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H Mochizuki

Publications and source records attributed to H Mochizuki.

At least 19 recordsLinked to original sources
PubMed2006

Neuronal specificity of alpha-synuclein toxicity and effect of Parkin co-expression in primates.

Recombinant adeno-associated viral (rAAV) vector-mediated overexpression of alpha-synuclein (alphaSyn) protein has been shown to cause neurodegeneration of the nigrostriatal dopaminergic pathway in rodents and primates. Using serotype-2 rAAV vectors, we recently reported the protective effect of Parkin on alphaSyn-induced nigral dopaminergic neurodegeneration in a rat model. Here we investigated the neuronal specificity of alphaSyn toxicity and the effect of Parkin co-expression in a primate model. We used another serotype (type-1) of AAV vector that was confirmed to deliver genes of interest anterogradely and retrogradely to neurons in rats. The serotype-1 rAAV (rAAV1) carrying alphaSyn cDNA (rAAV1-alphaSyn), and a cocktail of rAAV1-alphaSyn and rAAV1 carrying parkin cDNA (rAAV1-parkin) were unilaterally injected into the striatum of macaque monkeys, resulting in protein expression in striatonigral GABAergic and nigrostriatal dopaminergic neurons. Injection of rAAV1-alphaSyn alone decreased tyrosine hydroxylase immunoreactivity in the striatum compared with the contralateral side injected with a cocktail of rAAV1-alphaSyn and rAAV1-parkin. Immunostaining of striatonigral GABAergic neurons was similar on both sides. Overexpression of Parkin in GABAergic neurons was associated with less accumulation of alphaSyn protein and/or phosphorylation at Ser129 residue. Our results suggest that the toxicity of accumulated alphaSyn is not induced in non-dopaminergic neurons and that the alphaSyn-ablating effect of Parkin is exerted in virtually all neurons in primates.

Animals↗
PubMed2006

Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice.

AIMS/HYPOTHESIS: Recent studies have identified the involvement of inhibitor IkappaB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor kappaB (NF-kappaB), the distal target of IKK, in hepatic glucose metabolism. METHODS: To inhibit NF-kappaB activity, db/db mice were infected with adenovirus expressing the IkappaBalpha super-repressor. RESULTS: The IkappaBalpha super-repressor adenovirus infection caused a moderate reduction of NF-kappaB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1alpha (PPARGC1A, also known as PGC-1alpha). Furthermore, the production of super-repressor IkappaBalpha suppressed the increase in blood glucose level after pyruvate injection. CONCLUSIONS/INTERPRETATION: Our results indicate that moderate inhibition of NF-kappaB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1alpha gene expression in db/db mice, and suggest that inhibition of NF-kappaB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.

AMP-Activated Protein Kinases↗
PubMed2006

Disinhibition of somatosensory evoked potential recovery in alcoholics.

The pathogenesis of cognitive impairment in alcoholics remains unclear. Previous studies suggested that diffuse white matter atrophy is associated with cognitive impairment in alcoholics. To elucidate this issue, the present study evaluated alcoholics with cognitive impairment using the somatosensory evoked potential (SEP) recovery method, which is suitable for detecting subtle dysfunction at the cortical level. Subjects comprised 12 alcoholics with mild cognitive impairment [Mild group: Mini Mental State Examination Score (MMSE), > or =24; mean, 27.9 +/- 1.6], 12 alcoholics with moderate to severe cognitive impairment (Moderate group: MMSE score, < 24; mean, 21.0 +/- 2.5) and 12 normal subjects (Control group). SEP was recorded from the hand sensory area contralateral to the median nerve stimulated at the wrist. Single-pulse or paired-pulse stimuli at various interstimulus intervals (10-300 ms) were administered. Recovery functions of N9 (a peripheral nerve component), N20, N20-P25 and P25-N33 (cortical components) were studied. N20 recovery curves of both alcoholic groups were less suppressive than those of Controls, and P25-N33 recovery curves of the Moderate group were more excitatory than those of the Mild or Control groups. A disinhibited recovery pattern of N20 indicates subcortical dysfunction, and a disinhibited pattern of P25-N33 would be induced by cortical dysfunction. Therefore, subcortical dysfunction indicated by an abnormal N20 recovery pattern may contribute to the early cognitive impairment of alcoholics, whilst the cortical dysfunction indicated by an abnormal P25-N33 recovery pattern may contribute to the later cognitive impairment of alcoholics.

Alcoholism↗
PubMed2006

Retroperitoneoscopic radical nephrectomy in obese patients: outcomes and considerations.

OBJECTIVE: To determine whether obesity is associated with surgical outcome in Japanese patients undergoing retroperitoneoscopic radical nephrectomy (RRN). PATIENTS AND METHODS: Between November 1999 and March 2005, we performed 98 RRN procedures for patients with renal cell carcinoma. Patients with a body mass index (BMI) of 25.0 or more were defined as obese (group A, n=33) and those with a BMI of <25.0 were defined as non-obese (group B, n=65), in accordance with the criteria of the Japan Society for the Study of Obesity. Patient background, degree of surgical invasiveness, and period of convalescence were compared between groups A and B. RESULTS: No statistically significant differences were observed between the groups in terms of age, gender, tumor laterality, tumor size, and time until resumption of oral intake and ambulation. However group A had a significantly longer insufflation time (172.1 vs. 137.4 min), greater blood loss (195.3 vs. 48.4 ml) and higher renal specimen weight (440.0 vs. 306.0 g) than group B. CONCLUSION: Obesity is not a factor that affects patient eligibility for RRN, but is a risk factor for longer insufflation time and greater blood loss.

Carcinoma, Renal Cell↗
PubMed2006

Inflammation and infection in Parkinson's disease.

The hallmark of Parkinson's disease (PD) is a specific degeneration of dopaminergic neurons in the substantia nigra (SN). The cause of nigral dopaminergic neuronal cell death in PD and its underlying mechanisms remain elusive, however, involvement of inflammatory events has been postulated because inflammatory features have been described in the brain of PD patients. Some evidence also suggest that a possible deleterious effects of neuroinflammatory processes by infection in experimental models of neurodegenerative disease. In this review, we summarize and discuss the latest findings regarding inflammation in PD. Especially, we focused on the relationship between infection and PD.

Blood-Brain Barrier↗
PubMed2006

Alpha-synuclein overexpression model.

OBJECTIVES: To elucidate the role of alpha-synuclein in the pathogenesis of Parkinson's disease (PD), both human alpha-synuclein transgenic mice and targeted overexpression of human alpha-synuclein in rat substantia nigra (SN) by viral vector-based methods have been studied, however little is known about the pathogenetic changes of dopaminergic neuron loss. Therefore, it is necessary to address whether the pathogenetic changes in the brains of patients with PD are recapitulated in these models. METHODS AND RESULTS: We used the recombinant adeno-associated viral (rAAV) vector system for human alpha-synuclein gene transfer to rat SN and observed approximately 50% loss of dopaminergic neurons in SN at 13 weeks after infection. In the slower progression of neurodegeneration, we identified several important features in common with the pathogenesis of PD, such as phosphorylation of alpha-synuclein at Ser129 and activation of caspase-9. Both findings were also evident in cortical tissues overexpressing alpha-synuclein via rAAV. CONCLUSIONS: Our results indicate that overexpression of alpha-synuclein via rAAV apparently recapitulates several important features of brains with PD and dementia with Lewy bodies (DLB), and thus alpha-synucleinopathy described here is likely to be an ideal model for the study of the pathogenesis of PD and DLB. This model is also useful for the gene therapy research.

Adenoviridae↗
PubMed2005

Two Japanese brothers with hereditary gamma-glutamyl transpeptidase deficiency.

We report on two Japanese brothers with hereditary deficiency in gamma-glutamyl transpeptidase. The propositus was 48 years old when he first visited our medical center and had a 51-year-old brother. The brothers were both tall and slender and had long limbs; the younger was diagnosed as having Marfan syndrome. Both patients both showed a tendency to retarded mental development. gamma-Glutamyltranspeptidase activity was below the detection limit of 1 IU/L in both patients. Glutathionaemia and glutathionuria were evident in both brothers. The analyses of sulphydryl compounds in the plasma (and serum for certain test items) and urine indicated high concentrations of glutathione, gamma-glutamylcysteine, cysteine and cysteinylglycine. Urine amino acid analysis on an automatic analyser showed a slightly increased excretion of cystine and a large peak in the citrulline position due, at least in part, to thio-compounds.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

Cognitive impairment and diffuse white matter atrophy in alcoholics.

OBJECTIVE: Diffuse brain white matter atrophy is often seen in chronic alcoholics, but its relation with cognitive impairment remains to be solved. In order to address this issue, in alcoholics with cognitive impairment at different levels, we studied relations of the central sensory conduction time (CSCT) or brain magnetic resonance imaging (MRI) findings with the cognitive function. METHODS: Subjects were 35 alcoholics with mild cognitive impairment (mini-mental state examination score, MMSE, >/=24; mean+/-SD, 27.7+/-1.9), 12 with moderate to severe cognitive impairment (MMSE<24; 20.3+/-2.7), 15 with Alzheimer's disease (AD) (MMSE, 18.9+/-4.3) (disease control) and 20 healthy volunteers (MMSE, 28.5+/-1.6) (normal control). Median nerve SEPs were recorded in the all subjects, and the latencies and amplitudes of their N9, N11, P13/14, N20 and P25 components were measured. The ventriculocranial ratio (VCR) and the width of cortical sulci were measured on MRIs. These physiological parameters and MRI findings were compared between the 4 groups of the subject, and correlations between those all features were also analyzed. RESULTS: CSCT and VCR were significantly greater in alcoholics with moderate to severe cognitive impairment than those in the other 3 groups. Pearson's product-moment correlation analyses of the alcoholics disclosed that both the CSCT and VCR had significant negative correlations with the MMSE score. Moreover, the CSCT and VCR were positively correlated. CONCLUSIONS: Both physiological and morphological estimates of the white matter function (CSCT and VCR) had a significant correlation with the cognitive dysfunction. SIGNIFICANCE: The diffuse white matter atrophy may be one of the factors causing cognitive impairment in chronic alcoholics.

Aged↗
PubMed2005

A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci.

AIMS: Tumour budding is an adverse prognostic factor in colorectal cancer (CRC). We have investigated the significance of cytoplasmic fragments occurring in the immediate vicinity of tumour budding foci. METHODS AND RESULTS: Seventy-three CRCs with high-grade budding (> 10 budding foci in a x 20 objective field) were classified according to extent of budding (10-19 versus 20+ foci) and by the presence or absence of cytoplasmic fragments identified by immunostaining for cytokeratin. In serial sections, cytoplasmic fragments were shown to be dendritic cell processes in continuity with budding tumour cells and were renamed pseudo-fragments. Cytoplasmic pseudo-fragments, but not extent of budding, were associated with aberrant expression of beta-catenin (P = 0.045) and laminin-5 gamma2 (P < 0.0001), and with absent peritumoral lymphocytic infiltration (P = 0.0077). Cytoplasmic pseudo-fragments had a stronger association with infiltrating growth pattern (P = 0.0014) than extent of tumour budding (P = 0.014). There was no association between extent of budding and cytoplasmic pseudo-fragments (P = 0.12). CONCLUSIONS: Cytoplasmic pseudo-fragments may be a marker for an activated budding phenotype that is associated with cell motility and increased invasiveness in CRC and is independent of the extent of budding.

Adult↗
PubMed2005

Decreased tear lipocalin concentration in patients with meibomian gland dysfunction.

BACKGROUND/AIM: Recent studies have demonstrated that tear lipocalin (TL) and phospholipids have a crucial role in maintaining tear film stability. The level of TL in patients with meibomian gland dysfunction (MGD) was examined and these data were correlated with the severity of their clinical disorder. METHODS: 12 patients with obstructive MGD, 12 patients with seborrhoeic MGD, and 12 age matched normal control subjects participated in this study. 3 mul of unstimulated tears were collected with a micropipette from the inferior tear meniscus in the right eye of all subjects. Tear samples were fractionated by high performance liquid chromatography, and TL concentrations were assayed with a bicinchoninic acid technique. RESULTS: The mean concentration of TL in patients with obstructive and seborrhoeic MGD was significantly lower than in normal controls. TL concentration correlated positively with tear film break up time and negatively with fluorescein staining scores. CONCLUSION: These results suggest that TL deficiency may be a predisposing factor for the manifestation of symptoms in MGD.

Aged↗
PubMed2004

Predictors of extrahepatic recurrence after resection of colorectal liver metastases.

BACKGROUND: It is important to identify patients at high risk of extrahepatic recurrence after surgery for liver metastases, in order to maximize the survival benefit obtained by prophylactic regional chemotherapy. METHODS: Data from 68 patients who underwent resection of colorectal liver metastases but who did not receive hepatic arterial chemotherapy or intravenous systemic chemotherapy were collected. Twenty-two variables were examined by univariate and multivariate analyses to determine which factors were relevant to extrahepatic recurrence. A scoring system was developed that included the most relevant factors. RESULTS: The extrahepatic recurrence rate at 3 years after hepatectomy was 57.8 per cent. Three variables were independently associated with extrahepatic recurrence including raised serum level of carcinoembryonic antigen after hepatectomy (relative risk (RR) 5.4, P < 0.001), venous invasion of the primary tumour (RR 4.0, P = 0.001) and high-grade budding of the primary tumour (RR 3.1, P = 0.006). Patients with none of these risk factors had a 3-year extrahepatic recurrence rate of 7.1 per cent, compared with 61.6 per cent for those with one risk factor and 100 per cent for those with two or three risk factors. CONCLUSION: It was possible to identify patients at high risk of disease relapse at extrahepatic sites. This system might be used on an individual basis to select patients with colorectal liver metastases for regional chemotherapy or systemic chemotherapy after surgical intervention.

Colorectal Neoplasms↗
PubMed2004

Seasonal variation of multiple sclerosis exacerbations in Japan.

Several reports have described the seasonal variation of multiple sclerosis (MS) attacks in the European countries and in the US. Some have insisted that attacks occurred more frequently in winter or spring. We investigated the possibility of a seasonal variation in the frequency of MS attacks among patients in Japan. A total of 172 MS exacerbations in 34 MS patients were analyzed retrospectively. Attacks were divided into two groups: opticospinal type and brain type. The 12 months of the year were assigned to 6 groups based on average monthly temperature. Of the 172 MS exacerbations, 123 were opticospinal type and 49 were brain type of attacks. The total number of attacks was significantly more frequent in the warmest (July and August) and coldest (January and February) months. The heat of summer in warmer, low latitude areas may be a risk factor for MS attacks.

Adult↗
PubMed2004

Intraspinal sarcoidosis: clinical features, MR imaging and electrophysiological study.

We presented the case of a 58-year-old woman with spinal sarcoidosis at the C4-C6 level. The lesion itself as visualized with magnetic resonance imaging, and its neurological findings responded favorably to treatment with prednisolone. Comparison of pre- and post-treatment values for somatosensory evoked potential (SEP) and central motor conduction time (CMCT) also showed improvement. Analysis of SEP and CMCT can be a useful tool for following up spinal sarcoidosis.

Cervical Vertebrae↗
PubMed2004

Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice.

Neurogenesis occurs during development and in the normal adult brain. Recent studies identified areas exhibiting postlesional selective neurogenesis and neuronal repair. In the olfactory bulb (OB), one of the most studied regions of the brain for neurogenesis, seizures and strong odor exposure are known to enhance neurogenesis. Here, we report enhanced neurogenesis in OB after dopaminergic neuronal loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective toxin for dopaminergic neurons. The neurogenesis has been previously confirmed mainly by the uptake of 5-bromodeoxyuridine (BrdU), a marker of proliferating cells, but methodological problems related to BrdU labeling might result in inaccurate findings with respect to specificity, toxicity and incorporation into normal/lesioned brain. For a better identification of neurogenesis, we used a retroviral vector. First, we investigated the population dynamics of newly formed neurons in different regions of OB including the glomerular layer, the most superficial layer of OB. Quantification of neurogenesis in OB revealed by our retroviral vector was substantially similar to that by BrdU-based method. One week after MPTP application and dopaminergic neuronal loss in OB, neurogenesis of dopaminergic neurons in OB increased by three-fold, but no such process was noted in non-dopaminergic neurons. Our results indicate selective dopaminergic neurogenesis in OB in response to neuronal damage/loss.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Assessment of tissue-engineered stomach derived from isolated epithelium organoid units.

OBJECTIVE: Isolated stomach epithelial organoid units developed on biodegradable polymers were transplanted to assess the feasibility of a tissue-engineered stomach. BACKGROUND: Despite recent advances in reconstruction techniques, total gastrectomy is still accompanied by various complications. An alternative treatment would be a tissue-engineered stomach, which replaces the mechanical and metabolic functions of a normal stomach. METHODS: Stomach epithelial organoid units isolated from neonatal rats were seeded onto biodegradable polymers. The constructs implanted into the omenta of adult rats were harvested for examination at designated times. Nine rats underwent a second operation for anastomosis. RESULTS: The constructs resulted in cyst-like formations showing vascularized tissue with neomucosa lining the lumen. The surface morphology as assessed using scanning electron microscopy was similar to that of a native stomach. Immunohistochemical staining for alpha-actin smooth muscle and gastric mucin indicated the presence of a smooth muscle layer and a well-developed gastric epithelium, respectively. The luminal surface of the anastomosed tissue-engineered stomach was well-covered with epithelium. CONCLUSIONS: Epithelium-derived stomach organoid units seeded on biodegradable polymers and transplanted into donor rats were shown to vascularize, survive, and regenerate into complex tissue resembling native stomach. Anastomosis between the units and native small intestine may have the potential to stimulate epithelial growth. This research may provide insight into new approaches to alleviate complications following total gastrectomy.

Animals↗
PubMed2004

Near-field optical microscope observation of dye-containing nano-domains.

A novel method for forming dye-containing nano-domains in thin films using a polymer alloy system has been developed. The polymer alloy system (PS-b-PMMA), which consists of polystyrene (PS) and polymethyl methacrylate (PMMA), forms microphase separation in thin films. The film was treated using a previously reported technique under vacuum conditions, and an organic dye was selectively dispersed into the PS. Selective association of the dye (diarylethene; cis-1, 2-dicyano-1, 2-bis (2,4,5-trimethyl-3-thienyl) ethene) with the PS nano-domains was then observed, with both transmission electron microscopy and scanning near-field optical microscopy with an absorption spectrum.

Journal Article↗
PubMed2003

Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic beta cells.

AIMS/HYPOTHESIS: Bone marrow cells contain at least two distinct types of stem cells which are haematopoietic stem cells and mesenchymal stem cells. Both cells have the ability to differentiate into a variety of cell types derived from all three germ layers. Thus, bone marrow stem cells could possibly be used to generate new pancreatic beta cells for the treatment of diabetes. In this study, we investigated the feasibility of bone marrow-derived cells to differentiate into beta cells in pancreas. METHODS: Using green fluorescent protein transgenic mice as donors, the distribution of haematogenous cells in the pancreas was studied after bone marrow transplantation. RESULTS: In the pancreas of green fluorescent protein chimeric mice, green fluorescent protein-positive cells were found in the islets, but none of these cells expressed insulin. Previous data has suggested that tissue injury can recruit haematopoietic stem cells or their progeny to a non-haematopietic cell fate. Therefore, low-dose streptozotocin (30 or 50 mg/kg on five consecutive days) was injected into the mice 5 weeks after bone marrow transplantation, but no green fluorescent protein-positive cells expressing insulin were seen in the islets or around the ducts of the pancreas. CONCLUSIONS/INTERPRETATION: Our data suggests that bone marrow-derived cells are a distinct cell population from islet cells and that transdifferentiation from bone marrow-derived cells to pancreatic beta cells is rarely observed.

Animals↗