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Biomedical subjects

A Kakita

Publications and source records attributed to A Kakita.

At least 19 recordsLinked to original sources
PubMed2005

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex.

Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Beta-synuclein gene alterations in dementia with Lewy bodies.

OBJECTIVE: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD). METHODS: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. RESULTS: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. CONCLUSION: Mutations in the beta-synuclein gene may predispose to DLB.

Aged↗
PubMed2003

Stimulatory effect of prostaglandin F(2alpha) on Na-dependent phosphate transport in osteoblast-like cells.

Prostaglandin F(2alpha) (PGF(2alpha)) has been reported to activate protein kinase C (PKC) through both phospholipase (PL) C and D, resulting in the proliferation of osteoblast-like cells. In addition, it has also been reported that Erk mitogen-activated protein kinase is also involved in the mechanism of PGF(2alpha)-induced proliferation of these cells. Recently, we have reported that several growth factors stimulate Na-dependent phosphate transport (Pi transport) activity of osteoblast-like cells, which has been recognized to play an important role in their mineralization. In the present study, we investigated the effect of PGF(2alpha) on Pi transport in MC3T3-E1 osteoblast-like cells. PGF(2alpha) stimulated Na-dependent Pi transport dose dependently in the range between 1nM and 10 micro M in MC3T3-E1 cells. The effect was time dependent up to 24h. Kinetic analysis revealed that PGF(2alpha) induces newly synthesized Pi transporter. Pretreatment with actinomycin D and cycloheximide suppressed PGF(2alpha)-induced enhancement of Pi transport. Combined effect of PMA and PGF(2alpha) was not additive in Pi transport. Calphostin C, a PKC inhibitor, dose-dependently suppressed Pi transport induced by PGF(2alpha). On the contrary, U0126, which inhibits an upstream kinase of Erk (MEK), did not affect PGF(2alpha)-induced enhancement of Pi transport. In conclusion, PGF(2alpha) stimulates Pi transport through activation of PKC in osteoblast-like cells.

3T3 Cells↗
PubMed2003

Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development.

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood.

Animals↗
PubMed2002

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients.

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.

Adult↗
PubMed2001

A quantitative study on the expression of synapsin II and N-ethylmaleimide-sensitive fusion protein in schizophrenic patients.

The application of DNA array technology to schizophrenic studies enabled us to assess molecular features of this disease. The expression of synapsin II and N-ethylmaleimide-sensitive fusion protein (NSF) mRNAs is reported to decrease in the prefrontal cortex of these patients. We attempted to reproduce this result with two distinct approaches. With high quality samples, mRNA and protein levels for synapsin II and NSF were measured by real-time polymerase chain reaction and by immunoblotting. Both experiments led to the same conclusion: The expression of these presynaptic markers is not altered significantly in the prefrontal cortex of our schizophrenic samples, compared to that in control subjects. These observations suggest that the neurochemical impairments of synapses reported in schizophrenia are not evident for all presynaptic markers and needs to be re-evaluated at molecular levels.

Adult↗
PubMed2001

Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains.

Tau in Alzheimer neurofibrillary tangles has been shown to be hyperphosphorylated and CDK5, GSK3, MAP kinase and SAP kinases are the candidate kinases for the phosphorylation of tau. Recently, it was reported that the conversion of p35, the activator of CDK5, to p25 was upregulated in Alzheimer's disease (AD) brains, and that p35 is cleaved to yield p25 by calpain. Here we show that p35 is rapidly cleaved to p25 in rat and human brains within a short postmortem delay and that the conversion of p35 to p25 is partially dependent on calpain activity. Immunoblot analysis of brains prepared from patients with AD or age-matched control individuals with a short postmortem delay revealed no specific increase in the levels of p25 in AD brains, whereas the levels of active form of calpain were increased in AD brains compared to the those in controls. These observations suggest that the conversion of p35 to p25 is a postmortem degradation event and may not be upregulated in AD brains.

Aged↗
PubMed2001

Collective inhibition of pRB family proteins by phosphorylation in cells with p16INK4a loss or cyclin E overexpression.

The activity of the retinoblastoma protein pRB is regulated by phosphorylation that is mediated by G(1) cyclin-associated cyclin-dependent kinases (CDKs). Since the pRB-related pocket proteins p107 and p130 share general structures and biological functions with pRB, their activity is also considered to be regulated by phosphorylation. In this work, we generated phosphorylation-resistant p107 and p130 molecules by replacing potential cyclin-CDK phosphorylation sites with non-phosphorylatable alanine residues. These phosphorylation-resistant mutants retained the ability to bind E2F and cyclin. Upon introduction into p16(INK4a)-deficient U2-OS osteosarcoma cells, in which cyclin D-CDK4/6 is dysregulated, the phosphorylation-resistant mutants, but not wild-type p107 or p130, were capable of inhibiting cell proliferation. Furthermore, when ectopically expressed in pRB-deficient SAOS-2 osteosarcoma cells, the wild-type as well as the phosphorylation-resistant pRB family proteins were capable of inducing large flat cells. The flat cell-inducing activity of the wild-type proteins, but not that of the phosphorylation-resistant mutants, was abolished by coexpressing cyclin E. Our results indicate that the elevated cyclin D- or cyclin E-associated kinase leads to systemic inactivation of the pRB family proteins and suggest that dysregulation of the pRB kinase provokes an aberrant cell cycle in a broader range of cell types than those induced by genetic inactivation of the RB gene.

Cyclin E↗
PubMed2001

Expression of calbindin D-28k and parvalbumin in cerebral cortical dysgenesis induced by administration of ethylnitrosourea to rats at the stage of neurogenesis.

It has been reported that transplacental administration of ethylnitrosourea (ENU), which is cytotoxic immediately after administration, to rat fetuses at the neurogenesis stage induces dysgenesis of the cerebral cortex, characterized by neuronal sparseness and architectural irregularity. In the present study, we examined the topographic distribution of neurons containing 5-bromo-2-deoxyuridine (BrdU), and those containing calbindin D-28k (CaBP) and parvalbumin (PV), most of latter two are considered to be interneurons located in particular layers of the normal cerebral cortex in rats with experimentally induced cerebral cortical dysgenesis. Pregnant Wistar albino rats were given a single transplacental administration of ENU on embryonic day 16, followed 4, 8, 16, 24, 36, or 48 h later by a single intraperitoneal injection of BrdU. The pups were killed 10 weeks after birth. In the normal cerebral cortex, BrdU-immunopositive neurons showed an inside-out pattern according to the time of BrdU injection, whereas in ENU-treated rats the topographic localization of the BrdU-immunopositive neurons was irregular and the inside-out pattern was disrupted. Although the number of CaBP- and PV-immunopositive neurons was lower in ENU-treated animals, no topographic difference was evident between the normal and the dysgenetic cerebral cortices. These findings indicate that the expression of CaBP and PV in the neurons of the rat cerebral cortex is extrinsic, and depends on the position of the neurons rather than on the time of their formation or on genetic control. This suggests the existence of re-regulation of the expression of CaBP and PV in the developing brain, which may be one of the effective mechanisms by which the cerebral cortex can maintain its normal function in spite of cytoarchitectural abnormality.

Abnormalities, Drug-Induced↗
PubMed2001

Aprosencephaly: histopathological features of the rudimentary forebrain and retina.

Aprosencephaly/atelencephaly is an extremely rare central nervous system defect of the human fetus, which has been attributed to an encephaloclastic process. We report here the histopathological features of the rudimentary forebrain and retina of a case of aprosencephaly in a male fetus that was examined at 20 weeks of gestation, in which there was no evidence of destruction. The prosencephalon was excessively small and replaced by a solid, cylindrical mass without a hemispheric cleavage or a ventricle. Histologically, the rudimentary forebrain tissue consisted of primitive cells that had accumulated in the anterior portion, and of differentiated neurons and glia that were distributed in a random-manner in the posterior portion. The most rostral portion of the tissue penetrated the sphenoidal bone through a single canal: an extracranial ectopic nest consisted of primitive cells that were located at the posterior portion of the face. There were no eyelid openings, eyeballs, or optic nerves, although a nest of dysplastic retinal rosettes and two nests of melanin-pigmented epithelium were identified. This case seems to represent a primary malformation, and the features imply that the failure occurs after neurulation and before the prosencephalic medium began its growth.

Abnormalities, Multiple↗
PubMed2001

History of pancreaticojejunostomy in pancreaticoduodenectomy: development of a more reliable anastomosis technique.

The history of pancreaticojejunostomy in pancreaticoduodenectomy is described. Many types of operations have been devised in search of a more reliable method of anastomosis. To perform a safe and reliable pancreaticoenteric anastomosis it is necessary to understand the organ characteristics of the pancreas. We investigated factors required for a reliable pancreaticojejunostomy and devised a new surgical technique that meets those requirements. We introduce the theoretical substantiation and clinical usefulness of our new surgical technique while reviewing the history of pancreaticojejunostomy after pancreaticoduodenectomy. The unique aspect of our method is approximation of the pancreas stump and jejunal wall by six to eight interrupted sutures. It is speculated that too many sutures and tying too tight in the anastomosis may cause ischemia and necrosis of the pancreatic stump by restricting the tissue blood flow. Our method allows us not only to reduce the number of sutures, but also to avoid some of the complicated manipulations done in any other existing methods. The newly devised pancreaticojejunostomy is an excellent surgical technique with anastomotic failure seen in only two patients and no deaths out of 162 consecutive patients.

Adenocarcinoma↗
PubMed2001

Alpha-Fetoprotein-producing esophageal adenocarcinoma: report of a case.

Alpha-fetoprotein (AFP)-producing esophageal tumors are extremely rare. We report herein the case of a 51-year-old man found to have an AFP-producing adenocarcinoma arising from esophageal proper mucosa. The patient presented for investigation of dysphagia, and esophagogram and endoscopy revealed a lesion about 2 cm in size with a depressed center surrounded by low nodular protrusions in the lower esophagus. The preoperative serum AFP concentration was elevated to 52.4 ng/ml. A subtotal esophagectomy was performed, and macroscopic examination of the resected specimen revealed a superficial protruding lesion. Histopathological studies showed a poorly differentiated adenocarcinoma with a single lymph node metastasis. The tumor had infiltrated the submucosal layer, but there was no evidence of lymphatic or venous invasion. Immunohistochemical study revealed tumor cells positive for AFP. There were no findings of Barrett's epithelium or any mucosal changes due to reflux esophagitis. An elevated AFP level 2 years after the operation led us to suspect tumor recurrence; however, diagnostic imaging studies showed no evidence of a recurrence or metastases. The serum AFP levels responded well to chemotherapy with transient decreased levels, but continued to rise until finally, 5 years after the operation, adenocarcinoma cells were detected in the pleural effusion. Thus, careful monitoring of the serum AFP levels at regular intervals could be a useful marker to indicate recurrence of esophageal carcinoma.

Adenocarcinoma↗
PubMed2001

Cause of death in renal transplant patients: a comparison between azathioprine and ciclosporin.

The results of renal transplantation have improved due to advances in immunosuppression techniques of preservation, and pre- and postoperative treatments; however, both morbidity and mortality remain serious problems. To decrease the morbidity and mortality rates we analyzed the causes of death after renal transplantation in our hospital. Between 1972 and 1999, we performed 364 renal transplantations, 257 of which were living-related and 107, cadaveric. There were 178 patients given azathioprine and 186 given ciclosporin. The survival rate of the patients on ciclosporin therapy was much better than that of those on azathioprine therapy. Of the total 364 renal transplant patients, 59 (16.2%) died, and 28 (47.5%) of these 59 deaths occurred within 1 year after renal transplantation. The causes of death were infection in 19 (32.2%) patients, gastrointestinal diseases in 16 (27.1%), cardiovascular diseases in 11 (18.6%), cerebrovascular diseases in 6 (10.2%), suicide in 3 (5.1%), and other causes in 4 (6.8%). These findings reinforce that early diagnosis and treatment are essential to decrease the morbidity and mortality rates assoiated with renal transplantation.

Azathioprine↗
PubMed2001

Migration of steel-wire coils into the stomach after transcatheter arterial embolization for a bleeding splenic artery pseudoaneurysm: report of a case.

Transcatheter arterial embolization (TAE) represents the primary, and often definitive, mode of therapy for bleeding splanchnic artery pseudoaneurysms (PSA). Nevertheless, a number of complications associated with this procedure have been described. We report herein the case of a 59-year-old man with chronic pancreatitis who was referred to us with hematemesis and hemorrhagic shock. Computed tomography revealed a splenic artery PSA bleeding into a pancreatic pseudocyst, and TAE was performed using steel-wire coils, placed inside the aneurysmal cavity, which resulted in the immediate cessation of bleeding. However, several weeks later some of the coils were found to have dislodged through a gastropseudocystic fistula. Furthermore, an early gastric cancer was incidentally found proximal to the fistula. We finally performed open surgery to treat both disorders; primarily for the gastric cancer, but also for the pseudocyst and fistula, with the intermittent discharge of the steel-wire coils. To our knowledge, migration into the stomach of steel-wire coils after TAE has not been described before. It is generally believed that the embolization procedure should occlude normal portions of the artery both distal and proximal to the PSA with embolization materials. By occluding the PSA in this way, the subsequent migration of steel-wire coils into the pseudocyst and stomach might have been prevented in our patient.

Aneurysm, False↗