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Biomedical subjects

J M Nelson

Publications and source records attributed to J M Nelson.

At least 73 records · Page 4Linked to original sources
PubMed1989

Analyzing the role of biochemical processes in determining response to ionizing radiations.

The interaction of biochemical processes and radiation damage appears to play a major role in determining long-term biological effects. It is responsible for both the removal of radiation-induced alterations in macromolecules and for the time-dependent changes in survival of irradiated cells. Restoration of macromolecules by such means as the rejoining of strand breaks in DNA suggests a variety of possible mechanisms which could lead to the observed enhancement of cell survival. However, even though a number of molecular repair mechanisms have been identified, specific links between any such mechanisms and a subsequent modification of cell survival have proved difficult, if not impossible, to demonstrate. Models of cellular response provide a means of attempting to establish this connection. Although details of radiation chemistry, chromatin structure, enzymatic repair, molecular genetics, and cell cycle kinetics are generally simplified, each individual model incorporates features based on a set of assumed mechanisms. For example, one group of models assumes that all damage is potentially lethal (capable of killing the cell unless it is repaired), while another assumes that part of the damage is sublethal (innocuous until it interacts with other damage). Using split-dose, dose-rate, and delayed-plating techniques, we have demonstrated two distinct components of repair in plateau-phase Chinese hamster ovary cells. One process has a characteristic time of about 1 h; the other, about 18 h. In both cases, the reaction rates and the fractions of damage repaired appear to be independent of the initial amounts of damage produced. These observations suggest that none of the simpler models adequately describes cell inactivation; i.e., reproductive death is inconsistent with all assumptions regarding any of them. Consequently, more-complex models involving combinations of sublethal and potentially lethal damage or multiple-step damage processes may be required. These findings help to define the effects of exposure at low doses and dose rates and to develop an understanding of the underlying biochemical mechanisms involved.

Animals↗
PubMed1988

Transforming growth factor beta (TGF-beta) induces fibrosis in a fetal wound model.

The adult cellular response to tissue injury is characterized by acute inflammation followed eventually by fibroblast proliferation and collagen synthesis. Fetal tissue responses to injury differ markedly from those of the adult; an early acute inflammatory response is absent, few fibroblasts participate, and no collagen is deposited. The object of the present study was to analyze the effects of transforming growth factor beta (TGF-beta), an important regulatory molecule in adult healing events, on the fetal tissue response following wounding. Fetal cellular and extracellular matrix responses to injury were evaluated by placing subcutaneous wound implants containing TGF-beta (0.01 to 10 ng) in fetal rabbits at 24 days gestation (term = 31 days). Histologic responses one to seven days later were compared with fetal and adult control implants without TGF-beta. The histology of the adult implant was characterized by an early acute inflammatory response: by day 7 fibroblasts and collagen were predominant. In contrast, control implants removed from fetal rabbits had no histologic evidence of acute inflammation or fibroblast penetration and no collagen was deposited. When implants containing 1.0 ng TGF-beta were removed from fetal rabbits at seven days, a grossly fibrotic reaction was observed: histology confirmed marked fibroblast penetration with collagen deposition. Fetal implants containing 0.01 ng or 10 ng TGF-beta showed few fibroblasts but had increased numbers of inflammatory cells compared with controls. These observations demonstrate that the fetal response becomes adultlike with fibroblast proliferation and collagen accumulation when TGF-beta is added, thus documenting the responsiveness of the fetal system to adult repair signals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of beta-aminopropionitrile and ascorbate on fibroblast migration.

Ascorbate and beta-aminopropionitrile (BAPN) have direct, but diverse affects on collagen matrix production. Ascorbate is necessary for the intracellular hydroxylation of prolyl and lysyl residues during collagen biosynthesis whereas BAPN inhibits the enzyme lysyl oxidase in the extracellular space thus preventing collagen crosslink formation. To study the influence of these two agents on fibroplasia, an in vitro model was used to analyze fibroblast migration, proliferation, and collagen synthesis. Biopsies of chicken tendon were covered with a fibrin clot to simulate an in vivo wound environment, and then they were exposed to either ascorbate or BAPN for up to 7 days. Fibroblast migration into the fibrin clot was measured using a Zeiss Mopp II planimeter, DNA synthesis by 125IUDR incorporation, and collagen synthesis by [3H]proline incorporation into collagenase-digestible protein. Tendon biopsies treated daily with fresh ascorbate (0.1 mM) had significantly greater fibroblast migration than controls without ascorbate (P less than 0.05). Cellular proliferation, collagen synthesis, and total protein synthesis were not significantly altered by ascorbate treatment. In contrast, BAPN inhibited fibroblast migration in a dose-dependent fashion without inhibiting proliferation (0.25 and 0.5 mM), collagen, and noncollagen protein synthesis. Therefore, the effect of BAPN on migration does not appear to be due to generalized cytotoxicity. These combined studies suggest that compounds such as ascorbate and BAPN which can modify collagen may also modify fibroblast migration.

Aminopropionitrile↗
PubMed1987

Risk factors and the Child Behavior Checklist in a child mental health center setting.

The relationship between risk factors and the severity and type of childhood disorder, as measured by parent-completed Child Behavior Checklists, was examined for 768 children, ages 4-16, seen at a child mental health center. Regression analyses revealed no significant relationships between any combination of risk factors and the total number of behavior problems, internalizing, or externalizing scores for the entire group, males and females separately, or for the age and sex groupings of 6- to 11- and 12- to 16-year-olds. Chi-square tests revealed no relationship of profile type with any risk factor or with total number of risk factors. Implications for broad-based child assessment and risk factor research within a clinical population are discussed.

Adolescent↗
PubMed1987

Fetal response to injury in the rabbit.

Fetal, neonatal, and adult tissue response to a standardized injury was studied using subcutaneous wound implants, linear incisions, and punch wounds in New Zealand white rabbits. In the fetus, sutured incisions healed by primary intention without antecedent inflammation. However, neither contraction nor healing by secondary intention was seen in punch or unsutured wounds. Healing both by primary and secondary intention following inflammatory infiltration was observed uniformly in neonatal and adult rabbits. Wound implants were extensively infiltrated with collagen in the adults studied; however, no collagen was seen in fetal implants and collagen hydroxyproline content could not even be detected by high performance liquid chromatography techniques; rather, a matrix rich in hyaluronic acid was found. The fetal tissue response to injury differs from the adult, proceeding in the absence of a classical inflammatory stimulus and lacking contractile capabilities. The deposition of extracellular matrix rich in hyaluronic acid but devoid of collagen suggests that the fetal response to injury may be a process more closely resembling regeneration or growth rather than repair by scar deposition.

Animals↗
PubMed1987

The impact of alanine aminotransferase testing on Hispanic blood donations.

The American Association of Blood Banks, Arlington, Va, has required that all blood donors must be tested for serum alanine aminotransferase (ALT), and that donations from donors with ALT levels above a certain cutoff value must be discarded. To assess the impact of this requirement on different ethnic/racial groups, the ALT levels of 1781 blood donors were compared. Hispanic blood donors had significantly higher ALT levels than did black and non-Hispanic white blood donors. No significant difference in ALT was seen between black and non-Hispanic white blood donors. We conclude that there are statistically significant differences in the ALT levels between Hispanic and non-Hispanic blood donors, and that a disproportionate number of Hispanic blood donations (11% to 13%) will be discarded as a result of testing blood donors for ALT.

Alanine Transaminase↗
PubMed1986

Cell cycle effects of trimetrexate (CI-898).

The cell cycle phase specificity of trimetrexate (CI-898) was examined. CHO cells synchronized by mitotic selection were exposed to 50 microM trimetrexate for 2 h at various time points after release from Colcemid block. Only S phase cells were sensitive to trimetrexate when survival was measured by a cloning assay. Comparison of plateau phase and log phase cultures indicated that plateau phase CHO cells were relatively insensitive to 5 microM trimetrexate. Exponentially growing L1210 cells were continuously exposed to either 30 nM or 3 nM trimetrexate and analyzed by DNA flow cytometry. Incubation with 30 nM trimetrexate produced cell cycle arrest in late G1 or early S phase, while exposure to 3 nM trimetrexate caused only a delay in progression through S phase. In an in vivo schedule dependence study with mice bearing approximately 3 X 10(6) P388 leukemia cells, trimetrexate was most effective with frequent administration. Mice treated on the optimal schedule, every 3 h X 8 on days 1, 5, and 9 after tumor implant, had life-span increases in excess of 100%.

Animals↗
PubMed1985

Experience with a cost-effective crossmatch protocol.

Pretransfusion blood samples were routinely tested for ABO group, Rh type, and the presence of unexpected red blood cell antibodies. Patients who had unexpected red blood cell antibodies received transfusions of blood that was crossmatched using an immediate spin test, a 37 degrees C incubation step, and an indirect antiglobulin test. Patients who did not have unexpected red blood cell antibodies received transfusions with blood that was crossmatched by an immediate spin crossmatch only. Because the average immediate spin crossmatch required only 3.25 minutes to be performed, crossmatches were not done for patients without unexpected antibodies until blood was actually requested to be issued for transfusion. During the first 8 1/2 months this protocol was used, 27,742 crossmatches were performed and 46,959 unnecessary crossmatches were avoided, thus reducing direct costs by at least +49,300. This protocol also allowed for optimal blood inventory control and minimized the outdating of units of blood to only 0.19%.

Blood Banks↗
PubMed1985

Dose-rate evidence for two kinds of radiation damage in stationary-phase mammalian cells.

Survival based on colony formation was measured for starved plateau-phase Chinese hamster ovary (CHO) cells exposed to 250 kVp X rays at dose rates of 0.0031, 0.025, 0.18, 0.31, and 1.00 Gy/min. A large dose-rate effect was demonstrated. Delayed plating experiments and dose response experiments following a conditioning dose, both using a dose rate of 1.00 Gy/min and plating delays of up to 48 hr, were also used to investigate the alternative repair hypotheses. There is clearly a greater change in survival in dose-rate experiments than in the other experiments. Thus we believe that a process which depends on the square of the concentration of initial damage, and which alters the effect of initial damage on cell survival is being observed. We have applied the damage accumulation model to separate the single-event damage from this concentration-dependent form and estimate the repair rate for the latter type to be 70 min for our CHO cells. Use of this analysis on other published dose-rate studies also yields results consistent with this interpretation of the repair mechanisms.

Animals↗
PubMed1985

Anthrapyrazoles, a new class of intercalating agents with high-level, broad spectrum activity against murine tumors.

A series of 5-[(aminoalkyl)amino]-substituted anthra[1,9-cd] pyrazol-6(2H)ones (anthrapyrazoles) were synthesized. These compounds, which differ from the anthracenediones in that an additional pyrazole ring has been fused to the anthracene system in place of one carbonyl group, were evaluated in vivo for their anticancer activity in eight different mouse tumor systems. Compounds were selected for testing primarily on the basis of their high levels of activity P388 leukemia and occasionally for structural considerations. Sixty-seven % of the 21 analogues studied were curative in the National Cancer Institute P388 screen. Many of the compounds tested were highly active against each of the tumors of the National Cancer Institute panel. Thus 82, 73, 45, and 80% of the compounds tested were curative for L1210 leukemia, B16 melanoma, M5076 sarcoma, and the MX-1 mammary xenograft, respectively. Several of the compounds studied were curative against every tumor of the above panel. Because of the high activity of the anthrapyrazole series as a class in the National Cancer Institute tumor panel, additional testing was necessary to allow selection of clinical candidates. Twenty-one anthrapyrazoles were tested against mammary adenocarcinoma 16C, colon adenocarcinoma 11a, and the Ridgway osteogenic sarcoma. Four compounds, PD 113,309 (Cl-937), PD 113,785 (Cl-941), PD 111,815 (Cl-942), and PD 115,593, were judged superior to the rest on the basis of the expanded panel testing. The preclinical data to date suggest that these anthrapyrazoles are similar to doxorubicin in both degree and spectrum of activity. Each of these anthrapyrazoles were significantly more active than were the other synthetic intercalating agents, the anthracenediones mitoxantrone and ametantrone, against the tumors of the expanded panel. On the basis of their high level of broad spectrum activity in preclinical systems, ease of formulation, possible lack of cross-resistance with doxorubicin, and potential lack of cardiotoxicity, Cl-937, Cl-941, and Cl-942 have been selected for further preclinical evaluation and possible clinical development.

Animals↗
PubMed1984

Experience with the routine use of an abbreviated crossmatch.

Three years' experience with the routine use of an abbreviated crossmatch procedure is reported. If a patient had no known history of and/or no currently demonstrable unexpected antibodies, ABO and Rh type specific blood was crossmatched at the time of need by using an immediate spin saline abbreviated crossmatch. Once blood was issued, both a 37 degrees C incubation and an antiglobulin crossmatch were done using the same tube employed for the abbreviated crossmatch. This served as a check that clinically significant antibodies were not overlooked. None of the 19,818 patients transfused following an abbreviated crossmatch suffered an acute hemolytic transfusion reaction as a result of this strategy; however, two patients may have manifested asymptomatic hemolysis. This approach to compatibility testing might be appealing to hospitals faced with fiscal limitations and new regulations affecting hospital reimbursement.

Adult↗
PubMed1984

Kinetic differences between fed and starved Chinese hamster ovary cells.

When Chinese hamster (CHO-K1) cells are grown as monolayer cultures, they eventually reach a population-density plateau after which no net increase in cell numbers occurs. The kinetics of aged cells in nutritionally deprived (starved) or density-inhibited (fed) late plateau-phase cultures were studied by four methods: (i) Reproductive integrity and cell viability were monitored daily by clonogenic-cell assay and erythrosin-b dye-exclusion techniques. (ii) Mitotic frequencies of cells from 18 day old cultures were determined during regrowth by analysing time-lapse video microscope records of dividing cells. (iii) Tritiated-thymidine ([3H]TdR) autoradiography was used to determine the fractions of DNA-synthesizing cells in cultures entering plateau phase and during regrowth after harvest. (iv) The rate of labelled nucleoside uptake and incorporation into DNA was measured using liquid scintillation or sodium iodide crystal counters after labelling with [3H]TdR or [125I]UdR. Non-cycling cells in starved cultures accumulate primarily as G1 phase cells. Most cells not in G1 phase had stopped in G2 phase. Very few cells (less than 2%) were found in S phase. In contrast, about half of the cells in periodically fed cultures were found to be in DNA-synthetic phase, and the percentage of these S phase cells fluctuated in a manner reflecting the frequency of medium replacement. Populations of both types of plateau-phase cultures demonstrate extremely coherent cyclic patterns of DNA synthesis upon harvest and reculturing. They retain this high degree of synchrony for more than three generations after the resumption of growth. From these data it is concluded that nutritionally deprived (starved) late plateau-phase cells generally stop in either G1 or G2 phase, whereas periodically fed late plateau-phase cultures contain a very large fraction of cycling cells. Populations of cells from these two types of non-expanding cultures are kinetically dissimilar, and should not be expected to respond to extracellular stimuli in the same manner.

Animals↗