similar. CONCLUSION: sIL-1RII was detected more often in CP GCF than in AgP GCF, and there was no correlation between GCF sIL-1RII concentration and clinical parameters.

Simultaneous monitoring by real-time polymerase chain reaction of epstein-barr virus, human cytomegalovirus, and human herpesvirus-6 in juvenile and adult liver transplant recipients.

Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) cause symptomatic diseases in liver transplant recipients. The loads of these viruses, the associations between viral DNAemia, serologic status, and acute rejection reactions were investigated in a group of 17 juvenile and 17 adult recipients of living donor liver transplantation (LDLT) for a median of 8 weeks posttransplantation. At least 1 plasma sample from 15/34 (44.1%) patients was positive for CMV DNA. For most of the CMV-positive patients, the CMV DNA appeared in the second week of LDLT, and disappeared by the eighth week. A minimum of 200 EBV DNA copies/mug peripheral blood mononuclear cell DNA (defined as positive for EBV) was detected in 5/34 (14.7%) patients, and the number of EBV-positive children was significantly greater than the number of EBV-positive adults. In most of the EBV-positive patients, the EBV loads increased after 4 weeks posttransplantation. Plasma HHV-6 was detected in 7/34 (20.6%) patients. HHV-6 DNA appeared for a short period from the second week of LDLT. In addition, 8 of the 19 virus-positive recipients carried 2 viruses, with the combination of CMV and HHV-6 being the most frequent. Serologic status seemed to be an important factor for all 3 viral infections. The rate of acute cellular rejection was not significantly higher in the CMV-, EBV-, or HHV-6-positive groups. Simultaneous monitoring for 3 herpesviruses revealed the impact of these viruses on LDLT recipients.

Diagnostic Usefulness of APRI and FIB-4 for the Prediction of Liver Fibrosis After Liver Transplantation in Patients Infected with Hepatitis C Virus.

BACKGROUND: Aspartate transaminase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) are well known as representative indirect serum biomarkers related to liver fibrosis. The usefulness of these markers for the diagnosis of liver fibrosis after liver transplantation (LT) in hepatitis C virus (HCV)-infected patients and the influence of splenectomy were investigated. METHODS: From June 2003 to May 2014, 31 HCV-infected patients who underwent LT and postoperative follow-up liver biopsies were included in this study. The association between liver fibrosis and serum biomarkers and the influence of splenectomy on APRI and FIB-4 were also investigated. RESULTS: A total of 195 biopsy specimens were collected, and liver fibrosis was identified as: F0, 59.7%; F1, 34.1%; and F2, 6.3%. Both APRI and FIB-4 were significantly higher in patients who showed F1 and F2 in liver biopsy specimen than F0 (P values, .009 and .022, respectively); sensitivity and specificity of APRI were, respectively, 63.4% and 66.7%, and those of FIB-4 were 57.7% and 69.6%. In 11 patients (35.5%) who underwent splenectomy at the time of LT, the cutoff values for APRI and FIB-4 were 0.61 and 1.41, which were significantly lower than the corresponding values (1.00 and 3.64) of patients without splenectomy. CONCLUSIONS: APRI and FIB-4 could effectively estimate liver fibrosis after LT for HCV-related liver disease. For LT patients with splenectomy, APRI and FIB-4 were also useful to estimate liver fibrosis, but the standard values should be adjusted lower than those for patients without splenectomy.

17beta-estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats.

Several lines of evidence suggest that hormonal changes after menopause may play an important role in the incidence of cognitive dysfunction, and also in the development of Alzheimer's disease. In this study, we investigated the effect of estrogen on cognitive function in rats under different stress environment. Female rats were divided into four groups: two groups were ovariectomized (OVX) and two were sham-operated. One group each of OVX and sham rats was kept in a normal environment, and the other groups were assigned to a daily restraint stress (6 h/day) for 21 days from 2 months after the operation. Following the stress period, subjects were tested for performance in novel object recognition test and then used for morphological and neurochemical analyses. The OVX plus stress (OVX/stress) group showed a significant impairment of recognition of novel objects, compared with the other groups. The OVX/stress group also showed a marked decrease in the number of pyramidal cells of the CA3 region and levels of brain-derived neurotrophic factor mRNA in the hippocampus. We further examined the effect of estrogen against cognitive dysfunction and hippocampal changes of OVX/stress rats. Vehicle or 17beta-estradiol (E2) at 20 microg/day was s.c. administered to OVX/stress rats from 2 days before the stress period to the end of behavioral analysis through an implantable osmotic pump. Chronic E2 treatment decreased stress response and improved the cognitive and morphological impairments relative to vehicle group. These data have important implications for cognition enhancing effect of estrogen treatment in postmenopausal women.

Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats.

We have recently found that a combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and that estrogen replacement suppresses the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of Ginkgo biloba extract (EGb 761), a popular herbal supplement, on the cognitive dysfunction and neuromorphological change in OVX/stress-subjected rats. Female Fisher 344 rats were randomly divided into three groups: vehicle-treated OVX, EGb 761 (50 mg/kg) -treated OVX and vehicle-treated sham-operated control groups. Two months after ovariectomy, all animals received restraint stress for 21 days (6 h/day), and were then subjected to a novel object recognition test followed by morphological examination by Nissl staining. EGb 761 was orally administered once daily until the behavioral analysis was done. Treatment with EGb 761 improved memory impairment and neuronal loss of hippocampus in the OVX/stress-subjected group in the same ways as 17beta-estradiol. On the other hand, EGb 761 did not affect the loss of bone mineral density and increase in body weight after OVX, although 17beta-estradiol attenuated them. These results have important implications for neuroprotective and cognition enhancing effects of EGb 761 in postmenopausal women and suggest that the effects are mediated by a different mechanism from estrogen.

Successful Blood Transfusion Management of a Living Donor Liver Transplant Recipient in the Presence of Anti-Jra: A Case Report.

A 48-year-old Japanese woman was diagnosed with Budd-Chiari syndrome and transferred for possible living donor liver transplantation (LDLT). Examinations before LDLT revealed that the recipient had anti-Jra and preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA). Rituximab was administrated at 16 days prior to the patient's scheduled LDLT for the prophylaxis of antibody-mediated rejection by DSA. The clinical significance of anti-Jra has not been clearly established because of the rarity of this antibody, so we discussed blood transfusion strategy with the Department of Blood Transfusion Service and prepared for Jra-negative packed red blood cells (RBCs). Intraoperative blood salvage was used during LDLT procedures to reduce the use of packed RBCs. Although post-transplantation graft function was excellent, a total of 44 U of Jra-negative RBCs were transfused during the entire perioperative period. Because sufficient amounts of Jra-negative packed RBCs were supplied, Jra mismatched blood transfusion was avoided. The patient was discharged from our hospital on postoperative day 102 without clinical evidence of any blood transfusion-related adverse events. Although there are some controversies of blood transfusion related to anti-Jra antibodies, the current strategies of blood transfusion for liver transplantation with anti-Jra are as follows: (1) sufficient supply and transfusion of Jra-negative matched packed RBCs and (2) application of intraoperative blood salvage to reduce the total amount of rare blood type RBCs. These strategies may be changed when the mechanism of anti-Jra alloimmunization is fully understood in the future.

Growth suppression of subcutaneously inoculated hepatic tumors after injection of syngeneic liver cells into the subcutaneous tissue of rats.

One week after the sc injection of minced tissues of the livers, kidneys, or spleens of W, Donryu, and MP rats into the left back of syngeneic rats, ascites-type tumor cells derived from rat hepatoma (AH 130) or Walker carcinosarcoma cells derived from rat breast tumor were inoculated sc into the right back. Ascites hepatoma cell growth was slowest in the group given the liver preparation, whereas no significant difference was noted in the growth of Walker carcinosarcoma in all groups. The results were similar in all strains.

Changes in Muscle Strength and Six-Minute Walk Distance Before and After Living Donor Liver Transplantation.

BACKGROUND: Impaired exercise capacity and muscle weakness are important characteristics of liver transplantation recipients. Perioperative rehabilitation has been introduced to promote early mobilization of patients and to prevent postoperative pulmonary complications. However, it is unknown how physical status recovers during the hospital stay after a liver transplant. The purpose of this study was to evaluate the changes in clinical indicators that represent the functional exercise capacity and muscle strength before and after living donor liver transplantation (LDLT). METHODS: We retrospectively reviewed 21 consecutive patients who underwent LDLT with perioperative rehabilitation from April 2014 to December 2015. Twelve patients who were tested for 6-minute walk distance, hand-grip strength, and isometric knee extensor muscle strength before and 4 weeks after LDLT were enrolled. RESULTS: At the preoperative baseline, the 6-minute walk distance significantly correlated with the Model for End-stage Liver Disease score and pulmonary functions (vital capacity, forced vital capacity, and forced expiratory volume in 1 second of predictive values). Comparisons between the preoperative and postoperative values revealed significant decreases in weight, Barthel Index, hand-grip strength, and isometric knee extensor muscle strength. Changes in hand-grip strength and isometric knee extensor muscle strength after LDLT correlated with the preoperative Model for End-stage Liver Disease score. CONCLUSIONS: Physical functional status had not been fully recovered 4 weeks after LDLT. Further investigation regarding developing a strategy for prevention of muscle atrophy before LDLT and recovery of physical fitness after LDLT would be helpful.

Proinflammatory and antiinflammatory cytokine production during ischemia-reperfusion injury in a case of identical twin living donor liver transplantation using no immunosuppression.

BACKGROUND: Bolus steroids are usually administered prior to graft reperfusion in an attempt to provide protection against ischemia reperfusion injury (IRI). However, the anti-IRI properties of steroids have not been established. Living donor liver transplantation (LDLT) between identical twins provides a unique opportunity to study the natural production of cytokines during transplantation without the confounding influences of the alloimmune response or of immunosuppression in particular steroids. METHODS: A 38-year-old male with hepatitis C virus-related cirrhosis and multiple hepatocellular carcinomas received a hepatic right lobe graft from his identical twin. No immunosuppression was administered, not even intraoperative bolus steroids. IRI was assessed by serum transaminases as well as by proinflammatory interleukin (IL) IL-1beta, tumor necrosis factor (TNF)-alpha, IL-8 cytokines and for potent regenerative/anti-inflammatory (IL-6, IL-10) mediators. RESULTS: Despite no administration of steroids, low peak levels of serum transaminases were observed. Serum IL-6 and IL-10 dramatically and rapidly increased during liver transplantation, namely, 160 and 20 times higher than baseline, respectively. In contrast, IL-1beta and TNF-alpha remained low during and after transplantation and an increase in IL-8 was less obvious. CONCLUSION: Syngeneic LDLT without intraoperative bolus steroids is feasible, yielding no penalty in terms of IRI. A predominance of protective cytokines was observed in the absence of steroids. Thus, the concept that intraoperative administration of steroids is necessary to protect liver transplants from IRI must be revisited.

Successful Living-Donor Liver Transplantation for Cholestatic Liver Failure Induced by Allopurinol: Case Report.

A 39-year-old man was diagnosed with allopurinol-induced hepatic injury. He did not show any sign of hepatic encephalopathy, but his serum total bilirubin level was >40 mg/dL when he visited the local hospital. The therapeutic effects of initial medical treatments were transient, and both renal function and coagulation ability were gradually deteriorated. Four months after the onset of hepatic injury, he was referred to our hospital for the purpose of liver transplantation (LT). Although he was wasting and severely jaundiced, his consciousness level was not disturbed at all, with normal serum ammonia blood concentration before LT. Owing to allopurinol-induced severe cholestatic liver failure, living-donor LT (LDLT) was performed with the use of a right lobe graft from his younger brother. The explanted liver was extremely enlarged, with a weight of 2,480 g, and severely cholestatic. Microscopic findings were also compatible with drug-induced cholestatic liver injury. He was discharged from hospital 55 days after LDLT, whereas his renal dysfunction remained at 6 months after LT. There are 3 types of pathophysiology of drug-induced hepatotoxicity: hepatocellular, cholestatic, and mixed liver injury. Although allopurinol hepatotoxicity is rare, it can be severe and even fatal. This is the 1st case report of successful LDLT for a patient who had developed allopurinol-induced cholestatic liver failure.

Considerable Risk of Restenosis After Endoscopic Treatment for Hepaticojejunostomy Stricture After Living-Donor Liver Transplantation.

BACKGROUND: There are few reports on the short- and long-term follow-up of endoscopic retrograde cholangiography (ERC) in adult patients with hepaticojejunostomy (HJS) stricture after living-donor liver transplantation (LDLT). METHODS: Nine LDLT recipients underwent ERC with the use of double-balloon endoscopy (DBE) for HJS stricture at Nagoya University Hospital. We assessed the rate of reaching biliary anastomosis, procedure success rate, procedure duration, complications, improvement in liver function test results, and biliary anastomosis patency. RESULTS: In total, 19 ERC procedures with the use of DBE were performed for 9 adult LDLT recipients with HJS stricture from June 2006 to September 2014. Balloon dilation with the use of DBE was successfully performed in 5 of the 9 patients during the 1st procedure. Of the 4 patients in whom DBE-ERC failed to be completed, 3 patients underwent 2nd procedures successfully. Liver function test results were significantly improved in the successful cases. Four patients underwent 2nd DBE-ERC for stricture recurrence at a mean time of 2.3 years after the 1st successful procedure. Of those, 2 patients required 3rd procedures for stricture recurrence after the 2nd procedure. CONCLUSIONS: DBE-ERC is promising as a treatment for HJS stricture in adult LDLT recipients in the short term. However, the DBE-ERC procedure may have a considerable risk of restenosis.

Postoperative Psychiatric Complications in Living Liver Donors.

BACKGROUND: To understand the impact of psychologic variables on donor quality of life, we studied long-term data on postoperative psychiatric complications in living liver donors. This study is a focused psychological investigation of diagnoses, treatments, and long-term clinical courses of living liver donors with psychiatric complications. METHODS: Of the 142 donors who underwent live-donor liver transplantation at Nagoya University Hospital between April 2004 and July 2014, we investigated those without a history of mental illness who had developed such illness after transplantation and required psychiatric treatment. RESULTS: A total of 6 (4.2%) donors developed the following psychiatric complications after transplantation: major depressive disorder (n = 2), panic disorder (n = 2), conversion disorder (n = 1), and substance use disorder (n = 1). Concerning psychiatric treatment, all donors received antianxiety drugs, 3 took antidepressants, and supportive psychiatric therapy was concomitantly provided to all subjects. The average treatment period was 53.3 months. Regarding subject outcomes, 3 donors achieved remission, and the other 3 continued treatment. All subjects showed improvement in Global Assessment of Functioning Scale. CONCLUSION: It is important to accurately diagnose postoperative psychiatric complications and provide long-term treatment in close coordination with transplant surgeons.

Swelling of neuronal processes in motor neuron disease.

We investigated serial sections of the anterior horns of the lower lumbar cord by a modified Bielschowsky's silver impregnation, in a case of sporadic lower motor neuron disease. We paid special attention to any direct connection between the swellings of neuronal processes and the perikarya. Focal swellings of neuronal processes were occasionally directly connected with the perikarya; some had morphologic peculiarities of axons, and others originated in dendrites.

A patient with dementia with Lewy bodies and codon 232 mutation of PRNP.

The authors describe a patient who had a point mutation at codon 232 of the prion protein gene, resulting in the substitution of methionine for arginine (M232R). The patient developed dementia and died 6 years after its onset. Autopsy revealed dementia with Lewy bodies, not Creutzfeldt-Jakob disease. Although the M232R mutation has been reported to cause Creutzfeldt-Jakob disease, findings in our patient suggest that not all patients presenting progressive dementia with M232R mutation have Creutzfeldt-Jakob disease.

Repeated phencyclidine treatment induces negative symptom-like behavior in forced swimming test in mice: imbalance of prefrontal serotonergic and dopaminergic functions.

Repeated treatment with phencyclidine (PCP) prolonged the immobility time in a forced swimming test, compared with saline treatment, this behavioral change being regarded as avolition which is one of the negative symptoms of schizophrenia. In the present study, we investigated an involvement of serotonergic (5-HTergic) and dopaminergic systems in PCP-induced enhancement of immobility in mice, since an alteration in 5-HTergic and dopaminergic systems has been hypothesized in schizophrenia. The enhancing effect of PCP on the immobility in a forced swimming test was attenuated by clozapine, risperidone and olanzapine, which have serotonin (5-HT) and dopamine receptor antagonistic properties. These attenuating effects were significantly antagonized by a 5-HT(2) receptor agonist, (+/-)-2,5-dimethoxy-4-iodamphetamine (DOI) without affecting the immobility itself. (-)Sulpiride at a low dose and methylphenidate reversed the PCP-induced enhancement of immobility whereas pimozide, chlorpromazine and levomepromazine had no effect. There was no difference in the frequency of DOI-induced head twitches, which are mediated via 5-HT(2) receptors, between PCP- and saline-treated mice following the forced swimming test, indicating no functional changes in post-synaptic 5-HT(2) receptors. 5-HT utilization in the prefrontal cortex was increased, but dopamine utilization was decreased in mice showing PCP-induced enhancement of immobility. These results suggest that the enhanced effect of PCP on the immobility is mediated by imbalance of 5-HTergic and dopaminergic systems in the prefrontal cortex and could be used as a model of the negative symptoms of schizophrenia.