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Biomedical subjects

A Graham

Publications and source records attributed to A Graham.

At least 55 records · Page 3Linked to original sources
PubMed1995

Structural requirements for oxidation of low-density lipoprotein by thiols.

Oxidation of low-density lipoprotein (LDL) by macrophages, endothelial cells and smooth muscle cells, may be mediated by production of free thiols in the presence of transition metals. We examined the structural requirements, within a series of cysteinyl derivatives, for oxidation of thiols and of LDL in Hams F10 medium. The primary mechanism by which such thiols mediate oxidation of LDL is largely independent of superoxide production, but strongly correlated with the susceptibility of each thiol to iron-catalysed auto-oxidation. These effects are compared and contrasted with thiol-dependent oxidation of LDL by stimulated human monocytes and macrophages.

Animals↗
PubMed1995

Regulation of lysophosphatidic acid-stimulated tyrosine phosphorylation of mitogen-activated protein kinase by protein kinase C- and pertussis toxin-dependent pathways in the endothelial cell line EAhy 926.

In the endothelial cell line EAhy 926, 1-oleoyl-lysophosphatidic acid (LPA) stimulated the tyrosine phosphorylation of the pp42 isoform of mitogen-activated protein (MAP) kinase. Maximum phosphorylation was observed within 5 min of LPA addition, but the response was sustained for up to 120 min. Re-addition of LPA after 60 min stimulated a further sustained increase in the tyrosine phosphorylation of MAP kinase. In cells pretreated with phorbol 12-myristate 13-acetate (PMA; 24 h) or preincubated with the protein kinase C inhibitor Ro-318220, LPA-induced tyrosine phosphorylation of pp42 MAP kinase was substantially reduced at 2 min but potentiated at 60 min. Ro-318220 in combination with either PMA or pertussis toxin pretreatment abolished the LPA response at all time points, suggesting an involvement of protein kinase C in the pertussis toxin-sensitive part of the pathway. Agents which raised intracellular cyclic AMP levels did not affect the initial phase of LPA-stimulated MAP kinase activation, but abolished the late phase. However, this effect was prevented by Ro-318220, implicating a greater role for protein kinase C than protein kinase A in the regulation of sustained MAP kinase responses. LPA stimulated an increase in the tyrosine phosphorylation of focal adhesion kinase pp125 (pp125FAK) in EAhy 926 cells which was both protein kinase C- and pertussis toxin-independent. These results are discussed in terms of the pathways regulating both MAP kinase and pp125FAK in response to LPA in the EAhy 926 endothelial cells line.

Cell Adhesion Molecules↗
PubMed1995

An animal model for hemolytic disease of the fetus and newborn. I. Alloimmunization techniques.

OBJECTIVE: Our purpose was to establish an animal model for hemolytic disease of the fetus and newborn by developing red blood cell alloimmunization techniques in the rabbit. STUDY DESIGN: Twenty-six nonpregnant New Zealand White or Red does underwent blood typing to identify them as homozygous at the HgA or HgF red blood cell antigen locus. Alloimmunization to incompatible red blood cells was attempted through a series of subcutaneous injections using complete then incomplete Freund's adjuvant. RESULTS: Successful induction of an antibody response occurred in 96% of cases. The median response in FF rabbits was 2560 (range 40 to 10,240), whereas the response in AA does was 2560 (range 320 to 20,480). These responses were not statistically different (p = 0.77). Responses were categorized as poor, moderate, or good. No difference was noted between FF and AA does in distribution of the categories of response (p = 0.53). CONCLUSION: Red blood cell alloantibodies of high titer can be induced successfully in the rabbit.

Animals↗
PubMed1995

An animal model for hemolytic disease of the fetus and newborn. II. Fetal effects in New Zealand rabbits.

OBJECTIVE: The addition of ultrasonography and ultrasonographically directed fetal blood sampling was attempted in an effort to study the fetal effects of red blood cell alloimmunization in a rabbit model. STUDY DESIGN: Nineteen New Zealand does were alloimmunized to incompatible red blood cells. Sensitized does were bred twice, once with a homozygous buck of incompatible blood type and once with a homozygous buck of compatible blood type. Ultrasonographic examinations were performed on days 20 and 27 of gestation (term 28 to 31 days). Fetal blood sampling was undertaken on day 27 of gestation, and hematologic data were compared between compatible and incompatible litters. RESULTS: A total of 41 pregnancies occurred in 19 does. Fetal hemoglobin was higher in the compatible litters (9.7 gm/dl vs 5.8 gm/dl, p < 0.001), whereas no difference could be detected between the respective reticulocyte counts (31.9 vs 36.0/100 red blood cells, p = 0.2). Hydrops fetalis was noted in none of 18 compatible litters versus 12 of 19 incompatible litters (p < 0.01). CONCLUSION: A disease analogous to human hemolytic disease of the newborn can be induced in the rabbit fetus.

Animals↗
PubMed1995

Pharmacological characterization of a new class of nonpeptide neurokinin A antagonists that demonstrate species selectivity.

We examined the pharmacology of ZM253,270 and two representative examples of the pyrrolopyrimidines, a new class of nonpeptide, NK-2 receptor (NK-2R) antagonists. ZM253,270 competitively inhibited [3H]NKA binding to native or cloned NK-2R from hamster urinary bladder (Ki = 2 nM), but was a weaker (48-fold) inhibitor of [3H]NKA binding to cloned human NK-2R. A similar species selectivity was observed with less potent analogs of ZM253,270. The pyrrolopyrimidines demonstrated only marginal inhibition of [3H]SP binding to NK-1R in guinea pig lung membranes (Ki > 2 microM). In hamster trachea, ZM253,270 competitively antagonized the contractile response evoked by neurokinin A (NKA, -logKB = 7.5). In human bronchus, ZM253,270 was about 90-fold less potent as a competitive antagonist of NKA. The data from ligand binding assays in cloned receptors combined with functional receptor assays in airway smooth muscles, demonstrate that the nonpeptide antagonist ZM253,270 is selective for the NK2 receptor species that are prevalent in hamster, compared with those found in human tissues.

Animals↗
PubMed1995

Evolution of regional identity in the vertebrate nervous system.

When and how did the mechanisms controlling regional identity in the vertebrate neural tube arise during evolution? The anatomy and embryology of the major deuterostome phyla (echinoderms, hemichordates, chordates) suggest that a true neural tube with dorsoventral and mediolateral regionalization arose with the chordates. We suggest that this was intimately associated with the origin of the notochord; this leads us to propose a modification of Garstang's century-old scenario for origins of the chordate neural tube. Differences along the rostrocaudal axis are seen in all chordates, but became particularly pronounced with the origin of a brain in craniates. Recent molecular data are starting to give insights into these evolutionary transitions. Here we review how Hox gene expression patterns are giving clues to brain origins and we examine the role of molecular phylogenetics in these analyses. We also ask whether the molecular evolution of genes such as noggin, Brachyury, Sonic hedgehog, Wnt, and En may have played direct or permissive roles in the origins of the neural plate, notochord, floor plate, and brain.

Animals↗
PubMed1995

Subcutaneous jugulofemoral bypass: a simple surgical option for palliation of superior vena cava obstruction.

BACKGROUND: Percutaneous placement of an intraluminal stent is usually a successful intervention for the disabling symptoms of Superior Vena Cava (SVC) obstruction. However, on occasion this may not be feasible and, as malignant disease is responsible for 90% of cases, the morbidity associated with median sternotomy or thoracotomy usually precludes surgical bypass. OBJECTIVE: To achieve good palliation of the symptoms of SVC obstruction by surgical bypass without performing sternotomy or thoracotomy. PATIENTS: Two patients with SVC obstruction secondary to lung cancer and a third after radiochemotherapy for malignant mediastinal teratoma. In all patients intraluminal stenting was considered but was not possible. METHODS: Jugulofemoral bypass was performed using long saphenous vein which was tunnelled subcutaneously from the femoral to the jugular vein. RESULTS: One patient required wound exploration for haemorrhage. Good palliation was achieved in all patients. One patient died 3 months post-operatively from lung cancer and the remaining two are alive without symptoms at 13 months and 6 weeks postoperatively. CONCLUSIONS: Though the majority of patients with SVC obstruction can be treated with non-surgical methods, subcutaneous jugulofemoral bypass may provide good palliation if these are not feasible.

Adult↗
PubMed1994

The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest.

The pattern of skeletal structures and muscles in the branchial region of the head is profoundly influenced by the neural crest, whose cells arise at discrete segmental levels of the chick hindbrain: specifically, rhombomeres (r)1+2, r4 and r6, whereas r3 and r5 are crest-depleted. We have demonstrated that an interaction between even-numbered rhombomeres and r3/r5 effects this depletion of neural crest, resulting in the sculpting of discrete migratory streams of neural crest. This mechanism acts through increased expression of msx2 and the induction of apoptosis in dorsal cells of r3 and r5 (ref. 3) (Fig. 1A). Here we demonstrate that the signalling molecule Bmp4 is expressed in r3 and r5 and is dependent on the neighbouring rhombomeres. Addition of recombinant BMP4 protein to explant cultures of r3 or r5, which produce neural crest when isolated from their neighbouring rhombomeres, upregulates msx2 and reinstates apoptosis in the neural crest population.

Animals↗
PubMed1994

Developmental patterning. The Hox code out on a limb.

Studies of limb development in mice lacking particular hoxd genes have cast doubt on the suggestion that Hox genes combine to control vertebrate morphogenesis by specifying positional information in a 'Hox code'.

Animals↗
PubMed1994

Regulation of endothelin-1- and lysophosphatidic acid-stimulated tyrosine phosphorylation of focal adhesion kinase (pp125fak) in Rat-1 fibroblasts.

The characteristics of protein tyrosine phosphorylation were examined in Rat-1 fibroblasts in response to endothelin-1 (ET-1) and 1-oleoyl-lysophosphatidic acid (LPA). Both agonists stimulated the biphasic tyrosine phosphorylation of at least three major proteins of approx. 120 kDa (pp116, pp120 and pp130) and two of 80 kDa (pp80 and pp70). Immunoprecipitation experiments indicated that the pp120 protein corresponded to the recently described focal adhesion protein kinase pp125fak. Phorbol 12-myristate 13-acetate, alone or in combination with the calcium ionophore A23187, also stimulated the phosphorylation of pp125fak but to a smaller extent than LPA or ET-1. Removal of both extracellular and intracellular Ca2+ did not significantly reduce LPA- and ET-1-stimulated tyrosine phosphorylation of pp125fak. In cells where protein kinase C activity was down-regulated or inhibited, ET-1-stimulated tyrosine phosphorylation of pp125fak was reduced to a greater extent than phosphorylation in response to LPA. In addition, ET-1-stimulated tyrosine phosphorylation of pp80 was decreased by 50-70% in response to protein kinase C inhibition at both 2 and 60 min whereas LPA-stimulated tyrosine phosphorylation of this protein was only reduced at 2 min. Pretreatment with pertussis toxin reduced the tyrosine phosphorylation of pp42 and pp44 forms of mitogen-activated protein kinase in response to both ET-1 and LPA but reduced the tyrosine phosphorylation of pp125fak only in response to LPA. These results indicate agonist-specific differences in the regulation of pathways mediating the tyrosine phosphorylation of pp125fak and other target proteins.

Amino Acid Sequence↗
PubMed1994

Stimulation of low-density lipoprotein uptake in HepG2 cells by epidermal growth factor via a tyrosine kinase-dependent, but protein kinase C-independent, mechanism.

Epidermal growth factor (EGF), a potent mitogenic polypeptide, stimulated the uptake and degradation of [3H]sucrose-labelled low-density lipoprotein (LDL) by HepG2 cells. The increase in LDL uptake was prevented by the presence of the tyrosine kinase inhibitor genistein. Activation of protein kinase C with phorbol 12-myristate 13-acetate (PMA) also stimulated the uptake of [3H]LDL by HepG2 cells. When EGF and PMA were added together, PMA increased the response to EGF in an additive manner. The protein kinase C inhibitor Ro-31-8220 prevented the increase in LDL uptake caused by PMA, but did not affect EGF stimulation of LDL uptake. Similarly, down-regulation of protein kinase C activity by chronic treatment with PMA also did not affect the EGF stimulation of LDL uptake. These results suggest that the EGF stimulation of LDL uptake and degradation by HepG2 cells is mediated by a tyrosine kinase-dependent, but protein kinase C-independent, mechanism.

Acetates↗
PubMed1994

A multiple interval physical map of the pericentromeric region of human chromosome 10.

Five intervals in the pericentromeric region of human chromosome 10 have been defined using a panel of somatic cell hybrids carrying portions of the chromosome. The map positions of twelve markers, consisting of four genes and eight anonymous DNA segments, have been localized by assignment to one of the five intervals. Several other markers could be placed in specific intervals by genetic linkage to assigned loci. When previously published data are incorporated, the summary map of the pericentromeric region encompasses thirty-two loci in bands 10p11.2-q11.2.

Base Sequence↗
PubMed1994

Vehicle crashworthiness ratings in Australia.

The paper reviews the published vehicle safety ratings based on mass crash data from the United States, Sweden, and Great Britain. It then describes the development of vehicle crashworthiness ratings based on injury compensation claims and police accident reports from Victoria and New South Wales, the two most populous states in Australia. Crashworthiness was measured by a combination of injury severity (of injured drivers) and injury risk (of drivers involved in crashes). Injury severity was based on 22,600 drivers injured in crashes in the two states. Injury risk was based on 70,900 drivers in New South Wales involved in crashes after which a vehicle was towed away. Injury risk measured in this way was compared with the "relative injury risk" of particular model cars involved in two car crashes in Victoria (where essentially only casualty crashes are reported), which was based on the method developed by Folksam Insurance in Sweden from Evans' double-pair comparison method. The results include crashworthiness ratings for the makes and models crashing in Australia in sufficient numbers to measure their crash performance adequately. The ratings were normalised for the driver sex and speed limit at the crash location, the two factors found to be strongly related to injury risk and/or severity and to vary substantially across makes and models of Australian crash-involved cars. This allows differences in crashworthiness of individual models to be seen, uncontaminated by major crash exposure differences.

Acceleration↗
PubMed1994

Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism.

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.

Buthionine Sulfoximine↗