Abstract: Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. Recent research on alcoholism implicates impaired function of neural stem cell (NSC) in the pathogenesis of ethanol-induced brain dysfunction. We previously reported that the differentiation of NSCs into neurons was significantly influenced by ethanol. We also found that neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/ REST) binding activity potentiated by ethanol underlies the mechanism of ethanol inhibition of neuronal differentiation. Epigenetics refers to post-translational modifications of DNA and nuclear proteins that produce lasting alterations in patterns of gene expression. Epigenetic mechanism plays a critical role of neuronal plasticity and there is clear evidence that dysfunction of epigenetic mechanism also contributes to neurological and psychiatric illness. We will review epigenetic regulation in pathogenesis of psychiatric illness including alcoholism. We also demonstrated that trichostatin A, histone deacetylase inhibitor, reduced the ethanol-induced suppression of neuronal differentiation of NSCs. We suggest that ethanol alters the function of neural differentiation through the mechanism of potentiation of NRSF/REST binding and histone modifications.
Abstract: INTRODUCTION: Medication is a necessary part of treatment for severe psychiatric illnesses such as schizophrenia and nonadherence to prescribed medication is one of the most important public health issues in psychiatry today. The devastating consequences of nonadherence have motivated the development of novel therapeutic strategies, including a new long-term implantable medication delivery system. METHODS: The current study assesses attitudes towards implantable medication in psychiatric patients and their family members. Patients included in the study had diagnoses of Schizophrenia, Schizoaffective Disorder, Mood or Anxiety related disorders. RESULTS: 49.62% of patients and 74.47% of family members endorse support for implantable medication. CONCLUSIONS: This study demonstrates that implants may be an acceptable alternative to oral and injectable medication for a subset of psychiatric patients and their families.
Abstract: Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.
Abstract: INTRODUCTION: Donepezil, an acetylcholinesterase inhibitor, has been reported to have an effect that improves cerebral blood flow (CBF) alongside its primary effect on memory function. The aim of this study was to investigate the effects of long-term, low-dose donepezil therapy on blood perfusion in Alzheimer's disease (AD) by using a fully automated regional CBF quantification program named 3DSRT. MATERIALS AND METHODS: Fifteen subjects with mild to moderate AD according to NINCDS/ADRDA criteria underwent 99mTc-ethylcysteinate dimer (ECD) brain perfusion single photon emission computed tomography (SPECT) twice with an interval of 55.1 +/- 11.0 weeks. The dose of donepezil was fixed at 5 mg/day following the induction period (3 mg/day) of 2 weeks. Clinical efficacy of donepezil was assessed by using the Mini-Mental State Examination (MMSE). The results of SPECT imaging under exactly identical conditions were analyzed by 3DSRT, which enables us to perform a very objective assessment. RESULTS: Despite a decrease of the MMSE score from 20.9 +/- 4.7 to 18.7 +/- 5.7, CBF was increased in almost all cerebral areas except the left temporal segment. The increase was statistically significant in the left callosomarginal, right central, and bilateral pericallosal and lenticular nucleus segments. CONCLUSION: Thus far, no direct cerebrovascular effects have been reported for donepezil. We hypothesize that these CBF-promoting effects of donepezil might be related to increased neuronal activity and enhanced connection of neurons.
Abstract: In the latest criteria for the clinical diagnosis of dementia with Lewy bodies (DLB), supportive features include generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity. In this study, we investigated the usefulness of a cerebral blood flow (CBF) quantification program '3DSRT' in detecting occipital hypoperfusion in DLB. Twenty two patients with probable DLB, 38 patients with probable Alzheimer's disease (AD) and 16 normal controls underwent brain perfusion SPECT. Compared with AD, DLB patients had a bilateral lower CBF in the posterior cerebral segments. The correlation of clinical symptoms and brain blood perfusion was examined by dividing the subjects into subgroups. DLB patients with Parkinsonism, when compared to non-Parkinsonism subgroup, had a lower CBF throughout the cerebrum with statistical significance in the posterior cerebral segments. The quantitative analysis of brain perfusion SPECT by 3DSRT could be a useful supportive measurement in the diagnosis of DLB.
Abstract: Clinical diagnostic criteria for dementia with Lewy bodies (DLB) include abnormal findings on MIBG myocardial scintigraphy and occipital hypoperfusion as supportive features. In this study, 36 patients with probable DLB underwent MIBG scintigraphy and brain perfusion SPECT. The results of SPECT were analyzed using three different cerebral blood flow (CBF)-analyzing programs, an easy Z-score imaging system (e-ZIS), 3DSRT, and FineSRT. Among these assessments, delayed heart-to-mediastinum (dH/M) ratios on MIBG scintigraphy showed superior sensitivity (92%) to detect characteristic abnormalities in DLB. The sensitivities of CBF-analyzing programs to detect occipital hypoperfusion were 67%, 74%, and 81% for e-ZIS, 3DSRT, and FineSRT, respectively. Our results demonstrate that the combination of MIBG scintigraphy and brain perfusion SPECT could increase the accuracy of the clinical diagnosis of DLB. MIBG scintigraphy could be recommended for DLB patients in the clinical setting.
Abstract: Lithium, a mood-stabilizing drug, is widely used to treat bipolar affective disorder. Recent studies have demonstrated that lithium has neuroprotective and neurotrophic properties, which may relate to its clinical effectiveness. Ethanol is a deleterious agent that causes various kinds of neuronal damage to both the developing and adult brain. In this study, we investigated the potential of lithium to produce recovery of ethanol-induced suppressed neuronal differentiation at ethanol concentrations lower than those that affect the viability of neural stem cells (NSCs). We evaluated the effect of lithium on neuronal differentiation of NSCs obtained from rat embryos. To elucidate the molecular mechanisms underlying the altered neuronal differentiation induced by lithium and ethanol, we focused on neuron-restrictive silencer factor (NRSF), which represses transcription of neuronal genes in the terminal stage of NSC differentiation. Lithium increased neuronal differentiation and decreased ethanol-induced suppression of neuronal differentiation of NSCs. Furthermore, lithium reduced the DNA binding activity and protein level of NRSF enhanced by ethanol. Based on our findings, we speculate that lithium may be efficacious in the treatment of ethanol-induced neurological deficits.
Abstract: BACKGROUND: Supportive features in the diagnostic criteria for dementia with Lewy bodies (DLB) include occipital hypoperfusion and decreased cardiac uptake of (123)I-metaiodobenzylguanidine (MIBG). In this study, we performed both brain perfusion single photon emission computed tomography (SPECT) and MIBG myocardial scintigraphy in the same subjects and evaluated their sensitivity to detect the characteristic features of DLB. METHODS: Twenty-five patients with probable DLB (76.8 +/- 5.1 years old, 10 male) underwent (99m)Tc-ethylcysteinate dimer brain perfusion SPECT and (123)I-MIBG myocardial scintigraphy. The results of SPECT were analyzed using a qualitative analysis program, easy Z score imaging system (eZIS), and an automated quantitative analysis program, 3DSRT. RESULTS: Qualitative analysis using eZIS demonstrated occipital hypoperfusion in 17 subjects (68%). The quantified mean blood perfusion in the occipital segment on the 3DSRT template was 40.7 +/- 5.03 ml/100 g/min (right) and 40.5 +/- 5.38 ml/100 g/min (left), and in 19 DLB patients these values were below the normal limit. Twenty-four of 25 subjects (96%) had decreased cardiac MIBG uptake in the delayed image. CONCLUSION: MIBG myocardial scintigraphy was superior to brain perfusion SPECT in detecting a characteristic feature of DLB. Our results suggest that combining SPECT and MIBG scintigraphy could increase the accuracy of clinical diagnosis of DLB.
Abstract: ABSTRACT: BACKGROUND: This study examines pathways to psychiatric care in Japan using the same method as the collaborative study carried out in 1991 under the auspices of the World Health Organization. METHODS: Thirteen psychiatric facilities in Japan were involved. Of the 228 patients who contacted psychiatric facilities with any psychiatric illness, eighty four visiting psychiatric facilities for the first time were enrolled. Pathways to psychiatric care, delays from the onset of illness to treatment prior to reaching psychiatrists were surveyed. RESULTS: Thirty three patients (39.4%) directly accessed mental health professionals, 32 patients (38.1%) reached them via general hospital, and 13 patients (15.5%) via private practitioners. The patients who consulted mental health professionals as their first carers took a longer time before consulting psychiatrists than the patients who consulted non-mental health professionals as their first carers. The patients who presented somatic symptoms as their main problem experienced longer delay from the onset of illness to psychiatric care than the patients who complained about depressive or anxiety symptoms. Prior to the visit to mental health professionals, patients were rarely informed about their diagnosis and did not receive appropriate treatments from their physicians. Private practitioners were more likely to prescribe psychotropics than physicians in general hospitals, but were less likely to inform their patients of their diagnosis. CONCLUSION: This first pathway to psychiatric care study in Japan demonstrated that referral pathway in Japan heavily relies on medical resources. The study indicates possible fields and gives indications, underlining the importance of improving skills and knowledge that will facilitate the recognition of psychiatric disorders presenting with somatic and depressive symptoms in the general health care system and by private practitioners.
Abstract: INTRODUCTION: Recent clinical studies have demonstrated that Yi-Gan San (YGS, Yokukan-San in Japanese), a Chinese herbal medicine, alleviates various dementia-related symptoms. However, Chinese herbal medicines have rarely been investigated scientifically and the underlying mechanism of YGS remains uncertain. In this study, we investigated the effect of YGS on beta amyloid protein (Abeta)-induced cytotoxicity in a primary culture of rat cortical neurons. METHODS: Cortical neurons prepared from rat embryos were exposed to Abeta in the presence or absence of YGS. The protective effect of YGS was measured as the % of control (unexposed neurons) by using MTT assay and LDH assay. RESULTS: Abeta significantly decreased the number of surviving cortical neurons at a dose of 20 microM and higher. In the presence of 20 microM Abeta, YGS concentrations of 10(-5) g/L (W/V) and higher significantly increased the number of viable neurons. CONCLUSION: Our study demonstrated a neuroprotective effect of Yi-Gan San against Abeta-induced cytotoxicity. Since according to traditional herbal medicine beliefs, YGS most likely exerts its clinical effects not through a single constituent but as a mixture of several herbal ingredients, the true mechanism of this neuroprotective action remains unclear. However, our results suggest that this Chinese herbal medicine might be a valuable treatment for clinical symptoms associated with dementia having fewer side effects and possible additional neuroprotective effects in the elderly.
Abstract: PURPOSE: The clinical symptoms of Alzheimer's disease (AD) show great diversity depending on the clinical stage. We investigated the correlation of regional cerebral blood flow (rCBF) changes and the clinical severity of AD patients. METHODS: Thirty-nine AD patients and 16 normal subjects participated in this study. AD patients were divided into three subgroups by clinical severity. Quantitative brain perfusion SPECT analyses were performed using a rCBF quantification software, 3DSRT. RESULTS: In mild AD, significant decreases of rCBF were detected in the bilateral parietal, angular gyrus, pericallosal, thalamus, right temporal and left hippocampal regions. Moderate AD patients showed significantly lower blood flow than those with mild AD only to the right hippocampus. Analysis of the severe AD group revealed a nearly diffuse decrease of rCBF throughout the cerebral cortex except for part of the frontal lobe compared with moderate patients. CONCLUSIONS: These results were consistent with previous findings demonstrated by qualitative analysis of CBF. The decreased thalamic blood flow was noteworthy as this finding has rarely been reported. In consideration of the structure and function of the Papez circuit, which connects the medial temporal lobe and thalamus, a remote metabolic effect might be the cause of lower rCBF in the thalamus.
Abstract: The neuron-restrictive silencer factor (NRSF), or repressor element-1 silencing transcription factor (REST), is a transcription factor that mediates negative regulation of neuronal genes. NRSF represses multiple neuronal target genes in non-neuronal and neuronal precursor cells to regulate the proper timing of neuronal gene expression during neurogenesis. In the present study, we investigated the effects of ethanol and MEK inhibitor U0126 on the DNA binding activity of NRSF in neural stem cells prepared from rat embryos. Both ethanol and U0126 enhanced NRSF binding activity measured by the method based on the principal of electrophoretic mobility shift assay (EMSA) and decreased neuronal differentiation in a concentration dependent manner. Western blot analysis revealed that ethanol suppressed phosphorylation of extracellular signal-regulated kinase (ERK) without affecting expression of total ERK. These results suggest that ethanol-induced potentiation of NRSF binding activity underlies the mechanism of ethanol inhibition of neuronal differentiation and decreased neurogenesis.
Abstract: BACKGROUND: Recent studies have described the possible relevance of impaired neural stem cell (NSC) functions to the pathophysiology of psychiatric disorders, including alcoholism. However, relatively little is known about ethanol's effects on the determination of cell fate in NSCs. In this study, we investigated the effect of ethanol on neuronal and glial differentiation of NSCs. METHODS: Under neuron-inductive culture conditions, NSCs were induced to differentiate and exposed to ethanol for 96 hr. Immunocytochemistry with cell-type-specific markers was performed (microtubule-associated protein 2 (MAP2) for neurons, glial fibrillary acidic protein (GFAP) for astrocytes and O4 for oligodendrocytes). The cells positive to MAP2, GFAP or O4 were counted, and the number of MAP2-positive cells was quantified by enzyme-linked immunosorbent assay (ELISA) following immunostaining with anti-MAP2 (MAP2-ELISA). The alteration of MAP2, GFAP or myelin basic protein (MBP, a marker for oligodendrocytes) expression was evaluated by Western blot analysis. RESULTS: Ethanol exposure increased astrocytic and oligodendrocytic differentiation with a statistically significant difference at 100 mM, while 25 to 100 mM ethanol reduced neuronal differentiation without affecting the viability of NSCs. The enhanced expression of glial markers was revealed by Western blot analysis for GFAP or MBP. CONCLUSIONS: Glial cells are known to increase in response to various kinds of insults to the central nervous system. It is possible that the increase of astrocytes and oligodendrocytes after ethanol exposure is a compensatory mechanism to repair the impaired neural network by promoting neurite outgrowth and increasing newly generated neurons.
Abstract: Advances in the neurosciences over the past two decades have elucidated that alcoholism is a chronic and easily recurring disorder, which is based on brain damage induced by long-term ethanol consumption. Researchers have identified neural circuits that subsume the actions of ethanol and they have also elaborated many of the intracellular signalling pathways that follow receptor activation by ethanol, suggesting a substantial difference between the addicted brain and non-addicted brain. However, most of the molecular biological changes, which are likely based on the transition from occasional drinking to alcohol dependence, remain to be elucidated. This review summarizes the findings on the biological background of alcoholism concerning the brain rewarding system, its related receptors, and the second messenger-mediated signal transduction system within the cells, especially focusing on the cyclic AMP signaling pathway calcium (Ca2+) system in neurons. In addition, our studies with neural stem cells are introduced to indicate future directions of research on the pathophysiology of alcoholism.
Abstract: BACKGROUND: Ethanol exposure during development leads to various forms of neuronal damage. Because neural stem cells (NSCs) play a pivotal role in the development and maturation of the central nervous system, it is important to understand the effect of ethanol on NSC differentiation. In this study, we investigated the effect of ethanol on differentiation of cultured NSCs in the presence and absence of neurotrophic factors. METHODS: NSCs were derived from rat embryos on embryonic day 14. Cells were exposed to ethanol with or without neurotrophic factors, insulin-like growth factor-1 (IGF-1), or brain-derived neurotrophic factor (BDNF). The effect of ethanol on differentiation was quantified by measurement of optical density of each sample following to microtubule-associated protein 2 enzyme-linked immunosorbent assay and counting of the number of microtubule-associated protein 2-positive cells microscopically. In addition, cell viability of cultured cortical neurons that were exposed to similar concentrations of ethanol was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. RESULTS: Ethanol (20-100 mM) inhibited NSC differentiation induced by basic fibroblast growth factor removal, whereas those concentrations of ethanol did not affect neuronal survival. Both IGF-1 and BDNF promoted generation of neurons in the absence of ethanol. Moreover, they suppressed the inhibitory effect of ethanol on NSC differentiation. CONCLUSIONS: Ethanol inhibited NSC differentiation at concentrations much lower than what compromised neuronal survival. Ethanol-induced differential inhibition was reduced by both IGF-1 and BDNF. These results suggest that ethanol inhibits stem cell differentiation through alteration of cellular pathways related to neurotrophic factor signaling.
Abstract: The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia.
Abstract: Recently, stent implantation has become the treatment of choice for patients with tracheobronchial stenosis due to malignant tumours, tuberculosis and recurrent stenosis following lung transplant. However, reports on this procedure in infants with congenital bronchial stenosis are extremely rare. We report successful stent implantation in an infant with congenital left bronchial stenosis followed by rapid improvement in his respiratory condition. CONCLUSION: The use of a stent in infants is still controversial because size mismatch will take place with growth. However, we believe that implantation of a metallic stent can be the preferred treatment of congenital bronchial stenosis even in small infants.
Abstract: An 11-year-old boy with severe aplastic anemia underwent unrelated BMT following TBI, antithymocyte globulin and CY. On day +23, CMV antigenemia was detected which resolved with ganciclovir. Eight days after discontinuing ganciclovir, he complained of impaired visual acuity. Ophthalmologic findings and a positive PCR study using anterior chamber fluid from the right eye confirmed the presumptive diagnosis of CMV retinitis, although CMV antigenemia and PCR studies using PBMC were then negative. He was successfully re-treated with ganciclovir. CMV retinitis should be considered even when CMV antigenemia is not present or PCR using PBMC is negative.
