[Regional differences in reactivity of the arterial wall in atherogenesis: various examples of clinical interest].
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Arteries↗
Biomedical subjects
G Weber
Publications and source records attributed to G Weber.
Anesthetic management of marrow harvesting from a 7-week-old premature baby.
Bone marrow was harvested from a 3.95 kg premature 7-week-old female baby for donation to a 13 kg HLA-identical sister with severe aplastic anemia. Two hundred ml of donor bone marrow were aspirated, containing a calculated dose of 3 x 10(8)/kg nucleated bone marrow cells for the recipient. This was equivalent to two-thirds of the donor's calculated blood volume (320 ml). Peri-operative care included invasive monitoring of intravascular pressures, arterial blood gas analysis, careful temperature control and the infusion of 150 ml of packed red cells, 150 ml of colloid and 50 ml of crystalloid. Rapid engraftment occurred. There were no complications and both donor and recipient are healthy 12 months later.
Anemia, Aplastic↗
[Does sonographic evidence of blood in the abdomen following blunt abdominal trauma present an indication for surgery in every case?].
In a comparative study based on the diagnosis of blunt abdominal trauma, the accuracy of ultrasound (US) proved inferior, with 82-91%, to that of diagnostic peritoneal lavage, with 97-100%. The sensitivity of US, i.e. the proportion of patients with blood in the abdomen who had an abnormal test result (positive sonography) was 94%. The reasons for this may be either patient-related (severe obesity, intestinal gas superposition) or examiner-related (differing previous experience). The specificity for correct elimination of abdominal lesions was 100%. When no intra-abdominal liquid was present none appeared in the US picture; however, 3-13% of cases where intra-abdominal liquid was present this was not revealed by US. If only a small amount of intra-abdominal liquid is demonstrated after blunt trauma, the adoption of a wait-and-see attitude is justified. In intensive care conditions US can be repeated several times if necessary. In this study US showed deterioration in these circumstances in 25%, and in 21% it must be expected that an operation will be necessary.
Abdominal Injuries↗
Septic arthritis--an experimental animal model useful in free oxygen radical research.
An experimental animal model for bacterial joint inflammation has been tested. Using 16 rabbits divided into 4 groups, we injected knee joints of two groups with Staphylococcus aureus and the other 2 with NaCl. One group in each was also injected with superoxide dismutase (SOD). A technique was developed which allowed frequent standardized aspirations of the joints carried out through the patella tendon. By this means, we aspirated 16 joints 112 times over 72 h, obtaining estimates of the activity of intra-articularly injected SOD. TBA-reactive substances (TBARS) measured in joint fluid and plasma were different in each of the groups, with the highest values found in animals with septic arthritis treated with SOD. Leucocyte and differential blood cell counts were checked at 12 hour intervals.
Animals↗
[Regression of atherosclerosis lesions].
The regression of even advanced atherosclerotic vascular lesions is now well-documented in various animal species (dogs, pigs, rabbits, birds and monkeys). In man, well-controlled studies in selected groups of patients have already shown that a reduction of luminal stenosis may take place. After a reliable morphological und morphometric validation has been obtained, non-invasive and easily applicable methods are available which allow reproducible documentation of the reduction in lesions.
Animals↗
[Treatment of acne with a yeast preparation].
In a randomized, controlled double-blind study involving 139 patients with various forms of acne, the effectiveness and tolerance of Saccharomyces cerevisiae Hansen CBS 5926 (Perenterol) was studied in comparison with a placebo over a maximum period of five months. The results of therapy were assessed by the physician as very good/good in 74.3% of the patients receiving the preparation, as compared with 21.7% in the placebo group. In more than 80% of the former patients, the condition was considered to be healed or considerably improved, while the corresponding figure for the placebo group was only 26%. Seasonal differences in the effect of treatment with Saccharomyces cerevisiae Hansen CBS 5926 were not observed. Side effects leading to a premature discontinuation of the test were seen neither in the test substance group nor in that receiving placebo. The therapeutic efficacy of Saccharomyces cerevisiae Hansen CBS 5926 makes this systemic form of therapy an alternative that is becoming more and more widely accepted by acne patients.
Acne Vulgaris↗
The accelerating role of Abelson murine leukemia virus in murine plasmacytoma development: in vitro infection of spleen cells generates donor-type tumors after transfer to pristane-treated BALB/c mice.
The role of Abelson murine leukemia virus (A-MuLV) in the accelerated development of murine plasmacytomas (PCs) (Potter et al., 1973: Science, 132, 592-594) was studied in a new experimental system. Spleen cells from pristane-treated or untreated BALB/c mice carrying Robertsonian 6;15 fusion chromosomes were infected in vitro with helper-free A-MuLV overnight and subsequently transplanted into the peritoneal cavity of pristane-treated or untreated BALB/c mice. Donor-derived PCs developed in 4 out of 76 pristane-treated recipients [latent periods: 38-82 (mean 51) days] that had received spleen cells from pristane-treated donors, and also in 2 out of 41 pristane-treated recipients that had received untreated donor-derived spleen cells (latent periods: 65 and 120 days). Three of the PCs in the former and both PCs in the latter group were tested for integration and expression of the v-abl gene, with positive results. This indicates that the spleen contains PC-precursor cells that can be activated by A-MuLV even before the impact of pristane. All 6 donor-origin PCs carried a translocation involving chromosome 15, band D2/3. Four of these corresponded to a typical 12;15 translocation, one was a variant 6;15 translocation and the 6th may represent a previously unidentified translocation between chromosome 15 and the lambda gene-carrying chromosome 16. No PCs developed among 29 pristane-untreated recipients that had received pristane-treated donor-derived spleen cells. In addition to PCs, monocytic tumors developed in 37 (26%) of all recipients. Their development was independent of pristane treatment of recipients but was particularly frequent in those who had received spleen cells from pristane-treated donors.
Abelson murine leukemia virus↗
Biochemically directed therapy of leukemia with tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193), a selective inhibitor of the activity of IMP dehydrogenase (EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, provided in end stage leukemic patients a rapid decrease of IMP dehydrogenase activity and GTP concentration in the blast cells and a subsequent decline in blast cell count. Sixteen consecutive patients with end stage acute nonlymphocytic leukemia or myeloid blast crisis of chronic granulocytic leukemia were treated with tiazofurin. Allopurinol was also given to inhibit xanthine oxidase activity to decrease uric acid excretion and to elevate the serum concentration of hypoxanthine, which should competitively inhibit the activity of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8), the salvage enzyme of guanylate synthesis. Assays of IMP dehydrogenase activity and GTP concentration in leukemic cells provided a method to monitor the impact of tiazofurin and allopurinol and to adjust the drug doses. In this group of patients with poor prognosis, five attained a complete hematological remission and one showed a hematological improvement. A marked antileukemic effect was seen in two other patients. All five evaluable patients with myeloid blast crisis of chronic granulocytic leukemia reentered the chronic phase of their disease. Five patients with acute nonlymphocytic leukemia were refractory to tiazofurin and three were unevaluable for hematological effect because of early severe complications. Responses with intermittent 5- to 15-day courses of tiazofurin lasted 3-10 months. Tiazofurin had a clear antiproliferative effect, but the pattern of hematological response indicated that it appeared to induce differentiation of leukemic cells. In spite of toxicity with severe or life-threatening complications in 11 of 16 patients, tiazofurin was better tolerated in most patients than other antileukemic treatment modalities and provided a rational, biochemically targeted, and biochemically monitored chemotherapy which should be of interest in the treatment of leukemias and as a paradigm in enzyme pattern-targeted chemotherapy.
Antimetabolites, Antineoplastic↗
Hysteresis and conformational drift of pressure-dissociated glyceraldehydephosphate dehydrogenase.
Pressure dissociation of yeast glyceraldehydephosphate dehydrogenase (GAPDH) was studied by fluorescence spectroscopy. Observations in the range of -5 to 30 degrees C indicate that monomer association into the tetramer proceeds with an enthalpy change of -14 kcal mol-1 and a large increase in entropy which at 25 degrees C amounts to 18 kcal mol-1. The large conformational drift and the low-temperature stability of the tetramer recovered after decompression facilitated a comparison of its properties with those of the native tetramer. Significant differences in absorption and fluorescence-excitation polarization spectra, yield of tryptophan fluorescence, and binding of anilinonaphthalenesulfonate and NADH were observed. At 0 degree C the standard free energies of association of the monomers into the native and drifted tetramers were respectively -32 and -29 kcal mol-1. The volume change upon association measured from the pressure span of the compression curves was 200-230 mL mol-1 but four times as large when derived from the displacement of the compression curves with total protein concentration. This large discrepancy can be explained by the existence in the native tetramer population of a distribution of free energies of association with a dispersion from the mean of about 6 kcal mol-1. At 0 degree C and 1 bar ATP and ADP decreased the stability of the GAPDH tetramer by changes in free energy of association of +3.7 and +4.1 kcal mol-1, respectively. NAD and c-AMP stabilized it by -2.3 and -1.3 kcal mol-1. The variation in sign and magnitude of the ligand-induced changes in free energy of association observed in this case, and previously in hexokinase [Ruan, K., & Weber, G. (1988) Biochemistry 27, 3295], and the heterogeneity of the free energy of association of GAPDH, revealed as indicated above, lead to the conclusion that oligomeric aggregates exist in a variety of conformations that depend upon the protein concentration, temperature, pressure, and the presence of specific ligands. The multiplicity of species revealed by the energetics raises questions about the significance of the structures of oligomeric proteins determined by X-ray crystallography.
Adenosine Diphosphate↗
Significance of purine salvage in circumventing the action of antimetabolites in rat hepatoma cells.
The flux activities of de novo and salvage purine synthesis were compared in rat hepatoma 3924A cells in various growth phases. The initial rate assays of [14C]adenine, [14C]hypoxanthine, and [14C]guanine incorporation yielded Michaelis-Menten kinetics with Kms of 5, 7, and 7 microM, respectively. After replating plateau phase cells in lag and log phases the activity of purine de novo pathway increased 4.5- to 8-fold with a preferential rise in guanylate synthesis, whereas purine salvage activities increased only 1.6- to 2.1-fold. However, for the syntheses of IMP, AMP, and GMP, the activities of purine salvage pathways were 2- to 7-fold, 5- to 28-fold, and 2- to 32-fold higher than those of the de novo purine pathway. Treatment of cells with acivicin, an inhibitor of the activity of amidophosphoribosyltransferase, phosphoribosylformylglycinamidine synthase, and GMP synthase, inhibited the flux activities of de novo purine, adenylate, and guanylate syntheses to 37, 73, and 3% of the controls and decreased the concentration of GTP to 42%; the concentration of ATP did not change and that of 5-phosphoribosyl 1-pyrophosphate increased 3.1-fold. Under these conditions the activities of salvage synthesis from hypoxanthine and guanine were enhanced 2.5-fold. Treatment of hepatoma cells with IMP dehydrogenase inhibitors, tiazofurin, ribavirin, and 4-carbamoylimidazolium 5-olate, to block de novo guanylate synthesis accelerated the flux activity of guanine salvage pathway. The higher capacity of purine salvage pathway than that of the de novo one and the further rise of the activity in response to the drugs targeted against the de novo pathway highlight the important role salvage synthesis might play in circumventing the impact of antimetabolites of de novo purine synthesis in cancer chemotherapy.
Animals↗
Isozyme shift of adenylosuccinate synthase in rat and human neoplasms.
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Adenocarcinoma↗
Two distinct target sites on IMP dehydrogenase in chemotherapy.
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Adenine Nucleotides↗
Recovery of the activities of IMP dehydrogenase and GMP synthase after treatment with tiazofurin and acivicin in hepatoma cells in vitro.
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Animals↗
Channeling of IMP into guanylate synthesis in the growth program of hepatoma 3924A cells.
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Adenine Nucleotides↗
Kinetic properties of IMP dehydrogenase purified from rat hepatoma 3924A.
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Animals↗
A method to quantify and correct for edge leaks in Ussing chambers.
A technique is presented which allows edge leaks in Ussing chambers to be detected and quantified. It is based on the fact that in leaky chambers direct current or low frequency alternating current passes preferentially around the edge of the tissue, while high frequency alternating current shunts the cell membranes and distributes homogeneously through the entire chamber. By measuring the current density in the center of the chamber with low and high frequency alternating current and using correction factors which account for the shape of the electrical field as a function of chamber geometry and of estimated tissue resistance, edge leaks can be quantified. This technique allows correct transepithelial resistance values to be obtained from leaky measurements, and enables the question of whether a given discrepancy between cellular and transepithelial resistances reflects leaky tight junctions or a leaky chamber or both to be answered.
Animals↗
Histone acetyltransferase activity in rat hepatomas.
In view of various reports describing differences in histone acetylation between normal rat liver and hepatomas, the behaviour of histone acetyltransferase (EC 2.3.1.48) activity was elucidated in normal rat liver and in a spectrum of well-characterized rat hepatomas of slow, intermediate and rapid growth rates. In all tumours the acetyltransferase specific activity, expressed as nmol h-1 mg total protein-1, was higher than in the corresponding normal livers and the rise correlated positively with the proliferation rates of the tumors. No difference is observed if acetyltransferase activity is expressed per milligram of histone. This is explained by elevated ratios of histones and of DNA to total protein in the hepatomas compared to the ratios in normal liver. Electrophoretic analysis of [3H]acetate-labeled histones revealed similar patterns in hepatoma and normal liver. The extent of histone H4 acetylation, as indicated by the frequency distribution of non-, mono-, di-, tri-, and tetraacetylated H4-species, was found to be identical in hepatomas and normal liver. The histone protein and acetate labeling patterns were near normal in the slowly growing hepatomas.
Acetylation↗
Clinical and molecular impact of inhibition of IMP dehydrogenase activity by tiazofurin.
The impact of tiazofurin on inhibition of IMP dehydrogenase was discussed at the clinical and molecular levels. 1. Evidence was provided for the role of IMP dehydrogenase and guanylates in the expression of the neoplastic program in cancer cells with particular relevance to human leukemic cells. 2. The argument for expecting an impact of tiazofurin in human myelocytic cells was provided. 3. Similarity of the kinetics of human leukemic cell IMP dehydrogenase to the rat hepatoma enzyme was documented. 4. New evidence was provided for the role of salvage in chemotherapy and the function of hypoxanthine in inhibiting guanine salvage. 5. The action of tiazofurin and retinoic acid was reported in HL-60 leukemic cells. 6. The effect of tiazofurin and retinoic acid on proliferation and cytotoxicity was outlined for hepatoma 3924A cells. 7. The effect of guanine on induced differentiation by tiazofurin and retinoic acid was examined. 8. Biochemical basis was provided for the lack of development of resistance in patients treated with tiazofurin. 9. Presumptive evidence was provided that tiazofurin treatment induced differentiation of leukemic cells in the patients. 10. The molecular biology of tiazofurin-induced differentiation in K-562 cells was reviewed with the possible relevance to clinical treatment that tiazofurin might also act through down-regulation of ras oncogene.
Animals↗