Biomedical subjects
Publications and source records attributed to G Hamilton.
Intraperitoneal ivalon mimicking peritoneal malignancy after plugged percutaneous liver biopsy is reported in a 20 year old woman with a history of nausea and abdominal distension.
During a 6 year period 60 patients with atherosclerotic renovascular disease were followed by a single renal unit. Angiotensin converting enzyme inhibitors were being taken by 22% of patients at the time of diagnosis of the atherosclerotic renovascular disease. Intervention to revascularize renal tissue by surgery or angioplasty was performed in 32 patients. Revascularization was not undertaken because of unilateral disease, patient preference, poor operative risk or renal size. The mean age for the nonintervention group was 66.9 years and 63.4 years for the intervention group. Peripheral vascular, disease was common in both groups (96% nonintervention group versus 86% intervention group). There was a statistically significant difference in improvement in renal function in the intervention group (34.4% versus 10.7%) in spite of more patients being dialysis dependent in the intervention group (28.1% versus 14.3%). There was no statistically significant difference in survival between the two groups although the trend was for better survival in the group with intervention. Patients presenting with impaired renal function and atherosclerotic renovascular disease can have useful improvement in renal function with revascularization without any detriment to survival.
During alveolar development and alveolar repair close contacts are established between fibroblasts and lung epithelial cells through gaps in the basement membrane. Using co-culture systems we have investigated whether these close contacts influence synthesis and secretion of the principal surfactant apoprotein (SP-A) by cultured rat lung alveolar type II cells and the synthesis and secretion of type I collagen by fibroblasts. The alveolar type II cells remained cuboidal and grew in colonies on fibroblast feeder layers and on Matrigel-coated cell culture inserts but were progressively more flattened on fixed fibroblast monolayers and plastic. Alveolar type II cells cultured on plastic released almost all their SP-A into the medium by 4 days. Alveolar type II cells cultured on viable fibroblasts or Matrigel-coated inserts above fibroblasts accumulated SP-A in the medium at a constant rate for the first 4 days, and probably recycle SP-A by endocytosis. The amount of mRNA for SP-A was very low after 4 days of culture of alveolar type II cells on plastic, Matrigel-coated inserts or fixed fibroblast monolayers: relatively, the amount of mRNA for SP-A was increased 4-fold after culture of alveolar type II cells on viable fibroblasts. Co-culture of alveolar type II cells with confluent human dermal fibroblasts stimulated by 2- to 3-fold the secretion of collagen type I into the culture medium, even after the fibroblasts' growth had been arrested with mitomycin C. Collagen secretion, by fibroblasts, also was stimulated 2-fold by conditioned medium from alveolar type II cells cultured on Matrigel. The amount of mRNA for type I collagen increased only modestly when fibroblasts were cultured in this conditioned medium. This stimulation of type I collagen secretion diminished as the conditioned medium was diluted out, but at high dilutions further stimulation occurred, indicating that a factor that inhibited collagen secretion also was being diluted out. The conditioned medium contained low levels of IGF-1 and the stimulation of type I collagen secretion was abolished when the conditioned medium was pre-incubated with antibodies to insulin-like growth factor 1 (IGF-1). There are important reciprocal interactions between alveolar type II cells and fibroblasts in co-culture. Direct contacts between alveolar type II cells and fibroblasts appear to have a trophic effect on cultured alveolar type II cells, increasing the levels of mRNA for SP-A. Rat lung alveolar type II cells appear to release a factor (possibly IGF-1) that stimulates type I collagen secretion by fibroblasts.
Multidrug-resistance (MDR) is a cellular mechanism, which in certain tumors reduces the chemosensitivity of cells to a characteristic group of structural different cytostatic drugs, as anthracyclines, Vinca alkaloids and others, and correlates with a unfavourable clinical prognosis. In MDR-cells the intracellular concentration of cytostatic drugs is reduced due to the action of the mdr-1-gene-encoded P-glycoprotein (P-gp/gp 170), which functions as drug efflux pump with broad substrate specificity. Many calcium channel blockers of all subclasses (phenylalkylamine, dihydropyridine and benzothiazepine type) and other calcium antagonists inhibit the P-gp-mediated drug efflux and represent modulators of MDR (resistance modifiers, chemosensitizers). Since the sensitized tumor cells express no voltage-gated calcium channels, the induction of changes in intracellular free calcium showed no effect on MDR and the MDR-activity of antagonists is not correlated with their cardiovascular effects, the chemosensitization by these drugs is independent from their action on calcium channels and Ca(++)-regulation. Photoaffinity labelling with reactive derivatives proved the direct competitive interaction of calcium antagonists with the binding site of P-gp for cytostatic drugs as mechanism of action. The MDR-modulation of the doxorubicin or Vinca alkaloid resistance of tumor cells in vitro by verapamil and other calcium channel blockers was confirmed in vivo as increased survival length in mice with tumor transplants in combination with cytostatic therapy. The clinical application of calcium antagonists is limited by their severe cardiovascular side effects associated with the high concentrations required for successful reversal of MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
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In 1980-81, the nursing and medical staff of Toronto's Hospital for Sick Children (HSC) were agonizing over an increased death rate on cardiac wards 4A and 4B and groping for the cause. The key to this diagnostic puzzle appeared to surface when hospital radioimmunoassay tests revealed very high autopsy readings of digoxin on four babies who died during this period, Janice Estrella, Justin Cook, Kevin Pacsai and Allana Miller. Since one nursing team was present during each of these infants' final hours, it was assumed that one or more of the nurses had intentionally poisoned the infants with digoxin. A web of circumstantial evidence entrapped team member Susan Nelles, who was charged with murder.
In cultured human umbilical vein endothelial cells, 5-HT and alpha-methyl 5-HT stimulated [45Ca2+] uptake in concentration-dependent manner, whereas the 5-HT1 agonists, m-CPP (1-(3-chlorophenyl)piperazine and 2-MPP (1-(2-methoxyphenyl)piperazine), were without effect. In turn, 5-HT-stimulated [45Ca2+] uptake was inhibited in concentration-dependent manners by the 5-HT receptor antagonists ketanserin (5-HT2), LY 53,857 (5-HT2) and methiothepine (5-HT1/2) and to a lesser degeree by MDL 72222 (5-HT3) and BRL 43694 (5-HT3) whereas (+/-)-propranolol (5-HT1) was without effect. These data indicate that 5-HT stimulates Ca2+ uptake by endothelial cells via activation of a 5-HT2 receptor subtype. 5-HT was without effect on de novo prostacyclin (PGI2) synthesis over the concentration of 5-HT that elicited [45Ca2+] uptake. Since 5-HT did not stimulate PGI2, an event associated with an increase in levels of intracellular Ca2+, it is postulated that the uptake of 45Ca2+ reflects changes of Ca2+ at the level of the plasma membrane rather than on intracellular changes. 5-HT-stimulated Ca2+ uptake may be of relevance to endothelium-dependent relaxation, vascular permeability and endothelial repair and proliferation.
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Comparative electron microscopic studies of pre- and postembedding immunolabeling experiments have shown that the antigenicity of some epitopes is lost during acrylic resin embedding of the respective tissues. In the present investigation we have tested the sensitivities of two embedding-labile epitopes (HBA-71 and HBA-45) of the Ewing's sarcoma-associated MIC2-encoded E2 antigen to the effects of the different treatment steps, which are necessary for the preparation of ultrathin sections. The extent of antigenic retention was quantitated using flow cytometry and enzyme-linked immunosorbent assays (ELISA) of tumor cell lines, thymocytes and cell membrane extracts. Fixation, dehydration and high temperature treatment of MIC2-positive cells showed only minor effects on the reactivity with the HBA-71 and HBA-45 antibodies. However, exposure of the cells to the monomeric acrylic resins LR White (LRW), LR Gold (LRG) and Lowicryl K4M at 4 degrees C for 2-18 h resulted in a significant reduction of the HBA-71 and HBA-45 reactivities. In contrast, the antigenicity of both epitopes was maintained during treatment with the apolar Lowicryl HM20 embedding medium under these non-polymerizing conditions. The resins have no direct effect on the HBA-71/HBA-45 antigen, since it could be extracted in intact form from membranes of native, but not of fixed, tumour cells using LRW for membrane solubilization. These data indicate that the HBA-71/HBA-45 antigen remains in the cell membrane and is indirectly influenced by the extraction/modification of adjacent membrane constituents. The adverse effects of the polymerization process, in the case of embedding at low temperature in Lowicryl HM20, destroyed MIC2-antigenicity.(ABSTRACT TRUNCATED AT 250 WORDS)
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The advent of intra-arterially administered thrombolytic agents of minimal antigenicity, together with small gauge good torque control catheters, enables thrombolysis to be used in patients that may previously have been deemed unsuitable for thrombolytic therapy. Thrombolysis may be used even in the presence of factors formerly and empirically considered to be contra-indications. The continued use of thrombolytic agent may also be warranted despite iatrogenic complications such as vessel wall perforation, particularly if the alternative is major amputation. We report on a series of eight patients in whom intra-arterial tissue plasminogen activator was used despite either recent vascular surgery, or iatrogenic vessel perforation. Suggestions for the use of thrombolysis in high risk patients and following iatrogenic complications are discussed.
A case of mycotic carotid aneurysm due to Salmonella enteritidis infection is reported. The features of the condition and the principles of treatment are described.
Clinical as well as experimental studies have shown a great interindividual variability in the immunosuppressive efficacy of CsA. Evaluating previous in vitro findings of a correlation between sensitivity of alloresponsiveness to CsA and the HLA-DR phenotype CsA levels were compared in kidney transplant recipients with and without rejections during the early posttransplant period and tested for a possible relationship to the HLA-DR phenotype of the recipient. In patients treated with CsA and prednisolone only, rejection frequency was significantly higher in HLA-DRw6 positive than in DRw6 negative graft recipients (77% vs. 53%, P = 0.045). In the DRw6 positive group incidence of rejection was independent of CsA blood levels, whereas in DRw6 negative patients frequency of rejection episodes decreased as a function of increasing CsA levels. Therefore the relative risk in developing graft rejection continuously increased in HLA-DRw6 positive patients. In HLA-DR2 positive graft recipients, however, a decrease in the relative risk could be observed with increasing CsA levels. Within patients with bioptically verified rejection episodes HLA-DR2 positive recipients had significantly lower CsA levels than DR2 negative patients (P = 0.01). In other HLA-DR phenotypes no association with CsA blood levels could be assessed. Also no statistically significant difference could be found in nonrejecting patients. These clinical findings demonstrate an association of sensitivity to immunosuppressive treatment and the HLA-DR phenotype of the graft recipient. Our results would indicate a very low CsA sensitivity of HLA-DRw6 positive graft recipients and thus might offer an explanation for previous findings about an increase in the incidence of rejection reported on those patients.
An important aspect of organ preservation is the maintenance of intrinsic dilator and antithrombotic mechanisms of blood vessels. Blood vessels synthesize prostacyclin (PGI2), a potent vasodilator and inhibitor of platelet adhesion and aggregation. PGI2 synthesis is controlled by complex mechanisms including adrenoceptor-linked calcium influx and protein kinase C. Since organ preservation solutions may influence these mechanisms, we investigated the effect on in vitro PGI2 synthesis of cold storage of rat aortic rings in lactobionate-raffinose solution (LRS) and hypertonic citrate kidney preservation solution (KPS) on in vitro PGI2 synthesis. Acute incubation of aortic tissue in both preservation solutions at 37 degrees C (compared with minimal essential medium) completely inhibited PGI2 synthesis when stimulated with noradrenaline (NA), phorbol ester (a protein kinase C activator), NaF (a G protein activator), or A23187. Following storage of aortic rings at 4 degrees C (for up to 72 hr) in LRS and KPS, subsequent washing and incubation in MEM, PGI2 synthesis was initially markedly enhanced in response to NA when compared with tissues stored in MEM. These enhanced responses disappeared, and PGI2 synthesis returned to normal following 1 hr incubation of tissues in MEM at 37 degrees C. These data demonstrate that cold storage in preservation fluids exerts minimal deleterious effects, not only on PGI2 synthesis, but possibly on other key processes (calcium homeostasis, protein kinase C activity) in blood vessels.
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The correlation of endotoxin (ET), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and cellular immune parameters with multiple organ failure and lethal outcome in intraabdominal infections was studied in a group of 18 patients with peritonitis, abscess or pancreatitis. Of these patients, 7 developed respiratory failure and 5 died due to multiple septic organ failure. The peak levels of ET (2.7 +/- 1.3 ng/ml) in the course of the disease were followed by moderate increases of TNF-alpha (mean 147 +/- 41 pg/ml) and IL-6 (170 +/- 61 pg/ml) within 2 days. Analysis of the parameters for the last 12 days prior to death or discharge showed, that the patient group with lethal outcome was characterized by significant lower mean plasma levels of TNF-alpha (less than 75 pg/ml versus greater than 160 pg/ml) and IL-6 (less than 130 pg/ml versus greater than 270 pg/ml), as well as high rates of unstimulated thymidine uptake into peripheral mononuclear blood cells (greater than 44000 cpm/8 x 10(6) PMBC/18 h versus less than 24000 cmp), T-lymphocyte depression (CD3; approximately greater than 40% reduction) with lower T-helper/inducer subset cell numbers (mean CD:CD8 ratio 1.0 +/- 0.55 versus 1.8 +/- 0.2) and lower lectin (PHA) stimulation values (1.9 +/- 1.4 versus 4.1 +/- 1.0). These data demonstrate an anergic immune status with low mediator levels and depressed T-lymphocyte function in patients with poor prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)