Polyclonal intravenous IgG (IVIG) was administered as an infusion 6 times every 3 weeks (weekO, 3, 6, 9, 12, 15) in doses of 0.1, 0.4 and 0.8 g/kg BW to determine the dose causing an increase in 12 pneumococcal antibody types above the protective level of 200 ng/ml of antibody N. The dose of 0.4 g/kg BW was found to be optimal in patients with chronic lymphocytic leukaemia (CLL). From the first infusion onwards at least 80% of CLL patients had increases in all 12 antibodies. Five weeks after the last infusion the antibody levels were still elevated in 80% of patients with CLL. The dose of 0.8 g/kg raised all 12 antibodies in 53–73% of CLLpatients when assessments were made after each infusion. In multiple myeloma (MM) patients, 73–82% and 73–91 % of patients had increased antibody levels, respectively, before and after the 4th–6th infusions at the 0.8 g/kg dose level. However, in only 45–50% of patients did the antibodies remain increased 2 weeks after the treatment at this dose. The dose of 0.4 g/kg caused antibody increases in only 30–50% of patients when measured before the 4^th–6th infusion. Serum IgG increased significantly only in the CLL patients, whereas in the MM patients it was high from the beginning owing to the disease. Therefore, the pneumococcal antibody levels were a better marker for the purpose of dose finding. The dosage recommendation in CLL is 0.4 g/kg every 3 weeks until week 12, when steady state is reached. The maintenance dose is 0.4 g/kg every 5 weeks. In MM patients, who have a faster elimination rate of antibodies, the recommended loading dose is 0.8 g/kg, followed by 0.4 g/kg every week as a continuous treatment. Treatment with IVIG in CLL and MM was generally well tolerated. Only 25% of patients experienced minor side-effects, the most frequent being febrile reactions, shivering and headache.

Objectives. To estimate the total cost of diabetes mellitus in Sweden in 1994 and to compare the cost structure with a former Swedish study and with American studies. The study also aims to investigate how the total cost is distributed between control of and complications of the disease. Design. In order to estimate the economic burden of diabetes mellitus in Sweden in 1994, the cost-of-illness method, based on the human capital theory, has been used. Both direct and indirect costs have been estimated using a prevalence approach and a 'topdown' method. Results. The economic burden of diabetes mellitus is estimated at 5746 MSEK (1US$ ϭ 7.50 SEK) in Sweden in 1994. The direct costs are estimated at 2455 MSEK and constitute about 43% of the total cost. The indirect costs (production loss due to morbidity and premature mortality) were the dominant costs and amounted to 3291 MSEK, or 57% of total cost. Comparisons with a previous Swedish study from 1978 show some interesting results. Firstly, the distribution of direct and indirect costs is identical between the two studies. Secondly, the distribution of costs between management/control of the disease and complications was about the same, comparing the situation 16 years apart. Four American studies show a cost structure similar to the cost structure presented in this study. Conclusions. The overall conclusion must be that very little has changed in the cost structure of diabetes in Sweden between 1978 and 1994.

Fifty-seven consecutive patients with Waldenström's Macroglobuliemia were studied retrospectively for autoimmune manifestations. 28 patients or 51% (16 women and 13 men) had clinical and/or serological autoimmune manifestations, two or more of these being concomitant in 20 (12 women and 8 men). The predominant findings were Coombs' positive autoimmune hemolytic anemia (16%), seropositive rheumatoid arthritis (16%), inflammatory gastric ulcer with parietal cell autoantibodies (12%), and IgM-cardiolipin syndrome (11%). 40% of the autoimmune manifestations were present at the time of diagnosis of the Waldenström's Macroglobulinaemia and 60% were observed over a mean period of 4.7 years. All patients had an IgM M-component. There was no correlation between autoimmunity and the size of the M-component or the degree of hypo-IgG and hypo-IgA gammaglobulinemia. The only correlation between autoimmunity and infection was found in patients with gastric ulcer and parietal cell autoantibodies, in whom the infection was caused by Helicobacter pylori.

Aims To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. Methods Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg −1 day −1 in 23 paediatric (aged 2-12 years) and 31 adult (aged 16-45 years) Vietnamese patients with uncomplicated falciparum malaria. The population model was developed using NONMEM, incorporating interoccasion variability and accounting for a systematic change in artemisinin pharmacokinetics with time, modelled as a change in oral bioavailability. Results Clinical efficacy, in terms of parasite clearance and fever subsidence times, was comparable between children and adults. A one-compartment model with separate pharmacokinetic estimates for children and adults was found best to describe the disposition of artemisinin after oral administration. The population estimates for artemisinin clearance and distribution volume, respectively, were 432 l h −1 and 1600 l for adults and 14.4 l h −1 kg −1 and 37.9 l kg −1 for children, with an intersubject variability (collectively for both age groups) of 45% and 104%, respectively. The oral bioavailability was estimated to decrease from Day 1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults. Conclusions Artemisinin pharmacokinetic data was successfully derived in both paediatric and adult patients using 2-3 capillary blood samples taken in conjunction with parasitaemia monitoring. This study's findings advocated the dosing of artemisinin to children according to bodyweight and to adults according to a standard dose.

51:548±556The cellular phenotypes and the expression of cytokines were studied in the lungs of mice, using immunohistochemistry, during different phases of slowly progressive primary murine tuberculosis infection. During the ®rst phase the small focal lesions in healthy mice contained predominantly interleukin-2 (IL-2)-expressing cells. A small number of tumour necrosis factor-a (TNF-a)-, monocyte chemoattractant protein-1 (MCP-1)-and IL-10-expressing cells were also present. IL-4-expressing cells were not detected. During the second phase the mice became unwell, but the bacterial counts and the size of focal lesions stabilized. IL-4-expressing cells appeared. The IL-10-, TNF-a-and MCP-1-expressing cells increased in number. On progression to phase three, the mice became seriously unwell and died rapidly. The in¯ammation spread to < 80% of the lung parenchyma. There was a marked increase in the number of IL-10-expressing cells. Expression of other cytokines was similar to that observed in the second phase. In the lesions, 3±6% of the macrophages (Mf) containing mycobacterial antigens expressed high levels of IL-10 and TNF-a. The absolute numbers of CD3-, CD4-and CD11b-expressing cells in the lesions increased with the progression of infection. The numbers of CD8 cells were reduced in the last phase of infection. The kinetics of T-lymphocyte subsets and the pattern of cytokine expression changed with the type and degree of tissue injury. The small number of Mf with a heavy load of mycobacterial antigens may be the cause of this disturbance in cytokine balance, thus leading to progression of in¯ammation.

Our previous study showed that the cell-activation responses and cytokine-secretion patterns were different in lungs and spleens of mice with slowly progressive primary Mycobacterium tuberculosis infection. The aim of the present study was to characterize the T-cell subsets in lungs and spleens of mice with a similar infection. The percentages of T-cell subsets were determined by flow cytometry and the absolute numbers were calculated. Spleens of infected mice showed a threefold expansion of CD4+ cells but no change in CD8+ cells, whereas lungs had a threefold increase of both subsets. A significant expansion of CD4-CD8-alphabeta+ [double negative (DN)alphabeta+] subsets was observed in the lungs of infected mice compared with uninfected mice. This was not the case in the spleens of infected mice. In infected mice the CD4-CD8- (DN) population preferentially expressed alphabeta-T-cell receptors (TCR) in the lungs but gammadelta-TCR in the spleens. The percentages of many T-cell subsets were significantly higher in the lungs than in the spleens of both uninfected and infected mice. However, the percentages of CD4+ and CD4-CD8+TCR- subsets in the lungs were significantly lower than in the spleens of infected mice. We also observed some previously unreported T-cell subsets: double positive-TCR- (DPTCR-), DPalphabeta+ and DPgammadelta+. So far their functions are unknown.

To ascertain whether the microbiological etiology of bacteremia among patients with hematological malignancies has changed in Denmark, the species distribution of clinically relevant blood culture isolates from the Hematological Department at Rigshospitalet, Copenhagen in 1990 was compared with 2 previous studies (1970-72; 1981-85). In addition, time trends of the etiology of bacteremia among hematological patients in Copenhagen (eastern Denmark) and in Arhus (western Denmark) were compared. In contrast to many other studies, a significant increase in the proportion of Gram-negative aerobes was observed in Copenhagen (from 43% in 1981-85 to 55% in 1990; p < 0.05), whereas in Arhus the proportion of Gram-positive aerobes increased steadily during the 1980s (from 34% to 51%; p < 0.05). In Copenhagen, non-hemolytic streptococci and Xanthomonas maltophilia increased significantly and accounted for 10% (p < 0.01) and 5% (p < 0.05) respectively, of all isolates in 1990, whereas Staphylococcus aureus during the 2 decades studied decreased from 25% to 8% (p < 0.001). In both regions, a decrease was observed in the proportion of Pseudomonas aeruginosa which accounted for only about 5% of all isolates in 1990. No changes were observed in the rates of anaerobes and yeasts. Several factors may contribute to the reported differences in the etiology of bacteremia among hematological patients, e.g. criteria used to assign the clinical significance of the isolate, blood culture system used, practice of using indwelling intravenous catheters, different policies with respect to antimicrobial treatment, and the degree of immunosuppression. A local surveillance of blood culture isolates is mandatory if changes in etiology and resistance development are to be detected.

The aim of the present study was to assess the compartmentalized immune response, in terms of cytokine secretion and cell activation, in lungs and spleens of mice with slowly progressive primary tuberculosis. Immunocyte populations from both organs were isolated and stimulated with concanavalin A, purified protein derivatives and MPT 59. Production of interferon-␥ (IFN-␥) and interleukin-4 (IL-4) was measured using an enzyme-linked immunosorbent assay, and cell activation was measured using a tetrazolium colorimetric assay. The IFN-␥ and IL-4 levels in the supernatants of Mycobacterium tuberculosis antigen (Ag)-stimulated lung immunocytes from infected mice were higher than the levels from uninfected mice. However, only IL-4 levels were raised in the supernatants of Ag-stimulated spleen immunocytes from infected mice. Spontaneous and Ag-stimulated immunocyte activation was lower only in the lungs of infected mice compared with uninfected mice. The level of lung immunocyte activation was inversely associated with the extent of gross pulmonary pathology. In conclusion, cytokine secretion and cell activation were different between lungs and spleens in slowly progressive primary murine tuberculosis. Cytokine diversity may explain the confinement of tuberculous lesions in the lungs and the absence of lesions in the spleens of mice with slowly progressive tuberculosis.