Biomedical subjects
Publications and source records attributed to E Neumann.
Repeated cytogenetic studies were carried out on a Sézary syndrome patient during a 1-year period. The presence of a single clone of heteroploid (60-86 chromosomes) cells was a permanent finding in the PHA-stimulated blood cultures. The bone marrow was normal. Sister chromatid exchange (SCE) value was relatively lower in heteroploid cells.
58 NHL-patients (9 large cell centrocytic, 18 centroblastic, 16 immunoblastic, 15 lymphoblastic lymphomas) were treated immediately after diagnosis with CHOP-chemotherapy regardless of the extent of disease. Because of the advanced age of the majority of patients (median age 61 years, range 22-85 years) a reduced dose in the first two cycles was administered. Statistically significant prognostic variables influencing survival were the following: histologic subtypes according to the Kiel-classification (p less than 0,05), B-symptoms (p less than 0,001), blood sedimentation rate (p less than 0,02) and LDH (p less than 0,0005). With regard to prognosis there was no difference between patients over 60 years of age and younger ones (p less than 0,4). Patients achieving complete remission survived significantly longer (p less than 0,0001). Ann Arbor stages were of limited value, since patients with CS II disease and accumulation of risk factors (B-symptoms, abdominal disease, bulky tumor masses) showed a poorer outcome than patients with CS III who did not have these risk factors. A risk factor score summarizing features influencing prognosis is described and might be a useful tool in stratifying the heterogeneous group of NHL with unfavorable prognosis.
Blast cells from 45 patients with chronic myeloid leukaemia in blast crisis (CML-BC) were immunologically phenotyped with a panel of 26 monoclonal antibodies and studied for terminal deoxynucleotidyl transferase (TdT) content. Out of 45 blast-populations, 28 showed a myeloid, 14 a lymphoid, two a mixed and one an unclassifiable marker profile. In contrast to acute myeloid leukaemia (AML), we found frequent involvement of the thrombopoietic and erythropoietic systems in myeloid CML-BC. Furthermore, the marker profile on blast cells in myeloid CML-BC was different from that seen in AML. The blast cells in lymphoid blast crises of CML displayed the same lymphoid marker profile as those in acute lymphoblastic leukaemia. In three of 16 patients who were serially tested, we observed phenotypic changes in the blast cell populations. In one patient the blasts changed from lymphoid to myeloid type while remaining TdT-positive; in another case the blasts switched from granulomonocytic TdT-negative to granulomonocytic TdT-positive. In the third patient erythroid precursor cells appeared as the disease progressed. The results indicate the capacity of blast populations in CML-patients during blast crisis to differentiate along several pathways.
In 4 patients with SAA treated with ATG and high-dose MP, an as yet unrecognized acquired deficiency of fibrinogen and factor VII was observed. The plasma level of fibrinogen fell to 39% (34-51%) and of factor VII:C to 50% (31-55%) of the pretreatment value. The nadirs were between days 10 and 35 (fibrinogen) and d 3 and 11 (factor VII) after the 1st dose of ATG/MP. From additional clotting studies it is concluded that disseminated intravascular coagulation, fibrinolysis, liver cell damage and synthesis of abnormal clotting factors are unlikely causes of these clotting abnormalities. The most probable explanation seems to be a selective inhibition of the synthesis of fibrinogen and factor VII by an as yet unknown mechanism. These clotting abnormalities might, to some extent, increase the bleeding tendency in these patients, which up to now had been solely attributed to thrombocytopenia.
12 patients with severe chronic idiopathic thrombocytopenic purpura (ITP) were treated with i.v. polyvalent intact immunoglobulin (0.14-0.4 g/kg body weight for 5 d) because of various bleeding episodes or prior to surgery. In 9 patients a significant rise in platelet counts was noted, starting on d 2 and reaching its maximum between d 4 and 11. Thereafter, platelet counts decreased slowly, approaching pre-treatment values after 20 d in most cases. Response to immunoglobulin was reproducible, when infusions were repeated. Response to high-dose immunoglobulin was independent of age of patients and duration of disease. Platelet-associated IgG decreased in all patients tested. A pepsin-treated immunoglobulin preparation was ineffective in 3 patients.
Explore the source record for details and available documents.
Studies of the binding of [3H]acetylcholine to receptor-rich membranes of Torpedo californica electric organ under conditions that normally lead to a state of equilibrium did not give rise to equilibrium binding curves. Instead, the acetylcholine receptor was found to develop very long lived metastable states resulting in hysteresis in binding. Under conditions where the concentration of free [3H]acetylcholine is both less than 0.1 microM and smaller or comparable to the total receptor concentration, the degree of binding of acetylcholine depends on the rate, i.e., the mode, of increasing the acetylcholine concentration (rapid mixing vs. dialysis). The equilibrium positive cooperativity in high-affinity acetylcholine binding previously inferred from the data is deceiving; the curvature in Scatchard representations is a consequence of long-lived nonequilibrium distributions between high-affinity and lower affinity receptor conformers. By manipulation of the experimental conditions, true equilibrium binding, resulting in a linear Scatchard binding curve, was obtained and yielded the apparent equilibrium constant, K = 5 +/- 1 nM at 4 degrees C. The stoichiometry of the high-affinity site associated with this K value was found to be one acetylcholine per receptor monomer (Mr 250 000) when carefully standardized [3H]acetylcholine analyzed for both radiopurity and acetylcholine concentration was used. While our fresh membrane fragments prepared in the presence of 4 mM Ca2+ revealed up to twice as many 125I-alpha-bungarotoxin sites in 0.1% nonionic detergent relative to those assayed in the absence of detergent, nonionic detergent treatment of membrane fragments did not result in any change in total available acetylcholine binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
The case of a 25-year-old man with the characteristic features of malignant histiocytosis (proliferation of abnormal histiocytic cells with erythrophagocytosis, hepatosplenomegaly, increased serum acid phosphatase, hypercalcemia, and bone pain) is reported. Chromosome studies revealed a near tetraploid karyotype with a pair of marker chromosomes. A few hours after initiation of chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), vincristine, and prednisolone (CHOP regimen), the patient developed an acute ascending paralysis. Cerebrospinal fluid (CSF) findings were consistent with a diagnosis of Guillain-Barré Syndrome. On the next day, disseminated intravascular coagulation (DIC) with severe hyperfibrinolysis occurred. After intensive chemotherapy, complete remission could be achieved.
37 consecutive, previously untreated patients with advanced multiple myeloma (16 patients Stage II, 21 patients Stage III) were treated with a five drug regimen consisting of carmustine, melphalan, vincristine, cyclophosphamide and prednisolone (M-2-protocol) in a prospective manner. Remission was achieved in 24 patients (65%). The median time to remission was 10 weeks, the median duration of remission 15,3 months. Median survival time from the onset of treatment was 24 months for all patients. Responding patients have a projected 65% three year survival. Median survival in non-responders was 10 months. 8 patients died during the first year of treatment. These results do not confirm the favourable results with this drug combination obtained in a previous trial. The discrepancy may be explained by a higher proportion of poor risk patients in the present study.
Electric impulses (1-20 kV cm-1, 1-5 microseconds) cause transient structural changes in biological membranes and lipid bilayers, leading to apparently reversible pore formation ( electroporation ) with cross-membrane material flow and, if two membranes are in contact, to irreversible membrane fusion ( electrofusion ). The fundamental process operative in electroporation and electrofusion is treated in terms of a periodic lipid block model, a block being a nearest-neighbour pair of lipid molecules in either of two states: (i) the polar head group in the bilayer plane or (ii) facing the centre of a pore (or defect site). The number of blocks in the pore wall is the stochastic variable of the model describing pore size and stability. The Helmholtz free energy function characterizing the transition probabilities of the various pore states contains the surface energies of the pore wall and the planar bilayer and, if an electric field is present, also a dielectric polarization term (dominated by the polarization of the water layer adjacent to the pore wall). Assuming a Poisson process the average number of blocks in a pore wall is given by the solution of a non-linear differential equation. At subcritical electric fields the average pore size is stationary and very small. At supercritical field strengths the pore radius increases and, reaching a critical pore size, the membrane ruptures (dielectric breakdown). If, however, the electric field is switched off, before the critical pore radius is reached, the pore apparently completely reseals to the closed bilayer configuration (reversible electroporation ).
It is demonstrated that the monomeric and dimeric structures of the nicotinic acetylcholine receptor of Torpedo californica electric tissue, reconstituted in planar lipid bilayers, are functionally different. The native dimer D of Mr 500,000 (heavy-form) exhibits a "single" channel conductance about twice as large as that of the monomer M of Mr 250,000 (light form). Under conditions where monomers aggregate, the conductance changes from the level of the monomer M to that of dimers M2. The dimer conductances (D and M2) seem to result from synchronous opening and closing of the two channels in the dimer, giving the impression of "single channel" activity. This channel cooperativity is apparently mediated by noncovalent interactions between the two monomers, since it requires no disulfide linkage between monomers. Both the monomers M and the dimers D and M2 show at least one substate of lower conductivity. The relative population of the two conductance levels depends on the ion type (Na+ and K+), indicating ion-specific channel states. Since the channel conductance of isolated dimers resembles those obtained from unextracted microsacs, the dimer with two synchronized channels appears to be the in vivo predominant gating unit. In the linear association of dimers, observed in the native membrane, channel synchronization may extend to more than two channels as suggested by oligomeric channel cooperativity in associations of monomers and dimers.
The transient transcription of a rearranged mouse immunoglobulin kappa gene was studied in a monkey fibroblast cell line. The gene was inserted into an SV40 expression vector and the calcium phosphate coprecipitation method was used for transfection. The transcripts were correctly spliced; transcription, however, was initiated within the vector and not at the correct site 23-26 bp upstream of the gene, irrespective of the length of the upstream sequences (90, 160, 370, and 870 bp) in the plasmid constructs. In contrast, accurately initiated transcripts were observed when a plasmid containing the kappa gene with 870 bp of its upstream sequence was introduced into a lymphoid cell line; the plasmid was constructed from the pSV2-gpt vector and the electric impulse method was used for gene transfer in most experiments. Tissue-specific expression of kappa light chain genes in lymphoid cells is known to depend on the presence of an enhancer element in the J-C intron. The results reported in this paper suggest that the sequence elements pd and dc which are located upstream of the leader gene segment also act in a tissue-specific manner and that it is the initiation of transcription which is a tissue-specific event.
Out of a series of 600 cataract extractions, 14 patients were found to have giant papillary conjunctivitis (GPC) due to 10-0 nylon sutures. When renewed conjunctival irritation appears weeks or months after surgery, GPC should be suspected and confirmed by eversion of the upper eyelid at the slit lamp. Free edges of protruding corneoscleral nylon sutures should be looked for. Signs and symptoms of GPC disappear within one to four weeks after removal of the offending suture.
Circulating granulocyte/macrophage progenitor cells (CFU-GM) were assayed serially during remission in 17 patients with acute leukaemia (9 ALL, 8 AML). In patients with ALL receiving cyclophosphamide, 6-mercaptopurine and methotrexate, CFU-GM numbers were significantly lower than in normal individuals; cycles of 'reinduction' chemotherapy (vincristine, prednisolone) caused a 10-fold increase in CFU-GM per ml of blood. In 2 ALL patients a substantial increase in CFU-GM numbers preceded the morphologically detectable relapse. In patients with AML receiving repeated courses of cytosine-arabinoside and 6-mercaptopurine, circulating CFU-GM were likewise reduced. In 6 patients who relapsed, a further reduction of CFU-GM was seen. A complete absence of circulating CFU-GM was observed in 10 of the 23 investigations performed within 6 weeks prior to the morphologically detectable relapse, while such a 'zero'-growth occurred in only 1 of 54 experiments performed during stable remission. In summary, in patients with ALL in remission, circulating CFU-GM are increased following treatment with vincristine and prednisolone. In patients with AML, declining numbers of circulating CFU-GM may predict an imminent relapse.
The dorsal lateral geniculate nucleus (dLGN) of the mouse (strain 944 with microphthalmus syndrome, P. Hertwig 1942) has been morphometrically investigated. The eyes of the gray littermates develop normally (control animals) while the white littermates show the microphthalmus syndrome (microphthalmic animals). Four male twentyone day old animals were examined. Following perfusion with formaldehyde (diluted 1:4 with H2O) Nissl stained frontal sections were used for classification of neurons. we differentiate between projection neurons (PN) (geniculo-cortical relay neurons) and interneurons (IN). We succeeded in identifying these two cell types using deimpregnated Golgi preparations (Fairén et al. 1977), which were counterstained with methylene blue (0.1%). The neuronal packing density and the ratio PN:IN were conventionally determined using 20 micron thick sections from both control and microphthalmic animals. In both cases this ratio was 12:1 (= 8% IN). Measuring fields distributed in a meander-like manner were selected for estimating the neuronal density. Measuring fields giving equal values were connected. The results show that we can distinguish between 3 regions of dLGN: lateral, medial and caudal. They differ with regard to neuronal packing density, size and structure of the PN. Using 3 micron thick Nissl stained sections from both control and microphthalmic animals the size and structure of PN were automatically determined using the picture processing device "MORPHOQUANT" VEB Carl Zeiss JENA). The distribution pattern of IN is apparently uniform. The microphthalmus syndrome produces a diminished number of pathologically changed retinal fibers. The morphometrically registered findings show that within the dLGN, of the microphthalmus mouse the neuronal packing density increased (diminution of neuropil), the size of PN decreased and their structural density increased (transneuronal dystrophy). Compared with the other parts, the medial part of the dLGN is minimally altered.
In the presence of high concentrations of free Ca2+ (10(-5) - 10(-4) M) chromaffin granules and adrenal medullary mitochondria take up large amounts of Ca2+. At low levels of buffered free Ca2+ (less than 10(-8) M), these mitochondria release almost all of their stored calcium, whereas chromaffin granules retain the major part of their calcium pool. In the presence of MgATP and at less than 10(-8) M free Ca2+, the mitochondria do not take up significant amounts of Ca2+. Chromaffin granules, however, under the same conditions, show active MgATP-dependent Ca2+ uptake even at nM-concentrations of free Ca2+. The implications of these results for the calcium metabolism of chromaffin cells are discussed.
Excitable acetylcholine receptor rich membrane fragments from Torpedo marmorata have been used to measure, in parallel, (1) the permeability response to the fluorescent cholinergic agonist Dns-C6-Cho (in the 0.1 microM to millimolar concentration range) characterized by both the initial rate of Li+ transport and the rate of channel closure using the rapid-mixing quench-flow technique and (2) the kinetics of interaction of Dns-C6-Cho with the acetylcholine receptor sites using the rapid-mixing stopped-flow technique. Analysis of the kinetics of Dns-C6-Cho binding in the millisecond to minute time scale leads to the identification of at least three conformational states of the acetylcholine receptor: a "low-affinity" one (approximately 50 microM) that can be interconverted in the fraction of a second to a transient state of "intermediate affinity" (approximately 1 microM), followed by the final stabilization, in the second to minute time range, of a state of "high affinity" (approximately 3 nM). Comparison of Dns-C6-Cho binding data with the permeability response to the same agonist demonstrates that the binding to the low-affinity conformation(s) of the acetylcholine receptor sites coincides with the triggering of the permeability increase--or "activation"--and the transitions to the intermediate- and high-affinity states with the two-step process of channel closing--or "desensitization". The data are interpreted in terms of a minimum four-state "allosteric" model for the acetylcholine receptor.
Various immunological parameters were determined in 46 patients with severe hemophilia A and in 9 patients with severe hemophilia B. All patients were treated over many years with commercial factor VIII or IX concentrates. Patients with severe classic hemophilia had a significantly reduced relative and absolute number of T-helper cells and a significantly increased relative and absolute number of T-suppressor cells. About half of these patients had an inverse T-helper/suppressor cell ratio. Patients with moderate hemophilia A and severe hemophilia B did not show these abnormalities. Hemophiliacs with an inverse ratio had a significantly higher concentration of serum total protein, IgG and IgM. No relationship between the amount of factor VIII concentrate administered, the HLA-type of the patient, the presence or absence of CMV-antibodies, hepatitis markers, thrombocytopenia and abnormal liver function tests to the T-cell abnormalities could be established. Lymphadenopathy was frequently associated with an inverse ratio. Indirect evidence suggests that the alterations of the immune system began in 1979/80.