Targeted in vivo gene transfection modulated hyperacute rejection of pig lungs perfused with human blood.
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Animals↗
Biomedical subjects
D G White
Publications and source records attributed to D G White.
Human saphenous vein contains both endothelin ETA and ETB contractile receptors.
We have investigated the endothelin receptor subtypes mediating contraction in isolated preparations of human saphenous vein. Endothelin-1 (EC50: 17.8 nM), endothelin-3 (EC50: 82.3 nM) and the endothelin ETB receptor-selective agonists, [Ala1,3,11,15]endothelin-1 (EC50: 63 nM) and sarafotoxin S6c (EC50: 0.75 nM) all produced concentration-dependent contractions of human saphenous vein, although [Ala1,3,11,15]endothelin-1 and sarafotoxin S6c only produced a contraction in approximately 50% of the preparations tested. The endothelin ETA receptor antagonist, BQ123 (D-Val,Leu,D-Trp,D-Asp,Pro; 10 microM), antagonized endothelin-1-induced contractions with an estimated potency (pKB approximately 6.0) which was an order of magnitude lower than reported previously for non-human isolated vascular tissues from other species (pA2 values approximately 7.0). These data suggest that both endothelin ETA and endothelin ETB receptors can mediate vascular smooth muscle contraction in human saphenous vein.
Dose-Response Relationship, Drug↗
Chronic rejection of liver transplants revisited.
We examined 27 hepatectomy specimens to assess the frequency of foam cell endovasculitis and bile duct loss in chronic rejection. Arterial lesions, defined as total occlusion by subintimal foam cells and/or fibromuscular proliferation, were found mainly in hilar and septal arteries, whereas bile duct loss, defined as the absence of bile ducts in more than 50% of portal tracts, affected mainly small tracts. Both were found in 20 livers (74%). In two livers (7%) there was significant bile duct loss but no arterial lesions, whilst in five cases (19%) there were occlusive arterial lesions but no bile duct loss. Small arteries were involved in only 10% of the cases. These results indicate that in one-third of the cases arterial and bile duct lesions develop independently of each other, suggesting different pathogenetic pathways. In addition, liver biopsy may not be pathognomonic since small arteries are involved in only 10% of cases and bile duct loss may not be extensive. In such cases the diagnosis of chronic rejection should only be made in the presence of progressive clinical deterioration.
Adolescent↗
An outbreak of Campylobacter infection associated with the consumption of unpasteurised milk at a large festival in England.
Seventy-two laboratory confirmed cases of Campylobacter infection were identified in people who attended a large festival in England. A case-control study was undertaken to identify the vehicle of infection. Potential risk factors included the water supply to the site, and food, bottled spring water and unpasteurised milk sold at the event. Only the consumption of unpasteurised milk showed a statistical association with having a Campylobacter infection, strongly suggesting that this was the vehicle of infection.
Adolescent↗
Medical school-community dialogue: a survey of current initiatives in Canada and the United States.
BACKGROUND: Medical schools are being challenged to respond to societal needs and to engage in dialogue with the public, but there are few empirical data on the extent and nature of such efforts. METHODS: In early 1992, the associate deans for medical education at all accredited medical schools in the United States and Canada were surveyed regarding public involvement in their schools. Their descriptive responses were analyzed by computer search for key words, and correlations were determined between response categories and the schools' characteristics. RESULTS: Of the 95 responding schools (66%), 59 (62%) regularly involved members of the public in administrative bodies, usually those related to research, admission, hospital boards, and undergraduate education. Community-based schools were more likely to involve the public. Sixty schools (63%) had taken steps to identify community needs, and these schools showed evidence of greater public involvement in administration. The respondents perceived public involvement as beneficial primarily for building commitment between a school and its community. CONCLUSION: In contrast to concerns about declining trust between medical schools and the public, the impressions of the 95 respondents about public involvement in their schools were positive. The survey results suggest that such involvement builds mutual understanding and represents a direct and constructive response to declining trust.
Canada↗
Characterization of three non-peptide endothelin receptor ligands using human cloned ETA and ETB receptors.
1. A number of putative endothelin (ET) receptor ligands were synthesized with a view to assessing their relative affinity for human recombinant ET receptors. 2. Human (h) and endothelin ETA and ETB receptor open reading frames were cloned by reverse transcription-polymerase chain reaction into the mammalian expression vector pcDNA1 and stable cell lines were created by transfection of Chinese hamster ovary cells. 3. Scatchard analyses of saturation isotherms for the specific binding of [125I]-endothelin-1 ([125I]-ET-1) to membranes, prepared from Chinese hamster ovary cells transfected with hETA or hETB receptors, yielded values for equilibrium dissociation constants (Kd) of 20.5 +/- 1.8 pM and 25.5 +/- 5.5 pM, respectively. Hill coefficients did not differ significantly from unity, suggesting binding to homogeneous, non-interacting receptor populations. 4. Pharmacological characterization of the transfected hETA and hETB receptors was undertaken by measuring the relative abilities of ETA and ETB receptor-selective peptide ligands to inhibit binding of [125I]ET-1. For interaction with hETA receptors, the relative order of potency was ET-1 > ET-3 = FR139317 = BQ123 >[Ala1,3,11,15]-ET-1 = sarafotoxin S6c (S6c). In contrast, the relative order of potency, at hETB receptors, was ET-1 = ET-3 = [Ala1,3,11,15]-ET-1 = S6c >> FR139317 = BQ123. 5. The novel non-peptide ligands, Ro 46-2005, SB 209670 and BMS 182874, were found to inhibit [125I]-ET-1 binding to human recombinant ETA and ETB receptors. At hETA receptors, the calculated pIC50 values were 6.7 (Ro 46-2005), 8.7 (SB 209670) and 5.8 (BMS 182874), while at hETB receptors, the corresponding pIC50 values were 6.8, 7.5 and <5, respectively.6. In conclusion, we have characterized the pharmacology of human cloned ETA and ETB receptors and used these in membrane binding assays to determine the affinity and selectivity of three structurally diverse non-peptide ET receptor ligands. SB 209670 is, to date, the highest affinity non-peptide ligand to be described for ET receptors. As such, it may prove to be a valuable tool in further examination of the physiological and pathophysiological roles of endothelins.
Animals↗
Xenograft rejection in the guinea pig.
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Animals↗
Diagnosis and treatment of metabolic acidosis in calves: a field study.
The history and results of a clinical examination were recorded for 32 spring-born suckler calves which were hospitalised for intravenous fluid therapy. Blood samples were taken before treatment, during treatment and before discharge and analysed for colostral status, total carbon dioxide as an indication of acid-base status, and haematocrit. All the calves were given intravenously 5 to 10 litres of electrolyte solution containing 144 mmol/litre sodium, 4 mmol/litre potassium, 113 mmol/litre chloride and 35 mmol/litre bicarbonate, supplemented, in 24 calves, with up to 450 ml of 1M sodium bicarbonate. Nearly all the calves were recumbent but less than half were dehydrated on admission. The signs of dehydration were well correlated with each other and with the haematocrit. Neither the history nor the clinical signs were useful predictors of acidosis. There was no relationship between the severity of acidosis and the degree of dehydration. Acidosis was more prevalent in older calves (P < 0.01). For the severely acidotic calves, supplementary intravenous fluid with sodium bicarbonate significantly (P < 0.05) improved the total blood carbon dioxide at discharge. All 32 calves recovered. It is possible to treat acidotic calves with intravenous fluid therapy effectively, economically and according to their individual needs. The Harleco apparatus is a simple, useful, cost-effective adjunct to the diagnosis and treatment of this life-threatening condition.
Acidosis↗
Some logistical aspects of the treatment of lactic acidosis in two calves.
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Acidosis, Lactic↗
Clonal relationships and variation in virulence among Escherichia coli strains of avian origin.
Average genetic relatedness among 44 Escherichia coli strains of serotypes O1, O2, and O78 isolated mainly from birds with colibacillosis or swollen-head syndrome from France or Saudi Arabia was estimated based on allelic variation detected by multilocus enzyme electrophoresis. For 20 enzyme-encoding loci, we resolved 2.8 alleles per locus and distinguished 17 electrophoretic types (ETs) that were used to mark naturally occurring cell lineages or clones. On average, ETs differed at 37% of their loci. Forty-eight percent of the isolates represent three ETs, two of which belong to previously defined complexes of clones identified in avian disease in North America and Europe. Virulence of strains, assessed in experimental infections of day-old chicks, showed little variation among isolates of a clone, but was significantly variable among isolates of different clone complexes. These findings add support to the evidence that a majority of avian isolates that cause colibacillosis belong to a few cosmopolitan pathogenic clones and indicate a substantial between-clone component of pathogenicity.
Alleles↗
Clonal diversity among strains of Escherichia coli incriminated in turkey colisepticemia.
The extent of genetic differentiation among 80 Escherichia coli isolates collected from turkeys with acute colisepticemia was assessed based on allelic variation at 20 enzyme-encoding loci detected by multilocus enzyme electrophoresis. Isolates were polymorphic at 17 loci and were classified into 32 multilocus genotypes, delineating clones, that differed on average at 36% of the loci. In the total sample, 29 (36%) of the isolates belonged to one of two closely related clones, differing only in a single electromorph, and 11 of these isolates were serogroup O78. Most isolates fell into one of 4 genetically distinct clusters of strains. Three of these clusters represent E. coli clone complexes that have been previously identified in avian diseases and a fourth cluster which is specific to colisepticemia in turkeys. Most (73%) isolates produced aerobactin, whereas none produced hemolysins. Assays for detecting K1 capsules, including the use of polyclonal antisera, monoclonal antibodies, and K1-specific bacteriophages, gave variable results, but showed that overall 18% of the strains from colisepticemia were K1 encapsulated with most of the K1+ isolates found in one clone cluster. The results show that many cases of colisepticemia in turkey flocks are caused by a small number of pathogenic clones representing at least three distinct clone complexes.
Animals↗
Beta-lactam susceptibility of Haemophilus influenzae strains showing reduced susceptibility to cefuroxime.
Minimum inhibitory concentrations of 13 beta-lactam antibiotics (ampicillin, amoxycillin, amoxycillin/clavulanate, imipenem, cefazolin, cefadroxil, cefaclor, cefuroxime, cefotaxime, cefepime, cefpirome, cefpodoxime and cefixime), were determined for 76 strains of beta-lactamase negative Haemophilus influenzae, isolated over a five year period (1985-1990) that gave reduced zones to cefuroxime on disc testing when compared to the control strain H. influenzae NCTC 11931. MIC90 values for all antibiotics (except imipenem) were approximately ten times higher than the MIC90 values for a susceptible control group. Increased resistance was not associated with any particular biotype, although three biotype III strains were highly resistant to imipenem. More than 50% of strains with reduced susceptibility to beta-lactam antibiotics were isolated from patients with chronic respiratory disease. Published data on the sputum concentration of each antibiotic were compared to the MIC90 values obtained for the susceptible and resistant strains.
Anti-Bacterial Agents↗
Endothelin ETA and ETB receptors mediate vascular smooth-muscle contraction.
Endothelin (ET) ETA receptors on vascular smooth muscle are believed to mediate the vasoconstrictor effects of ET isopeptides, and ETB receptors on the endothelium are thought to mediate the vasodilator effects. This study has investigated the receptors mediating endothelin-induced contraction of isolated ring preparations of rat thoracic aorta (RTA) and rabbit carotid artery (RCA), pulmonary artery (RPA), and jugular vein (RJV). In RTA and RCA, ET-1 (EC50 4.5 and 5.2 nM, respectively) was 82- and 108-fold, respectively, more potent than ET-3, whereas the ETB receptor-selective agonists sarafotoxin S6c (S6c) and Ala1,3,11,15-ET-1 (4-Ala-ET-1) were without effect up to > or = 1 microM. In contrast, in RPA and RJV, ET-1 (EC50 3.1 and 0.7 nM, respectively) and ET-3 (EC50 4.4 and 0.9 nM, respectively) were equipotent, and 4-Ala-ET-1 (EC50 10.7 and 2.1, respectively) and S6c (EC50 0.4 and 0.1 nM, respectively) were potent contractile agonists. The ETA receptor antagonist BQ123 (D-Val-Leu-D-Trp-D-Asp-Pro) competitively antagonized the effects of ET-1 in RTA and RCA (pA2 values 6.9 +/- 0.1 and 6.8 +/- 0.2, respectively) but did not antagonize (at 10 microM) contractions to ET-1, ET-3, or 4-Ala-ET-1 in RPA and RJV. In conclusion, contraction of vascular smooth muscle by endothelins can be mediated by both ETA and ETB receptors.
Animals↗
The effect of NG-nitro-L-arginine methyl ester upon basal blood flow and endothelium-dependent vasodilatation in the dog hindlimb.
1. The role played by the endothelium-derived relaxing factor (EDRF), nitric oxide (NO) in the regulation of blood flow to the skeletal muscle vasculature of the dog skinned hindlimb has been determined by examining the effects of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) upon (i) basal iliac artery blood flow, (ii) vasodilator responses to endothelium-dependent and -independent agonists and (iii) reactive hyperaemic responses to arterial occlusion. 2. L-NAME (0.1-3 mg min-1) infused directly into the iliac artery dose-dependently reduced basal iliac artery blood flow by a maximum of 48.6 +/- 6.9% (n = 4) and also increased mean systemic arterial blood pressure by 25.6 +/- 5.0 mmHg (n = 4) (at 3 mg min-1 L-NAME). 3. Over the same dose range, L-NAME also inhibited the peak vasodilator responses to intra-arterially administered, submaximal bolus doses of the endothelium-dependent agonists, bradykinin (3-300 ng) and acetylcholine (30-300 ng) by approximately 40%. In contrast, peak vasodilator responses to the endothelium-independent agonists, sodium azide (3-30 micrograms) and adenosine (0.3-1 mg), and peak reactive hyperaemic responses to arterial occlusion (60 s) were largely unaffected by L-NAME. 4. The dose-related effects of L-NAME on basal iliac artery blood flow, mean systemic arterial blood pressure and endothelium-dependent vasodilator responses were significantly attenuated by pretreatment with L-arginine (100 mg min-1) followed by co-infusion of L-arginine (100 mg min-1) with L-NAME. 5. In conclusion, these data suggest that NO plays some role in regulating basal blood flow and in mediating the vasodilator responses to the endothelium-dependent agonists bradykinin and acetylcholine in the skeletal muscle vasculature of the dog hindlimb. The substantial component (~60%) of the peak vasodilator responses to bradykinin and acetylcholine, unaffected by L-NAME, may be independent of NO, or be mediated by an alternative EDRF-dependent but L-NAME-insensitive mechanism.
Adenosine↗
The effect of endothelins on nitric oxide and prostacyclin production from human umbilical vein, porcine aorta and bovine carotid artery endothelial cells in culture.
1. This study has investigated the effects of the endothelin isopeptides, endothelin-1 (ET-1), ET-2 and ET-3 on the production of the endothelium-derived relaxing factors, nitric oxide (NO) and prostacyclin (PGI2) from primary cultures of endothelial cells obtained from human umbilical vein (HUVECS), porcine aorta (PAECS) and bovine carotid artery (BCAECS). 2. NO generation was assessed indirectly by measuring production of cyclic GMP and PGI2 formation was measured by radioimmunoassay of 6-keto PGF1 alpha. 3. In HUVECS, histamine (1 microM) increased cyclic GMP and 6-keto PGF1 alpha production by 12.6 +/- 2.0 and 4.9 +/- 0.7 fold respectively over the corresponding basal values. Haemoglobin (10 microM) and the NO synthase inhibitor NG-monomethyl-L-arginine (10 microM) significantly inhibited the increase in cyclic GMP formation in response to histamine but had no effect on 6-keto PGF1 alpha production. In contrast to histamine, the endothelin isopeptides (ET-1, ET-2 and ET-3; 0.01-1000 nM) produced no significant change in either cyclic GMP or 6-keto PGF1 alpha production in HUVECS. 4. In a separate series of experiments, ET-3 (0.01-1000 nM) also failed to produce any significant change in cyclic GMP or 6-keto PGF1 alpha production from primary cultures of PAECS and BCAECS. In contrast, bradykinin (0.1 microM) and sodium nitroprusside (1 mM) were used as positive control agents and increased cyclic GMP production in these cells. 5. In conclusion, the endothelin isopeptides do not release NO and PGI2 from primary cultures of HUVECS, PAECS and BCAECS. This suggests that endothelin receptors are either absent from these cells or are not coupled to NO or PGI2 production.
6-Ketoprostaglandin F1 alpha↗
A technique for perfusion of an isolated working heart to investigate hyperacute discordant xenograft rejection.
We developed an isolated working heart preparation to investigate hyperacute rejection of discordant xenografts. It is possible to correlate organ failure with the rejection process, and end points of rejection are easily identified. This unique model permits easy sampling of perfusates and examination of the rejected organ. The perfusate may be modified in ways not possible in in vivo preparations. Investigation of the discordant rabbit-to-pig combination with the technique has confirmed that hyperacute xenograft rejection can be reproduced. Rejection appears to be a complement-mediated immunologic phenomenon rather than the consequence of a nonspecific physical incompatibility. Hyperacute xenograft rejection can be prevented by depletion of C3 from the perfusing blood by treatment with cobra venom factor.
Animals↗
Fasting in the rat does not induce hyperfibrinogenaemia.
The effects of fasting in the rat on the plasma fibrinogen concentration have been investigated. Fasting for 24-48 hr produced the expected sustained increase (4-5-fold) in the concentrations in the plasma of non-esterified fatty acids, but no accompanying increase in that of fibrinogen was detected.
Animals↗