About five out of 1,000 patients admitted to hospital develop bacterial sepsis leading to shock, the mortality rate for which is high despite antibiotic therapy. The infection results in hypotension and poor tissue perfusion, and eventually leads to the failure of several organ systems. Bacterial endotoxin is thought to be the direct cause of shock in Gram-negative sepsis, because it can cause shock in animals, and antibodies against endotoxin prevent Gram-negative shock in animals and in humans. But, the symptoms of septic shock are the result of the actions of host cytokines induced by the endotoxin. The cytokine interleukin-1 has been implicated as an important mediator of septic shock because it can induce tachycardia and hypotension and act synergistically with tumour necrosis factor to cause tissue damage and death. We now report that a specific interleukin-1 receptor antagonist reduces the lethality of endotoxin-induced shock in rabbits, indicating that interleukin-1 does indeed play an important part in endotoxin shock.

A macrophage migration inhibitory factor (MIF), originally described as a product of activated lymphocytes, has been defined as a 12 kDa protein, expressed in a wide variety of tissues. Here MIF is identified as a phenylpyruvate tautomerase (EC 5.3.2.1) having /»-hydroxyphenylpyruvate and phenylpyruvate as its natural substrates. The definition of MIF as an enzyme may yield insight into the mechanism of action of this proinflammatory and immunomodulating cytokine.

Summary Congenital thrombotic thrombocytopenic purpura (TTP) is associated with ADAMTS13 mutations. The major site of ADAMTS13 synthesis is the liver. Expression in other tissues, and in TTP, has not been shown. In this study, ADAMTS13 protein expression was investigated in normal kidney and in renal tissue from two TTP patients, with a compound heterozygous mutation (P353L and P457L) and a homozygous mutation (4143insA). Real‐time polymerase chain reaction demonstrated ADAMTS13 mRNA in normal kidney. ADAMTS13 was detected in the glomeruli and tubuli of normal and TTP kidney using anti‐ADAMTS13 antibodies. In the glomeruli, expression was localised to podocytes (as demonstrated by counterstaining with two podocyte markers) and endothelium. Similar distribution was detected in the TTP kidneys. Electron microscopy detected ADAMTS13 in podocytes, endothelium and glomerular basement membrane. Cultured human podocytes expressed ADAMTS13 mRNA and protein, and podocyte lysate exhibited von Willebrand factor‐cleaving activity. Mutation expression studies of the P353L and P457L mutations showed partially impaired secretion and lower activity of the secreted mutants. Impaired secretion has previously been shown for the 4143insA mutation. Podocyte‐derived ADAMTS13 may offer local protection in the high‐shear microcirculation of the glomerulus. The mutations in the two TTP patients studied enabled protein expression in the podocytes but affected protease secretion.

The least known parameters in a Monte Carlo simulation of a linear accelerator treatment head are often the properties of the initial electron beam directed onto the exit vacuum window. Several initial beams with different spatial fluence distributions, angular divergences and energy spectra have been transported through the geometry of a scattering foil accelerator. The electron beam characteristics (energy spectrum and angular distribution) at the phantom surface and the subsequent relative absorbed dose distribution in a water phantom were calculated. The dose distribution was found to be insensitive to the geometrical properties of the initial beam. Furthermore, the lateral dose profiles are unaffected by the energy spectrum of the initial beam. The effect on the depth-dose curve is negligible if the initial energy spectrum is symmetric (e.g., Gaussian shaped) and its full width at half maximum (FWHM) is less than approximately 10% of the most probable energy. A larger FWHM will decrease the normalized dose gradient, but will not affect the dose in the build-up region. An asymmetric wedge shaped spectrum with a low-energy extension simultaneously increases the dose in the build-up region and decreases the dose gradient. The relationship between the energy spectral width and the normalized dose gradient is, however, smaller than published analytical expressions indicate. Some well-established energy-range relationships were shown to be accurate for most of the initial beams studied. The energy spectrum at the phantom surface was also derived from a measured depth-dose curve through different methods. The extracted spectrum depends on the beam model and the spectral reconstruction algorithm. Even though the depth-dose curve is fairly independent of initial beam characteristics, a correct description of the low-energy tail of the energy spectrum is important to obtain good agreement between measured and Monte Carlo calculated doses in the build-up region.

Summary:This retrospective study compares the reconstitution of T, B and NK cells in three groups of patients transplanted for haematological malignancies with grafts from their HLAidentical sibling donors. In all, 15 patients received PBSC after a nonmyeloablative conditioning regimen consisting of fludarabine and 200 cGy TBI, 13 patients received PBSC after myeloablative conditioning and 37 patients received BM after myeloablative conditioning. In the nonmyeloablative group, the NK cells normalised after 1 month, the CD8+ T cells normalised after 3 months, the CD4+ T cells reached near normal values after 9 months and the B cell values were reduced until 12 months after transplant. In the two myeloablative groups, recipients of PBSC had a significantly higher number of CD4+ T cells after 4 months (P ¼ 0.004) and after 12 months (P ¼ 0.001), than recipients of BM. We found no differences in the T cell reconstitution between the two PBSC groups. This was of interest as the recipients of nonmyeloablative conditioning were older (Po0.001) and had a higher occurrence of chronic GVHD (Po0.05) than the recipients of myeloablative conditioning. In contrast, the recipients of nonmyeloablative conditioning had a delayed B cell recovery when compared to the patients who received myeloablative conditioning (P ¼ 0.04). Bone Marrow Transplantation (2003) 32, 65-72. doi:10.1038/sj.bmt.1704084 Keywords: immune reconstitution; nonmyeloablative conditioning regimen; peripheral blood stem cell transplantation Allogeneic haematopoietic stem cell transplantation after nonmyeloablative conditioning is a treatment modality increasingly used for patients with haematological malignancies ineligible for conventional myeloablative BMT because of older age, comorbidity or the high treatmentrelated mortality after conventional BMT in particular diseases. The results of nonmyeloablative stem cell transplantation have so far been promising. 1,2 One advantage of the use of a nonmyeloablative conditioning regimen is the brief granulo-and thrombocytopenia, which allows the procedure to be performed in an outpatient setting. The reconstitution of the T, B and NK cells after stem cell transplantation is however also important for the defence against pathogens, 3 and low counts of CD4+ T cells and of B cells have been associated with an increased risk of infection. 4,5 Thymic function is impaired after conventional haematopoietic stem cell transplantation, and this is partially because of the high-dose radiochemotherapy included in the conditioning regimen. 6 As the thymic activity post-transplant has been shown to be important for the generation of a diverse and efficient T cell response, 7,8 the lower toxicity of a nonmyeloablative conditioning regimen could in theory enhance the T cell reconstitution. In this study, we retrospectively compared the reconstitution of absolute numbers of T, B and NK cells in patients transplanted with PBSC and conditioned with a nonmyeloablative regimen to patients who received conventional myeloablative conditio...