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.

Membranous glomerulonephritis induced in the pig by antibody to angiotensin-converting enzyme: considerations on its relevance to the pathogenesis of human idiopathic membranous glomerulonephritis.

In the course of studies on the humoral consequences of swine to primate xenotransplantation, the investigators induced formation of glomerular subepithelial immune deposits and tubular lesions in pigs injected with heterologous antibody to angiotensin-converting enzyme. This study describes the morphology of the lesions, discusses their mechanism, explains their relevance for understanding the pathogenesis of human idiopathic membranous glomerulonephritis, and proposes future directions for investigations.

Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity.

Antinuclear autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Autoantibodies to HRES-1/p28, a 28 000 M(r) nuclear protein, commonly occur in patients with SLE. HRES-1 is a single-copy endogenous retroviral element mapped to human Chromosome 1 at q42. A polymorphic Hin dIII site defines two different allelic forms of the genomic locus. The HRES-1/1 probe [5.5 kilobases (kb)] anneals to three polymorphic fragments and three genotypes can be differentiated: I, 5.5 kb fragment only; II, 3.7 kb and 1.8 kb fragments only; and III, all three polymorphic fragments. By cloning of the HRES-1 locus from homozygous type I and type II human DNA samples, the polymorphic Hin dIII site was identified as a G to C transition at position 653 of the long terminal repeat region. Family studies showed that Hin dIII genotypes of the HRES-1 locus are inherited in a Mendelian pattern. The relative frequency of genotype I with respect to genotype III was 3.1-fold lower in patients with SLE (14:40=0.35) in comparison to 100 ethnically matched control donors (47:43=1.09; P=0.0084). Frequency of genotype I vs genotype II alleles was lower in SLE (68/52) than in normal donors (137/63; P=0.033), suggesting that a genotype I allele of the HRES-1 locus may be protective against SLE. Western blot seroreactivity with recombinant HRES-1/p28 was noted in 4/14 (29%) of genotype I patients and 13/19 (68%) of genotype III patients (P<0.025). These data raise the possibility that the HRES-1 element or a gene in linkage disequilibrium with this genomic locus may influence autoimmunity in SLE.

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.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis.

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

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.

Treatment of aluminum overload using a cartridge with immobilized desferrioxamine.

Intravenous desferrioxamine (DFO) is the method commonly used to treat aluminum toxicity. This laboratory has developed a hollow fiber device with immobilized DFO, an "Aluminum DFO-HP" (DFO-HP), for the purpose of removing aluminum without the chelator (DFO) entering the blood. With Food and Drug Administration approval, a polysulfone DFO-HP, placed in the extracorporeal circuit in series with the patient's customary dialyzer, was tested for its safety and ability to remove aluminum in patients with ESRD who had aluminum overload. During treatment with this device, no toxic reactions, side effects, or hematologic or clinical laboratory changes were seen other than those associated with dialysis. Average aluminum clearance with the DFO-HP device was 25.3 mL/min with a range of 7.2 to 52.4 mL/min, whereas aluminum clearance with the F-60 polysulfone high-flux dialyzer was 8.4 mL/min. Aluminum clearance of the cuprophane dialyzers in series with the DFO-HP was negligible. The amount of aluminum removed over a 2-h treatment with DFO-HP ranged from 94 to 628 micrograms, which corresponded to 32 to 199% of the initial aluminum in the circulation before that particular treatment. The excess 99% was provided from aluminum released from tissue sites into the circulation throughout the duration of the treatment. It is expected that, because of the efficiency and safety of the DFO-HP device, the time presently needed for aluminum depletion using intravenous DFO will be greatly shortened and the potential toxicity of intravenous DFO will be eliminated.

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.

Pentoxifylline and meclofenamic acid treatment reduces clinical manifestations in a murine model of AIDS.

C57/BL/6 mice infected with LP-BM5 MuLV virus developed an AIDS-like disease (MAIDS) with splenomegaly, leukopenia, thrombocytopenia, anemia, decreased numbers of helper/inducer and suppressor/cytotoxic T-cells and decreased production of interferon alpha. We have shown previously that HIV-associated Kaposi's sarcoma tissue contains high levels of prostaglandin E2 (PgE2), and this inhibits interferon synthesis through a cAMP-dependent second-messenger process. In this study we treated groups of MAIDS-infected mice with combinations of pentoxifylline, an agent which increases cAMP and inhibits phosphodiesterases, and sodium meclofenamic acid, a PgE2 inhibitor. Treated mice showed: 1) significantly higher total leukocyte and platelet counts, 2) higher total L3T4+ (helper/inducer) and Lyt-2+ (suppressor-cytotoxic) T-cell population. Pathologic examination also showed significantly less hepatosplenomegaly and lymphadenopathy in animals treated with pentoxifylline and meclofenamic acid. Partly, PgE2-induced suppression of interferon alpha production may mediate expression of retrovirus infection in this murine model of AIDS.

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.