A novel missense point mutation (S134N) of the Cu/Zn superoxide dismutase gene in a patient with familial motor neuron disease.
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Aged↗
Biomedical subjects
S Hirai
Publications and source records attributed to S Hirai.
Development of an intravascular pumping oxygenator using a new silicone membrane.
A new intravascular pumping oxygenator (IVPO) was developed for intravascular gas exchange and circulatory assistance in critically ill patients with respiratory and circulatory failure. The IVPO utilizes new silicone hollow fibers (diameter, 1 mm; membrane width, 50 microns) and consists of two driving tubes for the oxygenation and pumping of circulating blood. The performance characteristics of the IVPO were studied using an experiment ex vivo model. With a mean hemoglobin concentration of 10.5 +/- 2.3 g/dl, total oxygen transfer was 5.6 +/- 1.5 ml/min at a blood flow of 200 ml/min and 6.3 +/- 2.2 ml/min at a blood flow of 250 ml/min. Total CO2 transfer was 3.8 +/- 1.4 ml/min at a blood flow of 200 ml/min and 4.2 +/- 1.6 ml/min at a blood flow of 250 ml/min. Blood flow increased to a maximum of 250 ml/min during IVPO pumping. This preliminary experiment demonstrated that the IVPO has the capacity to function both as circulatory assist pump and as an intravascular hollow fiber oxygenator.
Animals↗
[Cerebral perfusion and oxygen metabolism in Parkinson's disease: positron emission tomographic study using oxygen-15-labeled CO2 and O2].
In many previous studies, positron emission tomography (PET) has been used to evaluate cerebral perfusion and oxygen metabolism in Parkinson's disease. In this article, these previous reports are reviewed together with our recent findings. Hypoperfusion and hypometabolism in parkinsonian brains reported previously seemed to be derived chiefly from psychiatric manifestations, including intellectual decline and depression. In our study on 34 patients with asymmetric symptoms, the blood flow and oxygen metabolism were significantly higher in the caudate head and putamen, contralateral to the predominant patient's symptoms, than in the opposite nuclei. The asymmetry in the perfusion and metabolism is clearer in the early stage of the disease or in patients without DOPA therapy. These findings suggest that the striatal dysfunction is caused by uninhibited activities, supersensitivities, or compensatory hyperactivities of the striatum.
Brain↗
The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1.
SPRK (also called PTK-1 and MLK-3), a member of the mixed lineage kinase subfamily of (Ser/Thr) protein kinases, encodes an amino-terminal SH3 domain followed by a kinase catalytic domain, two leucine zippers interrupted by a short spacer, a Rac/Cdc42 binding domain, and a long carboxyl-terminal proline-rich region. We report herein that SPRK activates the stress-activated protein kinases (SAPKs) but not ERK-1 during transient expression in COS cells; the p38 kinase is activated modestly (1.3-2 fold) but consistently. SPRK also activates cotransfected SEK-1/MKK-4, a dual specificity kinase which phosphorylates and activates SAPK. Reciprocally, expression of mutant, inactive SEK-1 inhibits completely the basal and SPRK-activated SAPK activity. Immunoprecipitated recombinant SPRK is able to phosphorylate and activate recombinant SEK-1 in vitro to an extent comparable to that achieved by MEK kinase-1. These results identify SPRK as a candidate upstream activator of the stress-activated protein kinases, acting through the phosphorylation and activation of SEK-1.
Amino Acid Sequence↗
MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappaB activation and degradation of IkappaB-alpha.
Signal-dependent activation of the transcription factor NF-kappaB is dominantly regulated by degradation of IkappaB-alpha protein. However, the signaling pathways that lead to the degradation are not clear. Here we report that mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) kinase, an activator of stress-activated protein kinases/jun kinase-1 (SAPKs/JNK1), is involved in such signaling pathways. The transient overexpression of MEK kinase in NIH3T3 fibroblasts activates kappaB-CAT reporter expression in a synergistic manner with TNFalpha stimulation. In contrast, overexpression of kinase-negative MEK kinase suppresses TNFalpha-induced reporter expression. The overexpression of MEK kinase suppresses the inhibitory activity of co-transfected IkappaB-alpha on the kappaB-CAT or human immunodeficiency virus-long terminal repeat-luciferase reporter expression and causes the simultaneous disappearance of the overexpressed IkappaB-alpha. The disappearance of exogenous IkappaB-alpha by the overexpression of MEK kinase is prevented by calpain inhibitor-I, an inhibitor of IkappaB-alpha degradation. These results suggest that MEK kinase is a signal mediator involved in TNFalpha-induced NF-kappaB activation and that the activation of NF-kappaB by MEK kinase is regulated through the degradation of IkappaB-alpha.
3T3 Cells↗
Differential effects of overexpression of PKC alpha and PKC delta/epsilon on cellular E2F activity in late G1 phase.
Introduction of a reporter gene containing E2F binding sites linked to the luciferase gene permitted us to detect transient cellular E2F activity in late G1 phase rat 3Y1 fibroblasts. Overexpression of three major protein kinase C (PKC) isozymes expressed in 3Y1 cells caused differing effects on E2F activity depending on the isozymes overexpressed. Overexpression of PKC alpha inhibited E2F activity while the overexpression of PKC delta or PKC epsilon enhanced it, suggesting that these PKC isozymes play different roles in the regulation of E2F activity. Consistent with previous findings that the activation of PKC by TPA in late G1 phase results in the inhibition of DNA synthesis (Huang, C., and Ives, H.E., 1987, Nature 329, 849-850), the addition of TPA in late G1 phase specifically inhibited E2F activity. Overexpression of PKC isozymes resulted in an enhancement of the TPA-induced inhibition of E2F in late G1 phase. This enhancement was observed for all three PKC isozymes examined, suggesting that these PKC isozymes all are potent mediators of the TPA-induced inhibition of E2F activity in late G1 phase.
Animals↗
Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK.
JNK/SAPKs are identified as new members of the MAPK family; they phosphorylate c-Jun protein in response to several cellular stimuli including ultraviolet irradiation, TNF and osmotic shock. We have identified a protein kinase, MUK, as an activator of the JNK-pathway, whose kinase domain shows significant homology to MAPKKK-related proteins such as c-Raf and MEKK. The over-expression of MUK or MEK kinase (MEKK) in NIH3T3 or COS1 cells results in the activation of JNK1 and the accumulation of a hyper-phosphorylated form of c-Jun. While MEKK also activates the ERK pathway, MUK is a rather selective activator of the JNK pathway. On the other hand, c-Raf activates the JNK pathway only slightly despite its remarkable ability to activate the ERK pathway. Even though we originally identified MUK as a MAPKKK-related protein kinase, a greater similarity to mixed lineage kinase (MLK) is found not only in the catalytic domain but also in the 'leucine-zipper'-like motifs located at the C-terminal side of the catalytic domain. The structural divergence between MUK and MEKK reveals the multiplicity of signaling pathways that activate JNK/SAPKs.
3T3 Cells↗
Platelet-derived growth factor activates protein kinase C epsilon through redundant and independent signaling pathways involving phospholipase C gamma or phosphatidylinositol 3-kinase.
Protein kinase C (PKC), a major cellular receptor for tumor-promoting phorbol esters and diacylglycerols (DGs), appears to be involved in a variety of cellular functions, although its activation mechanism in vivo is not yet fully understood. To evaluate the signaling pathways involved in the activation of PKC epsilon upon stimulation by platelet-derived growth factor (PDGF) receptor (PDGFR), we used a series of PDGFR "add-back" mutants. Activation of a PDGFR mutant (Y40/51) that binds and activates phosphatidylinositol 3-kinase (PI 3-kinase) caused translocation of PKC epsilon from the cytosol to the membrane in response to PDGF. A PDGFR mutant (Y1021) that binds and activates phospholipase C gamma (PLC gamma), but not PI 3-kinase, also caused the PDGF-dependent translocation of PKC epsilon. The translocation of PKC epsilon upon stimulation of PDGFR (Y40/51) was inhibited by wortmannin, an inhibitor of PI 3-kinase. Activation of PKC epsilon was further confirmed in terms of PKC epsilon-dependent expression of a phorbol 12-tetradecanoate 13-acetate response element (TRE)-luciferase reporter. Further, purified PKC epsilon was activated in vitro by either DG or synthetic phosphatidylinositol 3,4,5-trisphosphate. These results clearly demonstrate that PKC epsilon is activated through redundant and independent signaling pathways which most likely involve PLC gamma or PI 3-kinase in vivo and that PKC epsilon is one of the downstream mediators of PI 3-kinase whose downstream targets remain to be identified.
Cell Compartmentation↗
Intracellular generation of amyloid beta-protein from amyloid beta-protein precursor fragment by direct cleavage with beta- and gamma-secretase.
Two amyloid beta protein precursor (beta APP) fragments involving Met and 103 amino acids of C-terminus of beta APP (delta NOR-beta) and its KM-NL substitution (delta NL-beta) were expressed in COS-7 cells to clarify the proteolytic cleavages to generate amyloid beta protein (A beta). The 4.5-kD protein, A beta with additional N-terminal amino acids, and 4-kD A beta were directly produced and released from 12.5-kD expression proteins without any production of 11.4-kD C-terminal fragment starting at N-terminus of A beta and 3-kD "p3" A beta derivative. Intracellular 4-kD A beta was also detected. The substitution of KM-NL of beta APP found in Swedish familial Alzheimer's disease (AD) promoted the production of intracellular A beta and its release with no increase in level of 11.4-kD C-terminal fragment. These results suggested the presence of a distinct pathway in which A beta is directly cleaved at both N- and C-termini from beta APP fragment intracellularly to release A beta. Since KM-NL substitution enhanced intracellular A beta generation, this pathway may be associated with amyloidogenesis in AD.
Alzheimer Disease↗
Disappearance of actin-binding protein, drebrin, from hippocampal synapses in Alzheimer's disease.
The actin-binding protein drebrin is localized in postsynaptic terminals in adult brain and is considered to be related to synaptic plasticity. Immunocytochemical study demonstrated that widespread drebrin immunoreactivity was observed in hippocampal formations of control human brains, while Alzheimer's disease (AD) brains showed remarkable reductions in this immunoreactivity. Western blot analysis demonstrated that drebrin E (116kD) as well as drebrin A (125 kD) presented in adult human brains, and that these isoforms were decreased in parallel in AD brains. On the other hand, synaptic vesicle-specific 38-kD protein (SVP-38), a presynaptic marker was not so changed in AD brains in comparison with control brains by both techniques. These findings suggest that drebrin E and A in the adult human brain may be co-localized in postsynaptic terminals, and that drebrin may be more sensitive as a marker of synaptic damage than SVP-38, and that the disappearance of drebrin may contribute to the pathogenesis of memory disturbance in AD.
Aged↗
Extensive leukemic cell infiltration into skeletal muscles.
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Humans↗
The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients.
We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.
Adult↗
Improvement of glucose tolerance with immunomodulators on type 2 diabetic animals.
Cytokine-inducers prevent insulin-dependent diabetes mellitus (IDDM) in animal models. We extend this therapy to non-insulin-dependent diabetes mellitus (NIDDM), because it was reported that diabetes of KK-Ay mice, a model for NIDDM, was recovered by allogenic bone-marrow transplantation that also prevented IDDM in animal models. An i.p. or i.v. injection of streptococcal preparation (OK-432) lowered fasting blood glucose (FBG) levels and markedly improved glucose tolerance test (GTT) in KK-Ay mice for more than 32 h regardless of the glucose loading routes (oral, i.v. or i.p.), while an i.v. injection of BCG improved FBG and GTT for more than 4 wks without body weight loss. The improvement of FBG and GTT with OK-432 was brought about in other NIDDM animals, GK rats and Wistar fatty rats. Among various cytokines possibly induced by OK-432 and BCG, IL-1 alpha, TNF alpha and lymphotoxin significantly improved FBG and GTT in KK-Ay mice, whereas IL-2 and IFN gamma did not. There were no differences between the OK-432-treated KK-Ay mice and control in histology of the pancreas, degree of insulin-induced decrease in blood glucose levels, and muscle glycogen synthase activities. As to insulin secretion, there is a tendency that the OK-432-treatment less that 1 week did not affect insulin levels during GTT, whereas the treatment more than 2 weeks increased the insulin levels. Thus, cytokine-inducers improved FBG and glucose tolerance of NIDDM animals probably via cytokines. The results imply a role of the cytokines in glucose tolerance of NIDDM, although precise immune and metabolic mechanisms remain to be elucidated.
Adjuvants, Immunologic↗
Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease.
There are currently some types of autosomal dominant cerebellar ataxias such as Machado-Joseph disease (MJD), spinocerebellar ataxia types 1-5 (SCA1-5), or hereditary dentatorubropallidoluysian atrophy. It is very important for these ataxias to be clinically differentiated, but that is sometimes difficult. In particular, the differential diagnosis between MJD and SCA1 is thought to be the most difficult. Recently, both MJD and SCA1 have been proven to be related to expansions of CAG trinucleotide in their causative genes. In this study, 20 cases of MJD in 13 unrelated Japanese families were genetically and clinically examined in comparison with 20 cases of age at onset- and duration-matched Japanese SCA1. The CAG repeat number of expanded MJD and SCA1 alleles was 72.2 +/- 3.1 (mean +/- SD, n = 20) and 47.3 +/- 4.4 (n = 20), respectively, and each repeat size was inversely correlated with age at onset in both MJD and SCA1. The repeat number in leukocytes increased from parents to children with acceleration of age at onset (anticipation) in MJD. In MJD, the number of CAG repeats in the expanded allele was lower in sperm than that of leukocytes, but was more in SCA1. However, the number of peaks in the expanded allele was greater in sperm than in leukocytes in both MJD and SCA1 (increased mosaicism level). MJD was clinically characterized by a relatively higher frequency of ocular signs such as eyelid retraction, bulging eyes, ophthalmoparesis, and nystagmus, spasticity in lower limbs, and sensory and urinary disturbances in contrast to the SCA1 patients except for slow eye movement. These results indicate that the expanded CAG repeat and clinical features are correlated in both MJD and SCA1, and MJD can be differentiated from SCA1 by clinical characteristics mentioned above as well as DNA analysis.
Adolescent↗
Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations.
We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with 4 different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine46 by arginine (H46R), leucine84 by valine (L84V), isoleucine104 by phenylalanine (I104F), and valine148 by isoleucine (V148I), in 5 Japanese families. Although features of progressive neurogenic muscular atrophy were common in patients of these families, patients of each family showed characteristic clinical features. FALS patients with the H46R mutation showed a benign clinical course and stereotype progression of muscular weakness and atrophy beginning from the legs. In FALS with the L84V mutation, while the clinical course of the disease was similar, the age at onset was younger in men than women. The patients with I104F showed wide ranges of age at onset and duration with ophthalmoparesis and sensory involvement in one patient. Those with the V148I mutation showed younger age at onset and variable first symptoms within the family. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and the Babinski sign was not observed in any case. Bulbar palsy was frequent with I104F, but not with H46R. SOD activity of the red blood cells was severely reduced with I104F and V148I, but was slightly reduced with H46R. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene each showed clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.
Adolescent↗
Effect of manidipine and delapril on insulin sensitivity in type 2 diabetic patients with essential hypertension.
The open trial was designed to evaluate the effects of long-term antihypertensive treatment with the calcium-channel blocker, manidipine and the angiotensin converting enzyme (ACE) inhibitor, delapril on insulin sensitivity in Japanese non-insulin dependent diabetes mellitus (NIDDM) patients with essential hypertension. We measured the insulin sensitivity index (SI) and the glucose-effectiveness (SG) by the use of Bergman's minimal model method in 18 hypertensive NIDDM patients before and after administration of manidipine (group A) or delapril (group B) for 3 months. Manidipine treatment for 3 months significantly improved SI in group A from 3.35 +/- 0.61 (x 10(-4) min-1 microU-1 ml-1) to 4.70 +/- 1.34 (P < 0.05). Delapril treatment for 3 months also significantly improved SI in group B from 3.56 +/- 1.04 to 5.00 +/- 0.87 (P < 0.05). Manidipine significantly improved SG in group A from 1.60 +/- 0.64 (x 10(-2) min) to 2.19 +/- 0.38 (P < 0.05). Delapril treatment also significantly improved SG in the group B from 1.41 +/- 0.56 to 1.91 +/- 0.35 (P < 0.05). Manidipine and delapril did not affect urinary C-peptide excretion for 24 h in the hypertensive NIDDM patients. Treatment with manidipine or delapril significantly reduced systolic and diastolic blood pressures in the hypertensive NIDDM patients. There were no differences between plasma glucose, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions, heart rate and body weight after 3 months on manidipine or delapril. This study confirmed the improving effects on SI and SG by long-term treatment with manidipine or delapril in the hypertensive NIDDM patients.
Antihypertensive Agents↗
Sjögren's syndrome associated with thymoma.
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Adult↗
Multiple gastric involvement by myeloid antigen CD13-positive non-secretory plasma cell leukaemia.
Gastrointestinal tract involvement is a rare complication of plasma cell neoplasia. We present a case of non-secretory type primary plasma cell leukaemia (PCL) with multiple gastric involvement. Dual surface antigen analysis of bone marrow cells revealed that atypical plasma cells coexpressed CD38 and myeloid antigen CD13. Upper gastrointestinal endoscopy disclosed multiple submucosal masses in the body of the stomach. Endoscopic biopsy specimens showed marked infiltration of atypical plasma cells consistent with a diagnosis of gastric involvement by PCL. Since CD13 antigen is identical to aminopeptidase N, a membrane-bound glycoprotein thought to be involved in the process of tumour invasion, CD13 expression on neoplastic plasma cells may be related to the gastric involvement in this patient.
ADP-ribosyl Cyclase↗