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Cell division and apoptosis (programmed cell death) are the two major physiological processes which control the size of cell populations. Chronic lymphocytic leukaemia arises as a result of the clonal expansion of, usually B-, lymphocytes in which a dysregulation of apoptosis leads to prolonged cell survival. The same process becomes exaggerated with increasing drug resistance, the usual cause of treatment failure in this condition. The identification of points in the apoptotic pathway at which dysregulation occurs is beginning to open up new therapeutic opportunities where the conventional cytotoxic chemotherapy approach is found to fail. Although these strategies are still in their infancy they may increase understanding of the pathogenesis of the disorder and overcome the problem of drug resistance.

The inhibition of 3H-thymidine incorporation into the DNA of mitogen-stimulated lymphocytes from patients with chronic lymphocytic leukaemia by chlorambucil was measured in vitro and the results related to clinical drug resistance. The assay proved to be both sensitive and specific showing a clear separation of those patients with responsive disease from those with disease resistant to treatment. There was evidence of primary drug resistance in untreated patients. In almost all patients who received treatment this led to increasing resistance to chlorambucil in vitro. The assay is predictive of clinical responsiveness and provides a potential means whereby new therapeutic agents and treatment modifiers may be investigated.

SummaryReversal of the anticoagulant effect of warfarin in patients with no active haemorrhage can be achieved by administration of intravenous vitamin K1. Currently recommended doses of intravenous vitamin K1, for this purpose often result in subsequent difficulties in anticoagulation. We observed the response to low dose intravenous vitamin K1 in patients requiring reversal of anticoagulant therapy. Ten consecutive patients received L mg and 2l further patients received 0.5 mg of intravenous vitamin K1. In 50% of the patients who received 1 mg of vitamin K1 the INR (International Normalised Ratio) fell below 2 at 24 h whereas in patients who received 0.5 mg the INR fell below 5.5 in all subjects after 24 h and in none did it fall below 2.0. No patient had any thrombotic or haemorrhagic complications and no difficulty was encountered in re-establishing anticoagulant control after 24 h. We recommend 0.5 mg of vitamin K1 as an effective and convenient method of predictable and fine control of oral anticoagulant therapy.

Cell division and apoptosis (programmed cell death) are the two major physiological processes which control the size of cell populations. Chronic lymphocytic leukaemia arises as a result of the clonal expansion of, usually B-, lymphocytes in which a dysregulation of apoptosis leads to prolonged cell survival. The same process becomes exaggerated with increasing drug resistance, the usual cause of treatment failure in this condition. The identification of points in the apoptotic pathway at which dysregulation occurs is beginning to open up new therapeutic opportunities where the conventional cytotoxic chemotherapy approach is found to fail. Although these strategies are still in their infancy they may increase understanding of the pathogenesis of the disorder and overcome the problem of drug resistance.

Reversal of the anticoagulant effect of warfarin in patients with no active haemorrhage can be achieved by administration of intravenous vitamin K1. Currently recommended doses of intravenous vitamin K1, for this purpose often result in subsequent difficulties in anticoagulation. We observed the response to low dose intravenous vitamin K1 in patients requiring reversal of anticoagulant therapy. Ten consecutive patients received 1 mg and 21 further patients received 0.5 mg of intravenous vitamin K1. In 50% of the patients who received 1 mg of vitamin K1 the INR (International Normalised Ratio) fell below 2 at 24 h whereas in patients who received 0.5 mg the INR fell below 5.5 in all subjects after 24 h and in none did it fall below 2.0. No patient had any thrombotic or haemorrhagic complications and no difficulty was encountered in re-establishing anticoagulant control after 24 h. We recommend 0.5 mg of vitamin K1 as an effective and convenient method of predictable and fine control of oral anticoagulant therapy.

Chronic lymphocytic leukemia (CLL) is a progressive disease in which chemotherapy may result in temporary suppression of the peripheral blood lymphocyte count, but cure is not usually possible. Drug resistance mechanisms and the multidrug resistant (MDR) phenotype may be relevant to the therapeutic response. We have studied 34 patients with CLL (seven untreated, 27 treated), screening both DNA and RNA with the mdr 1 gene probe. In pure lymphocyte populations from 10 normal subjects, low levels of mdr 1 RNA expression were found. Eighteen CLL patients (four untreated, 14 treated) had levels of mdr 1 RNA expression above the normal range. No evidence of mdr 1 gene amplification could be found in these patients. Sequential estimations of RNA levels in three patients suggest that malignant lymphocytes in CLL can increase mdr 1 expression in response to chemotherapy and return to basal levels on withdrawal of the treatment. Such data raise important questions about the type of timing of cytotoxic therapy in CLL.

We have recently encountered six patients with myelodyplasia (MDS) in whom biopsy proven cuteneous vasculitis was a major feature of their illness. In three patients there was, in addition, evidence of systemic vasculitis

Objective To determine the optimum duration of oral anticoagulant therapy after an episode of deep vein thrombosis or pulmonary embolism, or both.Design Multicentre, prospective, randomised study with follow-up for one year.Setting 46 hospitals in United Kingdom.Participants Patients aged ≥18 with deep vein thrombosis or pulmonary embolism, or both.Interventions Three (n=369) or six months (n=380) of anticoagulation with heparin for five days accompanied and followed by warfarin, with a target international normalised ratio of 2.0-3.5.Main outcome measures Death from deep vein thrombosis or pulmonary embolism; failure to resolve, extension, recurrence of during treatment; recurrence after treatment; and major haemorrhage during treatment.Results In the patients allocated to three months' treatment two died from deep vein thrombosis or pulmonary embolism during or after treatment, compared with three in the six month group. During treatment deep vein thrombosis or pulmonary embolism failed to resolve, extended, or recurred in six patients in the three month group without fatal consequences, compared with 10 in the six month group. After treatment there were 23 non-fatal recurrences in the three month group and 16 in the six month group. Fatal and non-fatal deep vein thrombosis or pulmonary embolism during treatment, and after treatment thus occurred in 31(8%) of those who had received three months' anticoagulation compared with 29 (8%) of those who had received six months' (P=0.80, 95% confidence interval for difference −3.1% to 4.7%). There were no fatal haemorrhages during treatment but there were eight major haemorrhages in those treated for six months and none in those treated for three months (P=0.008, −3.5% to −0.7%). Thus 31 (8%) of the patients receiving three months' anticoagulation experienced adverse outcomes as a result of deep vein thrombosis or pulmonary embolism or its treatment compared with 35 (9%) of those receiving six months' (P=0.79, −4.9% to 3.2%).Conclusion For patients in the UK with deep vein thrombosis or pulmonary embolism and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from three to six months. Any possible advantage would be small and would need to be judged against the increased risk of haemorrhage associated with the longer duration of treatment with warfarin.Trial registration Clinical Trials NCT00365950.

Summary. A colloidal suspension of hydrolysed radio-iron of high specific activity has been developed for the investigation of reticuloendothelial (RE) iron kinetics in man. Following intravenous injection this material is cleared rapidly by the RE system and the iron released into the plasma where it is bound to transferrin. There is no significant addition to the endogenous RE iron load, and it has proved possible to measure RE iron release without disturbing the normal iron flow.

In 55 patients in whom warfarin control had been satisfactory for at least 4 months, warfarin dose, plasma warfarin concentration and plasma clearance were measured. The mean dose to maintain the BCR (INR) between 2.3 and 3.3 was 5.1 +/- 2 mg day-1 (range 1.5-10 mg). Plasma warfarin concentrations and warfarin clearance were log-normally distributed with 95% confidence limits between 0.8 and 2.4 mg l-1 and 2.5 and 8.71 day-1 respectively. These confidence limits were used to construct algorithms which correctly predicted the cause of abnormal warfarin sensitivity in two patients and resistance in two further patients. These algorithms should help to identify the cause of abnormal warfarin responsiveness in the clinical setting.

Summary One hundred hospital in-patients treated for pulmonary embolism (PE) and/or deep vein thrombosis (DVT) were randomly allocated to receive 3 or 6 weeks' anticoagulation with heparin and warfarin. At one year recurrence rates were 12% in the 6 week group and 10% in those treated for 3 weeks. No patient died as a result of recurrence. Our study suggests that 3 weeks' anticoagulation therapy, using intravenous heparin for the first 5 days and warfarin from the third day, is adequate for patients without persisting risk factors.

Eleven patients with acute myeloblastic leukaemia have received repeated intravenous injections of BCG containing 4-9 X 10(6) live organisms per millilitre. Non-caseating epithelioid granulomas, sometimes with giant-cell formation, have been demonstrated in eight bone marrow aspirates. Seven patients had granulomas in the liver, three in the lung, one in the spleen, one in lymph nodes, and one in a skin biopsy. One patient had a raised serum alkaline phosphatase, but none of the patients had any illness which could be related to the presence of granulomas. Granuloma formation appeared more extensive in four patients who were probably anergic before BCG treatment. Until the significance of this finding becomes clear great care should be taken when giving BCG by the intratumour of intravenous routes to potentially immunoincompetent patients.

Serum ferritin concentration has been compared with semi-quantitative histochemical estimates of bone marrow iron deposits in 60 anaemic patients with rheumatoid arthritis. There was considerable variation in the visual assessment of iron stores made by different observers. Serum ferritin appears to be a particularly sensitive index of iron status when stores are low. The best means of detecting iron deficiency in rheumatoid arthritis are discussed.

Erythropoietic activity and mean red-cell lifespan were measured using 59Fe-transferrin in 32 anaemic patients with active rheumatoid arthritis (RA) and in 20 haematologically normal subjects. Marrow iron turnover (MIT) in the patients was normal and in only 11 was red-cell lifespan less than 70 d. Ineffective iron turnover (IIT) was significantly increased in those patients in whom there was evidence of iron deficiency (serum ferritin less than 12 microgram/l) but in the remaining patients IIT was significantly less than in the normal subjects. In a further 19 patients with simple iron deficiency anaemia IIT was significantly increased. The marrow response to chronic inflammatory disease is clearly distinct from that seen in simple iron deficiency and this suggests different pathogenic mechanisms for these two anaemias.

Reticuloendothelial iron kinetics were investigated in a simultaneous dual-isotope study in 10 healthy adult subjects in whom 55Fe-ferric hydroxide phosphate colloid was used to label the reticuloendothelial iron pools, and 59Fe-transferrin was used to define plasma iron kinetics. The simultaneous clearance of 55Fe and 59Fe from plasma and the uptake of each into red blood cells were measured over 14 days. The 55Fe-colloid was cleared almost immediately, and its iron was rapidly released to bind to plasma transferrin. Red cell incorporation of 55Fe was, however, much slower than that of 59Fe bound to transferrin in vitro. The data were analyzed by a new model of reticuloendothelial iron metabolism that contained two reticuloendothelial iron pools; one had a rapid turnover and donated iron to transferrin, and the other, a storage pool, had a slower turnover. The transit pool contained a mean of 164 mumol iron with little variation between subjects, whereas the storage pool was somewhat larger (mean 873 mumol iron) and showed more marked variation between subjects. In general an equal proportion of the iron leaving the transit pool went to transferrin and to the storage pool. The distribution between the two routes did not appear to be related either to plasma iron concentration, latent iron-binding capacity, or transferrin saturation.

Fifty patients with venous thromboembolic disease being treated by heparin infusion received a three day warfarin induction regimen tailored according to the prothrombin time (British comparative ratio) measured on days 2 and 3. A prediction of the final maintenance dose of warfarin was made on the basis of a prothrombin time measured on day 4. All patients were safely anticoagulated by day 6, and the prediction was accurate to within 1 mg in 46 patients. Predicted and actual maintenance doses were closely related (r = 0.867; n = 50; p less than 0.001). This scheme should prove helpful in the control of anticoagulation, particularly in patients likely to be sensitive to warfarin, and should shorten hospital stay.

Thirty anaemic patients with active rheumatoid arthritis were each given 800 mg of iron , as iron dextran, intramuscularly over an interval of four weeks. The haemoglobin concentration rose significantly within two months in 26 of the patients but this was followed by a significant fall to the pre-treatment level nine months after treatment. The response to iron therapy was not related to the initial haemoglobin concentration, serum iron concentration, transferrin saturation nor to the amount of storage iron, whether assessed by bone marrow stainable iron or the serum ferritin concentration. There was an unexpected fall in the serum ferritin concentration within the first two months after treatment in half of the patients and this was followed by a rise towards the pre-treatment level during the following seven months, such that there was no apparent addition to the amount of storage iron over the period of the study. The possible mechanisms for these findings are discussed. A response to parenteral iron therapy in patients with active rheumatoid arthritis should not be regarded as evidence of iron deficiency and only by correction of the underlying inflammatory process will lasting improvement in the anaemia be obtained.

The red cell mass was measured in 44 normal subjects and showed a closer correlation with total body water or surface area than with body weight. The results obtained in a group of patients with polycythaemia, however, still overlap with the normal range. When the total number of circulating red cells is measured these patients form a group quite separate from the normals. The diagnostic value of this measurement is therefore considerably greater than results obtained with the red cell mass.

Seven patients with small cell lung cancer were treated with high-dose etoposide (1400-2400 mg/m2), given as a single course over 3 days, in conjunction with autologous bone marrow transplantation. Five patients achieved a partial response and two had no response. All patients required further treatment. The lack of any complete responder or good partial responder dissuaded us from entering further patients into the study, and high-dose, single-agent etoposide cannot be recommended in the initial treatment of small cell lung cancer.

The mechanism by which anaemia develops in pregnancy is well understood: haemodilution causes a fall in the haemoglobin concentration during the first and second trimesters of normal pregnancies. Negative iron balance throughout pregnancy, particularly in the latter half, may lead to iron deficiency anaemia during the third trimester. The increase in iron demand is required to meet the expansion in maternal haemoglobin mass and to meet the needs of fetal growth. Fetal demand for iron results in a unidirectional flow of iron to the fetus against a concentration gradient regulated by fetal requirements for iron; this iron transfer occurs almost entirely irrespective of maternal iron status. The development of maternal iron deficiency during pregnancy may be detected by monitoring the haemoglobin concentration frequently; values falling to less than 11 g/dl should be regarded as abnormal, but specific red cell changes, such as microcytosis, may be lacking. A diagnosis of iron deficiency can be most conveniently confirmed by the serum ferritin concentration falling to less than 12 micrograms/l. Women at risk from iron deficiency anaemia can therefore be readily identified and corrective treatment instituted prior to the development of severe anaemia. A serum ferritin concentration of less than 50 micrograms/l in early pregnancy is an indication for iron supplements. Women in whom the serum ferritin concentration is greater than 80 micrograms/l at booking are unlikely to require iron supplements during pregnancy. This approach would eliminate the need for routine prophylactic iron therapy, which, in populations enjoying a good nutritional status, can no longer be justified in early pregnancy. Furthermore, any risk to the fetus from severe maternal anaemia would be avoided by prophylaxis and prompt treatment.

Successful tether deployment and retrieval, consistent with established control laws, is predicated upon statusing real time tether dynamic conditions. This paper reports on the initial phase of engineering tests performed on various components and subassemblies integral to the TSS-1 tether control system as part of the TSS Deployer. The tests were conducted as part of the tether control system development and verification plan to confirm the functionality and map the performance of the hardware in both ambient and environmental test conditions. The result of this development effort is a lessons-learned list and design upgrades to both the flight and test hardware and to the test methods and procedures.

L'etoposide n'est pas un agent neurotoxique et peut etre utilise meme en presence de lesions nerveuses preexistantes

With new guidelines for the control of heparin infusion rates the proportion of kaolin cephalin clotting time ratios was significantly improved compared with ratios achieved without their use. Further improvement might result from careful preparation and delivery of the infusion.