The safety of flexible fibre-optic bronchoscopy and proceduralist-administered sedation: a tertiary referral centre experience.

BACKGROUND: Flexible fibre-optic bronchoscopy has become an essential investigation and is widely regarded as safe, but wider published prospective data regarding delayed complications are limited. There is continuing debate concerning the safety of proceduralist-administered sedation. We evaluated complication rates of bronchoscopy and proceduralist-administered sedation at our tertiary institution, and their clinical significance. METHODS: Prospective evaluation of all patients undergoing bronchoscopy over a 12-month period at a tertiary referral centre. Immediate minor and major complications were documented within 4 h of bronchoscopy, delayed complications at 48 h, case notes and bronchoscopy records were reviewed 1 month later. RESULTS: Five hundred and fifty-eight flexible fibre-optic bronchoscopies were performed, 216 with transbronchial biopsy or nodal aspiration, 19 had therapeutic airways intervention. The minor complication rate at 4 h was 4.12% (23), rising to 26% (145) at 48 h. All 2.2% (12) major complications occurred exclusively within 4 h of bronchoscopy. No complications could be attributed to proceduralist-administered sedation. DISCUSSION: Complication rates at 4 h were comparable with previously reported data. Delayed minor complications were greater than expected, and did not require additional medical input. There were no complications from proceduralist-administered sedation. Flexible fibre-optic bronchoscopy and proceduralist-administered sedation within our institution's guidelines are safe.

Cancer morphology, carcinogenesis and genetic instability: a background.

Morphological abnormalities of both the nuclei and the cell bodies of tumour cells were described by Müller in the late 1830s. Abnormalities of mitoses and chromosomes in tumour cells were described in the late 1880s. Von Hansemann, in the 1890s, suggested that tumour cells develop from normal cells because of a tendency to mal-distribution and other changes of chromosomes occurring during mitosis. In the first decades of the 20th century, Mendelian genetics and "gene mapping" of chromosomes were established, and the dominant or recessive bases of the familial predispositions to certain tumour types were recognised. In the same period, the carcinogenic effects of ionising radiations, of certain chemicals and of particular viruses were described. A well-developed "somatic gene-mutational theory" of tumours was postulated by Bauer in 1928. In support of this, in the next three decades, many environmental agents were found to cause mitotic and chromosomal abnormalities in normal cells as well as mutations in germ-line cells of experimental animals. Nevertheless, mitotic, chromosomal, and other mutational theories were not popular explanations of tumour pathogenesis in the first half of the 20th century. Only in the 1960s did somatic mutational mechanisms come to dominate theories of tumour formation, especially as a result of the discoveries of the reactivity of carcinogens with DNA, and that the mutation responsible for xeroderma pigmentosum causes loss of function of a gene involved in the repair of DNA after damage by ultraviolet light (Cleaver in 1968). To explain the complexity of tumourous phenomena, "multi-hit" models gained popularity over "single-hit" models of somatic mutation, and "epigenetic" mechanisms of gene regulation began to be studied in tumour cells. More recently, the documentation of much larger-than-expected numbers of genomic events in tumour cells (by Stoler and co-workers, in 1999) has raised the issue of somatic genetic instability in tumour cells, a field which was pioneered in the 1970s mainly by Loeb. Here these discoveries are traced, beginning with "nuclear instability" though mitotic-and-chromosomal theories, single somatic mutation theories, "multi-hit" somatic theories, "somatic, non-chromosomal, genetic instability" and epigenetic mechanisms in tumour cells as a background to the chapters which follow.

Bacterial lipopolysaccharide and tumor necrosis factor alpha synergistically increase expression of human endothelial adhesion molecules through activation of NF-kappaB and p38 mitogen-activated protein kinase signaling pathways.

One of the recognized associations of bacterial infection with cardiovascular events is the activation of endothelium and upregulation of adhesion molecules. The two major proinflammatory mediators implicated in the causation of cardiovascular events, bacterial lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF), were found to cooperate to enhance the adhesive properties of endothelial cells. These caused synergistic upregulation of intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 in human umbilical vein endothelial cells as determined by flow cytometry analysis and enzyme-linked immunosorbent assay. This synergism was not due to TNF causing an upregulation of CD14 expression. Treatment with both LPS and TNF resulted in a marked increase in the translocation of NF-kappaB into the nucleus. The activity of p38 mitogen-activated protein kinase was also synergistically enhanced, while the activity of c-jun N-terminal kinase was increased in an additive manner. The results demonstrate that LPS and TNF act synergistically to upregulate the expression of endothelial cell adhesion molecules, possibly by amplification of signaling pathways upstream of transcription. These findings have implications for the understanding of the acceleration of atherosclerotic events seen in low-grade infections with gram-negative organisms.

Synthesis and surface expression of CD14 by human endothelial cells.

Previous studies have reported that human vascular endothelial cells lack the membrane-bound lipopolysaccharide (LPS) receptor, CD14 (mCD14). By optimizing assay conditions, including the selection of anti-CD14 monoclonal antibody, we now demonstrate that human umbilical vein endothelial cells (HUVEC) express CD14 on the cell surface. Single-passage HUVEC showed approximately 20 times less expression of CD14 than monocytes. Interestingly, there was significant loss of surface CD14 expression with increasing numbers of culture passages. Evidence for synthesis of CD14 by HUVEC was provided by the finding that L-[(35)S]methionine was incorporated into CD14. In addition, the expression of CD14 on HUVEC was upregulated by LPS, lysophosphatidic acid, and tissue culture supplements, and this upregulation was dependent on protein synthesis. Furthermore, the results imply that mCD14 is required for LPS-induced activation of endothelial cells in the absence of serum and that it acts in concert with serum factors (soluble CD14). Our results provide evidence that CD14 is expressed by endothelial cells and suggest that the previous inability to observe expression of this molecule has been due to culture and staining conditions. This finding has important implications for the understanding of the mechanisms by which LPS stimulates endothelial cells and the management of sepsis caused by gram-negative bacteria.

Enhancement of lipopolysaccharide-induced neutrophil oxygen radical production by tumor necrosis factor alpha.

Although tissues become exposed to both exogenous and endogenous cell-activating mediators during infection, there is little appreciation of the effects of subjecting cells to multiple mediators. We examined the hypothesis that the response of neutrophils to bacterial lipopolysaccharide (LPS) is significantly altered in the presence of the endogenous mediator tumor necrosis factor alpha (TNF). The data showed that human neutrophils pretreated with TNF for 10 to 30 min, displayed significantly enhanced superoxide production in response to LPS (from either Escherichia coli K-235 or E. coli O127:B8), measured as lucigenin-dependent chemiluminescence (CL), seen as an increase in the initial peak rate as well as the total CL accumulated over the incubation period. TNF amplified the response to LPS at 1 to 100 U of TNF/10(6) neutrophils and was able to enhance the response to a wide range of concentrations of LPS (0.01 to 1,000 ng/ml). The TNF-induced increase in the LPS response was paralleled by an increase in LPS binding to the neutrophils, which could be abrogated by an anti-CD14 monoclonal antibody. The results demonstrate that TNF significantly increases the LPS-induced release of oxygen radicals in neutrophils through the upregulation of cell surface CD14.

Continuous subcutaneous heparin infusion for treatment of Trousseau's syndrome.

OBJECTIVE: To describe the use of continuous subcutaneous heparin infusion in the treatment of 2 cases of Trousseau's syndrome. CASE SUMMARIES: Two patients with metastatic carcinoma presented to the hospital with acute coagulopathies consistent with a diagnosis of Trousseau's syndrome. In both cases conventional anticoagulant therapies proved to be impractical and ineffective. DISCUSSION: Considerable literature suggests that oral anticoagulants such as warfarin are ineffective in the treatment of Trousseau's syndrome. Heparin is more effective for this purpose, although continuous intravenous infusion may prove difficult in the ambulatory setting. Intermittent subcutaneous injections of heparin or low-molecular-weight heparin may not provide reliable anticoagulation for the entire dosage interval. Although the use of continuous subcutaneous infusion of heparin has been used for anticoagulation during pregnancy, this is the first report of the use of sodium heparin administered by continuous subcutaneous infusion in the treatment of Trousseau's syndrome. CONCLUSIONS: Continuous subcutaneous heparin infusion may be an effective option for the treatment of Trousseau's syndrome in the ambulatory setting.