Citations

AbstractThe course of clonal evolution of 2 related clones in the blood of a patient with Waldenstrom macroglobulinemia (WM) indicates the functional importance for the expression of the B-cell receptor for the survival of these malignant cells. Protein and nucleotide sequencing of the paraproteins' variable regions revealed 2 predominant Vλ and 2 VH sequences, each set comprised in the ratio 1:1.5. The 2 VH sequences and 2 Vλ sequences shared the same VDJ and VJ junctional sequences, respectively, indicating that 2 malignant clones had evolved from a common ancestor. This is the first report on intraclonal heterogeneity in WM. Comparison of the Vλ and VH sequences with the closest matching known germline genes showed that they contained approximately 10 somatic mutations each. The distribution and type of mutations demonstrate that mutations have continued to accumulate in the malignant clones and that selection has been operating to preserve immunoglobulin structure.

▪ Abstract The potent immunosuppressive drugs FK506 and rapamycin interfere with signal transduction pathways required for T cell activation and growth. The distinct inhibitory effects of these drugs on the T cell activation program are mediated through the formation of pharmacologically active complexes with members of a family of intracellular receptors termed the FK506 binding proteins (FKBPs). The FKBP12 · FK506 complex specifically binds to and inhibits calcineurin, a signaling protein required for transcriptional activation of the interleukin (IL)-2 gene in response to T cell antigen receptor engagement. The FKBP12 · rapamycin complex interacts with a recently defined target protein termed the mammalian target of rapamycin (mTOR). Accumulating data suggest that mTOR functions in a previously unrecognized signal transduction pathway required for the progression of IL-2-stimulated T cells from G1into the S phase of the cell cycle. Here we review the immunopharmacology of rapamycin, with particular emphasis on the characterization of mTOR.

Renal insufficiency, which is present initially in almost half of patients with multiple myeloma, usually results from myeloma kidney or hypercalcemia. Neither the class of light chain nor the isoelectric point plays an important role in kidney failure. Acute renal failure must be treated with appropriate fluids and with electrolytes and hemodialysis if necessary. Plasma exchange may be helpful, but has not been proven as such. The presence of a nephrotic syndrome and a monoclonal κ or λ light chain in the urine almost always indicates primary amyloidosis (AL) or light-chain deposition disease. Amyloid fibrils must be distinguished from the fibrils of immunotactoid glomerulopathy.

ABSTRACT Cytomegalovirus (CMV) DNA quantitation in clinical specimens is progressively becoming a cornerstone in the diagnosis and management of CMV infection in the immunocompromised host. We evaluated two automated and reproducible PCR tests, the LightCycler (Roche Molecular Biochemicals, Indianapolis, Ind.) and the COBAS AMPLICOR CMV Monitor (Roche Diagnostics, Pleasanton, Calif.), for the detection of CMV DNA in blood samples from transplant recipients with CMV infection as determined by shell vial culture. Following a log transformation analysis, the mean CMV DNA in plasma (PL), whole blood (WB), peripheral blood leukocytes (PBL), and peripheral blood mononuclear cells (PBMC) using the LightCycler was 6.79 copies per ml, 7.23 copies per ml, 6.38 copies per 2 × 10 6 cells, and 6.27 copies per 2 × 10 6 cells, respectively. This compares to 7.86 copies per ml, 8.37 copies per ml, 7.59 copies per 2 × 10 6 cells, and 7.44 copies per 2 × 10 6 cells, respectively, using COBAS AMPLICOR CMV Monitor. While higher CMV DNA levels were observed for the various blood compartments analyzed using COBAS AMPLICOR CMV Monitor, a high degree of correlation was evident between the two automated systems (jackknife correlation r = PL 0.77 [95% confidence interval (CI); 0.64, 0.90], WB 0.77 [95% CI; 0.62, 0.92], PBL 0.77 [95% CI; 0.67, 0.88], and PBMC 0.81 [95% CI; 0.72, 0.89], all P < 0.001). Therefore, we conclude that either automated diagnostic system is accurate for CMV DNA quantitation.

ABSTRACT Mycobacterium triplex was first named in 1996 as an acid-fast bacillus with features that most resemble Mycobacterium simiae and Mycobacterium avium-intracellulare complex but which possesses a distinct mycolic acid pattern as well as a distinctive 16S rRNA hypervariable region. It has been isolated from lymph node, sputum, and cerebrospinal fluid specimens, but to date only rare clinical cases of this organism have been reported in the literature. The following is a case report of M. triplex that was isolated from the pericardial and peritoneal fluid of a 13-year-old female liver transplant patient.

The immunosuppressant rapamycin interferes with G 1 -phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E–binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G 1 -phase progression in mammalian cells.

Abstract Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease caused by platelet destruction resulting from autoantibodies against platelet surface proteins, particularly platelet glycoprotein IIb/IIIa (αIIbβ3). To localize the auto-epitopes on platelet αIIbβ3, the binding of autoantibodies to Chinese hamster ovary (CHO) cells expressing either αIIbβ3 or αvβ3was studied. Thirteen of 14 ITP autoantibodies bound only to CHO cells expressing αIIbβ3. Because these 2 integrins have the same beta chain (β3), these results show that most epitopes in chronic ITP are dependent on the presence of glycoprotein αIIb.