Mastocytosis is characterized by accumulations of mast cells in various organs (1). Most cases are indolent and confined to the skin, where discrete mast cell infiltrates are associated increased epidermal melanin, a clinical picture known as urticaria pigmentosa (UP). Other forms of mastocytosis combine UP with aggressive involvement of other organs or with haemotologic abnormalities (1-4). It is not known whether all forms of mastocytosis are true neoplasms or whether some might represent reactive hyperplasias (5-7). The c-KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT) that is critical to the development and survival of mast cells and melanocytes (8-11). The ligand for KIT (KL) can stimulate mast cell development, proliferation, and mediator release (9,12-17), as well as melanocyte proliferation and pigment production (18-20). To determine the role of c-KIT in the pathogenesis of mastocytosis, we examined tissue and cells isolated from a patient with UP and aggressive systemic mastocytosis with massive splenic involvement. We found a mutation that results in constitutive activation and expression of c-KIT in mast cells of both skin and spleen. This is the first in situ demonstration of an activation c-KIT mutation in neoplastic cells. It also demonstrates the clonal and neoplastic nature of this form of mastocytes.

1. It has been suggested that the physiological consequences of strenuous exercise are analogous to those of the acute-phase response. 2. In 70 male and 20 female competitive distance runners, a marked, but transient, neutrophil leucocytosis occurred immediately after these athletes completed a standard (42 km) marathon race. Concomitant significant increases were noted in the plasma cortisol levels, creatine kinase activity, C-reactive protein level, total protein level and albumin level (P less than 0.01). 3. The plasma fibrinogen, C-reactive protein and total protein concentrations were markedly increased both 24 h and 48 h after exercise (P less than 0.01). The serum haptoglobin level was significantly decreased after exercise (P less than 0.01), and increased 48 h later (P less than 0.05). There was no change in the serum iron level, total iron-binding capacity, per cent saturation of transferrin and serum ferritin level. 4. A significant increase in interleukin-1-type activity was demonstrated immediately and 24 h after exercise (P less than 0.01). 5. It is concluded that the metabolic sequelae of sustained exercise are similar, but not analogous, to the acute-phase response, and interleukin-1, probably plays a significant role in linking the haematological and immunological changes observed after sustained strenuous exercise.

Summary:Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34 + cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 g/ml and 120 g/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic

A controlled, prospective study comparing streptokinase and heparin treatment has been completed in 51 patients presenting with acute proximal venous thrombosis of less than 8 days' clinical duration. Patients were studied by means of pre-treatment, post-treatment, 3- and 12-monthly phlebography and pulmonary perfusion scanning and were followed up at 3-monthly intervals. Of the 26 patients randomized to receive streptokinase, therapy was stopped in 3 because of complications. Phlebography 5 days after starting treatment showed 80--100 per cent lysis in 17 of the 23 patients who completed the course of streptokinase. Two patients later developed partial rethrombosis. One patient developed an asymptomatic pulmonary embolus during treatment. During follow-up (mean 19 months) only 1 of the 17 patients with 80--100 per cent lysis developed postphlebitic symptoms, 3 patients died of unrelated causes and 1 patient was lost to follow-up. In patients randomized to heparin therapy no significant lysis was achieved in any of the 25 patients and only 2 of these patients were found to have asymptomatic legs on follow-up. Two patients in this group died and autopsy confirmed massive pulmonary embolus during treatment. These data suggest that streptokinase is superior to heparin in the treatment of acute proximal venous thrombosis of less than 1 week's clinical duration especially if the thrombus is largely non-occlusive. It must be stressed that in order to avoid the bleeding complications of thrombolytic therapy, streptokinase must not be used within 10 days of major surgery, or even longer after vascular, neurosurgical or eye operations.

Antibodies specific for human T-cell leukemia-lymphoma virus type I (HTLV-I) were demonstrated in serum samples from various groups of people in South Africa, Uganda, Ghana, Nigeria, Tunisia, and Egypt. The samples had been collected for other purposes and were presumably selected without bias toward clinical conditions associated with HTLV infections. Regional differences in antibody positivity were observed, indicating widely distributed loci of occurrence of HTLV on the African continent in people of both black and white ancestry. Two patients with high titers of antibody to HTLV-I had some signs of adult T-cell leukemia-lymphoma. In several groups a high frequency of false positive serum reactions was indicated when specific confirmation steps were included in the assay. Further characterization of these sera revealed highly elevated immunoglobulin levels, possibly due to polyclonal activation of immunoglobulin synthesis in these subjects. The possibility that related cross-reactive human retroviruses coexist in the same groups was not eliminated.

One hundred therapeutic plasmaphereses were carried out at biweekly intervals in seven patients, without morbidity or mortality, using the IBM 2997 blood fraction separator. In standardised procedures, 1.5 times the calculated plasma volume was replaced with an electrolyte solution containing 4% salt-free human albumin. Anticoagulation was achieved using a whole venous blood to acid-citrate dextrose ratio of 11 to 1. Median flow rates, plasma collection, and procedure times were respectively 40 ml/minute, 20 ml/minute, and 3 hours. Haemoglobin and total white cell counts were not significantly affected by the procedures. In contrast, platelet count, fibrinogen, immunoglobulin levels, total haemolytic complement, as well as C3 and C4 fractions fell, and the prothrombin and partial thromboplastin times were lengthened by the exchanges. All these measurements had returned to normal within 24 hours, apart from the fibrinogen, which took between 48 and 72 hours, and the immunoglobulin level, which required 35 days to return to baseline. In a further patient, more detailed studies (n = 13) were carried out to characterise the behaviour of antithrombin III and factor VIII. Both levels were markedly reduced immediately following the procedure and, like fibrinogen, had returned to normal within 48 hours. These data indicate that in an isovolemic plasmapheresis there was a transient but rapidly reversible effect on all the factors studied, with fibrinogen level, antithrombin III, and factor VIII returning more slowly to normal than the others, and immunoglobulin levels responding the slowest. None of these changes was associated with clinically significant haemostatic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Exercise-induced haemolysis has been implicated in the sub-optimal iron status of endurance-trained athletes. Accordingly, erythrocyte survival studies using 51Cr were performed on male and female distance runners (n = 20) and sedentary control subjects (n = 10) in order to determine whether the rate of erythrocyte destruction was altered as a consequence of repetitive exercise training. 2. The chromium half-disappearance time of the male (25.4 +/- 3.6 days, mean +/- SD) but not the female (28.3 +/- 4.6 days) athletes was significantly lower than that of the male (33.1 +/- 4.5 days) and female (32.3 +/- 2.6 days) control subjects (P less than 0.01). The mean erythrocyte lifespan of the male and female distance runners (67.2 +/- 22.2 and 72.4 +/- 26.0 days, respectively) was significantly shorter than that of the non-exercising male and female subjects (113.4 +/- 31.0 and 114.1 +/- 29.0 days, respectively) (P less than 0.01). 3. There was no correlation between the mean erythrocyte lifespan and the haemoglobin concentration, serum ferritin levels, body mass, weekly training distance, number of years running or daily protein intake. The mean cell volume and reticulocyte count measured in the same athletes before and after completing a standard 42 km marathon race were within the normal range, whereas the plasma haemoglobin levels were elevated (77.0 +/- 50.5 mg/l) and the serum haptoglobin levels were decreased (0.89 +/- 0.4 g/l) at rest, with a further significant decrease after running (0.69 +/- 0.4 g/l) in the latter measurement (P less than 0.05). 4. It is concluded that the demonstrated increase in erythrocyte turnover may be sufficient to precipitate an iron deficiency in endurance athletes when dietary intake or absorption does not meet the accelerated erythropoietic demands.

BackgroundAbsolute iron deficiency, irrespective of aetiology, remains a major and worldwide cause of morbidity. After correction of the causative lesion, reconstitution of haemoglobin level and body iron stores is traditionally achieved with oral administration of ferrous salts. The latter have significant gastrointestinal tract side-effects that, in the short-term, may impair compliance. With protracted administration these products can cause lipid peroxidation which, in turn, may accelerate atherogenesis. An alternative formulation is an iron polymaltose complex where animal data supported a promoting effect of glycerophosphate. Setting and Trial Design This was a single-centre, open, randomised, multidose four treatment parallel group study. A standard dose of ferric polymaltose complex with two differing levels of glycerophosphate was compared with an equivalent amount of iron supplied as ferrous sulphate in anaemic volunteer blood donors. The endpoints were rate of haemoglobin rise and re-expansion of body iron stores reflected in blood ferritin concentration, as well as percentage saturation of transferrin. Secondary observations were changes in the proportion of hypochromic red cells during the course of treatment, erythropoietin levels and tolerability of the two formulations. Results Outcome in the rat model suggested that the utilisation of iron from polymaltose might be enhanced by glycerophosphate. However, in donors this difference was not evident and, accordingly, the data from the three polymaltose groups combined and compared to those receiving ferrous sulphate. The rate at which haemoglobin level improved, red cell indices returned to normal, and the number of hypochromic and microcytic red cells fell was not significantly different between the groups. Similarly the serum iron, percentage saturation of transferrin and red cell ferritin were comparable. In contrast the serum ferritin levels were higher for those receiving ferrous sulphate. Additionally, side-effects were significantly more frequently encountered with the latter preparation. Conclusion These data demonstrate that the addition of glycerophosphate, observed to be beneficial in rats, did not occur in humans. Secondly, in the blood donors, equivalent amounts of iron provided as the polymaltose, with or without glycerophosphate or ferrous sulphate, corrected haemoglobin concentration and morphologically abnormal erythropoiesis at comparable rates. Similarly iron stores are replenished to an equivalent extent as seen in the matching percentage saturation of transferrin and red cell ferritin levels. Interestingly, there is a discrepancy in the serum ferritin which is higher with the salt and this may reflect oxidative stress. Thirdly, corresponding efficacy can be achieved with better patient tolerance for the complex. Finally it is postulated that the iron polymaltose complex formulation more closely approximates the way in which enterocytes handle dietary iron and thus physiologic regulatory mechanisms would be expected to reciprocally...