Catheter Ablation of Refractory Ventricular Fibrillation Storm After Myocardial Infarction.

BACKGROUND: Ventricular fibrillation (VF) storm after myocardial infarction (MI) is a life-threatening condition that necessitates multiple defibrillations. Catheter ablation is a potentially effective treatment strategy for VF storm refractory to optimal medical treatment. However, its impact on patient survival has not been verified in a large population. METHODS: We conducted a multicenter, retrospective observational study involving consecutive patients who underwent catheter ablation of post-MI refractory VF storm without preceding monomorphic ventricular tachycardia. The target of ablation was the Purkinje-related ventricular extrasystoles triggering VF. The primary outcome was in-hospital and long-term mortalities. Univariate logistic regression and Cox proportional-hazards analysis were used to evaluate clinical characteristics associated with in-hospital and long-term mortalities, respectively. RESULTS: One hundred ten patients were enrolled (age, 65±11years; 92 men; left ventricular ejection fraction, 31±10%). VF storm occurred at the acute phase of MI (4.5±2.5 days after the onset of MI during the index hospitalization for MI) in 43 patients (39%), the subacute phase (>1 week) in 48 (44%), and the remote phase (>6 months) in 19 (17%). The focal triggers were found to originate from the scar border zone in 88 patients (80%). During in-hospital stay after ablation, VF storm subsided in 92 patients (84%). Overall, 30 (27%) in-hospital deaths occurred. The duration from the VF occurrence to the ablation procedure was associated with in-hospital mortality (odds ratio for each 1-day increase, 1.11 [95% CI, 1.03-1.20]; P=0.008). During follow-up after discharge from hospital, only 1 patient developed recurrent VF storm. However, 29 patients (36%) died, with a median survival time of 2.2 years (interquartile range, 1.2-5.5 years). Long-term mortality was associated with left ventricular ejection fraction <30% (hazard ratio, 2.54 [95% CI, 1.21-5.32]; P=0.014), New York Heart Association class ≥III (hazard ratio, 2.68 [95% CI, 1.16-6.19]; P=0.021), a history of atrial fibrillation (hazard ratio, 3.89 [95% CI, 1.42-10.67]; P=0.008), and chronic kidney disease (hazard ratio, 2.74 [95% CI, 1.15-6.49]; P=0.023). CONCLUSIONS: In patients with MI presenting with focally triggered VF storm, catheter ablation of culprit triggers is lifesaving and appears to be associated with short- and long-term freedom from recurrent VF storm. Mortality over the long-term follow-up is associated with the severity of underlying cardiovascular disease and comorbidities in this specific patient population.

Predictors of increase in pacing threshold after transcatheter pacing system implantation due to micro-dislodgement.

BACKGROUND: Achieving a favorable pacing threshold with a Micra transcatheter pacing system (Micra-TPS) is needed to reduce battery depletion. In some cases, the threshold increases shortly after the device is implanted, and a higher pacing threshold may be required. This study aims to identify the causes and predictors of the increase in pacing threshold observed shortly after Micra-TPS implantation. METHODS: The study included 64 consecutive patients who underwent Micra-TPS implantation between 2017 and 2020. The patients were divided into two groups depending on their pacing threshold: the increased pacing threshold (IPT) group (threshold increased by ≥0.5 V/0.24 ms within 1 month of implantation) and the stable pacing threshold (SPT) group. RESULTS: Excluding four patients who could not be followed up, of the 60 remaining patients, nine (15%) were in the IPT group and 51 (85%) were in the SPT group. The IPT group had significantly lower implant impedance values and higher implant thresholds than the SPT group (582 ± 59 vs 755 ± 167 Ω [P < .001] and 1.29 ± 0.87 vs 0.71 ± 0.40 V/0.24 ms [P = .014]). Implant impedance and threshold may serve as predictors of a threshold increase after implantation (area under the curve: 0.737-0.943 and 0.586-0.926, respectively). CONCLUSIONS: An IPT was noted shortly after Micra-TPS implantation owing to micro-dislodgement because of insufficient anchoring of the device to the myocardium. Impedance >660 Ω and threshold <1.0 V/0.24 ms may predict an increase in pacing threshold.

Dopamine stimulates differentiation and migration of cortical interneurons.

Cortical GABAergic interneurons originate and migrate tangentially from the medial ganglionic eminence (MGE), but its mechanism remains unknown. In this study, we show that dopamine (DA) stimulates the differentiation and migration of cortical interneurons derived from MGE cells. Using immunohistochemistry for the DA marker, tyrosine hydroxylase (TH), TH positive axons enter the MGE by E12.5. In E11.5 MGE primary cultures, DA enhances the expression of cortical interneuron marker proteins, such as GAD67 and neuropilin1, via D1 receptor, and also up-regulates D2 receptor. In E14.5 organotypic slice cultures, the migration of MGE cells is occurred in a D2 receptor-dependent manner, whose stimulation increased the synthesis of neurotrophins, in E11.5 MGE primary cultures. Furthermore, TH neurons-depletion by 6-hydroxydopamine treatments led to a significant reduction of cortical calbindin positive cells in the cerebral cortex, compared with the controls. Therefore, these results suggest that DA can stimulate the differentiation and migration of cortical interneurons.

[A Case of Malignant Peritoneal Mesothelioma Treated with Cisplatin and Pemetrexed].

A 65-year-old man was admitted to our hospital complaining of general malaise, anorexia and weight loss. A computed tomography(CT)scan showed massive ascites and multiple peritoneal masses. Although adenocarcinoma was suspected based on the cytology of the ascites, we were unable to determine the site of origin. We next performed a laparoscopy and a biopsy of the tumor on the omentum. The laparoscopy showed small, white, hard nodules that were disseminated throughout the abdominalcavity, and histologicaldiagnosis confirmed malignant peritonealmesothel ioma. The patient was administered chemotherapeutic treatment of cisplatin and pemetrexed. After treatment, the ascites decreased; however, tumor regression was not observed. The patient's performance status gradually decreased, and he died on hospital day 104. Prognosis of malignant peritoneal mesothelioma remains poor, and malignant peritoneal mesothelioma should be considered when diagnosing peritoneal tumors.

Population dynamics of neural progenitor cells during aging in the cerebral cortex.

Recent studies indicate that adult neurogenesis occurs in the cerebral cortex of rodents. Neural progenitor cells (NPCs) have been found in the adult cerebral cortex. These cells are expected to be regulated by various stimuli, including environmental enrichment, exercise, learning, and stress. However, it is unclear what stimuli can regulate cortical NPCs. In this study, we examined whether aging has an impact on population dynamics of NPCs in the murine cerebral cortex, using immunohistological staining for NPCs. The density of NPCs was kept from 5- to 12-month-old, dramatically decreased at 17-month-old, and thereafter maintained the same level until 24-month-old. Comparing the densities of NPCs in the cortical areas, such as the cingulate, primary motor, primary somatosensory, and insular cortices, we found that the degrees of decreased densities of NPCs in the cingulate and insular cortices were significantly smaller than those in the primary motor and somatosensory cortices. NPCs in aged cortex produced new neurons by ischemia. These results indicate that in aged mice, NPCs exist and produce new neurons in the cerebral cortex. Additionally, the extent of reduction of the density of NPCs in the cortices with higher cognitive functions may be less than that in the primary motor and somatosensory cortices.

Localization of truncated TrkB and co-expression with full-length TrkB in the cerebral cortex of adult mice.

Brain-derived neurotrophic factor (BDNF), one of the neurotrophins, and its specific receptor TrkB, are abundantly distributed in the central nervous system (CNS) and have a variety of biological effects, such as neural survival, neurite elongation, neural differentiation, and enhancing synaptic functions. Currently, there are two TrkB subtypes: full-length TrkB (TrkB-FL), which has a tyrosine kinase in the intracellular domain, and TrkB-T1, which is a tyrosine kinase-deficient form. While TrkB-FL is a typical tyrosine kinase receptor, TrkB-T1 is a main form expressed in the CNS of adult mammals, but its function is unknown. In this study, we performed fluorescent staining of the cerebral cortex of adult mice, by using TrkB-T1 antiserum and various antibodies of marker molecules for neurons and glial cells. We found that TrkB-T1 was expressed not only in neurons but also in astrocytes. In contrast, little expression of TrkB-T1 was found in oligodendrocytes and microglia. TrkB-T1 was expressed in almost all of the cells expressing TrkB-FL, indicating the direct interaction between TrkB subtypes. These findings suggest that a part of various functions of BDNF-TrkB signaling might be due to the interaction and cellular localization of TrkB subtypes in the cerebral cortex.

Injury-induced neurogenesis in the mammalian forebrain.

It has been accepted that new neurons are added to the olfactory bulb and the hippocampal dentate gyrus throughout life in the healthy adult mammalian brain. Recent studies have clarified that brain insult raises the proliferation of neural stem cells/neural progenitor cells existing in the subventricular zone and the subgranular zone, which become sources of new neurons for the olfactory bulb and the dentate gyrus, respectively. Interestingly, convincing data has shown that brain insult invokes neurogenesis in various brain regions, such as the hippocampal cornu ammonis region, striatum, and cortex. These reports suggest that neural stem cells/neural progenitor cells, which can be activated by brain injury, might be broadly located in the adult brain or that new neurons may migrate widely from the neurogenic regions. This review focuses on brain insult-induced neurogenesis in the mammalian forebrain, especially in the neocortex.

Change of hypothalamic adult neurogenesis in mice by chronic treatment of fluoxetine.

OBJECTIVE: More than half of patients with depression display eating disorders, such as bulimia nervosa and anorexia nervosa. Feeding centers are located in the hypothalamus, and hypothalamic adult neurogenesis has an important role in feeding and energy balance. Antidepressants, which can regulate adult neurogenesis in the hippocampus, olfactory bulb, and neocortex, are used for eating disorders, but it is unclear whether antidepressants change hypothalamic adult neurogenesis. In this study, we used immunohistological analysis to assess effects of the antidepressant fluoxetine (FLX) on hypothalamic adult neurogenesis of adult mice. RESULTS: Expressions of the proliferating cell marker, Ki67, and the neural stem cell marker, nestin, were significantly decreased in the hypothalamus by FLX. As regard to postmitotic cells, the number of the neural marker, NeuN, positive cells was significantly upregulated by FLX, but that of the astrocytic marker, S100B, positive cells was significantly reduced by FLX. The number of the oligodendrocyte marker, Olig2, positive cells was not changed by FLX. Interestingly, FLX treatment did not affect the total number of newly generated cells in the hypothalamus, comparing that in controls. These results suggest that FLX treatment influence hypothalamic adult neurogenesis and shift the balance between the numbers of neurons and astrocytes under studied conditions.

Effects of leptin on proliferation of astrocyte- and tanycyte-like neural stem cells in the adult mouse medulla oblongata.

Astrocyte- and tanycyte-like neural stem cells (NSCs) were recently detected in the area postrema (AP) and central canal (CC) of the adult medulla oblongata, respectively. The present study aimed to examine dynamical behaviors of the astrocyte- and tanycyte-like NSCs of the mouse medulla oblongata to leptin. The neurosphere assay identified astrocytes in the AP and tanycytes in the CC as NSCs based on their self-renewing neurospherogenic potential. Both NSCs in neurosphere cultures were multipotent cells that generate astrocytes, oligodendrocytes, and neurons. Astrocyte-like NSCs actively proliferated and tanycyte-like NSCs were quiescent under physiologically-relevant in vivo conditions. Chronic leptin treatment promoted proliferation of astrocyte-like NSCs in the AP both in vitro and in vivo. Leptin receptors were expressed in astrocyte-like, but not tanycyte-like NSCs. Food deprivation significantly diminished proliferation of astrocyte-like NSCs. Therefore, the present study indicates that proliferation of astrocyte-like, but not tanycyte-like NSCs is regulated by nutritional conditions.

Dopamine as a growth differentiation factor in the mammalian brain.

The catecholamine, dopamine, plays an important role in the central nervous system of mammals, including executive functions, motor control, motivation, arousal, reinforcement, and reward. Dysfunctions of the dopaminergic system lead to diseases of the brains, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. In addition to its fundamental role as a neurotransmitter, there is evidence for a role as a growth differentiation factor during development. Recent studies suggest that dopamine regulates the development of γ-aminobutyric acidergic interneurons of the cerebral cortex. Moreover, in adult brains, dopamine increases the production of new neurons in the hippocampus, suggesting the promoting effect of dopamine on proliferation and differentiation of neural stem cells and progenitor cells in the adult brains. In this mini-review, I center my attention on dopaminergic functions in the cortical interneurons during development and further discuss cell therapy against neurodegenerative diseases.

Transcriptomic evidence for immaturity induced by antidepressant fluoxetine in the hippocampus and prefrontal cortex.

AIMS: The molecular and cellular mechanisms underlying the antidepressant effects of fluoxetine in the brain are not fully understood. Emerging evidence has led to the hypothesis that chronic fluoxetine treatment induces dematuration of certain types of mature neurons in rodents. These studies have focused on the properties of typical molecular and/or electrophysiological markers for neuronal maturation. Nevertheless, it remains unknown whether dematuration-related phenomena are present at the genome-wide gene expression level. METHODS: Based on the aforementioned hypothesis, we directly compared transcriptome data between fluoxetine-treated adult mice and those of naive infants in the hippocampus and medial prefrontal cortex (mPFC) to assess similarities and/or differences. We further investigated whether fluoxetine treatment caused dematuration in these brain regions in a hypothesis-free manner using a weighted gene co-expression network analysis (WGCNA). RESULTS: Gene expression patterns in fluoxetine-treated mice resembled those in infants in the mPFC and, to a large extent, in the hippocampus. The gene expression patterns of fluoxetine-treated adult mice were more similar to those of approximately 2-week-old infants than those of older mice. WGCNA confirmed that fluoxetine treatment was associated with maturation abnormalities, particularly in the hippocampus, and highlighted respective co-expression modules for maturity and immaturity marker genes in the hippocampus in response to fluoxetine treatment. CONCLUSIONS: Our results strongly support the hypothesis that chronic fluoxetine treatment induces dematuration in the adult mouse brain from a transcriptomic standpoint. Detection of discrete transcriptomic regulatory networks related to fluoxetine treatment may help to further elucidate the mechanisms of antidepressant action.

Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset.

The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders. Chronic FLX treatment reportedly induces cellular responses in the brain, including increased adult hippocampal and cortical neurogenesis and reversal of neuron maturation in the hippocampus, amygdala, and cortex. However, because most previous studies have used rodent models, it remains unclear whether these FLX-induced changes occur in the primate brain. To evaluate the effects of FLX in the primate brain, we used immunohistological methods to assess neurogenesis and the expression of neuronal maturity markers following chronic FLX treatment (3 mg/kg/day for 4 weeks) in adult marmosets (n = 3 per group). We found increased expression of doublecortin and calretinin, markers of immature neurons, in the hippocampal dentate gyrus of FLX-treated marmosets. Further, FLX treatment reduced parvalbumin expression and the number of neurons with perineuronal nets, which indicate mature fast-spiking interneurons, in the hippocampus, but not in the amygdala or cerebral cortex. We also found that FLX treatment increased the generation of cortical interneurons; however, significant up-regulation of adult hippocampal neurogenesis was not observed in FLX-treated marmosets. These results suggest that dematuration of hippocampal neurons and increased cortical neurogenesis may play roles in FLX-induced effects and/or side effects. Our results are consistent with those of previous studies showing hippocampal dematuration and increased cortical neurogenesis in FLX-treated rodents. In contrast, FLX did not affect hippocampal neurogenesis or dematuration of interneurons in the amygdala and cerebral cortex.

Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis.

It is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call "dematuration," in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer's disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases.

Targeting green fluorescent protein to dendritic membrane in central neurons.

Dendritic and axonal processes are input and output sites, respectively, of neuronal information, and detailed visualization of these processes may be indispensable for elucidating the neuronal circuits and revealing the principles of neuronal functions. To establish a method for completely visualizing dendritic processes, we first developed green fluorescent protein (GFP)-based proteins and, by using lentivirus with a neuron-specific promoter, examined whether or not the protein fully visualized the dendritic processes of infected neurons. When GFP with a palmitoylation (palGFP) or myristoylation/palmitoylation site (myrGFP) was expressed in rat brain with lentiviruses, myrGFP labeled dendritic membrane better than palGFP. Subsequently, dendrite-targeting efficiencies of three basolateral membrane-sorting and three putative dendrite-targeting domains, which were attached to myrGFP C-terminus, were examined in striatonigral GABAergic and corticothalamic glutamatergic neurons, and in cultured cortical neurons. Of the six domains, C-terminal cytoplasmic domain of low density lipoprotein receptor (LDLRct) was most efficient in targeting the protein to dendrites, showing 8.5-15-fold higher efficiency in striatonigral neurons compared with myrGFP. Finally, dendritic membrane-targeting potency of myrGFP-LDLRct was confirmed in transgenic mice using Thy1 or Gad1 expression cassette. Thus, myrGFP-LDLRct is an excellent synthetic protein for dendritic visualization, and may be a useful tool for the morphological analysis of neuronal circuits.

BDNF pro-peptide: a novel synaptic modulator generated as an N-terminal fragment from the BDNF precursor by proteolytic processing.

Most growth factors are initially synthesized as precursors and it was cleaved into bioactive mature domain and pro-domain. However, compared with the expression and function of bioactive mature domain, the biological role of the pro-domain is poorly understood. Unexpectedly, we found that the pro-domain (or pro-peptide) of brain-derived neurotrophic factor (BDNF), which is well-known neurotrophic factor in brain, has a potential ability to facilitate hippocampal long-term depression. Furthermore, a BDNF polymorphism Val66Met, which substitute valine into methionine at 66 amino acid, impacted the biological activity of the BDNF pro-peptide. We lastly discuss the possible roles of BDNF and its pro-peptide in the generation of neural stem cells and progress of ischemia.

Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability.

Accumulating evidence suggests that subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/pathophysiology of schizophrenia and intellectual disability. Previously, we proposed mice lacking Schnurri-2 (Shn2; also called major histocompatibility complex [MHC]-binding protein 2 [MBP-2], or human immunodeficiency virus type I enhancer binding protein 2 [HIVEP2]) as a schizophrenia and intellectual disability model with mild chronic inflammation. In the mutants' brains, there are increases in C4b and C1q genes, which are considered to mediate synapse elimination during postnatal development. However, morphological properties of subcellular-scale structures such as dendritic spine in Shn2 knockout (KO) mice remain unknown. In this study, we conducted three-dimensional morphological analyses in subcellular-scale structures in dentate gyrus granule cells of Shn2 KO mice by serial block-face scanning electron microscopy. Shn2 KO mice showed immature dendritic spine morphology characterized by increases in spine length and decreases in spine diameter. There was a non-significant tendency toward decrease in spine density of Shn2 KO mice over wild-type mice, and spine volume was indistinguishable between genotypes. Shn2 KO mice exhibited a significant reduction in GluR1 expression and a nominally significant decrease in SV2 expression, while PSD95 expression had a non-significant tendency to decrease in Shn2 KO mice. There were significant decreases in dendrite diameter, nuclear volume, and the number of constricted mitochondria in the mutants. Additionally, neuronal density was elevated in Shn2 KO mice. These results suggest that Shn2 KO mice serve as a unique tool for investigating morphological abnormalities of subcellular-scale structures in schizophrenia, intellectual disability, and its related disorders.

A truncated tropomyosin-related kinase B receptor, T1, regulates glial cell morphology via Rho GDP dissociation inhibitor 1.

Through tropomyosin-related kinase B (TrkB) receptors, brain-derived neurotrophic factor (BDNF) performs many biological functions such as neural survival, differentiation, and plasticity. T1, an isoform of TrkB receptors that lacks a tyrosine kinase, predominates in the adult mammalian CNS, yet its role remains controversial. In this study, to examine whether T1 transduces a signal and to determine its function, we first performed an affinity purification of T1-binding protein with the T1-specific C-terminal peptide and identified Rho GDP dissociation inhibitor 1 (GDI1), a GDP dissociation inhibitor of Rho small G-proteins, as a signaling protein directly associated with T1. The binding of BDNF to T1 caused Rho GDI1 to dissociate from the C-terminal tail of T1. Astrocytes cultured for 30 d expressed only endogenous T1 among the BDNF receptors. In 30 d cultured astrocytes, Rho GDI1, when dissociated in a BDNF-dependent manner, controlled the activities of the Rho GTPases, which resulted in rapid changes in astrocytic morphology. Furthermore, using 2 d cultured astrocytes that were transfected with T1, a T1 deletion mutant, or cyan fluorescent protein fusion protein of the T1-specific C-terminal sequence, we demonstrated that T1-Rho GDI1 signaling was indispensable for regulating the activities of Rho GTPases and for the subsequent morphological changes among astrocytes. Therefore, these findings indicate that the T1 signaling cascade can alter astrocytic morphology via regulation of Rho GTPase activity.

Differential expression of the truncated TrkB receptor, T1, in the primary motor and prefrontal cortices of the adult macaque monkey.

A truncated TrkB receptor, T1, which is one of the receptors for brain-derived neurotrophic factor, has been shown to regulate the morphology of neurons and glial cells in primary cultures and/or slices overexpressing T1 in the recent past. However, in vivo localization of T1 at protein level remains unclear. In the present study, we examined the localization of T1 in the primary motor and prefrontal cortices of adult monkeys by using immunohistochemistry. In the primary motor cortex, T1 immunoreactivity was observed mainly in the pyramidal neurons of layers II-VI, especially Betz cells of layer V. The apical and basal dendrites and cell bodies of Betz cells were strongly stained. In addition, we found that the interneurons were also T1-immunopositive and that there were no T1-positive astrocytes. In the prefrontal cortex, we observed strong immunoreactivity of T1 in astrocytes as well as pyramidal neurons of layer V. The pyramidal neurons and interneurons in layers II/III were faintly immunoreactive for T1. Thus, these findings, together with the fact that T1 is involved in morphological control of neurons and glial cells, suggest that the prefrontal cortex might possess a different degree of morphological plasticity than the primary motor cortex in the adult monkey.

Randomized placebo-controlled trial of interferon alpha-2b plus ribavirin with and without lactoferrin for chronic hepatitis C.

Lactoferrin (LF), an iron-binding glycoprotein, exhibits several biological activities, including anti-viral activity and immunomodulatory functions. LF has been reported to inhibit hepatitis C virus (HCV) infection in cultured human hepatocytes and HCV viremia in low pretreatment HCV RNA titers of patients with chronic hepatitis C (CHC). However, the combination of interferon (IFN) alpha-2b plus ribavirin with LF for CHC has not been previously investigated. Thirty-six CHC patients, who were positive for HCV RNA with high serum levels of HCV RNA or who did not respond to or relapsed after interferon monotherapy, were randomly assigned to two groups: IFN alpha-2b and ribavirin plus LF for 24 weeks (18 patients), and IFN alpha-2b and ribavirin plus placebo (18 patients). Treatment was discontinued in three patients (17%) in the LF group and eight patients (44%) in the placebo group. For the 25 patients who finished the 24 weeks of treatment, virological sustained response was seen in 6 (40%) patients in the LF group and in 5 (50%) patients in the placebo group and there was no statistically significant difference between the two groups (p=0.7). Serum alanine aminotransferase concentrations remained normal throughout the follow-up period in nine patients (60%) in the LF group as compared with five patients (50%) in the placebo group (p=0.7). The proportion of patients with a virological or biochemical response at the end of the treatment period did not differ between the two groups. Furthermore, there were no statistically significant differences between the two groups in hemoglobin concentration, serum iron, ferritin, Th1/Th2 ratio or ribavirin concentration throughout the treatment and follow-up periods. In conclusion, we could not demonstrate that LF in combination with IFN alpha-2b and ribavirin increases the virological and biochemical response rate for CHC patients with high serum levels of HCV RNA or for CHC patients who do not response to or relapse after IFN monotherapy.

Expression of BDNF and TrkB receptor subtypes in the postnatal developing Purkinje cells of monkey cerebellum.

In the previous study, we have shown the complementary expression of TrkB subtypes (TK+ and T1) in the adult monkey cerebellar cortex. In this study, to clarify when that expression pattern appeared, we examined the expressions of TrkB subtypes and its ligand brain-derived neurotrophic factor (BDNF) by immunohistochemistry and Western blot analysis. At the newborn stage, both TK+ and T1 were expressed uniformly in the cerebellar cortex. At postnatal month 3.5, the uneven expression of TrkB subtypes was observed, while the BDNF immunoreactivity was strongly detected in all regions of the cerebellar cortex. The expression patterns of TrkB subtypes and BDNF at both postnatal month 6 and year 7 were the same as those at postnatal month 3.5. Western blot analysis demonstrated that TK+ and T1 were expressed at high levels in the synaptic membrane from newborn to adult stages. Furthermore, the dimerization of TrkB subtypes changed at postnatal month 3, which was similar to the adult pattern: at the newborn stage, the TK+ and TK- homodimers; after postnatal month 3.5, the TK+ and TK- homodimers, and the TK+/TK- heterodimer. These findings suggest that the localization of TrkB subtypes in each Purkinje would be changed at postnatal month 3.5, resulting in the uneven expression of TrkB subtypes and the change of TrkB dimerization.