Improvement of psychiatric symptoms after electroconvulsive therapy in young adults with intractable first-episode schizophrenia and schizophreniform disorder

Schizophrenia is a serious psychiatric disorder that develops mainly in young adults. Electroconvulsive therapy (ECT) is known to be effective and safe in patients with schizophrenia with acute psychotic exacerbation. Because of the shortage of systematic studies, we conducted a prospective naturalistic study to examine the short-term effects of acute ECT and its safety in young adults with medically intractable first-episode schizophrenia. Subjects were seven consecutive patients, 15-35 years of age, with first-episode schizophrenia or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition; DSM-IV), who had failed to respond to neuroleptics. The seven patients were treated with a first course of ECT, and their clinical symptoms were evaluated on the basis of the Brief Psychiatric Rating Scale (BPRS) (18 items, rated 0-6) and Global Assessment of Functioning (GAF) Scale. The GAF Scale is presented in DSM-IV as a means of assessing global functioning of a psychiatric patient. Scores range from 1-100; the higher GAF score indicates the higher global functioning. Adverse effects resulting from acute ECT were also evaluated. The total BPRS score 1 week after the final session improved significantly compared to the total pre-ECT BPRS score. The GAF score also improved significantly compared to the pre-ECT GAF score. There were no adverse effects during the acute ECT course, except for mild delirium. We conclude that ECT may be an effective and safe treatment option for young adults with intractable first-episode schizophrenia.     

The protective effect of hepatocyte growth factor against cell death in the hippocampus after transient forebrain ischemia is related to the improvement of apurinic/apyrimidinic endonuclease/redox factor-1 level and inhibition of NADPH oxidase activity

Early oxidative DNA damage is regarded to be an initiator of neuronal apoptotic cell death after cerebral ischemia. Although evidence suggests that HGF has the ability to protect cells from oxidative stress, it remains unclear as to how HGF suppresses oxidative DNA damage after cerebral ischemia. Apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) is a multifunctional protein in the DNA base repair pathway that is responsible for repairing apurinic/apyrimidinic sites in DNA after oxidation. We demonstrated that both the immunoreactivity and the number of APE/Ref-1-positive cells in the hippocampal CA1 region were decreased after transient forebrain ischemia and that treatment with HGF suppressed this reduction. The expression of Cu/ZnSOD and MnSOD in the hippocampal CA1 region did not change after ischemia, regardless of treatment with or not with HGF. The activity of NADPH oxidase was increased mainly in glia-like cells in the hippocampal CA1 region after ischemia, and this increase was attenuated by HGF treatment. These results suggest that the protective effects of HGF against cerebral ischemia-induced cell death in the hippocampal CA1 region are related to the improvement of neuronal APE/Ref-1 expression and the inhibition of NADPH oxidase activity in glia-like cells.     

Relationship between changes of bone mineral density over seven years and A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene or lifestyle factors in Japanese female workers

A longitudinal study was conducted to investigate the relation between the changes of bone mineral density (BMD) over a seven-year period and A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 (LRP5) gene or lifestyle factors. The subjects were 113 premenopausal female employees from a large-scale integrated manufacturing facility in Japan aged 25.6 ± 4.2 years (mean ± standard deviation) at baseline. BMD was measured at the radius by dual energy X-ray absorptiometry. Lifestyle information was obtained by a questionnaire. The genotype frequencies of LRP5 gene polymorphism were 52%, 39%, and 9% for AA, AV, and VV, respectively. After seven years, BMD showed a significant decrease (from 0.463 ± 0.045 to 0.456 ± 0.046 g/m2) in subjects with the AV or VV genotypes, but not in subjects with the AA genotype. Analysis of covariance with adjustment for age and body mass index showed that subjects who drank alcohol displayed a significantly greater change of BMD if they had the AV or VV genotype than if they had the AA genotype (F=4.547, p=0.036). Investigation of LRP5 A1330V polymorphism may be useful for identifying individuals who are susceptible to osteoporosis, allowing early preventive measures to be provided.     

Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer

Pancreatic cancer is one of the most lethal malignancies. Epidermal growth factor receptor (EGFR), HER3, Akt, and amphiregulin have been recognized as targets for pancreatic cancer therapy. Although gemcitabine + erlotinib has been the recommended chemotherapy for pancreatic cancer, the prognosis is extremely poor. The development of molecularly targeted therapies has been required for patients with pancreatic cancer. To assess the validation of amphiregulin as a target for pancreatic cancer therapy, we examined its expression in pancreatic cancer using real‐time PCR analyses and ELISA. We also measured the apoptotic cell rate using TUNEL assays. In addition, alterations in signaling pathways were detected by immunoblotting analyses. Treatment with gemcitabine, which reduced the cell viability and augmented the cell apoptotic rate, activated and subsequently attenuated ERK and EGFR signals. However, gemcitabine, paclitaxel, or cisplatin treatment enhanced the Akt activation, heterodimer formation of EGFR with HER3, and secretion of amphiregulin, indicating that the presence of gemcitabine promoted the activity of targeted molecules including amphiregulin, Akt, and HER3 for pancreatic cancer therapy. Combined treatment with an inhibitor for amphiregulin and gemcitabine, paclitaxel, or cisplatin induced synergistic antitumor effects, accompanied by the suppression of Akt and ERK activation. Blockade of amphiregulin suppressed the activities of EGFR, HER3, and Akt and the expression of amphiregulin itself. According to this evidence, combination chemotherapy of conventional anticancer drugs plus an inhibitor for amphiregulin would allow us to provide more favorable clinical outcomes for patients with pancreatic cancer. (Cancer Sci 2010; 101: 2351–2360)     

Role of chemokines in ischemic neuronal stress

Chemokines constitute a large family of structurally related small cytokines originally identified as the factors regulating the migration of leukocytes in inflammatory and immune responses. Enhanced production and release of chemokines are observed also in the central nervous system under diverse neuronal stresses including ischemia, axonal injury, and neurotoxic substances such as an Abeta-peptide. There is growing evidence that brain chemokines play crucial roles in the neuro-glio-vascular interaction underlying the pathology of various brain disorders. Here the evidence of the involvement of chemokines in ischemic brain injury is reviewed.