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Biomedical subjects

M L Phillips

Publications and source records attributed to M L Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1995

Adjunctive selectin blockade successfully reduces infarct size beyond thrombolysis in the electrolytic canine coronary artery model.

BACKGROUND: An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model. METHODS AND RESULTS: A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias. CONCLUSIONS: Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.

Animals↗
PubMed1995

Facial processing in schizophrenia and delusional misidentification: cognitive neuropsychiatric approaches.

The human face is of great importance as a stimulus in view of the detailed information it contains--information vital to understand in order to survive in the complex social world. There are different aspects to facial processing, including: affect analysis, recognition of individuality and recognition of familiarity, all of which have been incorporated into the cognitive model of Bruce and Young (1986). The cognitive neuropsychiatric approach has recently been employed in the study of facial processing in schizophrenia. It has become apparent that schizophrenic subjects are impaired in facial processing tasks at all levels, and this may well be related to the misinterpretation of social interactions commonly found in such subjects. This approach has also led to a greater understanding of delusional misidentification, with particular syndromes explained in terms of processing deficits at different levels of the cognitive model above. At an anatomical level, the role of the right hemisphere in facial perception is well-known, with there being some evidence of right hemisphere hypofunction in subjects with schizophrenia and also in delusional misidentification. The review therefore emphasizes the importance of the neuropsychiatric approach for further investigation of facial processing and understanding of symptomatology in schizophrenia and related psychoses.

Capgras Syndrome↗
PubMed1995

Transcellular biosynthesis of lipoxin A4 during adhesion of platelets and neutrophils in experimental immune complex glomerulonephritis.

Polymorphonuclear neutrophils are important effectors of injury in host defense and inflammation. Many inflammatory diseases are self-limiting, raising the possibility that compounds are generated in vivo during the course of inflammation that inhibit neutrophil recruitment and tissue destruction. Lipoxins, a more recent addition to the families of bioactive eicosanoids, are potential candidates in this regard. Lipoxins are generated via pathways that initially involve the dual lipoxygenation of arachidonic acid and are potent inhibitors of several neutrophil trafficking events in vitro. Here, we present evidence that lipoxin A4 is generated in rat kidneys during experimental immune complex-mediated glomerulonephritis in vivo. Renal lipoxin A4 levels were markedly reduced by prior depletion of animals of either neutrophils or platelets, suggesting that most lipoxin A4 generated in vivo was derived from transcellular biosynthetic pathways during platelet-neutrophil interactions. Electron microscopic examination of glomerulonephritic kidneys revealed areas of intimate contact between neutrophils and platelets within the lumen of glomerular capillaries. P-selectin on platelets is an important mediator of platelet-neutrophil adhesion in vitro and in vivo. Prior treatment of animals with a blocking monoclonal antibody (mAb) against P-selectin (mAb CY1747), but not an isotype-matched non-blocking control mAb (mAb PNB1.6), caused striking inhibition of lipoxin A4 generation without attenuating neutrophil recruitment. Anti-P-selectin mAb also blunted transcellular lipoxin A4 generation during coincubations of activated neutrophils and platelets in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

Neutrophil adhesion in leukocyte adhesion deficiency syndrome type 2.

We have previously reported a newly discovered congenital disorder of neutrophil adhesion, leukocyte adhesion deficiency syndrome type 2 (LAD II). The clinical manifestations of this syndrome are similar to those seen in the classic leukocyte adhesion deficiency syndrome, now designated type 1 (LAD I), but the two syndromes differ in the molecular basis of their adhesion defects. LAD I is caused by a deficiency in the CD18 integrin adhesion molecules while LAD II patients are deficient in expression of sialyl-Lewis X (SLeX), a carbohydrate ligand for selectins. In this report we demonstrate that neutrophils from a LAD II patient bind minimally or not at all to recombinant E-selectin, purified platelet P-selectin, or P-selectin expressed on histamine-activated human umbilical vein endothelial cells, but have normal levels of L-selectin and CD11b/CD18 integrin, and adhere to and migrate across endothelium when CD11b/CD18 is activated. We compare LAD I and LAD II patient neutrophil function in vitro, demonstrating that integrin and selectin adhesion molecules have distinct but interdependent roles in neutrophil adhesion during an inflammatory response.

CD11 Antigens↗
PubMed1995

Role of P-selectin in total hepatic ischemia and reperfusion.

BACKGROUND: Ischemia and reperfusion of the liver are associated with changes in the interaction of leukocyte-endothelium cells. The role of an adhesion molecule, P-selectin, is studied in ischemia and reperfusion injury of the liver. STUDY DESIGN: Total hepatic ischemia was produced in the rat for 90 minutes, using a portosystemic shunt. To determine the role of P-selectin in ischemia and reperfusion, a murine IgG1 monoclonal antibody to P-selectin (1 mg/kg) was used at different times (30 minutes before and at reperfusion and five minutes and 24 hours after reperfusion). Rats survived for seven days, and tests showing hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies were analyzed at four hours postreperfusion. RESULTS: Survival improved from 15 percent for the rats in the ischemia control group to 55 percent for those in the group receiving anti-P-selectin antibody given 30 minutes before reperfusion (p < 0.05). We observed an improved statistically significant difference in tests demonstrating hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies in the treated and ischemia control groups. The other groups did not show consistent significant differences. CONCLUSIONS: P-selectin has a significant role in ischemia and reperfusion injury of the liver. Early modulation of the interaction between P-selectin and its ligand decreased neutrophil adhesion and migration and consequently diminished damage to the liver.

Analysis of Variance↗
PubMed1995

Immunoelectron microscopy of low density lipoproteins yields a ribbon and bow model for the conformation of apolipoprotein B on the lipoprotein surface.

In the present study, the relative positions of 11 anti-apolipoprotein B monoclonal antibodies have been mapped onto the surface of human low density lipoproteins by electron microscopy. As the epitopes recognized by these antibodies have been previously located on the primary sequence of apoB, these data provide a map of the configuration of the protein on the surface of the LDL. The first 89% of apoB-100 may be modeled as a thick ribbon that wraps once around the LDL, completing the encirclement by about amino acid residue 4050. The thickness of the ribbon is sufficient to penetrate the monolayer, so that it makes contact with the core. There is a kink in the ribbon beginning almost halfway along its length at approximately apoB-48. The C-terminal 11% of apoB constitutes the "bow," an elongated structure of about 480 residues, beginning at 4050 and stretching back into one hemisphere and then crossing the ribbon into the other hemisphere between residues 3000 to 3500, thus bringing sequences in the C-terminal portion of apoB-100 near to the suggested binding site for the LDL receptor. The C-terminal sequences may act as a negative regulator of LDL receptor binding, in agreement with Parhofer et al, 1992. J. Clin. Invest. 89: 1931-1937, who reported the enhanced clearance from plasma of apoB-89-containing lipoproteins. It is proposed that in VLDL the bow could function to inhibit binding to the receptor; during lipolysis to form LDL, it is suggested that these C-terminal inhibitory sequences forming the bow would move sufficiently to allow interaction with the LDL-receptor.

Antibodies, Monoclonal↗
PubMed1994

Electron-microscopic and hydrodynamic characterization of recombinant apolipoprotein (a) and its association with LDL.

A recombinant apo(a) containing 17 kringle 4 domains as well as the kringle 5 and protease domains of apo(a) was characterized by hydrodynamic studies and electron microscopy. Recombinant apo(a) is a monomer in solution with a molecular weight of 325,000 by sedimentation equilibrium and 320,000 by sedimentation and diffusion, and it is a highly asymmetric molecule with a frictional ratio of 2.2. In the electron microscope recombinant apo(a) is visualized as a flexible chain of domains approximately 800 A long. Sedimentation velocity studies also demonstrate that when it is mixed with LDL, recombinant apo(a) reversibly forms an Lp(a)-like complex with a 1:1 stoichiometry; moreover, complex formation is inhibited by 6-amino hexanoic acid. Hydrodynamic modeling and electron microscopy suggest that only a small portion of the r-apo(a) molecule interacts with the LDL and the rest of the chain extends into solution. Preliminary studies indicate that recombinant apo(a) also binds mouse LDL.

Animals↗
PubMed1994

Human/mouse chimeric monoclonal antibodies with human IgG1, IgG2, IgG3 and IgG4 constant domains: electron microscopic and hydrodynamic characterization.

The unique structure of the human IgG3 constant region with its greatly extended hinge can clearly be seen in electron micrographs, which compare a series of recombinant proteins with the same murine anti-dansyl variable domain but constant domains from human IgG1, IgG2, IgG3 and IgG4. The hinge region of IgG3 was found to be very long, with some measurements extending to 100 A. It exhibited considerable flexibility allowing the Fc to be displaced far toward either side. Upon addition of bivalent hapten, all of the monoclonal antibodies formed complexes. IgG1, IgG3 and IgG4 formed circular dimers, composed of two antibodies forming a ring-shaped complex, presumably through the binding of two bivalent haptens. IgG2, on the other hand, showed a distribution of complexes which was noticeably different from the other subclasses. Some circular dimers, some linear dimers and a large amount of monomer were seen. This was interpreted in terms of an energy barrier to ring closure arising from the orientation of the Fab arms of IgG2 probably leading to linear dimers as the predominate complex seen with the analytical ultracentrifuge. A substantial number of these dimers probably dissociated upon dilution for examination in the electron microscope. The distribution of the angles between the Fab arms of the monoclonal antibodies forming the circular dimers has been measured for the different subclasses. Most were open at wide angles (> 100 degrees) but some formed very shallow angles, with the Fab arms being nearly parallel to each other. The free energy for this transition was calculated from the ratio of open/closed angles, and it was found to be proportional to the length of the upper hinge of the monoclonal antibody, in agreement with previous nanosecond depolarization results (Dangl et al., Eur. molec. Biol. Org. J. 7, 1989-1994, 1988).

Animals↗
PubMed1994

Apolipoprotein B and low-density lipoprotein structure: implications for biosynthesis of triglyceride-rich lipoproteins.

ApoB100 is a very large glycoprotein essential for triglyceride transport in vertebrates. It plays functional roles in lipoprotein biosynthesis in liver and intestine, and is the ligand recognized by the LDL receptor during receptor-mediated endocytosis. ApoB100 is encoded by a single gene on chromosome 2, and the message undergoes a unique processing event to form apoB48 message in the human intestine, and, in some species, in liver as well. The primary sequence is relatively unique and appears unrelated to the sequences of other serum apolipoproteins, except for some possible homology with the receptor recognition sequence of apolipoprotein E. From its sequence, structure prediction shows the presence of both sheet and helix scattered along its length, but no transmembrane domains apart from the signal sequence. The multiple carbohydrate attachment sites have been identified, as well as the locations of most of its disulfides. ApoB is the single protein found on LDL. These lipoproteins are emulsion particles, containing a core of nonpolar cholesteryl ester and triglyceride oil, surrounded by an emulsifying agent, a monolayer of phospholipid, cholesterol, and a single molecule of apoB100. An emulsion particle model is developed to predict accurately the physical and compositional properties of an LDL of any given size. A variety of techniques have been employed to map apoB100 on the surface of the LDL, and all yield a model in which apoB surrounds the LDL like a belt. Moreover, it is concluded that apoB100 folds into a long, flexible structure with a cross-section of about 20 x 54 A2 and a length of about 585 A. This structure is embedded in the surface coat of the LDL and makes contact with the core. During lipoprotein biosynthesis in tissue culture, truncated fragments of apoB100 are secreted on lipoproteins. Here, it was found that the lipoprotein core circumference was directly proportional to the apoB fragment size. A cotranslational model has been porposed for the lipoprotein assembly, which includes these structural features, and it is concluded that in permanent hepatocyte cell lines, apoB size determines lipoprotein core circumference.

Amino Acid Sequence↗
PubMed1994

Optic neuritis. Differential losses of luminance and chromatic function near a scotoma.

Visual sensitivity to achromatic and chromatic stimulus flashes was determined at sites just inside, on the boundary and just outside scotomata in 11 patients with recovered optic neuritis. The colour of the flashes and the size of the steady background on which they appeared were such that detection was more likely to be mediated by either the large-diameter, magnocellular fibres or the small-diameter, parvocellular fibres of the anterior visual pathway. The spacing of the test sites ranged from 0.5 degrees to 4 degrees visual angle, depending on the shape and location of the scotomata. The greatest differences in sensitivity were between sites just inside and just outside the scotoma and in response to achromatic stimuli more likely to involve the magnocellular fibres. This effect may be due to the size of magnocellular fibres or to their relatively smaller numbers.

Adult↗
PubMed1994

Anthelmintic resistance in Australian sheep nematode populations.

The resistance status of gastro-intestinal nematodes to anthelmintics was evaluated on 881 sheep farms throughout Australia during 1991-92. Resistance was shown to be widespread. Overall, 85% of farms had sheep infected with nematodes resistant to benzimidazole, 65% to levamisole and 34% to combination (benzimidazole+levamisole) products. Resistance to ivermectin was not detected. On only 9% of farms did all anthelmintic groups reduce egg counts by greater than or equal to 95%. The culture of faeces from untreated sheep showed Telodorsagia circumcincta, Trichostrongylus spp, Chabertia ovina and Haemonchus contortus to be the principal species. The nature and prevalence of resistance was not significantly correlated with stocking rate. However, resistance to combination products was almost twice as prevalent on farms in areas with an average annual rainfall of greater than 500 mm.

Animals↗
PubMed1994

A novel sialyl LewisX analog attenuates neutrophil accumulation and myocardial necrosis after ischemia and reperfusion.

BACKGROUND: Polymorphonuclear leukocytes (PMNs) have been shown to mediate coronary vascular and myocardial tissue injury after coronary artery ischemia and reperfusion. Previous studies using specific monoclonal antibodies directed against P-selectin and L-selectin have demonstrated the involvement of the selectin family of glycoproteins in the early phase of PMN-induced myocardial ischemia-reperfusion injury. We examined the effects of a novel oligosaccharide analog of sialyl LewisX (SLeX), which blocks both P-selectin and E-selectin in an acute canine model of myocardial ischemia and reperfusion. METHODS AND RESULTS: Anesthetized, open-chest dogs were subjected to 1.5 hours of left circumflex coronary artery (LCx) occlusion followed by 4.5 hours of reperfusion and randomly received the SLeX analog CY-1503 (5 mg/kg IV), the nonfucosylated analog of CY-1503, SLN (5 mg/kg IV), or saline 5 minutes before reperfusion. The investigators were blinded to the treatment until all the data analysis was completed. All three groups of dogs exhibited similar and severe reductions in transmural myocardial blood flow in the LCx region as well as pronounced myocardial contractile dysfunction during occlusion, suggesting comparable degrees of myocardial ischemia. After reperfusion, dogs receiving saline (n = 6) displayed an enhanced degree of myocardial injury that was evidenced by a dramatic elevation in plasma creatine kinase (CK) activity, PMN accumulation, and myocardial necrosis. Plasma CK activity increased from 1.9 +/- 0.5 IU/microgram protein at baseline to 73.0 +/- 11.0 IU/micrograms protein (P < .001) at 4.5 hours of reperfusion and myocardial PMN accumulation, as measured by cardiac myeloperoxidase (MPO) activity, and was significantly enhanced (P < .01) within the necrotic zone compared with the nonischemic zone (4.3 +/- 0.6 versus 0.7 +/- 0.1 U/100 mg tissue). After 4.5 hours of reperfusion, 36% of the myocardium within the ischemic zone and 17% of the left ventricle became necrotic in the dogs receiving saline. Treatment with CY-1503 (n = 6) significantly (P < .05) blunted plasma CK activity by more than 50% throughout the reperfusion period, reduced necrotic zone PMN accumulation by 63% (P < .05), and reduced myocardial necrosis in the area at risk by 65% (P < .01) and by 72% within the left ventricle (P < .01). In contrast, administration of the nonfucosylated analog of CY-1503, SLN (n = 6), failed to exert any detectable cardioprotective effects after myocardial ischemia and reperfusion. CONCLUSIONS: Our results provide strong evidence that treatment with a unique carbohydrate analog of SLeX, CY-1503, significantly reduces the degree of myocardial injury associated with coronary artery ischemia and reperfusion. The profound cardioprotection appears to be related to a reduction in PMN accumulation within the ischemic-reperfused myocardium. Additional studies investigating more-prolonged periods of reperfusion are required to determine whether CY-1503 treatment merely delays the onset or actually reduces the full extent of myocardial necrosis after ischemia and reperfusion.

Animals↗
PubMed1994

Role of H1 receptors and P-selectin in histamine-induced leukocyte rolling and adhesion in postcapillary venules.

The objective of this study was to define the nature, magnitude, and mechanisms of histamine-induced leukocyte-endothelial cell interactions in postcapillary venules of the rat mesentery using intravital microscopic techniques. Superfusion of the mesentery with histamine (10(-7)-10(-5) M) resulted in a dose-related increase in the number of rolling leukocytes, a reduction in rolling velocity, and an increased clearance of FITC-labeled rat albumin from blood to superfusate. The histamine-induced recruitment of rolling leukocytes and increased albumin clearance were prevented by histamine H1 (hydroxyzine, diphenhydramine) but not H2 (cimetidine) receptor antagonists. Because histamine induces expression of the adhesion molecule P-selectin in cultured endothelial cells, a monoclonal antibody directed against rat P-selectin and soluble sialyl-LewisX oligosaccharide (the carbohydrate ligand to P-selectin) were also tested as inhibitors. Both were effective in preventing the histamine-induced recruitment of rolling leukocytes, but neither agent attenuated the increased albumin clearance. These observations suggest that (a) histamine recruits rolling leukocytes and increases albumin leakage in postcapillary venules via H1 receptor activation, (b) histamine-induced recruitment of rolling leukocytes is mediated in part by P-selectin expressed on the endothelial cell surface, and (c) the histamine-induced vascular albumin leakage is unrelated to leukocyte-endothelial cell adhesion. Our results are consistent with the view that histamine may act as a mediator of acute inflammatory reactions.

Animals↗
PubMed1994

Understanding the symptoms of schizophrenia using visual scan paths.

BACKGROUND: This paper highlights the role of the visual scan path as a physiological marker of information processing, while investigating positive symptomatology in schizophrenia. METHOD: The current literature is reviewed using computer search facilities (Medline). RESULTS: Schizophrenics either scan or stare extensively, the latter related to negative symptoms. Schizophrenics particularly scan when viewing human faces. CONCLUSIONS: Scan paths in schizophrenics are important when viewing meaningful stimuli such as human faces, because of the relationship between abnormal perception of stimuli and symptomatology in these subjects.

Attention↗
PubMed1993

Physical properties of recombinant apolipoprotein(a) and its association with LDL to form an LP(a)-like complex.

Recombinant apolipoprotein(a) has been studied by hydrodynamic techniques and electron microscopy. Recombinant apo(a) was primarily a monomer in solution with an s0(20,w) of 9.3 S, a D20,w of 2.29 ficks, and a molecular weight of 325,000 from sedimentation equilibrium and 318,000 from combining the sedimentation and diffusion coefficients. A small amount, approximately 10%, of the recombinant apo(a) was present as a high molecular weight aggregate. The Stokes radius of the monomer, determined either from the diffusion coefficient or by combining the sedimentation equilibrium data with the sedimentation velocity data, was 94 A. The frictional ratio was 2.2, suggesting a highly asymmetric or random coil structure. In the electron microscope, recombinant apolipoprotein(a) was visualized as a long, highly flexible chain of domains forming large, open coiled structures on the EM grid with contour lengths of about 800 A. Addition of 6-aminohexanoic acid at 50 mM, a concentration which should saturate the weak lysine binding sites, did not alter the sedimentation behavior. In vivo, apolipoprotein(a) is associated tightly with LDL to form a highly atherogenic lipoprotein, Lp(a). A single molecule of recombinant apo(a) also associated tightly with LDL to yield a 13.3-S Lp(a)-like complex. This complex dissociated upon the addition of 50 mM 6-aminohexanoic acid. A novel sucrose gradient centrifugation technique was employed to determine a dissociation constant for the reversible equilibrium between recombinant apo(a) and LDL; at physiological ionic strength the dissociation constant was 0.3 nM. Raising the salt concentration to 5 M NaBr caused the dissociation constant to increase to 500 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminocaproic Acid↗
PubMed1993

The effectiveness of pre-operative advice to stop smoking: a prospective controlled trial.

Patients who smoke cigarettes suffer increased postoperative morbidity. A prospective, controlled trial was designed to evaluate the effectiveness of written pre-operative advice to stop smoking before admission for elective surgery and to record the duration of abstinence immediately before the operation. Although the advice was ineffective in persuading patients to stop smoking, it was associated with a reduction in the amount of tobacco consumed. Nicotine and carbon monoxide have important short-term adverse effects but 15% of all patients continued to smoke within an hour of surgery. If patients are unable to give up cigarette smoking completely, it is still worthwhile stopping on admission to hospital.

Humans↗