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Biomedical subjects

A J Ritchie

Publications and source records attributed to A J Ritchie.

At least 19 recordsLinked to original sources
PubMed2001

Effect of the blood substitute diaspirin crosslinked hemoglobin in rat mesenteric and human radial collateral arteries.

The actions of the blood substitute diaspirin crosslinked hemoglobin (DCLHb) were investigated in rat (small mesenteric artery) and human (radial collateral artery) resistance vessels mounted in a wire myograph for isometric tension recording. DCLHb did not contract resting vessels from rats, but vasoconstrictor responses were observed in isolated arteries and perfused mesenteric beds prestimulated with threshold concentrations of methoxamine. The DCLHb contractile responses were greatly attenuated by N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME) or endothelial removal, whereas BQ-123 (endothelin A receptor antagonist), prazosin (alpha1-adrenoceptor antagonist), or indomethacin (cyclooxygenase inhibitor) had no effect. Endothelium-dependent relaxations to carbachol in both rat mesenteric and human radial collateral artery were inhibited by DCLHb. Relaxations to carbachol were studied in the presence of L-NAME or 25 mM KCl to investigate the effect of DCLHb on endothelium-derived hyperpolarizing factor (EDHF) and nitric oxide, respectively. In both rat and human vessels, EDHF-mediated relaxations were not affected by DCLHb preincubation, whereas the nitric oxide component of carbachol-induced relaxations was practically abolished. In conclusion, inhibition of the effects of basal nitric oxide release underpins the vasoconstrictor effects of DCLHb. DCLHb effectively abolishes the nitric oxide component of carbachol-induced relaxation, with no effect on the EDHF-mediated component in both isolated rat mesenteric and human radial collateral arteries.

Animals↗
PubMed2001

Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin.

Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb3) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-alpha) upregulates Gb3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-alpha treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb3 levels. Differential expression of Gb3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS.

Blood-Brain Barrier↗
PubMed2000

The action of diaspirin cross-linked haemoglobin blood substitute on human arterial bypass conduits.

BACKGROUND: Immediately available blood substitutes could transform medicine. In coronary artery surgery, vasoconstriction induced by some of these agents could have serious implications. We have examined some of the vasoactive effects of one of these blood substitute, diaspirin cross-linked haemoglobin (DCLHb), on isolated rings of human arterial conduits. METHODS: Sections of human left internal mammary artery (LIMA) and radial artery (RA) were cut into 3-mm rings, mounted in individual organ baths containing aerated (95% O(2)/5% CO(2)) Krebs-Heinseleit solution at 37 degrees C and attached to isometric strain gauge for measurements of tension. All rings were tested for the presence of endothelium by addition of carbachol to rings pre-contracted with phenylephrine. The relative importance of nitric oxide (NO) in contraction mediated by the addition of DCLHb was studied. RESULTS: Carbachol relaxed phenylephrine precontracted LIMA by 72.3+/-1.7% and RA by 97+/-0.7% confirming the presence of a functional endothelium. Sodium nitroprusside (SNP) caused complete relaxation of LIMA with an EC(50) value of 2.0+/-0.1x10(-8) M and RA with an EC(50) value of 1. 9+/-0.1x10(8) M. In the presence of DCLHb (10(-7) M), carbachol-induced relaxation was significantly reduced to 46.3+/-0. 7% (P<0.01) and the BC(50) value for SNP relaxation increased to 1. 2+/-0.1x10(-7) M (P<0.01). DCLHb caused rings to contract in the absence of phenylephrine with EC(50) values of 1.6+/-0.1x10(-7) M (LIMA) and 1.8+/-0.1x10(-7) M (RA). Presence of L-NAME (300 microM) caused no alteration in DCLHb-induced contraction. CONCLUSION: In this study of isolated rings of human vessels, DCLHb causes a significant reduction in relaxation mediated by carbachol and SNP, which is likely to be due to its ability to bind NO. However, it is possible that other mechanisms might contribute to the vasoconstrictor effects of DCLHb and these might be amenable to anti-vasospastic strategies.

Aged↗
PubMed2000

Clinical versus actual outcome in cardiac surgery: a post-mortem study.

BACKGROUND: Clinical attribution of the cause of death can be misleading, with the only true outcome measure being post-mortem analysis. Despite this there is very little published data on post-mortems following cardiac surgery. METHODS: Prospective consecutive post-mortem data were collected on 167 patients (84.4% of all in-hospital cardiac surgical deaths) in a single institution. Clinical diagnoses were compared with post-mortem findings. RESULTS: The mean age at death was 69.8 with 67.6% male. The proportion undergoing coronary artery bypass graft (CABG) alone was 52.1%, valve surgery 18.6%, valve+CABG 19.2% and other procedures 10.1%. The mean time to death was 7.9 days (range 0-87). The causes of death were cardiac 67.7%, gastrointestinal 9.6%, respiratory 8.4%, haemorrhage/technical failure 4.8%, stroke (cerebrovascular accident) 3.6%, multiorgan failure 3.0%, sepsis 1.8%, malignancy 0. 6% and trauma 0.6%. Post-mortem revealed an unsuspected cause of death in 19 (11.4%). These were gastrointestinal (infarction nine, perforation two), cardiac three, adult respiratory distress syndrome two, technical two and pulmonary embolus one. In addition, an unsuspected lung cancer was found in 1 patient who died of cardiac causes. When cardiac deaths were compared with non-cardiac causes the Parsonnet score was higher 20.0 (+/-1.4) vs. 15.3 (+/-1.6), P=0. 07; and a greater proportion tended to have poor ejection fractions (34 vs. 15%), P=0.12. There was no significant difference between the groups in terms of age, sex, operation, hypertension, diabetes, creatinine and body mass. CONCLUSIONS: Post-mortem can determine unsuspected diagnoses in a significant proportion of cases. Pre-operative risk factors do not correlate with eventual cause of death. Post-mortem still has an important role to play in cardiac surgery.

Aged↗
PubMed2000

Inhibitory effects of glibenclamide on the contraction of human arterial conduits used in coronary artery bypass surgery.

Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated. Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37 degrees C. Contractions were obtained by either the use of a thromboxane analogue (U46619), L-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2+/-0.17 (n = 7) for LIMA and 3.26+/-0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 microM) caused the concentration-response curves for U46619 and L-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 microM) also had an inhibitory effect on Ca2+-induced tension in radial artery. These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Mesothelioma--VATS biopsy and lung mobilization improves diagnosis and palliation.

OBJECTIVES: Mesothelioma is an increasingly frequent malignancy in which diagnosis is often delayed and disease diagnosed at an advanced stage. Earlier diagnosis and therapeutic intervention that can control recurrent pleural effusion may improve outlook and survival. METHODS: A prospective series of 25 patients in whom mesothelioma was suspected was referred for histological diagnosis by video assisted-thoracoscopy (VAT) after failure of other methods. At the same operative procedure drainage of pleural effusion, cytoreductive pleurectomy and lung mobilization was performed where possible. Complete follow-up was obtained. RESULTS: All patients had a histological diagnosis (100%) from the material sent for biopsy. In 23 patients this was mesothelioma, in two patients chronic empyema. All patients undergoing drainage of effusion, cytoreductive pleurectomy and lung mobilization subsequently were diagnosed of having mesothelioma stages III to IV. Fifteen out of 21 who underwent lung mobilization had closure of the pleural space. Post operative air leak in this group was a mean of 5 days (2-12 days). Recurrent effusion occurred in only one patient. Eleven patients remain alive at 1-2 years post operation with no hospital admissions for recurrent pleural effusion. In the six out of 21 who did not have closure of the pleural space, one remained alive 9 months post surgery. Five died within 1-6 months of the procedure. The average number of further hospital admissions for repeat drainage of effusion was 3 (1-6). CONCLUSIONS: VATs provides adequate tissue for histological diagnosis where other methods fail. At the same operative sitting it provides a therapeutic intervention that allows drainage of effusion cytoreductive pleurectomy and lung mobilization in a significant number of cases. Where the pleural space can be closed this results in significantly fewer hospital admissions and appears to improve quality of life and length of survival. The price is a longer hospital stay due to prolonged air leak.

Adult↗
PubMed1999

Current practice in thoracic sympathectomy.

Thoracic sympathectomy has been performed for many years. With the recent development of video assisted thoracic surgical techniques the indications for surgery have increased, and the outcome is much better.

Humans↗
PubMed1998

Comparison of p53 and DNA content abnormalities in adenocarcinoma of the oesophagus and gastric cardia.

This study examined the association between 17p allelic loss, p53 gene mutation, p53 protein expression and DNA aneuploidy in a series of adenocarcinomas arising in the oesophagus and gastric cardia. 17p allelic loss was detected in 79% (15 of 19) of oesophageal and in 83% (29 of 35) of gastric adenocarcinomas. p53 mutations were detected in 70% (14 of 20) and 63% (26 of 41) of oesophageal and of gastric adenocarcinomas respectively. Both tumour types were associated with a predominance of base transitions at CpG dinucleotides. In five cases of oesophageal adenocarcinoma, the same mutation was detected both in tumour and in adjacent dysplastic Barrett's epithelium. Diffuse p53 protein expression was detected in 65% (13 of 20) and 59% (24 of 41) of oesophageal and of gastric tumours, respectively, and was associated with the presence of p53 missense mutation (Chi-squared, P < 0.0001). DNA aneuploidy was detected in 80% (16 of 20) of oesophageal and in 70% (28 of 40) of gastric tumours. No association was found between p53 or DNA content abnormalities and tumour stage or histological subtype. In conclusion, this study detected a similar pattern of p53 alterations in adenocarcinoma of the oesophagus and gastric cardia--molecular data consistent with the observation that these tumours demonstrate similar clinical and epidemiological features.

Adenocarcinoma↗
PubMed1998

Barrett's oesophagus: microsatellite analysis provides evidence to support the proposed metaplasia-dysplasia-carcinoma sequence.

The development of adenocarcinoma in Barrett's oesophagus is proposed to occur via a stepwise progression recognised histologically as a metaplasia-dysplasia-carcinoma sequence. In order to identify chromosomal loci involved in the malignant transformation of Barrett's epithelium and the development of oesophageal adenocarcinoma, microsatellite analysis was carried out on 17 cases of Barrett's-associated oesophageal adenocarcinoma. Samples of premalignant Barrett's epithelium adjacent to adenocarcinoma were obtained from seven of these cases. Allelic imbalance was detected in > 45% of informative cases of oesophageal adenocarcinoma on chromosome arms 3q (65%), 4q (71%), 5q (59%), 6q (59%), 9p (50%), 9q (47%), 12p (47%), 12q (65%), 17p (76%), and 18q (75%). Allelic imbalance at 4q, 17p, and 18q was significantly higher than the upper 95% confidence interval for background allelic imbalance. Allelic imbalance was detected at several loci in the premalignant epithelium from five of the seven cases studied. These loci included several chromosomal arms that had demonstrated high levels of allelic imbalance in oesophageal adenocarcinoma, namely, 4q (one case), 5q (two cases), 9 (three cases), 12q (five cases), 17p (four cases), and 18q (two cases). Novel microsatellite alleles were detected in both premalignant and malignant Barrett's epithelium. In three cases, dysplastic Barrett's epithelium and adjacent adenocarcinoma demonstrated the same pattern of novel microsatellite alleles at a number of loci. In conclusion, these data indicate chromosomal loci which may be specifically involved in the histological progression of Barrett's epithelium. The detection of shared novel microsatellite alleles in premalignant and malignant Barrett's epithelium is consistent with a process of clonal expansion underlying this progression.

Adenocarcinoma↗
PubMed1998

Increased levels of advanced glycation endproducts in the lenses and blood vessels of cigarette smokers.

BACKGROUND: Advanced glycation endproducts (AGEs) arise from the spontaneous reaction of reducing sugars with the amino groups of macromolecules. AGEs accumulate in tissue as a consequence of diabetes and aging and have been causally implicated in the pathogenesis of several of the end-organ complications of diabetes and aging, including cataract, atherosclerosis, and renal insufficiency. It has been recently proposed that components in mainstream cigarette smoke can react with plasma and extracellular matrix proteins to form covalent adducts with many of the properties of AGEs. We wished to ascertain whether AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers. MATERIALS AND METHODS: Lens and coronary artery specimens from nondiabetic smokers and nondiabetic nonsmokers were examined by immunohistochemistry, immunoelectron microscopy, and ELISA employing several distinct anti-AGE antibodies. In addition, lenticular extracts were tested for AGE-associated fluorescence by fluorescence spectroscopy. RESULTS: Immunoreactive AGEs were present at significantly higher levels in the lenses and lenticular extracts of nondiabetic smokers (p < 0.003). Anti-AGE immunogold staining was diffusely distributed throughout lens fiber cells. AGE-associated fluorescence was significantly increased in the lenticular extracts of nondiabetic smokers (p = 0.005). AGE-immunoreactivity was significantly elevated in coronary arteries from nondiabetic smokers compared with nondiabetic nonsmokers (p = 0.015). CONCLUSIONS: AGEs or immunochemically related molecules are present at higher levels in the tissues of smokers than in nonsmokers, irrespective of diabetes. In view of previous reports implicating AGEs in a causal association with numerous pathologies, these findings have significant ramifications for understanding the etiopathology of diseases associated with smoking, the single greatest preventable cause of morbidity and mortality in the United States.

Aged↗
PubMed1997

Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF.

Thrombin is the central bioregulatory enzyme in hemostasis and is generated in vascular beds in which inflammatory responses are ongoing. In this study, we examined the effect of thrombin, both alone and in combination with TNF, on gene expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8, plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin blocked the induction of mRNA, suggesting that the increased gene expression was due to thrombin-specific activity. Because these genes are known to contain nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we next examined the ability of thrombin to activate this transcription factor. As detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding activity. Supershift analysis revealed that these complexes were comprised principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin alone did not substantively increase protein levels of E-selectin despite the increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10-fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E-selectin transcription by thrombin was observed in experiments utilizing luciferase reporter constructs expressed in bovine aortic EC. The ability of thrombin to potentiate TNF-induced EC activation thus provides an important mechanism by which products of the coagulation cascade may enhance cytokine-mediated inflammatory responses.

Animals↗
PubMed1997

Allelotype analysis of adenocarcinoma of the gastric cardia.

To identify chromosomal loci involved in the development of proximal gastric adenocarcinoma, this study delineated the pattern of allelic imbalance in a series of 38 adenocarcinomas arising in the gastric cardia. A total of 137 microsatellite markers covering all autosomal arms, excluding acrocentric arms, were analysed. A mean of 35 out of a total of 39 chromosomal arms studied were informative for each patient. The tumour group demonstrated a high level of allelic imbalance, with an observed median fractional allelic imbalance of 0.47 for the 29 intestinal-type adenocarcinomas and 0.54 for the nine diffuse-type adenocarcinomas. Allelic imbalance was detected in >50% of informative cases in both histological subtypes on a number of chromosomal arms. In the intestinal subtype, these included, 3p (61%), 4q (71%), 5q (59%), 8p (60%), 9p (65%), 9q (83%), 12q (52%), 13q (52%), 17p (78%) and 18q (70%). A higher incidence of allelic imbalance was detected on chromosome 16q in tumours of the diffuse type relative to those of the intestinal type. A more detailed mapping on chromosomes 4q and 6q identified a number of cases with subchromosomal breakpoints. In conclusion, this analysis has indicated regions of the genome potentially involved in the development of proximal gastric carcinomas.

Adenocarcinoma↗
PubMed1996

Widespread microsatellite instability occurs infrequently in adenocarcinoma of the gastric cardia.

Heredity non-polyposis colorectal cancer (HNPCC) is associated with an increased predisposition to colorectal cancer and extra-colonic cancers of the gastro-intestinal, urological and female reproductive tracts. These tumours are characterised by an underlying defect in DNA mismatch repair and exhibit numerous replication errors throughout the genome (RER+ phenotype). HNPCC-associated gastric tumours, and a subset of sporadic, distally-located gastric tumours exhibit this RER+ phenotype. It is recognised that proximal and distal gastric tumours exhibit distinct epidemiological features. In this study we investigated the occurrence of microsatellite instability in a series of 38 primary gastric adenocarcinomas, arising in the proximal stomach. A total of 138 microsatellite markers, comprising mainly dinucleotide and tetranucleotide repeat units and covering all autosomal arms, excluding acrocentric arms, were analysed. One tumour demonstrated somatic microsatellite alterations at 62% (26 of 42) of loci tested. A further 32 tumours demonstrated levels of microsatellite instability ranging from 0.8% (1 of 28)-11.4% (15 of 132) of loci tested. Five tumours demonstrated no microsatellite alterations at any of the loci tested. These findings suggest that a high percentage of proximal gastric carcinomas exhibit a low level of microsatellite alterations at dinucleotide and tetranucleotide repeat loci. However, ubiquitous somatic alterations at these loci, characteristic of HNPCC-associated tumours, occur in a relatively small proportion of tumours.

Adenocarcinoma↗
PubMed1996

Ubiquitous somatic alterations at microsatellite alleles occur infrequently in Barrett's-associated esophageal adenocarcinoma.

Microsatellite alterations have been documented in a subset of sporadic tumors, including those of the colon, lung, bladder, stomach, and esophagus. This study documented the frequency of microsatellite alterations at 139 loci, comprising predominantly dinucleotide and tetranucleotide repeat units, in 17 cases of primary esophageal adenocarcinoma arising against a background of Barrett's metaplasia. Each tumor demonstrated alterations in at least one locus studied. Widespread microsatellite alterations, occurring at 45.3% (58 of 128) of loci tested, were detected in a single case. The remaining 16 tumors exhibited low levels of microsatellite instability, ranging from 0.8% (1 of 128) to 8.1% (10 of 123) of loci tested. The single case with ubiquitous somatic alterations showed no significant difference in the incidence of novel alleles at di- and tetranucleotide repeat loci. The 16 cases showing a low level of microsatellite alterations demonstrated a 3.3-fold higher incidence of novel alleles at tetranucleotide repeat loci compared to dinucleotide repeat loci. These data suggest that ubiquitous somatic alterations at microsatellite loci, considered a phenotypic expression of defective mismatch repair, occur infrequently in Barrett's-associated adenocarcinoma. However, the majority of these tumors demonstrate a low level of microsatellite alterations, perhaps reflecting the inherent instability of these markers.

Adenocarcinoma↗
PubMed1996

Expression and activation of protein kinase C isoforms in a human megakaryocytic cell line.

Megakaryocytes undergo a unique differentiation program, becoming polyploid through repeated cycles of DNA synthesis without concomitant cell division. We have shown previously that phorbol 12-myristate 13-acetate (PMA) induces the Dami human megakaryocytic cell line to become polyploid and to express platelet-specific proteins, including von Willebrand factor (vWF) and glycoprotein Ib (GpIb). Phorbol esters are thought to regulate gene expression principally through the activation of protein kinase C (PKC), a family of structurally related kinases with potentially unique activation requirements and substrate specificities. A survey of PKC isoforms in Dami cells revealed that, by both Western and Northern analyses, PKC isoforms alpha, beta, delta, epsilon, eta, theta, and zeta were reproducibly detected. PKC-gamma was not detected. In order to define the role of individual PKC isoforms in megakaryocytic maturation, PMA and 2-deoxyphorbol 13-phenylacetate 20-acetate (dPPA), a putative selective activator of the PKC-beta 1 isotype, were compared for their effects on Dami cell maturation. Treatment with either dPPA or PMA caused Dami cells to cease proliferating, to become polyploid, and to express vWF. We also examined dPPA and PMA for their ability to activate and to downregulate expression of different PKC isoforms. Fifteen-minute treatment with PMA resulted in the translocation of PKC isoforms alpha, epsilon, and theta from the cytosolic to the membrane fraction; twenty-four hour treatment resulted in the downregulation of these isoforms. In contrast, dPPA was found to be a potent activator of PKC-epsilon alone and exhibited weaker effects on alpha and theta. These data suggest that PKC isoforms beta, delta, eta, and zeta, which appear not to be activated by either phorbol ester, are unlikely to be primarily involved in megakaryocytic maturation in response to these agents. The isoforms that are translocated by both phorbol esters-PKC isoforms alpha and theta, and particularly epsilon-are more likely to transduce the signals that stimulate Dami cell differentiation.

Cell Differentiation↗
PubMed1995

Base transitions at CpG dinucleotides in the p53 gene are common in esophageal adenocarcinoma.

This study examined the association between 17p allelic loss and p53 gene mutation in a series of 16 esophageal adenocarcinomas arising on a background of Barrett's esophagus. Two highly polymorphic dinucleotide repeat polymorphisms mapping to 17p13 were analyzed to assess the frequency of 17p allelic loss in these tumors. Mutations in the p53 gene were detected by direct DNA sequencing. Ninety-four % (15 of 16) of samples were informative at one or both polymorphic loci. Allelic loss at one or both loci was detected in 80% (12 of 15) of samples. Mutations were detected in 69% (11 of 16) esophageal adenocarcinomas, and there was a close association between 17p allelic loss and p53 gene mutation (P = 0.00879; Fisher's Exact Test). The tumors that were analyzed demonstrated a specific p53 mutation spectrum, with G:C to A:T base transitions at CpG dinucleotides accounting for 80% (8 of 10) of single-base substitutions. In three cases, the same p53 mutation was detected in both high-grade dysplasia and adjacent tumor. These results indicate that p53 gene alterations contribute to the development of esophageal adenocarcinoma and precede the development of invasive carcinoma in patients with Barrett's esophagus.

Adenocarcinoma↗