Biomedical subjects
M Bennett
Publications and source records attributed to M Bennett.
A pleomorphic hepatocellular carcinoma with biochemical features of fibrolamellar hepatocellular carcinoma.
A case of pleomorphic hepatocellular carcinoma with biochemical characteristics similar to those of fibrolamellar carcinoma is described. During chemotherapy there was a marked disorder of vitamin B12 metabolism.
Origin and differentiation of natural killer cells. III. Relationship between the precursors and effectors of natural killer and natural cytotoxic activity.
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Motoneurone survival factor produced by muscle increases in parallel with messenger RNA sequences homologous to beta NGF-cDNA.
Motoneurone survival in culture is enhanced by growth factors present in embryonic rat muscles and denervated adult muscles: extracts from mature muscle and 2-day denervated mature muscle do not produce survival effects whereas extracts from embryonic muscle and 4-day denervated mature muscle produce maximum survival effects. Here we show, using dot hybridization of mRNA with a 32P-labelled cDNA probe for beta-nerve growth factor (beta NGF), that mRNA sequences homologous to beta NGF appear in muscle in parallel with increased motoneurone survival activity. RNA gel blot hybridizations show that embryonic mRNA contains a sequence in the same molecular weight range as the mRNA for beta NGF.
Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes.
We have utilized a mouse mutant (C.B-17 scid) that lacks functional T and B lymphocytes to examine the relationship among transplantable progenitors of natural killer (NK) cells, T cells, and B cells. The NK-progenitor cells contained in the bone marrow were detected by their ability to generate mature NK cells, following transfer of bone marrow cells into NK cell-depleted and lethally irradiated mice. Regeneration of NK activity in the recipient mice was monitored by two different assays: the ability to rapidly clear infused YAC-1 cells in vivo and the ability of spleen cells to lyse YAC-1 cells in vitro. Recipients were also tested for the presence of mitogen-responsive T and B cells and for prethymocytes (thymus-repopulating cells). We found that the capacity of C.B-17 scid bone marrow cells to generate mature NK cells was equivalent to that of control C.B-17 bone marrow cells. The regenerated NK cells shared similar functional activity and surface phenotype. In contrast, bone marrow cells from C.B-17 scid mice failed to generate thymocytes and peripheral T and B cells. These data indicate that the transplantable NK-progenitor cells are not defective or deficient in C.B-17 scid mice and, therefore, are distinct from the transplantable progenitor(s) of T and B cells.
Topographical projections of segmental nerves to the frog glutaeus muscle during loss of polyneuronal innervation.
The development of synaptic connexions to the frog (Limnodynastes tasmaniansis) glutaeus muscle from segmental nerves 8 and 9 was determined using glycogen depletion, contraction and electrophysiological methods between stages 54 and 60 (Nieuwkoop & Faber, 1975). There was no change in the number of muscle cells in the glutaeus from stage 55 onwards; the maturation of muscle cells was most advanced at the point of nerve entry on the ventral surface of the glutaeus and least advanced at the dorsal surface. Electrophysiological determination of the segmental innervation of the dorsal surface of the muscle in low calcium (0.5 mM) indicated that the muscle was almost uniquely innervated by nerve 8 at stage 54. Weak nerve 9 terminals were detected at stage 54 only if the calcium concentration was raised to 6.0 mM. Innervation by nerve 9 was first detected in low calcium at stage 55. There was then a progressive decrease in the innervation of the glutaeus muscle by nerve 8 in regions apposed to the iliofibularis muscle, until stage 59 when this part of the glutaeus was almost completely innervated by nerve 9. Glycogen depletion of muscle fibres following tetanic stimulation of either segmental nerve confirmed that the region of the glutaeus muscle apposed by the iliofibularis becomes progressively innervated by nerve 9 during development. Contraction studies of the segmental innervation of the glutaeus muscle in normal calcium (2 mM) indicated that the muscle was predominantly innervated by nerve 8 at stage 54. There was then a progressive increase in the number of nerve 9 motor units up to stage 56. The size of individual motor units declined for both nerves 8 and 9 until stage 59, when the average motor unit size was about 9% of the muscle. It is suggested that the decline in the innervation by nerve 8 of the side of the glutaeus muscle apposing the iliofibularis muscle is due to this region of the muscle selectively favouring synapse formation by nerve 9 over nerve 8.
Competition between segmental nerves at end-plates in rat gastrocnemius muscle during loss of polyneuronal innervation.
1. The segmental innervation of the rat lateral gastrocnemius (l.g.) muscle is from lumbar nerves L4 and L5. A study has been made of changes in the innervation of the l.g. muscle by nerves L4 and L5 before and after removal of L4 during the loss of polyneuronal innervation which occurs over the first 2 weeks postnatal. 2. The rat l.g. muscle is a complex of three unipennate muscles; the lateral, intermediate and medial heads. Each of these has a characteristic distribution of type I and type II muscle fibres of different diameter by 12 days postnatal. Following the removal of nerve L4 at birth there is no change in the distribution of fibre types in the different heads of the l.g. muscle at 12 days postnatal. 3. The number of fibres in the l.g. muscle doubled between birth and 12 days postnatal and the maximum tetanic force generated by the muscle increased by fourfold. Removal of nerve L4 at birth did not alter the increase in fibre number and there was no difference between the tension generated by the l.g. muscle in the ipsilateral and contralateral limbs of operated animals. 4. The number of detectable motor units in a extracellular calcium concentration [( Ca]o) of 2 mM remained constant in L4 at about fifteen between birth and 12 days postnatal; the number of detectable motor units in L5 declined over this period from about fifteen to six in a [Ca]o of 2 mM. Following the removal of L4 at birth, the number of motor units in L5 increased to twenty by 3 days postnatal and remained there for at least 12 days in a [Ca]o of 2 mM. 5. The mean size of motor units and the range of motor unit sizes declined for both L4 and L5 during the postnatal period. Following the removal of L4, the mean size of motor units and the range of motor unit sizes in L5 failed to decline. 6. The number of motor units detected at birth in a raised [Ca]o of 3-5 mM increased in L4 and L5 to about twenty; this estimate in high [Ca]o remained constant during the postnatal period. Estimates of the size of the large, low threshold motor units declined whether these were made in low or high [Ca]o.(ABSTRACT TRUNCATED AT 400 WORDS)
Dextropropoxyphene induced hepatotoxicity mimicking biliary tract disease.
Three patients are described with recurrent jaundice, upper abdominal pain and rigors attributable to dextropropoxyphene hepatotoxicity. The diagnosis was established in each patient by rechallenge; post challenge hepatic histology is reported in two. Twelve previous patients with probable dextropropoxyphene hepatic toxicity have been described and are reviewed. In 10 of the 15 patients, a clinical diagnosis of gall stone disease was made. Liver function tests are usually hepatitic shortly after challenge, but more cholestatic after a few days. No fatalities have been described, but as dextropropoxyphene is widely available in many different analgesic preparations possible toxicity should be considered in patients with relapsing jaundice mimicking biliary disease, in whom gall stones have been excluded.
Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester.
Graft vs. host disease (GVHD) remains one of the main problems associated with bone marrow transplantation. The current studies were undertaken to determine whether treatment of the donor inoculum with the anticytotoxic cell compound L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) would alter the development of GVHD in a murine model. Irradiated recipient mice transplanted with a mixture of control bone marrow and spleen cells from naive semiallogeneic donors died rapidly from GVHD, whereas the recipients of cells incubated with 250 microM Leu-Leu-OMe all survived. In addition, Leu-Leu-OMe treatment of cells obtained from donors immunized against host alloantigens resulted in significantly prolonged survival. Phenotypic characterization of spleen cells from the various groups of mice that had received Leu-Leu-OMe-treated cells and survived consistently revealed the donor phenotype. Treatment of marrow cells with 250 microM Leu-Leu-OMe appeared to have no adverse effects on stem cell function. Erythropoiesis was undiminished, as assayed by splenic 5-iodo-2'-deoxyuridine-125I uptake. Moreover, granulocytic and megakaryocytic regeneration were histologically equivalent in the spleens of recipients of control or Leu-Leu-OMe-treated cells. Treatment of the donor inoculum with Leu-Leu-OMe thus prevents GVHD in this murine strain combination with no apparent stem cell toxicity.
Natural immunity to grafts of FLD-3 erythroleukemia cells by irradiated mice.
Mice were irradiated and infused with BALB/c Friend virus-induced FLD-3 erythroleukemia cells. Growth of the cells was estimated by measuring splenic incorporation of 5-iodo-2'-deoxyuridine-125I 5 days after cell transfer. BALB/cJ and C3H mice were 'poor responders' in that FLD-3 cells grew well in their spleens, while mice of other strains were 'good responders', resisting the growth of FLD-3 cells. No H-2 or Fv genetic locus was associated with resistance. Athymic nude mice and mice depleted of marrow tissue by 89Sr or estradiol resisted FLD-3 cells, indicating that the effectors were thymus- and marrow-independent. Silica, carrageenan and Propionibacterium acnes organisms all altered resistance, suggesting a function of macrophages. Neither interferon nor anti-interferon serum treatment altered resistance. Anti-asialo GM1 serum inhibited resistance to FLD-3 cells in vivo and inhibited natural cytotoxic (NC) activity against FLD-3 cells in vitro. NC (FLD-3) activity was greatly decreased in spleens 3 days after irradiation, in contrast with NK (YAC-1) and NC(WEHI-164.1) activities. Moreover, a 3-day delay in infusion of FLD-3 cells 'synergized' with silica in weakening genetic resistance in vivo. Thus, natural immunity to FLD-3 cells in vivo differs from that of genetic resistance to normal bone marrow cell allografts, and the lysis of FLD-3 cells in vitro seems to be mediated by cells which do not easily fit into the definition of natural killer (NK) or natural cytotoxic (NC) cells.
Medical implications of feline cowpox.
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Nursing care study: as normal a life as possible.
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Cryptosporidiosis in the domestic cat.
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Studies addressing the mechanism of anti-asialo GM1 prevention of graft-versus-host disease due to minor histocompatibility antigenic differences.
In mice, as in humans, lethal graft-versus-host disease (GVHD) with skin involvement often occurs in immunoincompetent recipients of donor hematopoietic cells in spite of matching at major histocompatibility loci and nonreactivity in mixed lymphocyte culture, if donor and recipient are disparate at several minor histocompatibility loci. In mice, both death and skin disease can be prevented by the use of an antiserum containing antibodies to a cell surface glycolipid, asialo GM1 (ASGM1). Because treatment of only the recipients with anti-asialo GM1 substantially reduces the subsequent proliferation of infused donor lymphoid cells, we infer that anti-asialo GM1 interferes with a host minor-antigen-presenting cell, so that donor lymphocytes fail to see minor host antigens as immunogenic. Of the tissues examined by immunofluorescence microscopy, ASGM1 was found on the epidermal Thy-1+ dendritic cell, on dendritic cells in the thymus, and as has been previously described, on lung and spleen cells. Following the intravenous administration of anti-asialo GM1, only the spleen showed an obvious change, losing approximately 80% of its ASGM1 + cells. Further analysis of spleen cells bearing ASGM1 may better define the phenotype of the inferred minor antigen-presenting cell and lead to a method of improving the outcome of human bone marrow transplantation.
Prolonged survival in chronic granulocytic leukaemia after busulphan induced hypoplasia and karyotype conversion.
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Stimulation of genetic resistance to marrow grafts in mice by interferon-alpha/beta.
Lethally irradiated mice were infused with syngeneic, H-2 allogeneic, parental strain, or H-2 heterozygous bone marrow cells. They were injected daily with rabbit anti-mouse interferons (IFN)-alpha/beta or gamma or with IFN-alpha/beta. The growth of donor-derived cells was judged 5 days later by measuring splenic incorporation of 5-iodo-2'-deoxyuridine-125I into DNA. Antibodies to IFN-alpha/beta, but not to IFN-gamma, weakened genetic (both hybrid and allogeneic) resistance to marrow cell grafts. IFN-alpha/beta stimulated hybrid and allogeneic resistance, the latter even in genetically "poor responder" mice. Mice pretreated with silica, which weakens genetic resistance, were stimulated by IFN-alpha/beta to resist incompatible marrow cell grafts; however, IFN-alpha/beta failed to reverse the effects of antiasialo GM1 serum on marrow graft rejection. IFN-alpha/beta did not inhibit the growth of syngeneic marrow cells and did not stimulate resistance to H-2 heterozygous bone marrow cells. We propose that genetic resistance occurs in two discrete steps. In the first step, hemopoietic histocompatibility (Hh) antigens are recognized by one host cell type, and this recognition leads to IFN-alpha/beta secretion by a silica-sensitive cell. In the second step, asialo GM1-positive natural killer cells stimulated by IFN-alpha/beta recognize Hh antigens on marrow stem cells and cause rejection. The defects in resistance observed in genetically poor responder mice and in mice treated with silica appear to involve the first step in recognition. The lack of rejection of H-2 heterozygous (Hh-) marrow cells by parental strain mice injected with IFN-alpha/beta indicated that specific Hh recognition is critical in the second step of genetic resistance.
Prolymphocytic leukemia of B cell type: rearranged immunoglobulin (Ig) genes with defective Ig production.
An unusual case of prolymphocytic leukemia of the B cell type (B-PLL) in a 79-year-old patient is reported. The clinical and cytomorphological features of the disease were typical of B-PLL, but membrane and cytoplasmic immunoglobulins (Ig) could not be demonstrated by immunofluorescence techniques; 3% to 4% of the cells were shown to have IgG kappa in the cytoplasm by a more sensitive immunoperoxidase method. The cells were unreactive with a panel of monoclonal antibodies against T cell antigens but they were positive with B cell lineage reagents: FMC4, anti-HLA-Dr determinants; FMC7, which reacts with most B-PLL; anti-B1 and anti-B4, which react with most B cell leukemias. Analysis of Ig genes at the DNA level demonstrated that both heavy-chain alleles and one kappa chain allele were rearranged, confirming that the patient's cells were of B lineage. Chromosome analysis revealed a consistent abnormality, t(17;21)(p11;p11), in all cells and, in addition, a 14q+ marker in 10% of the cells. This study highlights the value of DNA analysis techniques for the characterization of neoplastic B cells. The low rate of expression of Ig genes, despite their rearrangement, suggests that a specific transcriptional or posttranscriptional defect must exist in these cells.
Origin and differentiation of natural killer cells. I. Characteristics of a transplantable NK cell precursor.
To study the origin and differentiation of natural killer (NK) cells, we developed an assay for the transplantable precursor of NK(YAC-1) cells present in the bone marrow. Mice were depleted of endogenous NK(YAC-1) cells by injection of anti-asialo GM1 antibody, followed by lethal whole body irradiation. Normal syngeneic bone marrow cells were transplanted into such pretreated mice. Regeneration of NK(YAC-1) activity in the recipient mice was monitored by two different assays: the ability of spleen cells to lyse YAC-1 cells in vitro and the ability to clear i.v. injected, 125IUdR-labeled YAC-1 cells from the lungs. With both assays, a dose-response relationship between the number of bone marrow cells injected and the degree of NK(YAC-1) activity generated could be demonstrated. However, the lung clearance assay appeared superior because the NK regeneration could be detected earlier and with lower numbers of injected marrow cells. With this assay, several characteristics of the NK precursors and their differentiation could be defined. 1) The generation of mature, lytic NK cells from their transplantable precursor requires an intact "marrow microenvironment" in the recipient mice, because differentiation failed to occur in mice rendered osteopetrotic by estradiol treatment. 2) The NK(YAC-1) precursors lack the surface antigens (NK-2.1, asialo GM1, Qa-5, Thy-1) that are characteristically seen on mature NK cells. 3) The NK-precursors could be eliminated from the bone marrow with anti-Qa-2 or anti-H-2 antisera + complement, indicating that these two antigens are expressed on the precursors. The relationship between NK(YAC-1) precursors and multipotent myeloid stem cells (CFU-S) was investigated by utilizing W/Wv and Sl/Sld mutant mice. Bone marrow cells of W/Wv anemic mice, although markedly deficient in CFU-S, have a normal frequency of NK(YAC-1) precursors. Sl/Sld mice that lack a suitable microenvironment for the development of CFU-S allowed normal differentiation of NK(YAC-1) precursors when transplanted with normal bone marrow cells. Together, these data suggest that multipotent myeloid progenitor cells, as defined by the CFU-S assay, and the NK(YAC-1) precursors are not closely related.