Failure of polymyxin B nonapeptide to augment bactericidal activities of novobiocin, rifampin, and of defibrinated human blood against Serratia marcescens

Polymyxin B (PB) and polymyxin B nonapeptide (PBNP), when combined with rifampin or novobiocin, but not vancomycin, yielded additive inhibitory effects against test strains of Serratia marcescens of three varieties: those that produced cocarde growths around PB disks (coc+); those that grew adjacent to PB disks (coc-, 6); and those that yielded clear inhibition zones around PB disks (coc-, clear). However, time kill curve experiments disclosed that only the combination of rifampin + PB exerted a potent bactericidal effect against coc+ strains of S. marcescens; rifampin + PBNP and novobiocin + PB or PBNP merely effected transient decreases of colony counts. Assays involving 50% (v/v) of fresh defibrinated human blood + PB or PBNP revealed that only PB clearly augmented the antibacterial activity of blood against coc+, and less so against coc- test strains of S. marcescens.     

Membrane phenotype and response to deoxycoformycin in mature T cell malignancies

The adenosine deaminase inhibitor deoxycoformycin was used in low doses to treat 19 patients with clinically aggressive T cell malignancy with a mature membrane phenotype. The patients comprised eight with prolymphocytic leukaemia, two with chronic lymphocytic leukaemia, four with adult T cell leukaemia-lymphoma, three with Sézary syndrome, and two with T cell lymphoma. Two thirds of the patients had been resistant or minimally responsive to combination chemotherapy. Complete remission was obtained in five patients (two with prolymphocytic leukaemia and one each with chronic lymphocytic leukaemia, adult T cell leukaemia-lymphoma, and Sézary syndrome) and partial remission in two others. Unmaintained complete remission lasting more than one year was seen in three patients. Responses were obtained only in patients with CD4+,CD8-membrane markers (seven out of 10), and no responses were recorded in any of the nine patients with a different phenotype. In this series remission appeared to correlate with the membrane phenotype of the neoplastic cell and not with the cytopathological diagnosis. Future studies should establish the biochemical basis for the greater sensitivity of CD4+ lymphoid cells to deoxycoformycin.     

Influence of triethyl lead on neurofilaments in vivo and in vitro

The influence of triethyl lead chloride (TriEL) on the organization of neurofilaments in vivo was studied by indirect immunofluorescence microscopy employing mouse neuroblastoma cells (Neuro-2a). TriEL induces perinuclear coil formation of neurofilaments in those cells. The rearrangements observed are not correlated with significant changes of the microtubular system. Cells in which the microtubular network was stabilized by Taxol treatment prior to incubation with TriEL even show the rearrangement of the neurofilaments. The effect of TriEL is reversible. In vitro, the effect of TriEL on isolated neurofilaments and on filament formation as well as on the structure of preformed filaments was investigated by electron microscopy. If isolated neurofilaments from porcine spinal cord are incubated in the presence of TriEL, they show constrictions and bulges. Additionally, many fragments are seen. If preformed filaments are treated with TriEL, unraveling of fibers into protofilamentous strands is observed. The assembly of neurofilaments in vitro is disturbed in the presence of TriEL. The interaction of TriEL with neurofilaments in vivo is likely to be at least partly responsible for the neurotoxicity of TriEL.     

Lymphocyte interleukin 2 production and responsiveness are altered in patients with primary myelodysplastic syndrome

Immunoregulatory T and B cell functions in 15 patients with primary myelodysplastic syndrome (MDS) were studied by measuring the proliferative and the stimulatory capacity of T and B cells, respectively, in autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR). T cell proliferation in the auto MLR was 25% of the control (P less than .02), whereas proliferation in the allo MLR was normal. When control T cells were stimulated by MDS B cells, their proliferative response was only 57% of the control (P less than .01). The mechanism responsible for these abnormalities was studied by determining the capacity of MDS and normal T cells to produce interleukin 2 (IL 2) and to generate IL 2 receptors (IL 2R) following stimulation with control and MDS B cells. In the auto MLR of MDS patients, only 3% +/- 2% of T cells developed IL 2R positivity, whereas in control cultures 12% +/- 2% of T cells were positive, as determined by immunofluorescence, using a monoclonal antibody (MoAb) directed against the IL 2R, and FACS analysis. When MDS T cells were stimulated by control B cells, IL 2R generation and the production of IL 2 were within normal limits. In contrast, when control T cells were stimulated by MDS B cells or control B cells, the MDS B cells induced production of only 26% of IL 2 as compared with control B cells. In parallel experiments, IL 2R generation in control T cells stimulated by either MDS or control B cells was similar. We conclude that in the primary MDS, T and B cell interactions are impaired. Although MDS T cells develop normal quantities of IL 2R and produce normal amounts of IL 2 when stimulated by control B cells, they are markedly impaired when stimulated by self B cells. Similarly, MDS B cells can induce IL 2R generation in control T cells but not in MDS T cells. Myelodysplastic B cells are also defective in inducing IL 2 production by normal T cells in an allo MLR. These in vitro abnormalities strongly suggest that generation of lymphocytes with immunoregulatory functions is impaired in patients with MDS.