M. Chisholm

Controlled prospective study of the effect on liver function of multiple exposures to halothane.

Patients who had received halothane within a periof of one year and who required another anaesthetic were allocated at random to be given halothane or a control anaesthetic, the control being fiben using halothane-free apparatus. There were 76 patients entries in each group. Serum-glutamic-oxaloacetic-transaminase (S.G.O.T.) levels were measured before the anaesthetics and serially postoperatively for two to three weeks. The S.G.O.T. levels in the halothane group were significantly higher than in the controls. High levels were confined to patients who had had less than four previous halothane anaesthetics, increases above normal in the remainder and in the controls being rate. 1 patient in the halothane group had an S.G.O.T. of 440 I.U. per litre and hepatocellular necrosis on liver biopsy. 2 patients in the halothane group whose S.G.O.T.s rose to more than twice normal showed a similar reaction to re-exposure to halothane, although they had not shown a reaction to an intervening control anaesthetic.

A CONTROLLED CLINICAL TRIAL OF PROPHYLACTIC FOLIC ACID AND IRON IN PREGNANCY

A SURVEY carried out in this hospital to determine the magnitude of the problem of anaemia during pregnancy in Oxford revealed that in spite of prophylactic iron therapy, 12 per cent of women near term had a haemoglobin concentration of less than 11 g. per 100 ml. Overt megaloblastic anaemia due to folic acid deficiency was not common, however, and was found in approximately one woman in every hundred. The possibility that folic acid deficiency might also be a factor in producing non-megaloblastic anaemia was raised by finding increased excretion of formimino-glutamic acid in the urine and low levels of folk acid activity (F.A.A.) in the serum of pregnant women with normoblastic erythropoiesis (Chisholm and Sharp, 1964). These observations together with those of Chanarin et al. (1959), who showed that unsuspected folic acid deficiency can exist in normal, and especially multiple, pregnancies suggested that treatment with folic acid might prevent or correct anaemia which occurred in women already taking iron. Several studies have been reported of the use of prophylactic folic acid in different doses during pregnancy and a resulting reduction in the incidence of megaloblastic anaemia observed, (Lowenstein et al., 1955; Francis and Scott, 1959; Giles and Burton, 1960; Dawson et al., 1962; Chanarin et al., 1965). The use of small amounts of folic acid is considered by some to lessen the risk of precipitating subacute combined degeneration of the cord in a pregnant woman with unsuspected Addisonian pernicious anaemia but it has been only partially effective in the prevention of megaloblastic anaemia (Dawson et al., 1962; Chanarin et al., 1965). Since the minimal effective dose for the prevention of megaloblastic anaemia is not known, a trial was designed (a) to test the effectiveness of a large and a small dose of folic acid in maintaining a normal level of folic acid activity in the blood, and (b) to see if folic acid was effective in raising the haemoglobin in the absence of frank megaloblastic erythropoiesis, or if its sole value was to prevent the occasional case of megaloblastic anaemia in pregnancy. The high incidence of mild anaemia at term noted in women who were apparently taking iron had led to doubts about the value of routine prophylactic administration of iron. While physiological haemodilution might be partly responsible for this, the work of others (Fisher and Biggs, 1955; Lawrence, 1962) had indicated that hydraemia in pregnancy was not an important cause of anaemia, and it was felt that the value of routine iron therapy in pregnancy needed reassessing. A group of women not given iron therapy was therefore included in the trial.

Urinary tissue factor levels in patients with breast and colorectal cancer

Activation of blood coagulation is a common complication of cancer in man and experimental animals. The causes of such activation may be multifactorial, but increased production of tissue factor (TF) by the host mononuclear cells may be involved. TF is not only produced by human monocytes (mTF) and tumour cells, but is also found in urine (uTF), where measurements might be clinically important. Using a highly reproducible (intra‐assay CV 2·3 per cent and inter‐assay CV 8·1 per cent) one‐stage kinetic chromogenic assay (KCA) developed by this group, uTF levels were measured in controls [healthy volunteers (n = 57), patients with renal stones and a normal ESR (n = 30)] and in patients with benign and malignant diseases of the breast (n = 94) and large bowel (n = 62). Each benign disease group was sub‐divided into inflammatory and non‐inflammatory categories. There were no significant differences between the controls and the benign non‐inflammatory groups, so they were unified for further analysis. Malignant groups, irrespective of tumour types, showed significantly higher uTF levels than controls (p < 0·001 for breast and p < 0·01 for large bowel). Similarly, breast and colorectal benign inflammatory groups showed significant increases over controls (p < 0·01 and p < 0·001, respectively). Patients with malignant disease showed uTF activity above the upper quartile range of the normal control group for breast, 77·3 per cent, and large bowel, 73 per cent. uTF levels were related to histological tumour grading and were higher in non‐surviving patients. In conclusion, uTF levels are raised in malignant and inflammatory disease compared with controls and patients with non‐inflammatory conditions. uTF levels may reflect tumour progression. Copyright

The significance of measuring monocyte tissue factor activity in patients with breast and colorectal cancer

Monocytes express tissue factor (mTF) in several conditions including cancer where levels may be valuable in assessing tumour presence and progression. Using a two-stage kinetic chromogenic assay (KCA), mTF levels were measured in controls [normal subjects (n = 60) and patients undergoing hernia repair or cholecystectomy (n = 60)], in patients with benign and malignant disease of the breast (n = 83) and of the large bowel (n = 62). This was performed under fresh (resting) conditions and after incubation for 6 h without (unstimulated) and with (stimulated) Escherichia coli endotoxin. The malignant groups showed higher mTF levels than each of the three controls for resting (P < 0.05 breast, P < 0.05 colorectal) unstimulated (P < 0.05 breast, P < 0.05 colorectal) and stimulated cells (P < 0.001 breast, P < 0.01 colorectal). Similarly, the benign inflammatory groups had higher mTF levels than controls for resting (P < 0.05 colorectal), unstimulated (P < 0.05 colorectal) and stimulated cells (P < 0.01 breast, P < 0.01 colorectal). There was no significant difference between malignant and benign inflammatory groups in each organ. mTF levels showed an increase corresponding to that of histological tumour progression and were higher in non-surviving patients. In conclusion, mTF levels are raised in malignant and inflammatory disease compared to controls and patients with non-inflammatory conditions. Stimulated cells give better discrimination between the groups and may be of value in identifying high risk individuals. mTF levels showed an association with tumour grade or stage and the patients’ survival time.

Anticoagulation of women with prosthetic heart valves during pregnancy

The best method of maintaining adequate anticoagulation of women with mechanical heart valves during pregnancy remains controversial. All treatment modalities available are associated with a risk of morbidity or mortality to the mother or fetus. A recent report’ advises that warfarin is the safest anticoagulant for the mother and her unborn child. However, there are many reports of fetal loss and warfarin embry~pathy”~ when warfarin is taken during pregnancy. Clinicians caring for these high risk pregnancies must be aware of the hazards of treatment available and make an informed decision with the patient as to the best plan of management.

Urinary tissue factor in glomerulonephritis: a potential marker of glomerular injury?

AIM: To investigate the significance of urinary tissue factor (uTF) concentrations in patients with glomerulonephritis. METHODS: Urine samples were collected from normal subjects (n = 57), patients with uncomplicated renal stones (n = 30), and patients with glomerulonephritis (n = 150). Samples were then centrifuged and the pellets solubilised in n-octyl-beta-glucopyranoside. uTF concentrations were determined using a one stage kinetic chromogenic assay. RESULTS: The uTF concentration was higher in patients with glomerulonephritis than in normal controls (p < 0.01) or in patients with renal stones (p < 0.05). uTF activity correlated with the protein creatinine index (PCI, r = 0.41, p < 0.001) and seven patients with glomerulonephritis and a PCI < or = 0.1 g/mmol had raised uTF. Glomerulonephritis patients were subdivided into two groups depending on the PCI: < 0.2 g/mmol creatinine (mild to moderate proteinuria, group I) and > or = 0.2 g/mmol creatinine (heavy proteinuria, group II). In group I, uTF concentrations were higher in patients with either immune complex (IC) glomerulonephritis (p < 0.01) or non-IC (p < 0.05) glomerulonephritis than in normal controls. In group II, the IC glomerulonephritis group had higher uTF concentrations than normal controls (p < 0.001) or patients with renal stones (p < 0.01); and non-IC glomerulonephritis patients had higher uTF than normal controls (p < 0.01). When the glomerulonephritis groups were divided into broad WHO subtypes, the significance level varied with the type of glomerulonephritis. CONCLUSIONS: uTF is increased in patients with glomerulonephritis, and its concentration may reflect the aetiopathogenesis of glomerulonephritis.

Monocyte tissue factor levels in patients with urological tumours : an association between tumour presence and progression

To examine the hypothesis that increased monocyte tissue factor (mTF) levels may reflect urological tumour presence and progression.

Development and validation of an assay for urinary tissue factor activity.

BACKGROUND: Activation of blood coagulation is a common complication of cancer and inflammation in both humans and experimental animals. Increased production of tissue factor--the principal initiator of the coagulation process--by endothelial cells, monocytes, and macrophages has been implicated in these conditions. AIM: To investigate whether urinary tissue factor (uTF) might reflect the state of monocyte/macrophage activation and be a useful diagnostic test. METHODS: Urine was centrifuged at 51,000 g to sediment tissue factor containing membrane vesicles. The tissue factor was then solubilised in beta-octyl-glucopyranoside and assayed in a specific chromogenic assay adapted for use in microtitre plates. RESULTS: The assay proved to be sensitive, specific, and reproducible. The normal range of uTF was relatively narrow and unaffected by age, sex, or cigarette smoking. Levels were not significantly influenced by storage of urine samples before assay or by the presence of fresh blood in the urine sample. CONCLUSIONS: This method may have diagnostic application in the study of haemostatic activation in patients with cancer and other disease states.

URINARY TISSUE FACTOR LEVELS IN NEOPLASTIC DISEASES

BACKGROUND Abnormalities in laboratory coagulation and fibrinolysis parameters can be detected in cancer patients, and tissue factor (TF) is implicated. TF is produced by certain tumors and is increased in both tumor associated macrophages and blood monocytes (mTF). TF is also found in urine (uTF), and its levels may be clinically important. MATERIALS AND METHODS Using a simple and highly standardized kinetic chromogenic assay (KCA), we measured uTF levels in controls (normal, n=57; patients with renal stones, n=30), patients with benign and malignant conditions of the bladder (n=75), prostate (n=106), breast (n=94), and colorectum (n=62). Each benign disease group was subdivided into inflammatory and noninflammatory categories. RESULTS The controls and benign noninflammatory groups gave similar results and were, therefore, unified for further analysis. The malignant and inflammatory groups showed higher uTF levels than the controls (P<0.001 for bladder, P<0.01 prostate, P<0.001 breast, and P<0.001 for colorectum). The difference between malignant and benign inflammatory disease was significant for the bladder group (P<0.05). Cancer patients showed uTF activity above the upper quartile range of the normal control group--74.4% for bladder, 68.0% for prostate, 77.3% for breast and 73.0% for colorectal disease. uTF levels were related to tumor progression, patients survival time, serum prostate specific antigen (PSA), and static bone scan images (SBSI). Levels were also higher in patients with bladder cancer recurrence and those who subsequently died. CONCLUSION uTF levels are raised in malignant and inflammatory disease compared to controls and patients with noninflammatory conditions, and are related to tumor grade or stage, patients survival and to markers of tumor progression.

Tissue factor assays as diagnostic tools for cancer? Correlation between urinary and monocyte tissue factor activity.

Monocyte and urinary tissue factors (mTF and uTF) are both elevated in a number of pathologic conditions, including cancer. This study validates the best available uTF and mTF assays as diagnostic tools for cancer and examines if uTF levels reflect monocyte activation. Using kinetic chromogenic assays for uTF and mTF (measured on fresh resting cells [baseline], unstimulated cells, and lipopolysaccharide [LPS]-stimulated cells), we assessed TF levels in normal individuals, surgical controls, and patients with benign and malignant diseases. Each benign disease group was stratified as inflammatory or noninflammatory. Controls and benign noninflammatory results were indistinguishable. The malignant and inflammatory groups showed raised uTF levels over controls (p < 0.001). mTF levels differ similarly. For mTF and uTF assays, there was no significant difference between the malignant and inflammatory groups. The relative operating characteristic (ROC) curve plots sensitivity against false positive rate (1-specificity) for all possible cutoff values of a diagnostic test. Assay performance is assessed as the area under the curve (AUC). The ROC curve for the uTF assay displayed both sensitivity and specificity for cancer, the AUC being 0.83. Of the three mTF levels, LPS-stimulated cells gave the optimum curve (AUC = 0.71). uTF showed a weak to moderate association with mTF levels but correlated best and was statistically significant when compared with levels in the LPS-stimulated cells. uTF represents an intrinsic, kidney-derived, physiologic concentration rather than that of preactivated or postactivated monocytes. In conclusion, both uTF and LPS-stimulated mTF levels showed sensitivity and specificity in detecting cancer and inflammatory diseases. However, the two forms of TF appear to be independently derived.