Search PubMed⌕ Search

Biomedical subjects

M Park

Publications and source records attributed to M Park.

At least 109 records · Page 6Linked to original sources
PubMed1998

Ultrasound biomicroscopic findings in a case of cyclodialysis.

Ultrasound biomicroscopy (UBM) with a high frequency can be used to evaluate the structure of the anterior eye segment in vivo. A 24-year-old male was referred to us after 1 month of follow-up by a local ophthalmologist, because of decreased visual acuity and hypotony after a blunt eye injury. A cyclodialysis cleft in the 2- to 4-o'clock position and a cavernous pattern all over the choroid were found using UBM. The patient underwent surgical treatment to close the cleft. Even after the recovery of intraocular pressure (IOP), the peripheral ciliary body around 360 degrees was still separated from the sclera when examined by UBM. Despite the detached ciliary body, keeping IOP within normal levels is an interesting finding. UBM is helpful in the diagnosis and treatment of traumatic cyclodialysis.

Adult↗
PubMed1998

Clinical and neurocognitive effects of clozapine and risperidone in treatment-refractory schizophrenic patients: a prospective study.

BACKGROUND: Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients. The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospective 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals. METHOD: Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone. Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, neurologic rating scales, and plasma drug levels. Neurocognitive tests were administered at baseline and week 12. RESULTS: Both clozapine and risperidone brought about significant (p < .003) overall improvement in psychopathology. However, clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive, negative, excitement, and cognitive factors. Extrapyramidal side effects were minimal for clozapine, whereas some were present for risperidone. Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter. Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial. Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups. CONCLUSION: Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures. While the efficacy of clozapine was only numerically superior to that of risperidone, it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period, suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients.

Adult↗
PubMed1998

Salivary gland nucleotide receptors: evidence for functional expression of both P2X and P2Y subtypes.

A growing body of information now supports the suggestion that P2 receptors for extracellular nucleotides (primarily ATP) have a role in regulating salivary gland function. There is solid pharmacological and molecular evidence for the presence of P2X ligand-gated ion channel nucleotide receptors (P2X4 and P2X7/P2Z). More recently, our group and others have obtained evidence that multiple P2Y G protein-coupled nucleotide receptors (P2Y1 and P2Y2) are also expressed. Our studies have focused on defining the conditions under which P2Y receptors are expressed, the functional consequences of their activation, and the importance of co-expression of P2X and P2Y receptors. Functional and molecular approaches have been used to identify the P2 subtypes in salivary glands and in salivary cell lines. Assays include measurement of changes in [Ca2+]i, changes in transcellular short circuit current in monolayers, and RT-PCR to assess changes in receptor mRNA levels. The main observations are: (1) P2Y1 receptor activity is present in the submandibular gland (SMG) of immature rats but decreases over the first four weeks following birth, although mRNA levels remain relatively constant; (2) P2Y2 receptors are present in the cell lines and are up-regulated during short-term culture of normal parotid, sublingual, and SMG cells and following ligation of the main excretory duct of SMG; and (3) the P2X subtypes, P2X4 and P2X7, and the P2Y subtypes, P2Y1 and P2Y2, are co-expressed in salivary glands and salivary cell lines, and exhibit distinct basolateral versus apical localization in polarized cell monolayers as well as discrete patterns of intracellular signaling.

Animals↗
PubMed1998

The effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-amino-N-methylsuccinimides.

In connection with the development of new anticonvulsant agents with a broad spectrum, we found that N-Cbz-alpha-amino-N-alkylsuccinimides showed significant anticonvulsant activities, and the pharmacological activities of these compounds were dependent on their stereochemistry and N-substituted alkyl group. These results prompted us to define the effects of other functional group on the anticonvulsant activities of these compounds. Therefore a series of N-alkoxycarbonyl-alpha-amino-N-methylsuccinimide were prepared from N-Cbz-aspartic acid and were evaluated with their anticonvulsant activities against the MES and PTZ tests, in order to define the effect of N-substituted alkoxy carbonyl group with the anticonvulsant activities. From these studies, it was found that all the tested N-alkoxycarbonyl-alpha-amino-N-methylsuccinimides exhibited significant anticonvulsant activities in the PTZ test and were not active in the MES test. The most active compound in the PTZ test was (S) N-ethoxycarbonyl-alpha-amino-N-methyl-succinimide. We found that the pharmacological activities in the PTZ test were dependent on their N-alkoxycarbonyl groups. They follow as such; The order of anticonvulsant activities for (R) series as evaluated by ED50 was N-phenoxycarbonyl = N-4-nitrobenzyloxycarbonyl > N-ethoxycarbonyl > N-allyloxycarbonyl > N-tert. butoxycarbonyl compound; For the (S) series N-ethoxycarbonyl > N-phenoxycarbonyl > N-allyloxycarbonyl compound. From the above results, it was conceivable that N-substituted alkoxycarbonyl group had certain effects on the anticonvulsant activities of N-alkoxycarbonyl-alpha-amino-N-methylsuccinimides.

Animals↗
PubMed1998

The effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-aminoglutarimides.

In connection with the development of new anticonvulsant agents with a broad spectrum, we reported that N-Cbz-alpha-aminoglutarimides, combining common structures of other anticonvulsants such as N-CO-C-N and cyclic imides in a single molecule, showed significant anticonvulsant activities in the MES (maximal electroshock seizure) and PTZ (pentylenetetrazole induced seizure) tests. In these studies, a series of (R) and (S) N-alkyloxycarbonyl-alpha-aminoglutarimides 7a-7e and 8a-8e, which were substituted with various alkyloxycarbonyl group instead of Cbz group, were prepared from the corresponding (R) and (S) N-Cbz-glutamic acid 3 and 4, and were evaluated with their anticonvulsant activities against the MES and PTZ tests, including neurotoxicity, in order to define the effect of N-alkyloxycarbonyl group on the anticonvulsant activities of N-alkyloxycarbonyl-alpha-aminoglutarimides. Among them, (S) N-4-nitrobenzyloxycarbonyl-alpha-amino-N-methylglutarimide 8e was the most active in MES (ED50 = 35.6 mg/kg, PI = 2.7) and PTZ tests (ED50 = 15.6, PI = 6.1). Interestingly, (R) and (S) N-4-nitrobenzyloxycarbonyl-alpha-amino-N-methylglutarimide 7e and 8e and (R) N-phenoxycarbonyl-alpha-amino-N-methylglutrimide 7d showed significant anticonvulsant activities in both the MES and PTZ tests and other compounds showed anticonvulsant activities in only the PTZ test. In addition, it was found that their anticonvulsant activities were dependent on their stereochemistries and N-substituted alkyloxycarbonyl groups.

Animals↗
PubMed1997

Induction of parathyroid hormone-related peptide by the Ras oncogene: role of Ras farnesylation inhibitors as potential therapeutic agents for hypercalcemia of malignancy.

Parathyroid hormone related peptide (PTHRP) is the major causal agent in the syndrome of malignancy-associated hypercalcemia (MAH). Several studies have shown that PTHRP production is increased in response to growth factors and oncogenes, such as Tpr-Met, that are associated with the tyrosine kinase signaling pathway. Using site-directed mutagenesis of Tpr-Met and chemical inhibitors of phosphotidylinositol-3 kinase and Ras isoprenylation, we demonstrated previously that induction of PTHRP is mediated via the Ras signaling pathway. In the present study, we have directly investigated the role of the Ras oncogene in MAH. As a model system, we used Fisher rat 3T3 fibroblasts stably transfected with a Ras oncogene (Ras-3T3). Ras transfection enhanced PTHRP production 5-10-fold in these cells, and inoculation of this cell line into nude mice led to the development of hypercalcemia within 2 weeks. We used this system to evaluate the effect of a potent inhibitor of Ras processing, B-1086, on cell growth, PTHRP production, plasma calcium, and tumor growth. Treatment of Ras-3T3 cells in vitro with B-1086 at 0.1-10 microg/ml produced a significant reduction in PTHRP mRNA expression and PTHRP secretion and a significant decrease in cell proliferation. Treatment in vivo of BALB/c/nu/nu mice bearing Ras-3T3 tumors with B-1086 resulted in a significant inhibition in tumor growth. In addition, this treatment produced near normalization of serum Ca2+, a significant decrease in plasma PTHRP, and a reduction in tumoral PTHRP mRNA levels. These results show that the Ras pathway is involved in PTHRP production by tumors, identifies Ras as a potential target for treatment of MAH, and demonstrates Ras processing inhibitors as candidate therapeutic agents against this syndrome.

Alkyl and Aryl Transferases↗
PubMed1997

Electrophore mass tag dideoxy DNA sequencing.

Toward a goal of dideoxy sequencing DNA utilizing electrophore labels, we prepared four electrophore-labeled DNA oligonucleotide primers. Each primer has a different electrophore and DNA sequence but a common glycol keto (alpha,beta-dihydroxyketo) release group. Cleavage of this latter group by either periodate oxidation or a thermal retroaldol reaction releases the electrophores for detection by mass spectrometry. Successful sequencing data with these primers was obtained by capillary electrophoresis on an ABI Model 310 after fluorescence dideoxy terminator cycle sequencing reactions were conducted. In a separate experiment, it was demonstrated that a cocktail of the four electrophore DNA primers could be detected as a dried sample spot by CO2 laser desorption/capillary collection/gas chromatography electron capture mass spectrometry. These results establish some feasibility for our long-term goal of high-speed multiplex electrophore mass tag dideoxy DNA sequencing. Ultimately we plan to use a higher number of electrophore mass tags and to rely on direct detection of the desorbed electrophores by electron capture time-of-flight mass spectrometry.

Chromatography, High Pressure Liquid↗
PubMed1997

Sequence of two gonadotropin releasing hormones from tunicate suggest an important role of conformation in receptor activation.

The primary structure of two forms of gonadotropin releasing hormone (GnRH) from tunicate (Chelyosoma productum) have been determined based on mass spectrometric and chemical sequence analyses. The peptides, tunicate GnRH-I and -II, contain features unprecedented in vertebrate GnRH. Tunicate GnRH-I contains a putative salt bridge between Asp5 and Lys8. A GnRH analog containing a lactam bridge between Asp5 and Lys8 was found to increase release of estradiol compared with that of the native tunicate GnRH-I and -II. Tunicate GnRH-II contains a cysteine residue and was isolated as a dimeric peptide. These motifs suggest that the conformation plays an important role in receptor activation.

Amino Acid Sequence↗
PubMed1997

Association of the multisubstrate docking protein Gab1 with the hepatocyte growth factor receptor requires a functional Grb2 binding site involving tyrosine 1356.

Hepatocyte growth factor/scatter factor is a multifunctional factor that induces mitogenesis, motility, invasion, and branching tubulogenesis of several epithelial and endothelial cell lines in culture. The receptor for hepatocyte growth factor has been identified as the Met-tyrosine kinase. Upon stimulation with hepatocyte growth factor, the Met beta subunit becomes highly phosphorylated on tyrosine residues, one of which, tyrosine 1356 within the carboxyl terminus, is crucial for dissociation, motility, and branching tubule formation in Madin-Darby canine kidney epithelial cells. Tyrosine 1356 forms a multisubstrate binding site for the Grb2 and Shc adaptor proteins, the p85 subunit of phosphatidylinositol 3'-kinase, phospholipase Cgamma, and a phosphatase, SHP2. To investigate additional signaling molecules that are activated by the Met receptor, we have identified hepatocyte growth factor-induced phosphoproteins in tubular epithelial cells. We have established that proteins of 100-130 kDa are highly phosphorylated following stimulation of epithelial cells and that one of these is the Grb2-associated binding protein Gab1, a possible insulin receptor substrate-1-like signal transducer. We show that Gab1 is the major substrate for the Met kinase in vitro and in vivo. Association of Gab1 with Met requires a functional Grb2 binding site involving tyrosine 1356 and to a lesser extent tyrosine 1349. Met receptor mutants that fail to induce branching tubulogenesis are impaired in their ability to interact with Gab1, suggesting that Gab1 may play a role in these processes.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Efficient cellular transformation by the Met oncoprotein requires a functional Grb2 binding site and correlates with phosphorylation of the Grb2-associated proteins, Cbl and Gab1.

The Tpr-Met oncoprotein consists of the catalytic kinase domain of the hepatocyte growth factor/scatter factor receptor tyrosine kinase (Met) fused downstream from sequences encoded by the tpr gene. Tpr-Met is a member of a family of tyrosine kinase oncoproteins generated following genomic rearrangement and has constitutive kinase activity. We have previously demonstrated that a single carboxyl-terminal tyrosine residue, Tyr489, is essential for efficient transformation of Fr3T3 fibroblasts by Tpr-Met and forms a multisubstrate binding site for Grb2, phosphatidylinositol 3' kinase, phospholipase Cgamma, SHP2, and an unknown protein of 110 kDa. A mutant Tpr-Met protein that selectively fails to bind Grb2 has reduced transforming activity, implicating pathways downstream of Grb2 in Tpr-Met mediated cell transformation. We show here that the 110-kDa Tpr-Met substrate corresponds to the recently identified Grb2-associated protein, Gab1. Moreover, we show that tyrosine phosphorylation of the Cbl protooncogene product as well as Gab1 required Tyr489 and correlated with the ability of Tpr-Met to associate with Grb2 and to transform cells, providing evidence that pathways downstream of Gab1 and/or Cbl may play a role in Tpr-Met-mediated cell transformation.

3T3 Cells↗
PubMed1997

Activation of the JNK pathway is essential for transformation by the Met oncogene.

The Met/Hepatocyte Growth Factor (HGF) receptor tyrosine kinase is oncogenically activated through a rearrangement that creates a hybrid gene Tpr-Met. The resultant chimeric p65(Tpr-Met) protein is constitutively phosphorylated on tyrosine residues in vivo and associates with a number of SH2-containing signaling molecules including the p85 subunit of PI-3 kinase and the Grb2 adaptor protein, which couples receptor tyrosine kinases to the Ras signaling pathway. Mutation of the binding site for Grb2 impairs the ability of Tpr-Met oncoprotein to transform fibroblasts, suggesting that the activation of the Ras/MAP kinase signaling pathway through Grb2 may be essential for cellular transformation. To test this hypothesis dominant-negative mutants of Grb2 with deletions of the SH3 domains were introduced into Tpr-Met transformed fibroblasts. Cells overexpressing the mutants were found to be morphologically reverted and exhibited reduced growth in soft agar. Surprisingly, the Grb2 mutants blocked activation of the JNK/SAPK but not MAP kinase activity induced by the Tpr-Met oncoprotein. Additionally, cells expressing dominant-negative Grb2 mutants had reduced PI-3-kinase activity and dominant-negative mutants of Rac1 blocked both Tpr-Met-induced transformation and activation of JNK. These experiments reveal a novel link between Met and the JNK pathway, which is essential for transformation by this oncogene.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Primary structure of three forms of gonadotropin-releasing hormone (GnRH) from the pacu brain.

Perchlike fish are a vast group of advanced teleosts. The species examined to date have three forms of gonadotropin-releasing hormone (GnRH) within a single species, but the origin of the third GnRH peptide is unknown. In this study, the primary structure of three GnRH peptides is determined from the brain of the pacu, Piaractus mesopotamicus, an example of a teleost that is less advanced than the perchlike fish. The GnRH was purified from pacu brain extracts using high performance liquid chromatography (HPLC) and radioimmunoassay (RIA). The three forms identified by chemical sequencing and mass spectrometry are sea bream GnRH (pGlu-His-Trip-Ser-Tyr-Gly-Leu-Ser -Pro-Gly-NH2, 1113.4 Da); chicken GnRH-II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2, 1236.6 Da); and salmon GnRH (pGlu-His-Trp-Ser-Tyr-Gly-Trp-Leu-Pro-Gly-NH2, 1212.3 Da). In addition the number of forms of GnRH in the brains of male and female fish was determined separately. The same three forms of GnRH were present in the brains of both sexes as determined by antisera cross-reactivity and elution position from the HPLC column. The results indicate that the pacu brain has the identical forms of GnRH identified in perchlike fish and hence, the origin of three forms occurred earlier in evolution than previously thought.

Amino Acid Sequence↗
PubMed1997

Expression of scatter factor and c-met receptor in benign and malignant breast tissue.

BACKGROUND: Scatter factor (SF), also known as hepatocyte growth factor, is an angiogenic cytokine that stimulates epithelial cell motility and invasion. Its receptor is a transmembrane tyrosine kinase encoded by the c-met protooncogene. Several prior experimental and clinical studies have suggested that SF might play a role in the development and progression of breast carcinoma. To investigate the possible involvement of SF and c-met in the evolution of breast carcinoma, the authors studied their expression in sections of human breast tissue. METHODS: A variety of paraffin embedded tissue specimens (of normal breast tissue tissue, benign hyperplasia, ductal carcinoma-in-situ [DCIS], and invasive ductal carcinoma) from 125 patients were immunoperoxidase-stained using specific antisera against SF and c-met. The staining intensities of epithelial mammary cells were scored semiquantitatively, and the staining scores were analyzed as a function of tissue type. In addition, in situ hybridization to detect SF mRNA was performed for a small number of cancer sections. RESULTS: Specific SF staining was observed in tumor cells, normal cell types (epithelium and vascular smooth muscle), and acellular stroma, whereas c- met staining was observed in tumor cells and normal cell types but not in stroma. Analysis of the staining scores of epithelial mammary cells revealed several patterns: (1) SF and c-met staining scores each increased in the following order: normal breast/benign hyperplasias (lowest) --> DCIS (higher) --> invasive carcinoma (highest); (2) normal-appearing mammary ducts and lobules in invasive cancer sections showed less SF and c-met staining than tumor cells in the same specimens but more staining than normal ducts and lobules in sections of normal breast tissue and benign hyperplasia; (3) within the DCIS and invasive cancer groups, SF and c-met staining scores were correlated; and (4) among 40 consecutive cases of DCIS, higher levels of SF and c-met staining showed a trend toward association with other features suggestive of aggressive tumor biology (comedo histology, high nuclear grade, p53 positivity, and bcl-2 negativity). In situ hybridization analysis revealed that the same cell types that expressed SF protein (including tumor cells) also expressed SF mRNA transcripts. CONCLUSIONS: SF and c-met are overexpressed in breast carcinoma as compared with benign breast tissue, and they tend to be coexpressed in cancerous tissue. These findings are consistent with the idea that the SF:c-met ligand:receptor pair may have a role in breast carcinoma progression.

Breast↗
PubMed1997

Differential requirement of Grb2 and PI3-kinase in HGF/SF-induced cell motility and tubulogenesis.

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that induces mitogenesis, motility, invasion, and morphogenesis of several epithelial and endothelial cell lines in culture. The receptor for HGF/SF has been identified as the Met tyrosine kinase. To investigate the signaling pathways that are involved in these events, we have generated chimeric receptors containing the extracellular domain of the colony stimulating factor-1 (CSF-1) receptor fused to the transmembrane and intracellular domains of the Met receptor (MET). Madin-Darby canine kidney (MDCK) epithelial cells, expressing the CSF-MET chimera dissociate, scatter and form branching tubules in response to CSF-1. However, cells expressing a mutant CSF-MET receptor containing a phenylalanine substitution for tyrosine 1356 (Y1356F) are unable to scatter or form branching tubules following stimulation with CSF-1. Tyrosine 1356 is essential for the recruitment of multiple substrates including Grb2, the p85 subunit of PI3-kinase, and PLC gamma. To investigate the role of these signaling pathways, we have generated a mutant receptor that selectively fails to associate with Grb2, and have treated MDCK cells with potent inhibitors of PLC gamma, PI3-kinase, and p70S6K, a downstream target of PI3-kinase. Our results implicate pathways downstream from PI3-kinase in cell dissociation and scatter, whereas pathways downstream from Grb2 are required for branching tubulogenesis in MDCK cells.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Changes in the anterior chamber configuration after small-incision cataract surgery with posterior chamber intraocular lens implantation.

PURPOSE: To report quantitative changes in the anterior chamber configuration after small-incision cataract surgery with implantation of a posterior chamber intraocular lens by means of ultrasound biomicroscopy. METHODS: We examined the anterior chamber configuration of 20 eyes of 20 patients before and 3 months after small-incision cataract surgery (phacoemulsification and aspiration plus foldable intraocular lens implantation through a 3.0- to 4.0-mm self-sealing wound) by means of ultrasound biomicroscopy. The following variables were measured: the anterior chamber depth at the center of the cornea, the angle-opening distance 250 microns from the scleral spur (AOD250), the angle-opening distance 500 microns from the scleral spur (AOD500), and the trabecular-iris angle. RESULTS: The anterior chamber depth at the center of the cornea, AOD250, AOD500, and trabecular-iris angle increased significantly after surgery. The preoperative anterior chamber depth at the center of the cornea and trabecular-iris angle were negatively correlated with the differences between the postoperative and preoperative values (P < .01). The preoperative values of all variables examined were negatively correlated with the ratios of the postoperative value to the preoperative value (P < .002). CONCLUSIONS: The present results showed that small-incision cataract surgery significantly deepened the anterior chamber and widened its angle. The more shallow the preoperative anterior chamber was, the greater the postoperative change of the chamber was; and the more narrow the preoperative angle was, the greater the postoperative change of the angle was.

Aged↗
PubMed1997

New genes for male accessory gland proteins in Drosophila melanogaster.

The accessory gland of male insects produces components of the seminal fluid that alter the behavior, physiology and life span of the mated female, and contribute to her efficient storage and utilization of sperm. As a step towards understanding how this occurs, we have isolated genes encoding 12 previously unreported accessory gland-specific mRNAs from the fruit fly Drosophila melanogaster. We report here the restriction maps of the new genes, the chromosome positions--which are all autosomal--of the 11 non-repetitive genes, their expression patterns, and the sequences of the accessory gland proteins (Acps) encoded by nine of the genes. Eight of the proteins predicted from these sequences begin with putative secretion signals. Following their signal sequences, three of the predicted molecules are peptides and the other five are larger polypeptides with characteristics of cleavable prohormones. The ninth molecule, which has an N-terminal hydrophobic region but no consensus signal peptide cleavage site, is predicted to be a 716 amino acid glycoprotein. Of the nine proteins, two have intriguing similarities to sequences in protein databases. Acp76A is a 388 amino acid pro-protein which contains a signature sequence for the serpin class of protease inhibitors. The 115 amino acid Acp62F has a 28 amino acid region of high sequence similarity to a neurotoxin of the Brazilian armed spider Phoneutria nigriventer. Models are discussed in which Acp76A plays a role in the observed regulation of Acp proteolysis and/or in the coagulation of seminal fluid to form a mating plug, and in which Acp62F contributes to the reported toxicity of Drosophila seminal fluid.

Animals↗