Yoichiro Matsubara

Effects of repeated electroconvulsive seizure on cell proliferation in the rat hippocampus.

Electroconvulsive therapy (ECT) is known as a successful treatment for severe depression. Despite great efforts, the biological mechanisms underlying the beneficial effects of ECT remain largely unclear. In this study, animals received a single, 10, or 20 applications of electroconvulsive seizure (ECS), and then cell proliferation and apoptosis were investigated in the subgranular zone (SGZ) of the dentate gyrus. We analyzed whether a series of ECSs could induce changes in the dentate gyrus in a dose‐response fashion. A single‐ECS seizure significantly increased cell proliferation in the SGZ by ∼2.3‐fold compared to sham treatment. After 10 ECSs, a significant increase in cell proliferation was observed in the SGZ by ∼2.4‐fold compared to sham treatment. Moreover, 10 ECSs induced a significant increase in cell proliferation by 1.3‐fold compared to a single‐ECS group. However, cell proliferation did not differ between the group with 20 ECSs and sham group. In addition, a significant increase in the number of apoptotic cells was found in the group with 10 ECSs, whereas no significant change in it was found in either a single ECS or 20 ECSs group compared to sham treatment. These findings indicate that the optimal number of treatments and duration of stimulation requires investigation. Further studies are needed to elucidate the intracellular mechanisms underlying both effective and excessive ECT. Synapse 64:814–821, 2010.

Prenatal phencyclidine exposure alters hippocampal cell proliferation in offspring rats.

Multiple case reports have described pregnancy in phencyclidine hydrochloride (PCP) abusers. Characteristic clinical symptoms of PCP‐exposed infants have revealed neurobehavioral or physical abnormalities. We designed this study to evaluate whether chronic prenatal exposure to PCP during the last 2 weeks of gestation in rats produces alterations of hippocampal neurogenesis in offspring. Rats received repeated subcutaneous injection of PCP (5 mg/kg) once daily during the last 2 weeks of gestation. Control animals received subcutaneous injection of physiological saline during gestation. Dams receiving repeated PCP administrations showed markedly increased locomotor activities on days 1, 5, and 10 during the last 2 weeks of gestation. At 21 days after birth, 5‐bromo‐2′‐deoxyuridine (BrdU)‐positive cells of offspring were counted in the granule cell layer (GCL) and subgranular zone of the dentate gyrus. The numbers of BrdU‐positive cells in the GCL in male and female offspring of the PCP‐treated group were significantly increased by ∼77% compared with those from the control group. At 56 days, the number of surviving BrdU‐positive cells also remained to be increased by 74% in the GCL in PCP‐treated group. At 21 days, locomotor activities of offspring in the PCP‐treated group were significantly decreased by ∼30% compared with those in the control group. However, neuronal differentiation of newly formed cells and cell survival were not influenced at 5 weeks after BrdU injections. Some altered biochemical or physiological conditions of offspring from dams receiving repeated PCP injections during pregnancy could influence changes in cell proliferation in the GCL of offspring during early development. Changes to cell proliferation in the hippocampus may affect behavioral abnormalities during infancy in offspring. Synapse 63:729–736, 2009.

No genetic association between polymorphisms in the Fyn kinase gene and age of schizophrenic onset

Since the mRNA level of Fyn, a neurodevelopmental molecule, expression had been reported to be increased in postmortem schizophrenic prefrontal cortex and showed a strong correlation with age of disease onset, we investigated whether the three polymorphisms of the Fyn gene on genomic DNA (-93A/G, IVS10+37T/C and Ex12+894T/G) also had an effect on clinical onset in 139 unrelated schizophrenics. A comparison of the age of onset among the groups classified by polymorphisms showed no significant difference. Moreover, all allelic combinations also failed to show significant differences in age of onset among the groups. The present study reports that there is no indication that the three polymorphisms in the Fyn gene are associated with the age of schizophrenic onset.

Plasma Concentration of Risperidone Showed a Correlation with Daily Dose, but not with Age nor Cytochrome P-450 2D6 Gene Polymorphisms in Japanese Schizophrenics

Background: Risperidone, a neuroleptic, is mainly metabolized by the enzyme cytochrome P‐450 2D6 (CYP2D6), which has over 20 genetic polymorphisms, to its major active metabolite, 9‐hydroxyrisperidone (9‐OH‐risperidone). The clinical outcome in risperidone treatment is highly dependent on the plasma concentration of risperidone.

A case of frontotemporal dementia with sexual disinhibition controlled by aripiprazole

CASE PRESENTATION The patient began attending a local clinic for type 2 diabetes mellitus from about the age of 50 years. He then gradually became unable to work effectively, and spontaneous conversation decreased. He went cycling almost every day but usually was unable to find his way home. Beginning at around age 58, he shouted obscenities at his eldest son’s wife and at local primary school girls. In addition, he gradually became unable to manage money and was careless with fire. He presented to our department at age 60. Frontotemporal dementia (FTD) was diagnosed, and treatment with memantine (20 mg/ day) was commenced. The patient then started to attend an adult day-care centre. There, his problem behaviour, such as exposing his genitals to other attendees and frequently making sexual remarks to the female staff, gradually increased. Because he was considered too difficult for the day-care centre to handle, he was admitted to our hospital at age 62. He exhibited lability of mood and irritability towards his wife. Aripiprazole was initiated at 12 mg/day on the day of admission, and the dose was gradually increased to 18 mg/day over the next week. After admission, he walked around the ward at almost the same time each day in a stereotypic manner and tried to touch female nurses. About 2 weeks after admission, he started to walk around less frequently and often sat in the dayroom. About 3 weeks after admission, sexual remarks to the female staff and other features of disinhibition subsided. He became less likely to hold a conversation, was indifferent to his appearance, and did not exhibit excitement or restlessness. His problem behaviour subsided 3 months after admission, and he was discharged to receive day-care services at home. There was no worsening of the patient’s diabetes during hospitalization. DISCUSSION In recent years, it has been reported that selective serotonin reuptake inhibitors, including fluvoxamine, are effective for treating disinhibition, stereotypic behaviour, and abnormal eating behaviour in FTD. In the present case, there was a risk that the patient’s unstable mood and irritability could be exacerbated by the activating effect of selective serotonin reuptake inhibitors; hence, antipsychotic agents were considered for the first-line therapy. It was reported that treatment with olanzapine for 24 months improved delusions and behaviour, such as sudden crying, in 17 patients with FTD, but olanzapine could not be administered to the present patient because he had type 2 diabetes. Aripiprazole was reported to be effective for treating apathy, blunted affect, and indifference in a 73-year-old FTD patient, and positron-emission tomography showed improvement of glucose metabolism in the frontal lobe. In an FTD patient who made frequent sexual remarks, sertraline and paroxetine were reported to be ineffective, but administering aripiprazole at 30 mg/day for 2 weeks markedly improved the patient’s condition. In the present patient, improvement was noted approximately 2 weeks after the start of treatment with aripiprazole at 18 mg/day, with inappropriate sexual behaviour and other activities being suppressed. With regard to non-drug treatment for FTD, providing behavioural therapy during short-term hospitalization or at day-care services was reported to be effective. Such methods focus patients on a simple task by taking advantage of stereotypic behaviour, elicit procedure memory and introduce it in occupational therapy, and reduce the care burden. In the present case, correction of daily activities was achieved in the hospital environment, but the efficacy of aripiprazole was considered to be high because the patient started to improve within 2 weeks after admission, before the delivery of sufficient behavioural therapy. Although treatment of FTD

Acute renal failure caused by cilostazol in a patient with Alzheimer's disease

A 67-year-old man diagnosed with Alzheimer’s disease showing agitation and wandering was admitted to our hospital (Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan), and was treated with donepezil (5mg daily) alone. We increased the dose to 10mg, but reduced it back to 5mg after noting symptoms, such as dizziness and lightheadedness. Loss of appetite, easy fatigability and decreased volition were noted approximately 1month after admission; therefore, we administered cilostazol (100mg daily) to augment the effects of donepezil. Because the symptoms did not improve, we increased the dose to 200mg; however, the loss of appetite and decreased volition worsened. The patient vomited during the nurses’ rounds 2weeks after the dose was increased, and presented with disturbance of consciousness with a Glasgow Coma Scale score of 5 (eye: 2, verbal: 2, motor: 1). Blood tests before administration of cilostazol showed a blood urea nitrogen level of 34mg/dL and creatinine level of 0.87mg/dL, which worsened to 186mg/dL and 8.28mg/dL, respectively. These results showed that the patient developed acute renal failure. Upper gastrointestinal tract endoscopy, echocardiography and chest computed tomography on the same day revealed no findings of note. We suspected drug-induced renal damage and stopped all oral medication. We administered replacement fluid and monitored his clinical course. The urine output was favorable. Two days later, blood urea nitrogen and creatinine levels recovered to 94mg/dL and 2.28mg/dL, respectively, and the disturbance of consciousness improved. After 14days, the blood urea nitrogen level was 16mg/dL and the creatinine level was 0.98mg/dL, indicating that kidney function normalized (Fig. 1). Cilostazol specifically inhibits phosphodiesterase in platelets and vascular smooth muscle, increasing the concentration of cyclic adenosine monophosphate. It has antiplatelet and vasodilatory effects. In addition, cilostazol phosphorylates, and thus activates, cyclic adenosine monophosphate response element-binding protein, which is reported to improvememory impairmentmediated byAβ protein and increase cerebral blood flow. Increasing cerebral blood flow and preventing a decrease in cognitive function have been reported when cilostazol is used to treat Alzheimer’s dementia, either as concomitant treatment with donepezil or as monotherapy. The renal function before administration of cilostazol was almost within normal limits. The renal disorder rapidly improved after stopping the oral medication and carrying out fluid management. Furthermore, cilostazol was the only new drug added when the renal disorder appeared. Therefore, acute renal failure caused by cilostazol was diagnosed. The main adverse drug reactions LETTERS TO THE EDITOR CASE REPORTS

No genetic association between tumour necrosis factor receptor II 196R polymorphism and Japanese sporadic Alzheimer's disease.

Recent studies have reported that acute effects of tumour necrosis factor (TNF), a pro-inflammatory cytokine, are limited by binding to a soluble receptor, TNF receptor II, and the G allele at position 196 in exon 6 of the TNF receptor II gene (TNFRII 196R) has been associated with auto-immune diseases. Since complex interactions among cytokines have been suggested around senile plaques in Alzheimers disease, TNF might be associated with ageing and the pathophysiology of Alzheimers disease. We examined the TNFRII 196R polymorphism in 243 Japanese sporadic Alzheimers disease cases and 106 control cases using a polymerase chain reaction-restriction fragment length polymorphism method. Allelic frequencies with TNFRII 196R T/G polymorphism were 28.3% and 27.4% in the control and Alzheimers disease groups, respectively. The results showed no genetic association between TNFRII 196R polymorphism and Alzheimers disease. The TNFRII 196R G allele does not appear to be associated with Alzheimers disease susceptibility in a Japanese population.

POSSIBILITY OF UNDIAGNOSED DEMENTIA PATIENTS ARRESTED FOR VIOLENT BEHAVIOUR IN JAPAN

enrollment in the Care Ecosystem study, 97 caregivers of patients with dementia randomized to the intervention group were asked (1) whether patients premorbidly made their own purchases, paid household bills by themselves, or prepared taxes or other important documents; (2) if so, whether patients had performed these activities in the preceding year; and (3) if so, whether patients had made financial errors. Results:Among patients with mild disease, 26 of 43 (60%) who had previously made purchases continued to do so in the previous year, while 15/32 (47%) continued to pay bills and 5/21 (24%) continued to prepare taxes. One patient with moderate disease continued to pay bills and prepare taxes, suggesting high financial vulnerability. (Figure 1) Patients who had completed a college degree were more likely to continue to make purchases (p 1⁄4 0.032) and to pay bills (p 1⁄4 0.015). (Figure 2) Contrary to our initial hypotheses, living alone was not associated with continued financial activities. (Figure 3) Out of 35 still participating in financial activities in the preceding year, 11 were reported to have made financial errors. Conclusions:Responses are consistent with a graduated restriction of financial activities with disease progression. We will discuss clinical experiences in the Care Ecosystem care navigation intervention of working with caregiver/patient dyads identified as vulnerable to financial errors. This publication was made possible by Grant Number 1C1CMS331346 from the Department of Health and Human Services, Centers for Medicare & Medicaid Services. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the U.S. Department of Health and Human Services or any of its agencies.