Biomedical subjects
A J Davies
Publications and source records attributed to A J Davies.
Audit of the use of erythromycin in the treatment of community-acquired lower respiratory infections.
The British Thoracic Society (BTS) guidelines for the treatment of community-acquired pneumonia recommend initial therapy with a betalactam antibiotic, with the addition of erythromycin if there are features of an atypical pneumonia. To see if these guidelines were being followed, a prospective study was undertaken of all adult patients admitted to hospital over a 3-month period who were given erythromycin for a community-acquired lower respiratory tract infection. Erythromycin was given to 62 patients who could be fully assessed. Continued prescription of erythromycin was justified in 10 (16%)--two patients with penicillin allergy, two with M. catarrhalis infection and one patient with legionnaires disease. Five patients had infections severe enough on admission to warrant combined therapy in line with the BTS recommendations. Five patients had erythromycin stopped on day 2. Erythromycin was prescribed on admission and continued unnecessarily in 47/62 patients, showing that the BTS recommendations are not being followed correctly.
Hypothesis: impaired immunity as a factor which contributes to the spread of drug-resistance.
Evidence has accrued to indicate that host defence mechanisms enhance the efficacy of many of the drugs used to treat infectious diseases. Because of this, and also because of the likelihood of increased pathogen loads in immunoincompetent hosts, some infections are less likely to be completely cured by normal regimens of chemotherapy in individuals with drastically impaired immune responsiveness. In such circumstances natural selection could result in the accelerated emergence of drug-resistance pathogens.
Antibacterial therapy of community-acquired chest infections.
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Experience with an implantable venous access system for chemotherapy.
Seventy-one patients receiving prolonged outpatient chemotherapy for solid tumours had a totally implanted venous access system inserted (Port-A-Cath--Pharmacia). These remained in situ for a mean of 278 days. In 98.6% of patients the catheter functioned throughout treatment. This high reliability reflects low rates of sepsis (11%) and occlusion (1.4%). Six catheters were removed because of complications; for sepsis (2), catheter occlusion (1), erosion (2), and wound dehiscence (1). An implanted system may be more economical than external exiting systems for patients requiring a catheter for longer than two months despite a high capital cost, because of lower costs during use. The Port-A-Cath is safe, reliable and acceptable to patients.
The vascularity of cutaneous melanoma: a quantitative histological study of lesions 0.85-1.25 mm in thickness.
The vascularity of 107 primary cutaneous melanomas has been characterized by morphometric histological analysis. The lesions selected for study were of thickness 0.85-1.25 mm and the aim was to evaluate the prognostic significance of tumour vascularity. Two groups of patients were identified; 86 with no evidence of recurrence after a minimum follow-up period of 5 years and 21 with locoregional recurrence and/or metastasis. The lectin Ulex europaeus type I was used for endothelial cell staining of tissue sections and morphometric analysis was performed to derive the vascular length, surface and volume density from independent measurements of tumour, adjacent dermis and the junctional zone between tumour and underlying tissue. A wide range of values was obtained for each parameter with increased vascularity always found at the tumour base compared with the tumour as a whole. In relation to the adjacent normal dermis, vascularity was generally found to be higher at the tumour base but either higher or lower in the tumour overall. Tumour recurrence could not be predicted by any of the derived vascular parameters either independently or together with other histological and clinical features. This study suggests that tumour vascularity is of no prognostic significance in melanoma of the above thickness range. The highly variable extent of tumour vascularity was not correlated with other clinical or histological parameters, but may have implications for the delivery of pharmaceutical agents used for diagnosis or therapy.
The effect of ricin B chain on the intracellular trafficking of an A chain immunotoxin.
Covalent linkage of the A chain of ricin to the LICR-LOND-Fib75 monoclonal antibody produced an immunotoxin, Fib75-SS-ricin A, which demonstrated immunospecific toxicity to human bladder carcinoma cells in tissue culture (Forrester et al., 1984). The present studies have shown that ricin B chain potentiates the toxicity of the immunotoxin by two orders of magnitude and also significantly increases the rate of protein synthesis inhibition. Using immunoelectron microscopy, the receptor-mediated endocytosis and intracellular routing of the immunotoxin was studied with and without ricin B chain treatment after immunolocalisation of the conjugate. Fib75-SS-ricin A was internalised by the EJ cells predominantly in uncoated pits and vesicles and directed to the endosomes. Some degradation of the complex appeared to take place in multivesicular endosomes at early timepoints and 24 h after internalisation, most of the immunotoxin was found in lysosomes. Some ricin A chain epitopes were detected in Golgi vesicles. Cells treated with immunotoxin and ricin B chain endocytosed the complex predominantly in coated pits and coated vesicles. Using pre-embedding immunoperoxidase techniques, ricin chains were found in the whole Golgi complex and most of the conjugate escaped lysosomal degradation. Internalised immunotoxin was recycled back to the plasma membrane in an active form associated with vesicles which appeared to be derived predominantly from multivesicular endosomes. A similar mode of recycling has recently been reported (McIntosh et al., 1990) for ricin holotoxin in the same cell line. These observations may explain the potentiating effect of toxin B chains in the antibody-directed targeting of toxin A chains.
The trouble with T cells.
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Urothelial grafts in mice.
Mouse bladder epithelium has been successfully transplanted to the bladders of syngeneic mice and has survived for at least twenty weeks. The fate of the transplanted tissue was followed using a fluorescein label. The recipient bladders were prepared by stripping the urothelium either by a surgical or a chemical method. The possibility of adopting a comparable technique for the treatment of early bladder cancer in man is discussed.
Dosage volume or concentration?
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Strategies in antibody therapy of cancer.
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Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial abluminal microprocesses in the tumor stroma.
It has been reported that the human haemopoietic progenitor cell antigen CD34 is also expressed by vascular structures. To investigate its precise vascular localization, we have studied the cellular and subcellular distribution of CD34 in normal tissues and pathologic tissues with neovascularization. In normal resting tissues, anti-CD34 antibodies, ICH3 and QBEND-10 predominantly stain the luminal endothelial membrane, whereas the abluminal membrane is negative or weakly positive. In contrast, a striking staining of endothelial abluminal microprocesses (EAM) was found in the tumor stroma. These structures, measuring up to 20 microns in length, could be observed in thick vibratome sections both at the tips of vascular sprouts and, also frequently, on fully formed microvessels. The number of vascular sprouts and EAM varied widely between different tumors. CD34-stained EAM were sparsely present in fetal tissue of 10 weeks gestation, but they could not be demonstrated in granulation tissue of wound healing. By immunoelectron microscopy, the EAM were continuous with the cytoplasm of endothelial cells showing an immature phenotype as seen in regeneration. In cultured human umbilical vein endothelium, CD34 was preferentially found on a small subset of cells with the morphologic appearance of migrating cells. These findings suggest that CD34 is an endothelial marker for EAM present during angiogenesis.
The intracellular movement and cycling of ricin.
The binding, internalization and recycling of the plant toxin ricin, was studied using electron microscopy and biochemical techniques. For the electron microscope study, ricin was visualized using a gold-labeled second antibody, in the cells of the EJ human bladder carcinoma line growing in monolayer culture. The labeled antibody/toxin complex was found to enter the cell in coated pits and to accumulate in endosomes and to a lesser extent in vesicles associated with the Golgi system. The complex recycled to the cell surface partly in uncoated vesicles, but largely in multivesicular bodies which appeared to exocytose their contents to the extracellular space. Twenty hours after the initial contact with ricin as much as 50% of the cellular label was found on the cell surface mainly associated with shed vesicles. When cells were treated with unlabeled ricin holotoxin and then after 20 h stained post-fixation, ricin molecules, partly associated with vesicles, were present on the cell surface. Biochemical studies showed that ricin was internalized by cells and then released in an intact form to the extracellular space. It was found that less than 10% of the released material had been degraded during its passage through the cells, which is in accord with the low level of label found in the lysosomal system during the morphological study.
Cardiotoxic effect with convulsions in terfenadine overdose.
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Identification of vascular endothelial cells in murine omentum using the lectin, Dolichos biflorus agglutinin: possible applications in the study of angiogenesis.
The purpose of this study was to determine whether the plant lectin, Dolichos biflorus agglutinin (DBA), can be used to recognize capillary endothelial cells and their processes during angiogenesis. By means of a peroxidase conjugate of DBA, blood vessels were visualized in whole mounts and ultrathin sections of mouse omentum. A part of this mesentery normally comprises an avascular membrane that is approximately 30 microns in thickness. Changes in the vascular plexus bordering this membrane were induced by intraperitoneal injection of irradiated Landschutz cells. Vascular endothelial cells were precisely and intensely stained, and vasculogenic processes were reliably distinguished from those of other cells. This technique permitted observation of the structure and distribution of capillary sprouts, and their relationship to each other and to pre-existing blood vessels. It was discovered that filiform projections extend from sprout apices. These projections may fuse allowing adjacent sprouts to form a new capillary loop.
Therapy of serious gram-positive infections with teicoplanin.
Teicoplanin was used as monotherapy in 17 seriously ill patients (mean age 51 years, range 18-71) with infection due to Gram-positive organisms. The dose used was 200 mg teicoplanin intravenously once daily after an initial intravenous dose of 400 mg. Most of the patients (15 out of 17) were septicaemic (confirmed by blood culture), the other two had deep abscesses. The pathogens isolated were Staphylococcus epidermidis [15], Streptococcus faecium [1] and JK Coryneform [1]. The 15 patients with Staph. epidermidis infections had all been treated previously with a beta-lactam (usually flucloxacillin)/aminoglycoside combination to which Staph. epidermidis was resistant. All patients were still pyrexial after 48 h of therapy and were then changed to teicoplanin as monotherapy. Patients were treated with teicoplanin for 5 to 7 days. One was withdrawn because of vomiting associated with the teicoplanin infusion, and another was withdrawn because she was given amikacin for a separate Gram-negative infection, but all the other 15 patients responded well to therapy, usually becoming apyrexial within 48 h. All 15 septicaemic patients had central lines in situ: 10 responded to therapy with the line left in situ but in 5 the lines were removed, either before or during teicoplanin therapy. Teicoplanin levels were determined in all patients, usually on day 2, with no evidence of toxicity from these levels. Teicoplanin was found to be effective as monotherapy for septicaemia mainly due to Staph. epidermidis in patients with severe underlying disease.
Prevention of graft-versus-host disease in neonatal F1 hybrid mice by pre-immunisation of their mother with paternal spleen cells.
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