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Biomedical subjects

M J Edwards

Publications and source records attributed to M J Edwards.

At least 127 records · Page 7Linked to original sources
PubMed1997

En bloc pancreaticoduodenectomy and colectomy for duodenal neoplasms.

Duodenal malignancy is rare and generally considered to have both a low resectability rate and a poor prognosis. Historically, the involvement of the colon or its mesentery has been considered a criterion for unresectability by many surgeons because of the overall magnitude of surgery involved with an en bloc colectomy and pancreaticoduodenectomy. In the past few years, several reports have noted a decrease in morbidity and mortality rates for pancreaticoduodenectomy. The current safety of the procedure suggests that the classical criteria for resectability can now be reevaluated for certain neoplasms. We report two cases of pancreaticoduodenectomy with en bloc colectomy done as attempted curative resections for primary duodenal malignancies. The procedure was well tolerated by both patients; there were no major complications, and it provided both prolonged survival and effective palliation.

Adenocarcinoma↗
PubMed1997

Interleukin-2-induced hepatic injury involves temporal patterns of cell adhesion in the microcirculation.

The treatment of metastatic cancer with interleukin-2 (IL-2) is limited by systemic toxicities, including hepatic dysfunction. The objective of this study was to determine the cellular mechanisms of IL-2-induced hepatic injury. Intravital microscopy was used for the direct observation of the murine hepatic microcirculation after 2 h, 2 days, and 4 days of IL-2 treatment. At each interval, leukocyte- and platelet-endothelial adherence were observed and quantitated. Simultaneously, sinusoidal perfusion, serum levels of glutamate pyruvate transaminase, and edema were measured as indexes of hepatic toxicity. IL-2 increased neutrophil adhesion acutely in association with decreased sinusoidal perfusion. Leukocyte adhesion subsided at 2 days, but platelet-endothelial interactions were enhanced and 40% of mice receiving IL-2 had microvascular thrombi. These effects occurred in conjunction with decreased sinusoidal perfusion and the development of hepatic edema. After 4 days of IL-2, maximal hepatic edema, hypoperfusion, and increased serum levels of glutamate pyruvate transaminase were associated with increased lymphocyte adhesion and microvascular thrombosis. These data suggest coordinated, temporal roles of leukocytes and platelets in the generation of IL-2-induced hepatic injury.

Animals↗
PubMed1997

Hyperthermia, teratogenesis and the heat shock response in mammalian embryos in culture.

Hyperthermia is a recognized teratogen in animals and there is strong evidence that it also causes significant damage to human embryos. Studies with induced hyperthermia in pregnant animals defined the defects which are produced, the susceptible stages of development, and threshold doses of heat required to cause defects. The in vivo experiments lacked precision because of variability of embryonic development at a given conceptual age, varying maternal responses to agents causing temperature elevations, the difficulty in measuring embryonic temperature and the possibility that defects were caused by toxic changes in maternal metabolism. These variables were eliminated by the use of postimplantation whole rat and mouse embryo cultures, which were exposed to various doses of heat at closely defined stages of development. The studies showed that heat acts directly on embryos and that elevations of 2 degrees C and greater sustained over early rat organogenesis cause defects mainly by causing apoptotic cell death especially in the developing central nervous system. A moderate, non damaging exposure is followed within 15 min by protection for up to 8 h against a more severe and otherwise teratogenic exposure. The protective heat shock response is accompanied by a reduction of normal protein synthesis and concurrent synthesis of heat shock proteins (HSP90, 71, 47, 27). Most HSP in these families are also present constitutively in embryos, probably having important roles in protecting newly synthesized proteins from aggregation and facilitating folding into their normal functional configurations. The appearance of induced HSP and hsp mRNA at known sites of thermal damage suggests a protective role. Heat induced cell death by apoptosis is a feature of teratogenic damage to the developing brain. Apoptosis could be a by-product of a damaging heat exposure because of a priority favoring induction of the heat shock response over the normal gene program for organogenesis, survival being achieved at the expense of normal development.

Animals↗
PubMed1996

The role of cytokines, adhesion molecules, and chemokines in interleukin-2-induced lymphocytic infiltration in C57BL/6 mice.

IL-2 mediates the regression of certain malignancies, but clinical use is limited because of associated toxicities, including parenchymal lymphocytic infiltration with multiple organ failure. Secondarily induced cytokines are important mediators of IL-2 toxicity and IL-2-induced lymphocyte-endothelial adherence and trafficking. The recently discovered C-C chemokines, RANTES (regulated on activation, normal T expressed and secreted) and macrophage inflammatory protein-1alpha, have also been implicated in lymphocytic migration. We hypothesized that IL-2 alters cytokine, C-C chemokine, and adhesion molecule expression in association with parenchymal lymphocytic infiltration. C57BL/6 mice were injected with 3x10(5) IU of IL-2 or 0.1 ml of 5% dextrose intraperitoneally every 8 h for 6 d, then killed. IL-2 induced massive lymphocytic infiltration in the liver and lung and moderate infiltration in the kidney in association with organ edema and dysfunction. Immunostaining showed increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in association with this organ-specific lymphocytic infiltration. Flow cytometry showed increased expression of the corresponding ligands (lymphocyte function-associated antigen-1 and very late antigen-4) on splenocytes. IL-2 increased TNF-alpha mRNA and protein expression in the liver. Organs infiltrated by lymphocytes had increased TNF-alpha mRNA, whereas RANTES mRNA was increased in all organs, regardless of lymphocytic infiltration. IL-2 toxicity involves organ-specific TNF-alpha and RANTES production with increased ICAM-1 and VCAM-1 expression as potential mechanisms facilitating lymphocytic infiltration and organ dysfunction.

Animals↗
PubMed1996

Translocation of the retinoblastoma gene product during mitosis.

This study reports the immunocytochemical localization of the retinoblastoma gene product within synchronized normal human keratinocytes. Data suggest that mitotic spindles function in the transport of the retinoblastoma tumor suppressor gene product during cell division. A diffuse anti-pRB reactivity was detected within the nuclei of G1-phase keratinocytes, although staining was not evident within the nucleoli. During S-phase and G2-phase the anti-pRB reactivity was localized to discrete regions within the nuclear compartment. The anti-pRB reactivity of M-phase cells was localized to the mitotic spindles and microtubule nucleation centers. Immunoprecipitation and Western blotting of the pRB antigen from synchronized keratinocytes showed that the apparent polypeptide molecular weight of pRB increased from 105 kDa during G1-phase to 115 kDa during M-phase. Immunoprecipitation of the pRB antigen from mitotic spindles resulted in the coprecipitation of two polypeptides with apparent polypeptide molecular weights of 115 and 50 kDa. Western blotting of the immunoprecipitates from purified keratinocyte mitotic spindles showed that beta-tubulin was the 50-kDa polypeptide associated with hyperphosphorylated pRB.

Biological Transport↗
PubMed1996

Mechanisms of interleukin-2-induced hepatic toxicity.

Interleukin 2 (IL-2) mediates the regression of metastatic cancer, but its clinical use is limited by associated toxicities including hepatic dysfunction. To determine the mechanism for IL-2-induced hepatic dysfunction, we hypothesized that IL-2 activation of Kupffer cells causes leukocyte-endothelial adhesion and decreases hepatic sinusoidal blood flow. C57BL/6 mice were given injections of latex particles and prepared for intravital hepatic microscopy 2 h after i.p. IL-2 administration. Liver tissue was also prepared to quantitate hepatic tumor necrosis factor (TNF) mRNA and processed for light and electron microscopy. Phagocytosing Kupffer cells and leukocytes adherent to the endothelium were counted, and surface sinusoidal blood flow was quantitated. Kupffer cell activity was quantitated as the ratio of phagocytosing Kupffer cells to sinusoidal blood flow. IL-2 significantly increased Kupffer cell activity (0.56 +/- 0.05 for controls versus 0.84 +/- 0.05 for IL-2), significantly caused leukocyte-endothelial adhesion (26.7 +/- 7.9 for controls versus 87.0 +/- 27.6 for IL-2, WBC/mm2 endothelial surface), and significantly decreased the number of sinusoids containing blood flow per microscopic field (6.66 +/- 0.15 for controls versus 5.79 +/- 0.13 for IL-2) without causing changes in systemic hemodynamic parameters. In IL-2 treated livers, light and electron microscopy showed the constriction of sinusoids associated with swollen or ruptured mitochondria, which was consistent with hypoxic deterioration near central venules. Adherent platelets, neutrophils, and lymphocytes within sinusoids and central venules were also observed. PCR revealed that IL-2 significantly induced TNF mRNA expression in the liver. These data suggest that IL-2 activates Kupffer cells in association with the release of monokines including TNF, which causes activation of circulating leukocytes as well as hepatic sinusoidal endothelial cells. The resultant leukocyte and platelet adhesion to the endothelium may then physically impede the sinusoidal microcirculation, resulting in microscopic areas of hepatic ischemia and explaining the mechanism of IL-2-induced hepatic dysfunction.

Animals↗
PubMed1996

Mechanisms of alpha-thrombin, histamine, and bradykinin induced endothelial permeability.

alpha-Thrombin, bradykinin, and histamine are endogenous mediators that increase endothelial permeability. We examined the mechanism by which these three vasoactive mediators could alter permeability to albumin of human umbilical vein endothelial cells (HUVEC). HUVEC were grown to confluence on Transwell membranes and we monitored the flux of fluorescein isothiocyanate-labeled human serum albumin across the membrane from the upper to lower chamber of the Transwell. Addition of alpha-thrombin, bradykinin, or histamine increased the permeability coefficient of the HUVEC monolayer. At 30 min the permeability coefficient for alpha-thrombin was 4.92 x 10(-6) cm/sec while histamine was 4.47 x 10(-6) cm/sec. Maximum changes in the permeability coefficient were about three-fold control baseline values (1.59 x 10(-6) cm/sec). There was also a temporal difference in the magnitude of the permeability coefficient. alpha-Thrombin and bradykinin induced HUVEC permeability was increased for the first 90 min after which it returned to control levels. In contrast, histamine increased the permeability of the HUVEC monolayer throughout the 2 h experiment. To determine a possible intracellular mechanism of the altered permeability coefficients, HUVEC were labeled with FURA-2 and intracellular calcium was monitored by digital fluorescence ratio imaging. Maximum intracellular calcium in HUVEC was increased by alpha-thrombin (245 +/- 20 nM) and histamine (210 +/- 22 nM), but not by bradykinin (70 +/- 7 nM) as compared to control (69 +/- 10). Fluorescent photomicrographs of HUVEC stimulated with the three agonists indicated that alpha-thrombin and histamine substantially altered HUVEC f-actin arrangement, while bradykinin had no effect on HUVEC f-actin distribution. These data support previous in vitro and in vivo studies demonstrating increased permeability by all three agonists. These data also show, for the first time, that histamine and alpha-thrombin increased permeability by calcium-dependent intracellular pathways, but bradykinin operates through a calcium-independent mechanism.

Actins↗
PubMed1996

Interleukin-10 inhibits interleukin-2-induced tumor necrosis factor production but does not reduce toxicity in C3H/HeN mice.

Immunotherapy with interleukin-2 (IL-2) is limited by severe side effects thought to be mediated by the activation of immune effector cells and the induction of secondary cytokines including tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In C3H/HeN mice the primary IL-2 toxicity is the production of pleural effusion with subsequent respiratory compromise. IL-10 is a cytokine that has been shown to inhibit the generation of secondary cytokines in vitro and in vivo. In this study, in C3H/HeN mice, we tested the ability of IL-10 to inhibit IL-2-induced mononuclear cell and alveolar macrophage activation and IL-2-induced increases in serum TNF-alpha and IFN-gamma, all of which may contribute to the generation of toxicity. IL-10 was ineffective at reducing IL-2-induced pleural effusion. However, IL-10 did inhibit IL-2-induced increases in serum TNF-alpha, which was accompanied by a decrease in Golgi apparatus and rough endoplasmic reticulum in alveolar macrophages. In addition, IL-10 combined with IL-2 increased mononuclear cell activation, which may limit the ability of IL-10 to inhibit IL-2-induced IFN-gamma production and pulmonary injury.

Animals↗
PubMed1996

Interleukin-2 induces increased platelet-endothelium interactions: a potential mechanism of toxicity.

Cancer immunotherapy with interleukin-2 (IL-2) is limited by side effects that may cause organ dysfunction. The role of platelets in the generation of IL-2-induced organ dysfunction has not been studied, although various studies have shown that IL-2 therapy activates both platelets and the vascular endothelium. We hypothesized that IL-2 therapy may enhance the thrombogenic response to inflammatory stimuli through increased platelet-endothelial interactions and that these effects could lead to the development of organ dysfunction. C57BI/6 mice were treated with IL-2 intraperitoneally for 2 hours (short term) or 2 to 5 days (long term) and prepared for in vivo microscopy of the ear microcirculation. Mice were injected intra-arterially with fluorescein isothiocyanate conjugated to bovine serum albumin (FITC-BSA). Blue light activation of the FITC-BSA in ear arterioles induced thrombus formation. The time to initial thrombus formation was measured as an index of thrombogenicity. Platelet function was analyzed by aggregometry and platelet expression of IL-2 receptors, and the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) was analyzed by flow cytometry. Organ dysfunction was evaluated by serum markers. The administration of both short-term and long-term IL-2 reduced the time to initial thrombus formation as compared with controls. In vitro platelet aggregometry revealed no acute alterations in platelet function; however, long-term IL-2 treatment resulted in decreased disaggregation rates. There were no platelet IL-2 receptors present, and the expression of the adhesion molecule LFA-1 was not altered by IL-2. Increased thrombogenicity occurred before the generation of organ dysfunction. These data suggest that increased platelet adherence induced by IL-2 is caused by effects on the endothelium that could result in microvascular thrombus formation and contribute to organ dysfunction.

Adenosine Diphosphate↗
PubMed1996

The rationale for esophagectomy as the optimal therapy for Barrett's esophagus with high-grade dysplasia.

OBJECTIVE: The authors determined the incidence of invasive adenocarcinoma after esophagectomy in patients endoscopically diagnosed as having Barrett's esophagus with high-grade dysplasia. SUMMARY BACKGROUND DATA: Barrett's esophagus is a well-recognized premalignant condition. There is controversy with regard to the optimal treatment of high-grade dysplasia in Barrett's esophagus. Recognizing the morbidity and mortality associated with esophagectomy, some recommend a selective approach, reserving esophagectomy only for evidence of invasive cancer identified through endoscopic surveillance. Other advocate esophagectomy for all suitable operative candidates. METHODS: The authors reviewed their experience between 1985 and 1995 with 11 patients with high-grade dysplasia arising in Barrett's esophagus diagnosed by endoscopic biopsy and treated by esophagectomy. RESULTS: All patients were white men ranging in age from 47 to 70 years. Ten patients underwent esophagectomy by the Ivor Lewis technique; one had a transhiatal resection. Eight patients (73%) had invasive adenocarcinoma identified after esophagectomy; two (18%) had positive lymph nodes; one required a prolonged hospital stay for an anastomotic leak; two (18%) temporarily suffered delayed gastric emptying. The authors' review identified 85 additional patients previously reported during the same period. Including the current series, 39 patients (41%) had invasive adenocarcinoma identified in the resected specimen. A preponderance of early, potentially curable carcinomas are characteristically found in these patients. CONCLUSION: A high incidence of endoscopically undetected invasive carcinoma strongly supports esophagectomy as the preferred approach for suitable operative candidates with high-grade dysplasia in Barrett's esophagus.

Adenocarcinoma↗
PubMed1996

Attitudes to and knowledge about elderly people: a comparative analysis of students of medicine, English and Computer Science and their teachers.

Attitudes to and knowledge about elderly people were assessed in 1091 students and lecturers from the London Hospital Medical College (LHMC), London, UK and the English and Computer Science departments of Queen Mary and Westfield College (QMW), London, UK. General knowledge about elderly people was measured by the Palmore 'Facts about Aging Quiz 1'. Attitudes towards elderly people were measured by the Rosencranz and McNevin Semantic Differential scale. A higher level of knowledge about elderly people was found both in medical students and in medical lecturers compared to their counterparts in the English and Computer Science departments (P < 0.001). The cross-sectional data indicated that medical students developed a significantly increasing knowledge about elderly people as they progressed through their training, in contrast to students of English and Computer Science. Scores on the Rosencranz & McNevin scale indicated that attitudes towards elderly people across all three groups of students and lecturers were similar. The scores obtained for all groups indicated that they held approximately neutral attitudes towards elderly people. A significant correlation (P < 0.001) was found between high levels of knowledge about elderly people, and positive attitudes towards them. The necessity of interventions to improve general attitudes towards and knowledge of elderly people among medical students is questioned. It is suggested that future research should look beyond surveys of general attitudes towards elderly people for the causes of the current lack of interest in geriatric medicine.

Aged↗
PubMed1996

Diagnostic ultrasound in veterinary practice: How safe is it?

This paper provides information on the safety of ultrasonic diagnostic procedures as currently used in veterinary practice. The known mechanisms of action are described and selected literature on biological effects of ultrasound is reviewed. Current international consensus is presented on the safety of medical ultrasound with respect to thermal effects. To date, there is no independently verified clinical evidence that the level of exposure delivered to the tissues during scanned grey-scale ('B-mode') imaging has any adverse effects. Lung haemorrhage has been observed in animal experiments using diagnostic exposures, but the effects have not been reported in the foetus. Equipment that uses pulsed Doppler transmits higher acoustic outputs in a stationary beam, and can produce temperature increases that may have significant biological consequences. When considering sonographic and pulsed Doppler examinations of the prenatal animal, the safety margins are small and the operator should be aware of the acoustic output of the equipment, the exposure time, and the sensitivity of target tissues.

Animals↗
PubMed1996

Liver cryosurgery.

Liver cryosurgery is a relatively new form of treatment for unresectable liver cancer that involves in situ ablation of liver tumors by freezing them with liquid nitrogen. Cryosurgery has been used mainly to treat liver metastases from colorectal cancer, but other types of metastases and primary liver cancers have been treated as well. Results of liver cryosurgery over the past decade have demonstrated that it is a safe and effective treatment for malignant liver tumors. Because only a small percentage of primary and metastatic liver tumors are resectable, cryosurgery offers a potentially curative treatment option for patients with unresectable disease.

Chemotherapy, Adjuvant↗