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Biomedical subjects

M Park

Publications and source records attributed to M Park.

At least 145 records · Page 8Linked to original sources
PubMed1996

The key components of resistance to Ostertagia circumcincta in lambs.

One of the most remarkable features of parasitic infections in general, and Ostertagia circumcincta infection of sheep in particular, is the extensive variation among hosts in resistance to infection, as assessed by parasite burdens and production of eggs or infective larvae. Here Mike Stear, Michael Park and Stephen Bishop describe the factors that account for the variation among animals within a flock, including dam, sire, sex, date of birth and history of exposure to infection. There are no detectable genetic effects in lambs less than three months old. Genetic control of an acquired response develops in two stages: first, a reduction in the average egg production per worm, which is associated with the development of a parasite-specific local IgA response; and second, control of worm burden, which is associated with the production of globule leukocytes in the abomasal mucosa.

Journal Article↗
PubMed1996

High cellular concentration of peripheral blood progenitor cells during cryopreservation adversely affects CFU-GM but not hematopoietic recovery.

The effects of bone marrow (BM) and peripheral blood progenitor (PBPC) concentration during cryopreservation on subsequent hematopoietic engraftment following high-dose chemotherapy were studied in 24 patients. Seventeen BM harvests and 71 PBPC collections were performed between July 1991 and June 1994. The PBPC were frozen at significantly higher cellular concentrations than the BM (medians of 243 x 10(6)/ml versus 73 x 10(6)/ml respectively, p = 0.0003). The recovery of committed progenitor cell colonies (CFU-GM) was significantly lower from PBPC frozen at concentrations above the median, compared with 116% from those frozen at concentrations below the median (p = 0.0467). This phenomenon was not seen in BM, which was generally frozen at a threefold lower concentrations. Despite the lower recovery of CFU-GM when PBPC were frozen at a higher concentration, the patients receiving these grafts achieved good hematopoietic recovery. The higher number of PBPC probably compensated for the loss, and the patients still received a substantial number of clonogenic hematopoietic precursors.

Adolescent↗
PubMed1996

Moyamoya disease in an adult with Down syndrome: comparison of magnetic resonance angiography and conventional angiography.

Moyamoya disease, or idiopathic progressive arteriopathy, is a vascular occlusive disease that results in stenosis of the internal carotid arteries, stimulating the development of collaterals and telangiectatic vasculature from basilar and leptomeningeal arteries. Within the past several years, several reports have suggested that children with Down syndrome can develop moyamoya vasculopathy. We present the first reported magnetic resonance angiographic diagnosis of moyamoya disease in an adult with Down syndrome. This was also confirmed by conventional cerebral angiography.

Adult↗
PubMed1996

A longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women.

OBJECTIVE: To describe how menstrual cramps vary from cycle to cycle within a woman over time. To examine the influence of weight and lifestyle factors on occurrence, duration, and severity of menstrual pain. DESIGN: A one-year prospective menstrual diary study. PARTICIPANTS: One hundred and sixty-five women aged 17 to 19 years entering a local university in 1985. MAIN OUTCOME MEASURES: The occurrence, length, and maximum severity of pain during a menstrual period. RESULTS: Menstrual pain occurred during 71.6% of observed menstrual bleeds, most commonly beginning the first day of menses. The median duration was two days. Sixty percent of women reported at least one episode of severe pain, while 13% reported severe pain more than half the time. Earlier age at menarche and long menstrual periods increased the occurrence, duration and severity of pain. In smokers, cramps tended to last longer. Being overweight was an important risk factor for menstrual cramps and doubled the odds of having a long pain episode. Frequent alcohol consumption decreased the probability of having menstrual cramps, but in women who had pain it increased duration and severity. Physical activity was not associated with any pain parameter. CONCLUSIONS: Women who have pain lasting three days are an important target group for prophylactic therapy. The occurrence and severity of menstrual cramps is influenced by potentially modifiable characteristics including weight, smoking, and alcohol consumption. Doctors may wish to counsel women presenting with dysmenorrhoea about the importance of healthy lifestyles and about the inefficacy of alcohol consumption as a treatment for dysmenorrhoea.

Activities of Daily Living↗
PubMed1996

Increased PTHRP production by a tyrosine kinase oncogene, Tpr-Met: role of the Ras signaling pathway.

We have used the Tpr-Met oncogene as a model to examine signaling pathways of growth factors and tyrosine kinase oncogenes that can increase parathyroid hormone-related peptide (PTHRP) production. PTHRP production in Tpr-Met transfected cells, when assessed by Northern blot analysis and radioimmunoassay, was increased four- to eightfold. Treatment of these cells with the transcriptional inhibitor actinomycin D and nuclear run-off assays showed that the major cause of increased PTHRP mRNA was enhanced gene transcription. To analyze the intracellular signaling molecules involved in PTHRP production, stable cell lines expressing a Tyr489 Phe mutant of the Tpr-Met oncoprotein were examined. The mutant fails to activate phosphatidylinositol (PI)-3 kinase or associate with the Grb-2 adaptor protein and caused a significant reduction in PTHRP production. Treatment of wild-type Tpr-Met transfected cells with wortmannin, a PI-3 kinase inhibitor, had no effect on PTHRP production; however, treatment of these cells with lovastatin, an inhibitor of p21ran isoprenylation, significantly reduced PTHRP expression. These results show that PTHRP is a downsteam target of the Tpr-Met oncogene and indicate that the PTHRP stimulating activity is mediated via the Ras signaling pathway.

1-Phosphatidylinositol 4-Kinase↗
PubMed1996

Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice.

Hepatocyte growth factor/scatter factor (HGF/SF) stimulates proliferation, dissociation, migration and morphogenesis of cells in culture. To investigate a possible role for HGF/SF and its receptor, the Met tyrosine kinase, in embryonic development, we have analyzed their expression in mouse embryos from day 7.5 of gestation by whole-mount in situ hybridization. Met expression is first detected in the ventral portion of somites at day 9.25 of gestation (22 somite embryo) at the level of fore limb buds. As somites mature, met expression is detected in caudal somites, and is confined to the lateral and media] tips of the dermomyotome and dermomyotome/myotome respectively. In contrast, HGF/SF is expressed exclusively in the mesodermal core of the limb bud. As the dermomyotome elongates ventrolaterally, the met-expressing cells at the lateral tip appear to detach from the somite, invade the limb bud and localize at the dorsal and ventral limb sides in close proximity to HGF/SF-expressing cells. At later stages, both met- and HGF/SF-expressing cells appear to migrate distally and localize to the digit forming area of the developing hand plate. Met expression in the lateral dermomyotome and limb bud coincides with expression of Pax-3, a marker for migrating muscle precursor cells in the somite and limb. Splotch-2H and Splotch-delayed mice, which harbor mutations in Pax-3, show major disruptions in early limb muscle development. Significantly, no met-expressing cells were observed in the limbs of homozygous Splotch-2H and Splotch-delayed animals, whereas HGF/SF expression was not affected. The restricted expression of met to a sub-population of Pax-3-expressing cells in the lateral tip of the dermomyotome, demonstrates that met represents a unique molecular marker for this migratory cell population. From these observations, together with the biological activities of HGF/SF, we propose that in homozygous Splotch embryos the failure of muscle precursors to migrate into and populate the limb bud results from a loss of met expression in the cells at the ventrolateral edge of the somitic dermomyotome.

Animals↗
PubMed1996

Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma.

Expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR, product of the met proto-oncogene) mRNA were examined by nonisotopic in situ hybridization in a spectrum of benign and malignant human breast tissues. mRNA for both HGFR and HGF was detected in benign ductal epithelium. Epithelial expression of HGF mRNA was particularly intense in regions of ductal epithelial hyperplasia. Positive expression of HGF (but not HGFR) mRNA was also found in adipocytes, endothelial cells, and to varying degrees in stromal fibroblasts. In 12 of 12 cases of ductal carcinoma in situ and infiltrating ductal carcinoma, carcinoma cells showed a heterogeneous pattern of expression for both HGFR and HGF mRNA. In infiltrating ductal carcinomas, intense expression of HGFR mRNA was not restricted to ductular structures but as also seen in non-duct-forming carcinoma cells. The same zones of the tumors (most commonly at the advancing margins) that expressed strongly HGFR mRNA often were also strongly positive for HGF mRNA, suggesting a possible autocrine effect. The expression pattern of HGFR protein in 25 cases including the same series of tissues used for in situ hybridization analysis was similar to that of HGFR mRNA, as determined by an immunoperoxidase technique. The finding that HGFR is expressed by both benign and malignant epithelium, and its not restricted to duct-forming structures, suggests that, although the potential for HGF/HGFR binding is maintained in malignancy, the response to ligand binding at the level of the receptor or the cellular response to receptor activation may change at some point during progression.

Breast↗
PubMed1996

Identification of a hepatocyte growth factor autocrine loop in a murine mammary carcinoma.

Constitutive activation of growth factor receptors through autocrine/paracrine mechanisms occurs frequently in human cancers and is thought to play an important role in carcinogenesis. We have demonstrated previously that hepatocyte growth factor (HGF) is a potent mitogenic factor for murine mammary carcinoma (SP1) cells in vitro. We report here an autocrine HGF loop in SP1 cells. HGF receptor/Met is expressed in SP1 cells and is constitutively tyrosine phosphorylated. The phosphorylation of HGF receptor/Met is inhibited when cells are exposed to suramin or anti-HGF IgG. This finding suggests that constitutive tyrosine phosphorylation of HGF receptor/Met is sustained by an extracellular factor, most likely HGF. Using Northern blot and Western blot analysis, we detected expression of a 6-kb HGF mRNA in SP1 cells and a M(r) 85,000 HGF protein in SP1-conditioned medium, respectively. In vitro translation of mRNA from SP1 cells and metabolic labeling confirmed expression and synthesis of HGF by SP1 cells. SP1 cells also invade through Matrigel-coated transwell membranes in an in vitro invasion assay, and invasion of these cells was inhibited by neutralizing anti-HGF IgG. In addition, SP1-conditioned medium induced scatter activity of Madin-Darby canine kidney epithelial cells, and this activity was inhibited by neutralizing anti-HGF IgG. We have also shown that several signaling molecules including phosphatidylinositol 3-kinase, Src, focal adhesion kinase, and phospholipase C-gamma in SP1 cells are constitutively tyrosine phosphorylated, suggesting that coexpression of HGF and HGF receptor/Met may in part contribute to sustained tyrosine phosphorylation of these cytoplasmic proteins in SP1 cells. Our observations in the SP1 model suggest that HGF contributes to growth and invasive phenotypes of mammary carcinomas via both paracrine and autocrine mechanisms.

3T3 Cells↗
PubMed1996

Human breast cancer: genetic alterations in the MET gene region.

OBJECTIVE: to test whether the MET gene at chromosome 7q31, which encodes a receptor protein (tyrosine kinase) related to normal histological differentiation, undergoes structural changes in breast cancer. A previous study reported somatic alterations detected as loss of heterozygosity (LOH) at this locus in breast cancer. DESIGN: Analysis of DNA from tumours and matched normal tissue by Southern blot hybridization with the metH probe; the tumours were also analysed for estrogen and progesterone receptors, ploidy and S phase, and protein expression of the MET and c-erbB-2 protooncogenes. PARTICIPANTS: Eighty-two patients with breast cancer. RESULTS: Fifty-three percent of the patients were informative for polymorphism with the metH marker. Somatic alterations of MET, consisting of LOH, were demonstrated in 22% of women who were informative and had breast cancer. No correlation was found between LOH of MET and conventional prognostic factors, or status for c-erbB-2 proto-oncogene expression. Estrogen-receptor status correlated with progesterone-receptor status, and S phase correlated with ploidy and size of the tumour. CONCLUSIONS: Somatic alterations of MET, detected as LOH with the metH probe, occur in 22% of informative patients. These alterations do not correlate with the prognostic factors established when the mastectomy is performed. It remains to be determined whether the patients' overall survival and disease-free survival rates are correlated with genetic alteration of MET.

Breast Neoplasms↗
PubMed1995

Hepatocyte growth factor-induced scatter of Madin-Darby canine kidney cells requires phosphatidylinositol 3-kinase.

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 and scatter in response to CSF-1. However, cells expressing a mutant CSF-MET receptor containing a phenylalanine substitution for tyrosine 1356 were unable to scatter or form branching tubules following stimulation with CSF-1. Tyrosine 1356 is essential for the recruitment of multiple substrates including the p85 subunit of PI3-kinase, phospholipase C gamma, and Grb2. In this study, we have investigated the role of PI3-kinase and a downstream target of PI3-kinase, pp70S6K, in the induction of MDCK cell scatter in response to HGF/SF. Our results demonstrate that following stimulation with HGF/SF, activation of PI3-kinase but not pp70S6K is essential for MDCK cell scatter.

Amino Acid Sequence↗
PubMed1995

Primary structure of solitary form of gonadotropin-releasing hormone (GnRH) in cichlid pituitary; three forms of GnRH in brain of cichlid and pumpkinseed fish.

GnRH is a decapeptide family with at least nine distinct structures. Vertebrates, except for most placental mammals, have more than one of these GnRH forms within the brain. We report chromatographical and immunological evidence that three forms of GnRH are in the brains of both cichlid (Haplochromis burtoni) and pumpkinseed (Lepomis gibbosus) fishes. We argue that the three forms correspond to those previously described as sea bream GnRH (sbGnRH), chicken GnRH-II and salmon GnRH. In contrast, only one GnRH form was present in the pituitary of the cichlid and is identified as sbGnRH by amino acid sequence. This is the first report in which the primary structure of GnRH is determined from pituitary tissue. The N-terminus was identified by monitoring the digestion of the peptide by pyroglutamate aminopeptidase with matrix assisted laser desorption/ionization (MALDI) mass spectrometry (MS). The amidation of the C-terminus was established using an esterification procedure for monitoring with MALDI-MS. This report supports the idea that three forms of GnRH within one species is widespread in the order Perciformes. The present study establishes sbGnRH as the third GnRH form in H. burtoni and predicts that sbGnRH is synthesized in preoptic neurons, then transported to the pituitary in the preoptic-hypophyseal axons for the release of one or both gonadotropins.

Amino Acid Sequence↗
PubMed1995

Mammalian gonadotropin-releasing hormone (GnRH) identified by primary structure in Russian sturgeon, Acipenser gueldenstaedti.

The mammalian form of gonadotropin-releasing hormone (GnRH) was purified from the brains of Russian sturgeon, Acipenser gueldenstaedti, using reversed-phase high pressure liquid chromatography (HPLC). The total concentration of mGnRH within these fish was 5.4 ng/brain. Small amounts of immunoreactive chicken GnRH-II like molecules were also detected but at insufficient quantities for purification. The primary structure of mGnRH was determined using automated Edman degradation. Because sequence data could not be obtained until after digestion by bovine pyroglutamyl amino-peptidase, it was determined that the amino-terminal residue was modified. Furthermore, mass spectrometric data and co-elution with synthetic mGnRH on HPLC confirmed that the carboxy-terminal residue was amidated. The amino acid sequence of sturgeon GnRH is pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2.

Amino Acid Sequence↗
PubMed1995

Efficient cell transformation by the Tpr-Met oncoprotein is dependent upon tyrosine 489 in the carboxy-terminus.

The receptor for hepatocyte growth factor/scatter factor (HGF/SF) was originally identified as an oncogene, Tpr-Met, which consists of the cytoplasmic tyrosine kinase domain of the HGF/SF receptor (Met) fused down-stream of sequences encoded by the tpr gene. As a consequence of this rearrangement the Tpr-Met fusion oncoprotein is localized to the cytoplasm and is a constitutively activated kinase. To identify signalling pathways important for Tpr-Met-mediated cell transformation we have generated tyrosine to phenylalanine mutants of Tpr-Met that are compromised in their ability to transform Fischer rat 3T3 (Fr3T3) cells in culture. We show that a single tyrosine residue in the carboxy terminus of Tpr-Met (residue 489) is essential for efficient transformation of Fr3T3 cells by this oncoprotein. Mutation of tyrosine 489 to phenylalanine does not affect the exogenous kinase activity of the Tpr-Met oncoprotein toward casein, but it impairs the ability of the mutant protein to bind to and activate phosphatidylinositol 3 kinase in vivo and completely abolishes the in vivo association with the Grb2 adaptor protein as well as the association and/or phosphorylation of an unknown protein of 110 kDa. These data are consistent with a single tyrosine residue in the Tpr-Met oncoprotein being essential for the activation of several signalling pathways which lead to the transformation of Fr3T3 fibroblasts.

1-Phosphatidylinositol 4-Kinase↗
PubMed1995

Male and female cooperate in the prohormone-like processing of a Drosophila melanogaster seminal fluid protein.

Acp26Aa is a Drosophila seminal fluid protein that plays a role in the elevation of egg-laying by the mated female and has structural features of a prohormone. The protein, which has a region of sequence similarity to the egg-laying hormone of Aplysia, is transferred to the Drosophila female during mating. Acp26Aa is processed in the mated female's genital tract. We show here that the processing involves sequential proteolytic cleavages, and we map the position of these cleavages. Although Acp26Aa is not cleaved in the male, its processing in the mated female requires activities donated by the male. Acp26Aa ectopically expressed in unmated females is not processed. Processing of Acp26Aa in wild-type females mated to males with altered seminal fluid is dependent on the presence and amount of male accessory gland secretions. The need for molecular cooperation between the sexes for processing of Acp26Aa could restrict its activity to the mated female.

Amino Acid Sequence↗
PubMed1995

Acceptability of medical abortion with methotrexate and misoprostol.

A clinical trial of efficacy of methotrexate and misoprostol for abortion was performed involving 86 women requesting an abortion at < 56 days gestation. An acceptability evaluation was included in the design of the trial. Subjects were questioned before the study about their reasons for choosing a medical abortion and past experience with surgical abortion. After the study was completed, the women were questioned about their medical abortion experience. All questions were asked in an open-ended manner. Eighty-five of 86 (99%) patients completed both questionnaires. The most common reason cited as to why women chose to have a medical abortion was to avoid some aspect of the surgery (48%). Forty-one (48%) women had experienced a surgical abortion; 49% of these women chose to have a medical abortion because of a "bad" past experience related to the surgical procedure. Upon completion of this study, 67 (79%) patients stated the medical abortion was a good experience, 12(14%) a bad experience, and 6 (7%) had a neutral response. When asked what method they would choose if they were to have another abortion, 89% would choose this method of medical abortion rather than a surgical abortion. In women who choose to participate in a clinical research trail, methotrexate and vaginal misoprostol are an acceptable and desirable method of abortion.

Abortifacient Agents, Nonsteroidal↗