CD8 expression on B cells in chronic lymphocytic leukemia: a case report and review of the literature.

The expression of CD8, a restricted T-cell antigen, on B cells in B chronic lymphocytic leukemia is rare, and its significance, if any, remains unknown. We report herein a patient with B chronic lymphocytic leukemia in whom CD8 was strongly expressed on all B cells, both in the bone marrow and peripheral blood. The patient required no therapy for 6 years after being diagnosed as having B chronic lymphocytic leukemia. Then, when the disease progressed, he was treated with conventional doses of fludarabine phosphate (25 mg/m(2) daily for 5 days), but unlike other patients with B chronic lymphocytic leukemia he tolerated this therapy poorly. He received a total of only 4 series of fludarabine therapy, and following each course of treatment, he developed considerable myelosuppression. After the fourth course of therapy, his bone marrow failed to show any evidence of regeneration, and he died as a result of intercurrent respiratory tract infection 1 month after his last dose of fludarabine was given.

Removal of non-transferrin-bound iron from blood with iron overload using a device with immobilized desferrioxamine.

An extracorporeal hollow-fiber device with immobilized desferrioxamine (DFO) was developed for the removal of nontransferrin-bound iron (NTBI) from blood, without the toxicity of parenteral chelation. When blood circulates through the fibers having pores with 30 kD cut-off, non-transferrin-bound-iron (NTBI) crosses the fiber pores and is chelated by the immobilized desferrioxamine. Removal of circulating iron stimulates iron release from larger proteins and tissue stores, establishing continuous iron flow to the immobilized chelator. During in vitro circulation through a device, iron removed from blood of hemodialysis or sickle cell patients was proportional to, but always in less than 50% of the initial iron level. We attribute the inability to remove more serum iron to irreversible iron binding by transferrin. To investigate where removable and fixed iron was bound, iron binding proteins were analyzed in sera from six patients with genetic anemias and iron overload. Sera separated by sieving chromatography contained 1-14% of the iron in the < 30 kD protein pool, 26-48% was in the combined non-transferrin pools. Sera from hemochromatosis patients without iron overload did not contain NTBI. Circulation of hemochromatosis blood through the device removed one third of the iron, this came from all molecular weight fractions. Iron removal by the device from the < 30 kD pool appears to establish a disequilibrium, that stimulates continuous iron release from ligands with low iron affinity, renewing the pool in the < 30 kD range, which includes potentially toxic NTBI. Therapy with the chelator device having immobilized desferrioxamine should be beneficial for treatment of patients with iron overload.

Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene.

Complete deficiency of thyroxine-binding globulin (TBG-CD) is defined as undetectable TBG in the serum of affected hemizygous subjects. Four distinct mutations have been identified in the TBG gene that cause this phenotype: TBG-CDJ (Japan), TBG-CD6, TBG-CD5, and TBG-CD Yonago. We report a new mutation producing TBG-CD phenotype. Five family members were studied, including two affected males with undetectable TBG in serum and two obligatory heterozygote females with borderline low values. Sequencing of the exons encoding the mature protein, adjacent introns and the promoter region, revealed differences in two nucleotides compared to the common type TBG, both located in exon 3: TGG (Trp) TAG (Stop) at codon 280 and TTG (Leu) TTT (Phe) at codon 283. The former mutation was not previously described and the latter is a polymorphic variant. Genotyping revealed that the two affected males had the mutant and polymorphic allele and their obligatory heterozygous mothers have each a common type and a mutant allele associated with the polymorphic variant. The mutant TBG Trp280Stop causes premature termination of translation that results in the production of a truncated protein that lacks 116 carboxyl terminal amino acids. The latter is believed to be responsible for the TBG-CD either because the aberrant protein is not secreted or because of reduced abundance of its mRNA.

The influence of preoperative concentrations of beta-endorphin and met-enkephalin on the duration of analgesia after transurethral resection of prostate.

beta-Endorphin (beta-EP) and methionine-enkephalin (M-EK) are endogenous peptides that play a role in the modification of pain perception and analgesia threshold. In order to understand more about pathophysiology of pain in association with neuroaxial blocks, we evaluated cerebrospinal fluid (CSF) concentrations of beta-EP and M-EK prior to spinal anesthesia (SA) in patients undergoing transurethral resection of prostate (TURP) to determine the correlation between preanesthesia concentrations and the duration of postoperative analgesia and opioid requirements. Twenty-five healthy patients undergoing TURP under SA were enrolled. beta-EP and M-EK were measured with a competitive radioimmunoassay. Mean preoperative beta-EP and M-EK concentrations were 153 +/- 44 and 38 +/- 5 pg/mL, respectively. Those with beta-EP concentrations > 153 pg/mL had significantly longer analgesia (P < 0.01), and lower utilization of morphine in the first postoperative day (P < 0.01). Moreover, patients with milder postoperative pain (visual analog scale score < 4/10) had significantly higher beta-EP concentrations (P < 0.01). A similar correlation was not found with M-EK values. These data suggest that preoperative CSF beta-EP, but not M-EK, concentrations correlate with the duration and quality of postoperative analgesia, as well as opioid requirements after spinal anesthesia.

The severe combined immunodeficient (SCID) mouse as a model for the study of autoimmune diseases.

There are no readily available in vivo models to study immune cells from humans with autoimmune diseases. SCID mice, which virtually lack both T and B lymphocytes and accept xenogeneic cells, have been used during the last 5 years to provide a milieu for lymphocytes isolated from individuals with various autoimmune diseases, or for lymphocytes from mice that have a systemic lupus erythematosus-like syndrome. Whilst human autoantibodies to organ antigens have been demonstrated in most SCID mice engrafted with human lymphocytes from the peripheral blood or the target organ, inflammation of the mouse target organ has not generally been observed. This review critically analyses experiments in this area reported so far. Some pitfalls of the SCID mouse model of human autoimmune diseases are mentioned, and future experiments to study mouse and human autoimmunity with this model are proposed.

Very high values of serum high-density lipoprotein cholesterol.

Little is known about individuals who have very high values of serum high-density lipoprotein cholesterol (HDL-C) with the exception of those who have very rare genetic conditions, eg, familial hyperalphalipoproteinemia or hypobetalipoproteinemia. During a period of 60 months of testing for HDL-C, we found 46 individuals (of whom 43 were women) who had an HDL-C level equal to or higher than 2.58 mmol/L (greater than or equal to 100 mg/dL) (range, 2.58 to 6.15 mmol/L [100 to 238 mg/dL]). Sixteen of these individuals were treated with estrogens or ranitidine or were alcoholic, and several had evidence of coronary heart disease. We conclude that very high values of HDL-C can be found in the general population mostly in women, and this is often related to environmental causes, eg, the use of H2-blockers, estrogens, and alcohol. The finding of very elevated HDL-C levels in serum is probably not always due to a genetic condition and does not always signify absence of coronary heart disease and increased life expectancy.

Morphological basis of pulmonary edema in mice with cytokine-induced vascular leak syndrome.

Patients injected systemically with recombinant human interleukin-2 (rhIL-2) for treatment of solid tumor develop a vascular leak syndrome (VLS), characterized mainly by pulmonary edema whose pathogenesis is unknown. We have examined the structure of pulmonary vessels in mice with severe VLS induced by systemic injections of rhIL-2 and recombinant human interferon-alpha-A/D (rhIFN-alpha), which has a synergistic effect with IL-2. The pulmonary edema was associated with lesions of venous and capillary endothelia, alveolar basement membrane, and type I epithelial cells. These changes were more severe and diffuse than those seen in mice systemically injected with rhIL-2 alone, and in beige mice (deficient in NK cells and certain enzymes of polymorphonuclear leukocytes) injected with rhIL-2 and rhIFN-alpha. The endothelial lesions were comparable to those seen when leukocytes activated by cytokines react with activated endothelial cells in vitro, or at the site of injection of cytokines in vivo. The observations are in agreement with the interpretation that the severe lesions occurring in mice systemically injected with rhIL-2 with rhIFN-alpha result from the interaction of leukocytes with the endothelium. The results confirm the validity of previous studies performed in vitro or in animals injected intradermally with cytokines and extend their significance.

Polyclonal gammopathy with marked increase in serum viscosity.

A 45-year-old man with polyclonal hypergammaglobulinemia (gamma globulins, 102 g/L) had a serum relative viscosity of 13 nu but did not manifest clinical signs of hyperviscosity syndrome (e.g., retinopathy, bleeding diathesis, and neurological alterations), except for fatigue and anorexia. In contrast with other patients with polyclonal hyperviscosity reported so far, this patient did not have detectable rheumatoid factor in serum. Analytical ultracentrifugation of his serum showed aggregates of polyclonal IgG3 of various sizes (between 10 and 36 S). The serum also contained immune complex-like material, as demonstrated by the Raji cell immunoradiometric assay and the C1q solid-phase enzyme immunoassay.

Pathogenesis of an experimental model of Goodpasture's hemorrhagic pneumonitis.

The mechanisms that allow circulating basement membrane antibodies (Ab) to interact with the alveolar basement membrane (ABM) inducing Goodpasture's hemorrhagic pneumonitis are unknown. In laboratory animals the ABM is inaccessible to phlogogenic amounts of ABM Ab unless the permeability of the unfenestrated alveolar endothelium is increased. This study was designed to test the hypothesis that in the mouse polypeptide mediators, generated by activated lymphoid cells or cells infected by viruses, contribute to the pathogenesis of passive Goodpasture's hemorrhagic pneumonitis. In naive mice that received rabbit ABM Ab, these bound to the glomerular basement membrane but not to the ABM and their lungs were normal. In the lungs of mice injected with human recombinant IL-2 and IFN-alpha specific binding of ABM IgG, C3, and fibrinogen to the ABM, diffuse and severe erythrocyte extravasation, and accumulation of mononuclear and polymorphonuclear leukocytes were constantly observed. ABM Ab and IL-2 or ABM Ab and IFN-alpha did not produce comparable effects. Mice injected only with IL-2 and IFN-alpha had enlarged, edematous lungs without pulmonary hemorrhages. The results show that the synergism of IL-2 and IFN-alpha convert the lung into a preferential target for AMB Ab, suggesting that cytokines may have a role in the pathogenesis of human Goodpasture's pneumonitis.

Alteration of electrophoretic mobility of serum globulins after storage.

We observed a slower electrophoretic mobility (in agarose gel) of alpha- and beta-globulins of pooled serum samples stored at 4 degrees C compared with that of fresh pooled serum samples. This finding was also observed in a commercial preparation of lyophilized pooled serum samples stored in the refrigerator. The concentration of several serum proteins (as measured by rate nephelometry) was not affected by storage. It is possible that protein interactions in pooled serum samples after their electrophoretric mobility.

Circulating immune complexes and kidney lesions following 131I administration in mice with thyroglobulin antibodies.

Immune complexes containing thyroglobulin have been described in kidneys of some patients with thyroid disease. We investigated the circulating immune complexes (with the Raji cell radioassay) and the kidney histopathology (by immunofluorescence and electron microscopy) in mice that received radioiodine to release thyroglobulin in the circulation, 2 or 4 weeks after immunization with mouse thyroglobulin in Freund's complete adjuvant. Circulating immune complexes and thyroglobulin, antibodies were found in all mice. Granular deposition of IgG, IgM, C3, and thyroglobulin, mainly in the mesangium but also in the capillary walls of the glomeruli, were observed in most of the mice. These experiments suggest that circulating immune complexes composed of thyroglobulin are responsible for the glomerular lesions. Hyperthyroid patients should be tested for thyroglobulin antibodies before treatment with radioiodine to avoid formation of thyroglobulin-containing circulating immune complexes.