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Biomedical subjects

M Parsons

Publications and source records attributed to M Parsons.

At least 37 records · Page 2Linked to original sources
PubMed2000

Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions.

Inflammation is a basic pathological mechanism that underlies many diseases. An important component of the inflammatory response is the passage of plasma components and leukocytes from the blood vessel into the tissues. The endothelial monolayer lining blood vessels reacts to stimuli such as thrombin or vascular endothelial growth factor by changes in cell-cell junctions, an increase in permeability, and the leakage of plasma components into tissues. Other stimuli, such as tumor necrosis factor-alpha (TNF-alpha), are responsible for stimulating the transmigration of leukocytes. Here we show that angiopoietin-1, a cytokine essential in fetal angiogenesis, not only supports the localization of proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1) into junctions between endothelial cells and decreases the phosphorylation of PECAM-1 and vascular endothelial cadherin, but it also strengthens these junctions, as evidenced by a decrease in basal permeability and inhibition of permeability responses to thrombin and vascular endothelial growth factor. Furthermore, angiopoietin-1 inhibits TNF-alpha-stimulated leukocyte transmigration. Angiopoietin-1 may thus have a major role in maintaining the integrity of endothelial monolayers.

Angiopoietin-1↗
PubMed2000

Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3.

Glycogen synthase kinase (GSK)-3 is a protein serine/threonine kinase that regulates differentiation and cell fate in a variety of organisms. This study examined the role of GSK-3 in antigen-specific T cell responses. Using resting T cells from P14 T cell receptor (TCR)-transgenic mice (specific for the lymphocytic choriomeningitis virus and H-2D(b)), we demonstrated that GSK-3beta was inactivated by serine phosphorylation after viral peptide-specific stimulation in vitro. To further investigate the role of GSK-3, we have generated a retroviral vector that expresses a constitutively active form of GSK-3beta that has an alanine substitution at the regulatory amino acid, serine 9 (GSK-3betaA9). Retroviral transduction of P14 TCR-transgenic bone marrow stem cells, followed by reconstitution, led to the expression of GSK-3betaA9 in bone marrow chimeric mice. T cells from chimeric mice demonstrate a reduction in proliferation and interleukin (IL)-2 production. In contrast, in vitro assays done in the presence of the GSK-3 inhibitor lithium led to dramatically prolonged T cell proliferation and increased IL-2 production. Furthermore, in the presence of lithium, we show that nuclear factor of activated T cells (NF-AT)c remains in the nucleus after antigen-specific stimulation of T cells. Together, these data demonstrate that GSK-3 negatively regulates the duration of T cell responses.

3T3 Cells↗
PubMed2000

Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo.

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4(+)CD8(+) double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I-restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen-specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-X(L). In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-kappaB activation via accelerated degradation of the NF-kappaB inhibitory protein IkappaBalpha. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-X(L), and NF-kappaB) in vivo in T lymphocytes.

Animals↗
PubMed2000

Isolation and characterization of Leishmania mutants defective in glycosomal protein import.

Kinetoplastid parasites contain a unique microbody organelle called the glycosome. Several important metabolic pathways found in the cytoplasm of higher eukaryotes are compartmentalized within the glycosome in these pathogens. This fundamental difference between the host and parasite has led to consideration of the glycosome as a potential chemotherapeutic target. The genetic basis of glycosome biogenesis is therefore of great interest. This report describes the isolation of multiple Leishmania mutant cell lines defective in glycosomal protein import, and the detailed characterization of three such lines. The mutants examined partially mislocalize a subset of glycosomal proteins to the cytosol yet retain wild-type numbers of glycosomes. One of the mutants has a mutation in the previously identified LdPEX2 (GIM1) gene. The other two mutants are demonstrated to contain cell-specific lesions in one or more genes distinct from PEX2. The identification of multiple genetically distinct mutants with defects in glycosome import provides an important genetic tool to facilitate the identification of genes involved in glycosome biogenesis.

Animals↗
PubMed2000

Pathways involved in environmental sensing in trypanosomatids.

Digenetic parasites, such as those of the order Kinetoplastida, must respond to extracellular and intracellular signals as they adapt to new environments within their different hosts. Evidence for signal transduction has been obtained for Trypanosoma brucei, T. cruzi and Leishmania, as reviewed here by Marilyn Parsons and Larry Ruben. Although the broad picture suggests similarities with the mammalian host, there are large gaps in our understanding of these processes; this probably contributes to a perception of differences. Nonetheless, current evidence suggests that the trypanosomatids might lack certain classes of signalling molecules found in other organisms.

Animals↗
PubMed2000

Echoplanar magnetic resonance imaging in acute stroke.

Echoplanar magnetic resonance imaging (EPI) enables rapid, non-invasive imaging and analysis of cerebral pathophysiology in acute stroke. It represents an important clinical advance over computed tomography (CT) and conventional magnetic resonance (MR) scanning. It can rapidly delineate infarcted cerebral tissue and distinguish acute from chronic stroke. In addition, EPI has the potential to quickly determine the presence and degree of potentially viable brain tissue in the ischaemic penumbra. Thrombolysis is thought to reperfuse the penumbra and hence reduce infarct size. The thrombolytic agent tissue plasminogen activator (t-PA) improves outcome in ischaemic stroke when administered within the first 3 hours of onset. However, there is a significant risk of haemorrhage, and the time window for benefit may well exceed 3 hours in some patients. Hence, by facilitating diagnosis of 'at-risk' tissue in the ischaemic penumbra, a major clinical role of EPI may well become the rational selection of patients for acute interventional stroke therapy.

Brain↗
PubMed2000

Distinct cardioprotective effects of adenosine mediated by differential coupling of receptor subtypes to phospholipases C and D.

Adenosine released during cardiac ischemia exerts a marked protective effect in the heart that is mediated by the A(1) and A(3) subtypes of adenosine receptors. The signaling pathways activated by these adenosine receptors have now been characterized in a chick embryo ventricular myocyte culture model of cardioprotection against ischemia. Selective A(1) and A(3) receptor agonists were shown to activate phospholipases C and D, respectively, to achieve their distinct cardioprotective effects. The specificity of the A(3) receptor-phospholipase D interaction was also demonstrated in chick embryo atrial myocytes (which do not express endogenous A(3) receptors) that had been transfected with a vector encoding the human A(3) receptor. Activation of both endogenous A(1) and A(3) receptors in ventricular myocytes resulted in a protective response greater than that induced by stimulation of either receptor alone. Agonists that activate both adenosine A(1) and A(3) receptors may thus prove beneficial for the treatment of myocardial ischemia.

Adenosine↗
PubMed2000

Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2.

Mast cells play a potentially important role in fibroproliferative diseases, releasing mediators including tryptase that are capable of stimulating fibroblast proliferation and procollagen synthesis. The mechanism by which tryptase stimulates fibroblast proliferation is unclear, although recent studies suggest it can activate protease-activated receptor (PAR)-2. We therefore investigated the role of PAR-2 in tryptase-induced proliferation of human fetal lung and adult lung parenchymal and airway fibroblasts and, for comparative purposes, adult dermal fibroblasts. Tryptase (0.7-70 mU/ml) induced concentration-dependent increases in proliferation of all fibroblasts studied. Antipain, bis(5-amidino-2-benzimidazolyl)methane, and benzamidine inhibited tryptase-induced fibroblast proliferation, demonstrating that proteolytic activity is required for the proliferative effects of tryptase. RT-PCR demonstrated the presence of PAR-2 mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of lung fibroblasts. In addition, specific PAR-2 activating peptides, SLIGKV and SLIGRL, mimicked the proliferative effects of tryptase. In contrast, human dermal fibroblasts only weakly stained with the PAR-2 antibody, PAR-2 mRNA was almost undetectable, and fibroblasts did not respond to PAR-2 activating peptides. These results suggest that tryptase induces lung, but not dermal, fibroblast proliferation via activation of PAR-2 and are consistent with the hypothesis that the release of tryptase from activated mast cells may play an important role in the fibroproliferative response observed in asthma, chronic obstructive pulmonary disease, and patients with pulmonary fibrosis.

Adult↗
PubMed2000

Analysis of targeting sequences demonstrates that trafficking to the Toxoplasma gondii plastid branches off the secretory system.

Apicomplexan parasites possess a plastid-like organelle called the apicoplast. Most proteins in the Toxoplasma gondii apicoplast are encoded in the nucleus and imported post-translationally. T. gondii apicoplast proteins often have a long N-terminal extension that directs the protein to the apicoplast. It can be modeled as a bipartite targeting sequence that contains a signal sequence and a plastid transit peptide. We identified two nuclearly encoded predicted plastid proteins and made fusions with green fluorescent protein to study protein domains required for apicoplast targeting. The N-terminal 42 amino acids of the apicoplast ribosomal protein S9 directs secretion of green fluorescent protein, indicating that targeting to the apicoplast proceeds through the secretory system. Large sections of the S9 predicted transit sequence can be deleted with no apparent impact on the ability to direct green fluorescent protein to the apicoplast. The predicted transit peptide domain of the S9 targeting sequence directs protein to the mitochondrion in vivo. The transit peptide can also direct import of green fluorescent protein into chloroplasts in vitro. These data substantiate the model that protein targeting to the apicoplast involves two distinct mechanisms: the first involving the secretory system and the second sharing features with typical chloroplast protein import.

Amino Acid Sequence↗
PubMed2000

Sexuality and perversion a hundred years on: discovering what Freud discovered.

The author considers how Freud's original formulation of the sexual drive may be understood in contemporary terms. Parallels between psychoanalysis, art history and the social and natural sciences underline the idea of sexuality as a construct that can be revisited. The nature of sexuality depends on how its irreducible biological basis is interpreted by a particular society at a particular time. The importance of revisiting is illustrated by Klein's concept of a position, which revisits the theoretical construct of a developmental stage. Freud's own construction of sexuality is based on his view of drive as comprising source, aim and object. Freud, in the Darwinian climate of his time, considered the object in terms of whether it served the fulfillment of the aim, but his paradigm can today be understood more broadly than Freud himself was able to. A discussion of perversion shows that psychoanalysis has moved from seeing it as defensive against instinctual derivatives to seeing it as defensive against object-relatedness. This reflects a shift in the analytic conceptualization of sexuality in general. Freud's paradigm for the sexual drive can be reconceived in terms of source, aim and quality of relatedness to object. Such a view of sexuality also has implications for gender issues, for the comparison of male and female perversion, and for the relation between sexuality and love.

Defense Mechanisms↗
PubMed2000

A guide to the use of focus groups in health care research: Part 1.

Focus group interviewing is becoming a popular research method among nurses as well as allied health professionals. Prior to performing a focus group interview a novice must first search the literature to gain an understanding of the function, uses, preparation, conduct and analysis of this form of methodology. This paper has been compiled in an attempt to synthesise, condense and simplify the information from an extremely wide and varied focus group literature and provide a comprehensive review to assist nurses who are considering utilising this methodology in their research studies. The purpose of this paper was stimulated by one of the author's (MP) own experience learning about focus group methodology before commencing her first focus group.

Bias↗
PubMed2000

A guide to the use of focus groups in health care research: Part 2.

In this paper, the second in a two part series on focus groups, a comprehensive overview of the literature concerning the interviewing process, methodology and analysis is provided. We discuss the characteristics of the moderator and the way in which a focus group is conducted (the who, where, and how of the focus group process), the participants, the process, and the analysis. Nursing staff and allied health professionals, especially those contemplating using focus groups for the first time, will be able to gain an understanding of the conduct of focus groups from this one source. The comprehensive reference list will provide a wealth of primary sources for further reading.

Data Interpretation, Statistical↗
PubMed1999

Mechanical load enhances procollagen processing in dermal fibroblasts by regulating levels of procollagen C-proteinase.

Mechanical forces are emerging as key regulators of cell function. We hypothesize that mechanical load may influence dermal fibroblast activity. We assessed the direct effects of mechanical load on human dermal fibroblast procollagen synthesis and processing in vitro. Cells were loaded in a biaxial loading system (Flexercell 3000). Hydroxyproline levels were measured in the medium and cell layer as an estimate of procollagen synthesis and processing to insoluble collagen. Mechanical load (in the presence of serum or TGF-beta) enhanced procollagen synthesis by 45 +/- 3% (P < 0.001), and 38 +/- 4% (P < 0.001), respectively, over unloaded growth factor controls after 48 h. Insoluble collagen deposition was enhanced in the same cultures by 115 +/- 8% (P < 0.01) and 72% +/- 9% (P < 0.01), respectively. This effect was inhibited using l-arginine suggesting that procollagen C-proteinase, the enzyme which directly cleaves the C-terminal propeptide of procollagen to form insoluble collagen, is required for the fiber formation observed. Procollagen mRNA levels in loaded samples increased by more than two-fold in both serum and TGF-beta-treated cultures at 48 h. Procollagen C-proteinase mRNA levels were also enhanced by a similar magnitude, although the increase was observed at 24 h. Procollagen C-proteinase protein levels were also increased at this time. Protein and mRNA levels of the procollagen C-proteinase enhancer protein, which binds the C-terminal propeptide of procollagen to enhance the rate of peptide cleavage, were unaffected by mechanical load. This study demonstrates that mechanical load promotes procollagen synthesis in dermal fibroblasts by enhancing gene expression and posttranslational processing of procollagen.

Bone Morphogenetic Protein 1↗
PubMed1999

A dominant negative mutation in the GIM1 gene of Leishmania donovani is responsible for defects in glycosomal protein localization.

Kinetoplastid protozoa contain a unique microbody organelle called the glycosome. Several important metabolic pathways are compartmentalized within the glycosome that are found in the cytoplasm of higher eukaryotes. We have previously reported the identification of a Leishmania donovani cell line called gim1-1, in which several normally glycosomal proteins are partially mislocalized to the cytoplasm. The GIM1 gene complements the defect and restores import of proteins to the glycosome. Here we demonstrate that GIM1 encodes an integral membrane protein of the glycosome. We also report that the mutant gim1-1 allele behaves as a dominant negative mutation. Introducing the gim1-1 allele extrachromasomally led to mislocalization of a glycosomal reporter protein even in wild-type cells. Gene disruption experiments in heterozygous GIM1/gim1-1 cells showed that when the mutant gim1-1 allele was lost, cells re-established normal glycosomal protein localization. Interestingly, no disruptions of the wild-type allele were obtained. These data indicate that a dominant negative mutation in the GIM1 gene is the sole genetic lesion responsible for the glycosomal defects in gim1-1, and suggest that GIM1 is an essential gene in Leishmania.

Animals↗
PubMed1999

Diurnal changes in plasma prolactin during the last one third of pregnancy in the baboon.

Previous studies in our laboratory revealed that daily plasma prolactin (Prl) levels were higher in the evening than in the morning in the pregnant baboon suggesting a diurnal variation. The goal of this study was to examine in more detail the diurnal alterations in plasma Prl levels. A tethered pregnant baboon model was utilized for these studies. Hourly venous blood samples were taken from 0700 to 2400 hr (n=10) or until 0700 hr the following day (n=5). The studies were performed at various days of pregnancy from day 135 until delivery. Plasma samples were analyzed for Prl by radioimmunoassay. A surge in plasma Prl was detected, starting around 1500 to 1600 hr and lasting for 3 to 5 hr. The surge occurred before the lights went off in the colony (1800 hr). Baseline Prl levels were higher in animals < 15 days before delivery compared to those > 15 days before delivery (P < 0.05). In contrast, no differences were found in the average peak Prl values between these two groups of animals. In summary, in the pregnant baboon during the last one-third of pregnancy plasma Prl surges, beginning around 1500 to 1600 hr and lasting for 3 to 5 hr. Less than 15 days before delivery the mean baseline Prl levels are higher compared to animals greater than 15 days before delivery.

Animals↗
PubMed1999

Lateral microscopic extension of squamous cell carcinoma of the vulva.

PURPOSE: The aim of this study was to measure the radial occult microscopic spread of tumor in patients with invasive squamous cell carcinoma of the vulva. MATERIALS AND METHODS: In the operating room the gross tumor border was marked. The pathologist took a radial section in each quadrant and measured the distance of occult lateral spread of the tumor. RESULTS: From 7/01/93 to 6/30/96, 24 tumors from 21 patients were studied. The mean maximum tumor diameter was 3. 2 cm (0.5-7.0) and the mean depth of invasion was 9.1 mm (1.1-28.0). The gross and microscopic extent correlated in 20 tumors. Maximum lateral microscopic extent of the other 4 tumors was 3.5, 5 (to the margin), 10, and 16 mm. These 4 tumors were ulcerative and infiltrative and arose from or involved mucosa. CONCLUSION: The gross and microscopic periphery of most invasive squamous vulvar cancers are approximately the same. Ulcerative tumors with an infiltrative pattern of invasion which involve mucosal epithelium may be more likely to extend beyond what is grossly apparent. Measurement of the tumor-free margin should be included in future studies.

Adult↗
PubMed1999

Distal external iliac lymph nodes in early cervical cancer.

OBJECTIVE: To evaluate the utility of the deep circumflex iliac vein as a landmark for the caudal limit of external iliac lymphadenectomy for early cervical cancer. METHODS: During dissection of the distal (caudal), anterior (ventral) aspect of the external iliac vessels in conjunction with radical hysterectomy for carcinoma of the cervix, a careful search was made for the deep circumflex iliac vein. Lymph nodes immediately above this vein were sent as adjacent and lymph nodes caudal to the vein were sent as distal. The distance from the vein to the femoral canal was measured. RESULTS: Seventy-one women were studied over 40 months. Fifty-five had squamous cell carcinoma, 15 had adenocarcinoma, and one had adenosquamous carcinoma. The mean distance from the deep circumflex iliac vein to the femoral canal was 16 mm. Sixty-three patients had dissections distal to identified deep circumflex iliac veins and 49 (77%) of these had distal lymph nodes removed. The median number of pelvic lymph nodes removed was 24 (range nine to 68), and the median number of distal lymph nodes removed was 1.0 from each side. Lymph node metastases were found in 13 women (18%). One subject with multiple macroscopically positive nodes had a single positive distal lymph node. Thus, a small number of distal lymph nodes were found in most women with early invasive cervical cancer, and 8% of those with positive nodes had involvement of this nodal group. CONCLUSION: The deep circumflex iliac vein was an appropriate landmark for the caudal limit of external iliac lymphadenectomy.

Adult↗