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Biomedical subjects

Tsutomu Takahashi

Publications and source records attributed to Tsutomu Takahashi.

At least 19 recordsLinked to original sources
PubMed2006

Endocytic Ark/Prk kinases play a critical role in adriamycin resistance in both yeast and mammalian cells.

To elucidate the mechanism of acquired resistance to Adriamycin, we searched for genes that, when overexpressed, render Saccharomyces cerevisiae resistant to Adriamycin. We identified AKL1, a gene of which the function is unknown but is considered, nonetheless, to be a member of the Ark/Prk kinase family, which is involved in the regulation of endocytosis, on the basis of its deduced amino acid sequence. Among tested members of the Ark/Prk kinase family (Ark1, Prk1, and Akl1), overexpressed Prk1 also conferred Adriamycin resistance on yeast cells. Prk1 is known to dissociate the Sla1/Pan1/End3 complex, which is involved in endocytosis, by phosphorylating Sla1 and Pan1 in the complex. We showed that Akl1 promotes phosphorylation of Pan1 in this complex and reduces the endocytic ability of the cell, as does Prk1. Sla1- and End3-defective yeast cells were also resistant to Adriamycin and overexpression of Akl1 in these defective cells did not increase the degree of Adriamycin resistance, suggesting that Akl1 might reduce Adriamycin toxicity by reducing the endocytic ability of cells via a mechanism that involves the Sla1/Pan1/End3 complex and the phosphorylation of Pan1. We also found that HEK293 cells that overexpressed AAK1, a member of the human Ark/Prk family, were Adriamycin resistant. Our findings suggest that endocytosis might be involved in the mechanism of Adriamycin toxicity in yeast and human cells.

Animals↗
PubMed2006

Parietal lobe volume deficits in schizophrenia spectrum disorders.

There has been little attention given to whether parietal lobe structural deficits are present in patients with schizophrenia and related personality disorders. The current study was designed to examine parietal volume alterations between schizophrenia and schizotypal personality disorder. Twenty-five patients with schizotypal disorder, 53 patients with schizophrenia, and 59 healthy volunteers were scanned using high-resolution magnetic resonance imaging (MRI). Volume measurements of the postcentral gyrus (PoCG), precuneus, superior parietal gyrus (SuPG), supramarginal gyrus (SMG), and angular gyrus (AGG) were performed on consecutive 1-mm coronal slices. Gray matter volumes were reduced in all parietal subregions in patients with schizophrenia compared with healthy controls. White matter volumes were also reduced in the SuPG and PoCG. In contrast, the schizotypal subjects had gray matter reductions only in the PoCG, while other regions were not affected. In addition, there was a lack of normal significant-leftward asymmetry in the SMG in schizophrenia. These findings demonstrate that volume reductions in the somatosensory cortices are common morphological characteristics in schizophrenia spectrum disorders. The additional volume alterations in schizophrenia may support the notion that a deficit in the posterior parietal region is critical for the manifestation of overt psychotic symptoms.

Adult↗
PubMed2006

Multivariate voxel-based morphometry successfully differentiates schizophrenia patients from healthy controls.

Currently available laboratory procedures might provide additional information to psychiatric diagnostic systems for more valid classifications of mental disorders. To identify the correlative pattern of gray matter distribution that best discriminates schizophrenia patients from healthy subjects, we applied discriminant function analysis techniques using the multivariate linear model and the voxel-based morphometry. The first analysis was conducted to obtain a statistical model that classified 30 male healthy subjects and 30 male schizophrenia patients diagnosed according to current operational criteria. The second analysis was performed to prospectively validate the statistical model by successfully classifying a new cohort that consisted of 16 male healthy subjects and 16 male schizophrenia patients. Inferences about the structural relevance of the gray matter distribution could be made if the individual profile of pattern expression could be linked to the specific diagnosis of each subject. The result was that 90% of the subjects were correctly classified by the eigenimage, and the Jackknife approach revealed well above chance accuracy. The pattern of the eigenimage was characterized by positive loadings indicating gray matter decline in the patients in the lateral and medial prefrontal regions, insula, lateral temporal regions, medial temporal structures, and thalamus as well as the negative loadings reflecting gray matter increase in the patients in the putamen and cerebellum. When the eigenimage derived from the original cohort was applied to classify data from the second cohort, it correctly assigned more than 80% of the healthy subjects and schizophrenia patients. These findings suggest that the characteristic distribution of gray matter changes may be of diagnostic value for schizophrenia.

Adult↗
PubMed2006

Significant decrease in tropoelastin gene expression in fibroblasts from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation.

Costello syndrome is a connective tissue disorder associated with sparse, thin, and fragmented elastic fibers in tissues. In this study we demonstrated a significant decrease in the expression of tropoelastin mRNA in fibroblasts derived from a Japanese Costello syndrome patient with impaired elastogenesis and enhanced proliferation. In contrast, there were no changes in expression of the Harvey ras (HRAS), fibrillin-1, fibulin-5, microfibril-associated glycoprotein-1 (MAGP-1), lysyl oxidase (LOX), or 67-kDa non-integrin elastin-binding protein (EBP) gene. The proliferative activity of the Costello fibroblasts was about 4-fold higher than that of the normal and pathological control ones. However, no mutations were detected in the coding region of HRAS mRNA. Transduction of the bovine tropoelastin (bTE) gene with the lentiviral vector restored the elastic fiber formation and decreased the growth rate in the Costello fibroblasts. These results strongly suggest that the defect of human tropoelastin (hTE) gene expression should induce the impaired elastogenesis and enhanced proliferation of Costello fibroblasts, and that a primary cause other than the HRAS gene mutation should contribute to the pathogenesis in the present Costello case.

Abnormalities, Multiple↗
PubMed2006

Temporal lobe gray matter in schizophrenia spectrum: a volumetric MRI study of the fusiform gyrus, parahippocampal gyrus, and middle and inferior temporal gyri.

Although several brain morphologic studies have suggested abnormalities in the temporal regions to be a common indicator of vulnerability for the schizophrenia spectrum, less attention has been paid to temporal lobe structures other than the superior temporal gyrus or the medial temporal region. In this study, we investigated the volume of gray matter in the fusiform gyrus, the parahippocampal gyrus, the middle temporal gyrus, and the inferior temporal gyrus using magnetic resonance imaging in 39 schizotypal disorder patients, 65 schizophrenia patients, and 72 age and gender matched healthy control subjects. The anterior fusiform gyrus was significantly smaller in the schizophrenia patients than the control subjects but not in the schizotypal disorder patients, while the volume reduction of the posterior fusiform gyrus was common to both disorders. Volumes for the middle and inferior temporal gyri or the parahippocampal gyrus did not differ between groups. These findings suggest that abnormalities in the posterior region of the fusiform gyrus are, as have been suggested for the superior temporal gyrus or the amygdala/hippocampus, prominent among the temporal lobe structures as a common morphologic substrate for the schizophrenia spectrum, whereas more widespread alterations involving the anterior region might be associated with the development of full-blown schizophrenia.

Adult↗
PubMed2006

Morphologic alterations of the parcellated superior temporal gyrus in schizophrenia spectrum.

Morphologic abnormalities of the superior temporal gyrus (STG) as well as its sub-regions such as Heschl's gyrus (HG) or planum temporale (PT) have been reported in schizophrenia patients, but have not been extensively studied in schizotypal subjects. In the present study, magnetic resonance images were acquired from 65 schizophrenia patients, 39 schizotypal disorder patients, and 72 healthy controls. Volumetric analyses were performed using consecutive 1-mm coronal slices on the temporal pole (TP) and superior temporal sub-regions [planum polare (PP), HG, PT, rostral STG, and caudal STG]. The HG was significantly smaller in schizophrenia patients compared with controls but not in schizotypal patients, while volume reductions of the left PT and bilateral caudal STG were common to both disorders. The TP gray matter was larger in female schizotypal patients compared with female schizophrenia patients. There were no significant group differences in the PP and rostral STG volume. In the subgroup of early phase schizophrenia patients (illness duration <1.0 year), smaller volumes for the left PP and rostral STG were correlated with hallucinations and delusions. Our findings suggest that morphologic changes in the posterior regions of the STG are common to the schizophrenia spectrum, whereas less involvement of the HG, and possibly the PP and rostral STG might be related to the sparing of schizotypal patients from developing overt psychosis.

Adolescent↗
PubMed2006

A PTPN11 gene mutation (Y63C) causing Noonan syndrome is not associated with short stature in general population.

Human growth is a highly complicated process, but it is obviously influenced by a genetic factor. Recent genome-wide linkage analyses suggested some genetic regions underlying stature variations. However, any specific genes underlying stature variations have not been identified. Noonan syndrome (NS) is an autosomal dominant disorder clinically characterized by short stature, minor facial anomalies, and congenital heart defects. Recently, PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) has been identified as a major responsible gene for NS, causing about half of the affected individuals. We herein report a large family demonstrating NS caused by one of the common PTPN11 mutations, c.188 A > G (Y63C). In this family, the patients were apparently healthy, but heterozygosity of the c.188 A > G (Y63C) mutation was related to growth impairment. This finding suggested that PTPN11 genetic variants contribute to adult height in the general population. However, c.188 A > G (Y63C) was not identified in 96 short individuals from the general population of 2,281 healthy adults. Thus, it is unlikely that PTPN11 is one of the genes underlying stature variations in the general population.

Adult↗
PubMed2006

Serum uric acid as an obesity-related indicator in early adolescence.

In adults, serum uric acid levels are positively correlated with body mass index (BMI) and hyperuricemia is considered to be a common lifestyle disorder related with obesity. However, the relation of serum uric acid levels with obesity has not been elucidated in children and adolescents. Serum uric acid levels were determined in 1,729 healthy children, consisted of 923 boys and 806 girls, aged 9.1 - 15.0 years. The incidence of hyperuricemia (defined as more than 7.0 mg/dl) in boys and girls were 8.8% and 0.6%, respectively. In 1,281 children out of all subjects, including 684 boys and 597 girls, height, weight, aspartate aminotransferase, and alanine aminotransferase were also determined and the correlations between serum uric acid levels and obesity were analyzed. BMI is popularly used as a standard indicator of obesity in adults. However, BMI increases without fat accumulation as children grow. In Japan, percentage of overweight (POW) is usually used as an alternative indicator for obesity. In general, children are evaluated as obesity, when POW is equal to or more than 20% (>or= 20%). Serum uric acid levels are positively correlated with obesity-related indicators, BMI and POW, in both boys and girls. Serum uric acid levels of the subjects with high POW (>or= 20%) are significantly higher than those of the subjects with low POW (< 20%) in both boys and girls. These results suggest that serum uric acid levels are significantly increased with obesity and could be used as one of obesity-related indicators even in early adolescence.

Adolescent↗
PubMed2006

Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid.

Niemann-Pick disease type C (NPC) is an inherited lipid storage disorder, characterized by a defect in intracellular trafficking of exogenous cholesterol that leads to the lysosomal accumulation of unesterified cholesterol. We report a Japanese patient with NPC caused by a homozygous c.2974 G > T mutation of the NPC1 gene, which predicts a glycine (GGG) to tryptophan (TGG) change at codon 992 (designated as p.G992W). This is a well-known NPC1 gene mutation that causes a unique phenotype of NPC, which has been limited to a single Acadian ancestor in Nova Scotia, Canada. Our patient characteristically started presenting with cataplexy at the age of 9 years. Recent studies have shown reduced hypocretin-1 levels in the cerebrospinal fluid (CSF) of narcoleptic patients with cataplexy. In our patient, the level of hypocretin-1 was determined as moderately low, 174 pg/ml (normal, > 200 pg/ml). To date, CSF levels of hypocretin-1 have been determined by using an identical assay method in 7 cases of NPC, including our case. All of the NPC cases with cataplexy demonstrated low levels of CSF hypocretin-1, confirming the association of reduced CSF hypocretin-1 levels with cataplexy in NPC.

Carrier Proteins↗
PubMed2006

Split notochord syndrome: ileal duplication causing intermittent episodes of vomiting.

Split notochord syndrome is a group of developmental abnormalities caused by abnormal splitting or deviation of the notochord, clinically resulting in the duplicated bowel associated with vertebral anomalies. In this syndrome, initial presentations due to duplicated bowel, vomiting, abdominal pain, and failure to thrive, usually occur before 1 year of age. We here report a 12-year-old boy with intermittent vomiting, previously diagnosed with cyclic vomiting syndrome. On abdominal x-ray examination, a defect in the closure of posterior vertebral arches was observed in the 5th lumbar vertebral body, indicating the complication of spina bifida occulta. This finding suggested the diagnosis of split notochord syndrome. A magnetic resonance imaging study revealed a cystic mass lesion in the pelvic cavity. (99m)Tc-pertechnetate scintigraphy, which is frequently used to detect ectopic gastric mucosa for the diagnosis of Meckel's diverticulum, showed a positive spot corresponding to the cystic mass lesion. Surgical resection of the cystic mass lesion demonstrated ileal duplication with ectopic gastric mucosa. Surgical findings suggest that symptoms of the patient were due to ulceration, inflammation, or bleeding caused by acid-peptic juice secreted from ectopic gastric mucosa. Duplication of the alimentary tract should be considered as a possible cause in patients with symptoms suggesting cyclic vomiting syndrome.

Child↗
PubMed2006

Pulse methylprednisolone therapy in type 3 adenovirus pneumonia with hypercytokinemia.

Adenovirus pneumonia is uncommon but its severe infection has a mortality as high as 10%, and survivors may have residual airway damages, manifested by bronchiectasis, bronchiolitis obliterans, or pulmonary fibrosis. We report a case of adenovirus pneumonia demonstrating fatal respiratory distress. Adenovirus was isolated from pharyngeal specimens using cell culture and typed as serotype 3 by a combination of polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis. The patient characteristically showed hypercytokinemia, characterized by increased levels of lactate dehydrogenase, ferritin, and several cytokines including interferon-gamma and interleukin-6. We treated the patient with pulse methylprednisolne therapy (25 mg/kg/day, for 3 days), resulting in the rapid amelioration of respiratory distress. This is the first report describing the treatment of pulse methylprednisolone therapy in fatal adenovirus pneumonia. During the clinical course, serum Krebs von den Lungen-6 (KL-6), which is a marker for the activity of diffuse interstitial lung disease, was elevated, suggesting that serum KL-6 could be available as a marker of pulmonary prognosis in viral pneumonia.

Adenovirus Infections, Human↗
PubMed2006

Elastogenesis in cultured dermal fibroblasts from patients with lysosomal beta-galactosidase, protective protein/cathepsin A and neuraminidase-1 deficiencies.

The human GLB1 gene encodes a lysosomal beta-galactosidase (beta-Gal) and an elastin-binding protein (EBP). Defect of the EBP as a chaperon for tropoelastin and a component of receptor complex among neuraminidase-1 (NEU1) and protective protein/cathepsin A (PPCA) is suggested responsible for impaired elastogenesis in autosomal recessive beta-Gal, PPCA and NEU1 deficiencies. The purpose of this study is to determine effects of GLB1, PPCA and NEU1 gene mutations on elastogenesis in skin fibroblasts. Elastic fiber formation and the EBP mRNA expression were examined by immunofluorescence with an anti-tropoelastin antibody and RT-PCR selective for EBP in skin fibroblasts with these lysosomal enzyme deficiencies. Apparently normal elastogenesis and EBP mRNA expression were observed for fibroblasts from Morquio B disease cases with the GLB1 gene alleles (W273L/W273L, W273L/R482H and W273L/W509C substitutions, respectively), a galactosialidosis case with the PPCA allele (IVS7+3A/IVS7+3A) and a sialidosis case with the NEU1 allele (V217M/G243R) as well as normal subject. In this study, the W273L substitution in the EBP could impossibly cause the proposed defect of elastogenesis, and the typical PPCA splicing mutation and the V217M/G243R substitutions in the NEU1 might hardly have effects on elastic fiber formation in the dermal fibroblasts.

Base Sequence↗
PubMed2005

Prefrontal abnormalities in patients with simple schizophrenia: structural and functional brain-imaging studies in five cases.

Simple schizophrenia is an uncommon disorder with unknown pathophysiology, and its position in the current diagnostic system is ambiguous. Brain-imaging studies may help to elucidate its pathophysiology. Five patients fulfilling both ICD-10 criteria for simple schizophrenia and DSM-IV criteria for simple deteriorative disorder underwent computed tomography, magnetic resonance imaging, and single photon emission computed tomography. These scans were assessed individually by visual inspection as well as automatically by comparison with scans in normal controls or other schizophrenia subtype patients using voxel-based image analyses. Three of the five simple schizophrenia patients had findings of atrophy and reduced cerebral perfusion in the frontal areas. Voxel-based analyses also showed prefrontal grey matter deficits and hypoperfusion in simple schizophrenia patients compared with the controls. Although this study is limited by the small number of patients with simple schizophrenia, the results suggest that simple schizophrenia, or at least this subpopulation, may have rather homogeneous morphological and functional deficits in the prefrontal cortex. It is also suggested that simple schizophrenia may occupy an extreme position of the schizophrenic continuum where the prefrontal deficits and negative symptoms are most purely manifested.

Adult↗
PubMed2005

Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency.

Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder characterized by the lysosomal accumulation of free cholesterol in affected cells. Three novel mutations in the NPC1 gene (c.3615delA, c.2000C > T, and c.2240delT) were detected in two unrelated patients with the severe phenotype of NPC. The analyses showed that the c.2240delT mutation, which causes a premature stop at codon 748, resulted in nonsense-mediated decay of the mutant transcripts. Immunoblotting analyses for the NPC1 protein did not detect the mutant proteins in COS-1 cells transiently transfected with the two mutant NPC1 cDNA constructs (c.3615delA and c.2000C > T). In NPC cells, sphingomyelin accumulates with cholesterol, leading to an identical subcellular distribution of both lipids. Acid sphingomyelinase (ASM), which is responsible for the lysosomal hydrolysis of sphingomyelin, is partially reduced in NPC fibroblasts. Therefore, NPC fibroblasts were studied to determine if ASM activity was perturbed due to the accumulation of cholesterol. However, these studies demonstrated that the subcellular localization of ASM was preserved, suggesting that the high content of lysosomal cholesterol was not responsible for the decreased ASM activity.

Animals↗
PubMed2005

Volumetric analysis of sulci/gyri-defined in vivo frontal lobe regions in schizophrenia: Precentral gyrus, cingulate gyrus, and prefrontal region.

Methodological limitations in most previous magnetic resonance imaging (MRI)-based volumetric studies might have contributed to the inconsistent results regarding the frontal lobe regions of schizophrenia. Thus, applying the largest sample to date among those that have fully taken account of the intrinsic anatomical landmarks, this study aimed at clarifying the volumetric alterations of the frontal lobe and its subregions in schizophrenia. Participants comprised 59 patients with schizophrenia and 58 healthy controls. Measurements were performed on consecutive 1-mm-thick coronal slices reformatted from three-dimensional 1.5-T MR images. The whole frontal lobe was demarcated and then subdivided into the precentral gyrus (PCG), anterior cingulate, and posterior cingulate, and the remainder temporarily as the prefrontal region. Patients with schizophrenia had significant cortical volume reductions in the bilateral whole frontal lobe, prefrontal region, PCG, posterior cingulate, and right anterior cingulate. This study has confirmed that patients with schizophrenia do have cortical volume reductions in the whole frontal lobe and its subregions. Volume reduction in the PCG suggests that the primary motor cortex might contribute to the mechanisms of schizophrenia, considering its important role in the processing of multiple motor-related cognitive functioning suggested by the recent literature.

Adult↗
PubMed2005

Differential contributions of prefrontal and temporolimbic pathology to mechanisms of psychosis.

Common abnormalities within the schizophrenia spectrum may be essential for the pathogenesis of schizophrenia, but additional pathological changes may be required for the development of full-blown schizophrenia. Clarifying the neurobiological similarities and differences between established schizophrenia and a milder form of schizophrenia spectrum disorder would potentially discriminate the pathophysiological mechanisms underlying the core features of the schizophrenia spectrum from those associated with overt psychosis. High-resolution MRIs were acquired from 25 patients with schizotypal disorder, 53 patients with schizophrenia and 59 healthy volunteers matched for age, gender, handedness and parental education. Volumetric measurements of the medial temporal structures and the prefrontal cortex subcomponents were performed using consecutive 1-mm thick coronal slices. Parcellation of the prefrontal cortex into subcomponents was performed according to the intrinsic anatomical landmarks of the frontal sulci/gyri. Compared with the controls, the bilateral volumes of the amygdala and the hippocampus were reduced comparably in the schizotypal and schizophrenia patients. The parahippocampal gyrus volume did not differ significantly between diagnostic groups. Total prefrontal grey matter volumes were smaller bilaterally in the schizophrenia patients than in the controls and the schizotypal patients, whereas the schizotypal patients had larger prefrontal grey matter than the controls in the right hemisphere. In the schizophrenia patients, grey matter volumes of the bilateral superior frontal gyrus, left middle frontal gyrus, bilateral inferior frontal gyrus and bilateral straight gyrus were smaller than those in the controls. The schizophrenia patients also had reduced grey matter volumes in the right superior frontal gyrus, bilateral middle frontal gyrus and right inferior frontal gyrus relative to the schizotypal patients. Compared with the controls, the schizotypal patients had larger volumes of the bilateral middle frontal gyrus and smaller volumes of the right straight gyrus. There were no significant between-group differences in volumes of the ventral medial prefrontal cortex or the orbitofrontal cortex. These findings suggest that volume reductions in the amygdala and hippocampus are the common morphological substrates for the schizophrenia spectrum, which presumably represent the vulnerability. Additional widespread involvement of the prefrontal cortex in schizophrenia may lead to the loss of inhibitory control in other brain regions and suggests (although it is not specifically be related to) its critical role in the manifestation of overt psychosis.

Adult↗