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Biomedical subjects

R A Ward

Publications and source records attributed to R A Ward.

At least 19 recordsLinked to original sources
PubMed1992

Origin and fate of fetuin-containing neurons in the developing neocortex of the fetal sheep.

The development of the neocortex has previously been extensively studied in carnivores (cat and ferret), rodents (rat and mouse) and primates (monkey and human). In these species, it has been shown that the initial population of cells migrating from the ventricular zone forms the primordial plexiform layer. This is subsequently split into marginal zone and subplate zone by the insertion of later-migrating cells into the primordial plexiform layer, to form the cortical plate proper. Many of the cells derived from the split primordial plexiform layer are transient. The neurons of the subplate zone are found in the deeper part of layer VI, and white matter deep to layer VI in the more mature cortex; most of these neurons disappear by adulthood. [3H]-thymidine labelling in the present study has shown a similar pattern of neocortical development in Artiodactyla (sheep). In addition it has been shown that the previously described staining of subplate and cortical plate cells for the fetal protein fetuin indicates that fetuin is a useful marker for a proportion of this transient population of neurons and defines its extent in neocortical development more clearly. Dividing cells were labelled by a single intra-amniotic injection of [3H]-thymidine at E26 to E35 (birth is at E150). The brains were subsequently examined at E40 or E80 for [3H]-thymidine labelling and fetuin staining by a combination of autoradiography and immunocytochemistry. The earliest generated neocortical cells detected in this study (E26) were found in two layers by E40, the outer marginal zone and inner subplate zone. Neurons of the marginal zone were generated up to E28; those of the early subplate zone were generated up to E31. The cortical plate proper was generated by cells "born" on E32 and later. This sequence is similar to that described in other species, especially the cat. A proportion of the early-generated neurons in the marginal zone, subplate zone and early cortical plate stained for fetuin. By E80 these earliest-generated, fetuin-positive cells were found in the white matter deep to the forming neocortical layers and in layer VI. In adult brains no fetuin-positive neurons could be identified in the neocortex, and neurons had almost entirely disappeared from the white matter. The fetal glycoprotein fetuin seems to be specifically associated with a population of cells that has the same developmental history as the transient marginal zone and subplate neurons described in other species.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Effects of RU33368, a low affinity ligand for neuronal benzodiazepine receptors, on rodent behaviours and GABA-mediated synaptic transmission in rat cerebellar slices.

1. The effects of the low affinity benzodiazepine receptor ligand RU33368 were studied on rodent behaviours and on GABA-mediated synaptic transmission in rat cerebellar slices. 2. RU33368 inhibited stress induced ultrasounds in rat pups without inducing marked muscle relaxation. RU33368 also enhanced operant responding in rats that had been suppressed by mild footshock. These effects of RU33368 in these two models of anxiety were both blocked by the benzodiazepine antagonist Ro15-1788 (flumazonil). 3. In cerebellar slices RU33368 enhanced stimulus-induced synaptic inhibition of Purkinje layer cells with a minimal effective concentration in the order of 1 microM. The classical benzodiazepine agonist RU32007 was approx. 10 times more potent. This action of RU33368 was blocked by Ro15-1788. 4. The minimal effective concentration of RU33368 fully blocked the effect of RU32007 in 2 of 4 cells tested and partially antagonized it in a third cell. 5. These data suggest that RU33368 is a partial agonist at benzodiazepine receptors and this, at least in part, explains its non-sedative anxiolytic behavioural profile.

Animals↗
PubMed1992

Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance.

Although thromboxane and prostacyclin (PGI2) have long been described as major controllers of pulmonary vascular resistance, little has been reported on the characteristics of the interactions between the two arachidonic acid products. The current study uses segmental vascular resistance and compliance measurements to evaluate the actions of thromboxane and PGI2 in isolated blood-perfused rat lung. The thromboxane analogue U-46619 increases pulmonary vascular resistance by increasing only small artery resistance and decreases pulmonary vascular compliance in the middle compartment. Among the vascular effects of U-46619 are a maximum increase in resistance (RmaxU-46619) of 60.3 +/- 15.6 cmH2O.l-1.min.100 g-1 and a concentration required for 50% of maximum increase (K0.5,U-46619) of 1.60 +/- 0.85 nM for small artery resistance, a minimum vascular compliance (CminU-46619) of -0.93 +/- 0.58 cmH2O, and a K0.5,U-46619 of 1.10 +/- 1.60 nM for middle compartment compliance. Similar results were obtained for total resistance and total compliance. The effects of PGI2 on thromboxane-induced resistance and compliance changes were evaluated using K0.5,PGI2, RmaxPGI2, and CmaxPGI2 at each dose of thromboxane. PGI2 was more effective in reversing the thromboxane constriction at higher concentrations of thromboxane. These data show that the absolute concentration of PGI2 and thromboxane and not a simple ratio of thromboxane to PGI2 determines vascular tone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Evaluation of prostaglandin F2 alpha and prostacyclin interactions in the isolated perfused rat lung.

To characterize the interactions between prostaglandin F2 alpha and prostacyclin in controlling tone in the pulmonary circulation, isolated rat lungs were ventilated, perfused with blood, and subjected to challenge by prostaglandin F2 alpha in increasing doses. The pulmonary resistance was evaluated using occlusion techniques that separate the resistance into segments of large and small arteries and veins. The total vascular compliance was evaluated using outflow occlusion. Resistance increased after prostaglandin F2 alpha, and this resistance change was primarily in the small artery segment. The maximum resistance increase by prostaglandin F2 alpha (Rmax,PGF2 alpha), calculated from the Michaelis-Menton equation, was 16.6 +/- 3.6 cmH2O.l-1.min.100 g-1 for total vascular resistance with a concentration required to produce 50% Rmax (K0.5) of 5.26 +/- 3.57 nM. The Rmax,PGF2 alpha for small artery resistance was 13.5 +/- 2.4 cmH2O.l-1.min.100 g-1 with a K0.5 of 2.35 +/- 1.57 nM. The vascular compliance decreased during vasoconstriction by prostaglandin F2 alpha, and the maximum decrease in compliance (Cmin,PGF2 alpha) was -0.43 +/- 0.12 ml/cmH2O with a K0.5 of 2.84 +/- 2.99 nM. At each dose of prostaglandin F2 alpha, prostacyclin was administered in increasing doses to reverse the vasoconstriction caused by prostaglandin F2 alpha. For each concentration of prostaglandin F2 alpha, prostacyclin almost completely reversed the resistance increases and approximately one-half the compliance decrease. The maximum change in vascular resistance or compliance produced by prostacyclin was dependent on the dose of prostaglandin F2 alpha; yet the K0.5 for prostacyclin was within the picomolar range for all doses of prostaglandin F2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Modulation of GABA-mediated inhibition in rat cerebellar slices by benzodiazepine receptor ligands.

1. Extracellular recordings were made from the Purkinje cell layer of rat cerebellar slices. Compounds were perfused over the slice and bipolar stimulating electrodes placed in the external layer of the slice close to the recording electrode. 2. Stimulus-evoked inhibition of Purkinje layer cell activity was sensitive to bicuculline methiodide and picrotoxin, suggesting it was gamma-aminobutyric acid (GABA) mediated. The benzodiazepine ligands RU 32007 and Ro 19-0528 reversibly increased the period of inhibition, as did pentobarbital. This benzodiazepine effect was antagonised by Ro 15-1788. 3. Five inverse agonists all reduced the period of stimulated inhibition and this effect was reversed by Ro 15-1788, suggesting the involvement of benzodiazepine receptors. 4. It is concluded that this system provides a convenient physiological and possibly quantitative model for studying the action of benzodiazepine receptor ligands.

Animals↗
PubMed1991

Effects of hemodialysis on platelet-derived thrombospondin.

The effects on platelet-derived thrombospondin (TSP) of hemodialysis with a cellulose membrane were studied in patients during routine hemodialysis and in normal subjects using an ex vivo model. Plasma and platelet-bound TSP were determined pre- and post-dialysis, in blood entering and leaving the dialyzer after 1, 3, 5, 15, and 30 minutes of dialysis, and in blood leaving the ex vivo module after 5, 10, 15, 20, and 25 minutes of perfusion. Plasma concentrations of beta-thromboglobulin (beta TG) and thromboxane B2 (TxB2), and platelet membrane expression of the alpha-granule protein GMP-140, were also measured. Significant increases in plasma concentrations of TSP and beta TG occurred between the inlet and outlet of the dialyzer after 5, 15, and 30 minutes of dialysis, accompanied by a slow, but significant, increase in their arterial plasma concentrations. In contrast, initiation of dialysis was associated with an immediate increase in plasma TxB2 concentration between the inlet and outlet of the dialyzer and an abrupt increase in arterial plasma TxB2 concentration which plateaued at 250% of the pre-dialysis value after five minutes. Transit of platelets through the dialyzer had no effect on platelet-membrane-associated TSP or GMP-140. Plasma TSP and beta TG concentrations at the outlet of the ex vivo module also increased significantly during perfusion, but plasma TSP concentrations were twofold greater than those during hemodialysis. In vitro stimulation of platelets with thrombin and immunoblotting studies of platelet release proteins showed reduced TSP release by platelets of hemodialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Effect of extracorporeal membrane oxygenation on leukocyte function in neonates.

The impact of extracorporeal membrane oxygenation (ECMO) on neonatal leukocyte content and function was examined in six patients. Patients were treated with ECMO for a mean of 134 h (range 44-246 h). Absolute neutrophil counts decreased from 14679 +/- 2291/mm3 to 7791 +/- 1672/mm3 after 2 h of ECMO. However, neutrophil phagocytosis and oxidative burst remained unchanged during the first 48 h of bypass. Monocyte counts also decreased during bypass, and at times were undetectable in 50% of patients. Monocyte HLA-DR content was decreased compared to normal cord blood prior to initiation of ECMO, and remained low throughout ECMO. However, the content increased significantly after termination of bypass. Plasma C3a levels increased transiently, paralleled by an increase in neutrophil CR3 expression. While moribund infants had some impairment of host defenses prior to ECMO, there was no further impact of ECMO per se on the parameters measured, other than transient complement activation and decreased monocyte counts.

Complement Activation↗
PubMed1991

Understanding the regulatory requirements for dialysate.

It is important for providers to remember that dialysate is considered by federal regulatory agencies to be a medical device, but that most of the regulations are aimed at the manufacturers. The manufacturers are subject to FDA inspection and they must comply with Good Manufacturing Practices. Once the product reaches the provider's door, the manufacturer's responsibility ends, as does most close regulation. The best way for facilities to protect themselves is to develop a good quality assurance program that establishes and maintains policies and procedures which will ensure safe and effective use of dialysate.

Centers for Medicare and Medicaid Services, U.S.↗
PubMed1990

Quantitative analysis of gamma-aminobutyric acid (GABA) receptors of Purkinje cell layer from rat cerebellar slices.

1. Extracellular recordings were made from Purkinje cell layer of rat cerebellar slices. Cell activity was sensitive to both magnesium and manganese ions. 2. Glutamic and aspartic acids both excited cell activity while gamma-aminobutyric acid (GABA), muscimol, taurine, beta-alanine and delta-aminolaevulinic acid all inhibited activity. 3. The sensitivity to GABA varied with depth while no such effect was observed with muscimol. 4. Bicuculline methiodide, picrotoxin and pitrazepin blocked the action of muscimol with pA2 values of 5.92, 5.97 and 5.71 respectively. 5. The benzodiazepines flurazepam and RU 32007 both potentiated the GABA inhibition and this potentiation was blocked by Ro 15-1788, a benzodiazepine antagonist.

Animals↗
PubMed1990

Evaluation of phagocytic cell function in an ex vivo model of hemodialysis.

An ex vivo model of hemodialysis was used to evaluate the effect of dialysis membranes on phagocytic cell function. Blood was withdrawn continuously from healthy, non-uremic donors, heparinized, and pumped, single pass, through membrane modules under conditions which simulated normal dialysis conditions. The membrane modules contained membranes of cellulose, DEAE-substituted cellulose, or polysulfone. Blood was obtained from the module outlets for determination of complement activation, phagocyte elastase release, zymosan-induced phagocyte chemiluminescence, and monocyte interleukin-1 production. Significantly less complement activation occurred with the polysulfone and DEAE-substituted cellulose membranes than with cellulose membranes. Normal monocyte interleukin-1 production was not stimulated by any of the membranes used. In contrast, the cellulosic, but not the polysulfone, membranes primed the oxidative burst of the phagocytes and caused them to release elastase. DEAE-substituted cellulose had a lesser effect on elastase release than did cellulose and elastase release correlated significantly with the degree of complement activation. However, the correlation between complement activation and priming of phagocyte oxidative burst was weak, suggesting that membranes affect phagocyte oxidative metabolism through more than one mechanism. We conclude that some dialysis membranes stimulate the bacteriacidal functions of normal phagocytic cells, in part through complement-dependent mechanisms.

Humans↗
PubMed1990

Differential activation of monocytes in haemodialysis patients exposed to different types of membranes.

Peripheral blood mononuclear cells (PBMC) from haemodialysis patients treated with different types of membranes were isolated, incubated in vitro, and extracellular and cell-associated interleukin I (IL-1) assayed by radioimmunological methods. Extracellular IL-1 was low and not different from controls, regardless of the dialyser used. In contrast, cell-associated IL-1 was increased in patients treated with dialysers containing low-flux Cuprophan (CU, n = 5) and polyacrylonitrile sheet membrane (AN69, n = 5). Patients treated with dialysers containing high-flux polysulphone (PS, n = 7), and polymethylmethacrylate (PMMA, n = 8), exhibited no increase in cell-associated IL-1 under these conditions. To elucidate the mechanism of the activation, aqueous extracts of dialysers containing CU, PS, and AN69 were tested for their ability to induce IL-1 generation in PBMC from healthy donors. Extracts from unrinsed CU-containing dialysers caused significant IL-1 synthesis and release, whereas incubation with extracts from dialysers containing PS and AN69 sheet membranes did not. Hence, although both CU and AN69 sheet-type dialysers result in activation of blood monocytes the mechanism of action appears to be different. We speculate that functional signs of PBMC activation as evidenced by increased spontaneous IL-1 production observed in some patients on long-term haemodialysis may result from extractable dialyser membrane material while in other instances direct cell membrane interactions or endotoxin transfer from the dialysate may be relevant.

Adult↗
PubMed1989

The impact of erythropoietin on hemodialyzer design and performance.

The present study investigated theoretically and experimentally the effects of increases in hematocrit on the clearance of urea by the Baxter ST15 hollow fiber dialyzer. In a theoretical model that incorporates the three component resistances for the overall mass transfer rate, namely, the resistance of the blood (Rb)-, membrane (Rm)-, and dialysate side (Rd), it was predicted that a change in hematocrit would alter only the blood side resistance. The overall impact of this alteration is expected to be determined by the relative contribution of Rb to the overall resistance (RO). The modest contribution of Rb to RO implies that a major change in Rb (50%) would have only a minor effect on RO (11%) and consequently on urea clearance (5%). These theoretical conclusions were tested experimentally and the results confirmed the theoretical predictions. Indeed, there was little change in urea clearance in the clinically relevant range of variations in hematocrit (19-39%). Possible ways of compensation by minor changes in the hollow fiber geometry are discussed as well as the more complex relationships with larger solutes (creatinine) or unequally distributed solutes (potassium, phosphate).

Equipment Design↗
PubMed1989

Polymorphonuclear leukocyte function during hemodialysis: relationship to complement activation.

Phagocytosis, H2O2 production, and C3bi receptor (CR3) expression by polymorphonuclear leukocytes (PMN) obtained from patients before, during, and after a hemodialysis treatment were evaluated by flow microfluorometry. The results were compared to changes in plasma levels of C3ades Arg and C5ades Arg. Prior to hemodialysis C3ades Arg and C5ades Arg levels, CR3 expression and phagocytosis were not different from normal controls. However, both basal and phagocytosis-induced H2O2 production were increased. C3ades Arg and C5ades Arg were increased after 15 min of dialysis; this was accompanied by transient but significant reductions in PMN count and phagocytosis and increased CR3 expression. No changes in basal or stimulated H2O2 production were observed. We conclude that PMN of hemodialysis patients are primed for an enhanced respiratory burst before dialysis is initiated. Dialysis-induced complement activation after the initiation of dialysis does not further stimulate H2O2 production or enhance the response to phagocytosis. However, complement activation may cause leukopenia and CR3 expression.

Complement Activation↗
PubMed1989

Activation of mononuclear cells by aqueous extracts from hollow-fibre haemodialysers.

Monocytes from patients treated by long-term haemodialysis with cellulosic membranes can show functional signs of activation depending on the dialyser module. To elucidate the mechanism of this phenomenon, aqueous extracts of various hollow-fibre dialysers were tested for their ability to induce in-vitro interleukin-1 generation in peripheral blood mononuclear cells from healthy donors. Extracts were prepared by passing 0.5 litres of sterile endotoxin-free water from the dialysate to the blood compartment of the dialyser. Different dialysers containing cellulosic membranes, i.e. cuprophan, and hemophan, were studied. Extracts were dried by lyophilisation and resuspended in cell culture medium before incubation with peripheral blood mononuclear cells for 18 hours at 37 degrees C in a 5% CO2 atmosphere. Interleukin-1 was assayed by biological or radioimmunological methods. Extracts from steam-autoclaved, dry-stored, or gamma-sterilised, wet-stored cuprophan and hemophan modules resulted in interleukin-1 activity that did not differ from negative controls. By contrast, extracts from cuprophan caused significant interleukin-1 production when prepared from ethylene oxide-sterilised, dry-stored dialysers. This monokine-inducing activity could not be neutralised by the addition of polymyxin B and was heat unstable, indicating that the cell-activating stimulus was not endotoxin. Extensive rinsing of the module with water before extract preparation totally mitigated the in-vitro production of interleukin-1. Our results suggest that the extract-induced activation of peripheral blood mononuclear cells found with some dialysers containing membranes of cellulosic origin cannot be exclusively related to the membrane polymer, but depends on a number of other parameters such as sterilisation and storage mode of a given membrane.

Adjuvants, Immunologic↗
PubMed1989

Review of new Nearctic mosquito distributional records north of Mexico, with notes on additions and taxonomic changes of the fauna, 1982-89.

During the past 7 years, 24 species of Nearctic mosquitoes have had extensions to their known distribution in the form of 32 new state and province records in the United States and Canada. They are included in this report along with relevant references. Additionally, 3 new United States country records have been established, 3 species have had name changes, a new species of Anopheles and sibling species of another anopheline have been described. Details of these occurrences are covered.

Animals↗
PubMed1988

Immunologic complications of long-term implantation of a total artificial heart.

Bacterial infections are a significant complication of long-term total artificial heart implantation. We evaluated the functional capabilities of host defense mechanisms in two patients sustained long-term by a total artificial heart. Although serum complement and polymorphonuclear leukocyte function remained intact, both patients became B and T lymphopenic and there was an initial decrease in the ratio of helper/inducer to suppressor/cytotoxic cells. Histologic examination of their lymphoidal tissue at autopsy further revealed reduced numbers of germinal centers and atrophy of the T lymphocyte-dependent areas. In addition, the reticuloendothelial system was engorged with degenerate erythrocytes. We hypothesize that blockade of the reticuloendothelial system was induced by multiple blood transfusions necessitated by device-associated hemolysis and coagulopathy. This blockade may have led to a progressive loss of content of the antigen-specific lymphoidal elements and, perhaps, to a reduced ability to ingest microbe-antibody complexes.

Bacterial Infections↗