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Biomedical subjects

D O Nelson

Publications and source records attributed to D O Nelson.

At least 19 recordsLinked to original sources
PubMed1999

Elevated frequencies of hypoxanthine phosphoribosyltransferase lymphocyte mutants are detected in Russian liquidators 6 to 10 years after exposure to radiation from the Chernobyl nuclear power plant accident.

This study was conducted to determine whether the frequency of hypoxanthine phosphoribosyltransferase (HPRT) deficient lymphocyte mutants would detect an effect of radiation exposure in a population of Russians who were exposed to low levels of radiation while working in 1986 and 1987 as liquidators cleaning up after the Chernobyl nuclear power reactor accident. The HPRT lymphocyte cloning assay was performed on peripheral blood lymphocytes collected between 1992 and 1996 from 142 liquidators and 66 Russian controls, and between 1989 and 1993 from 231 American controls. Russian and American controls were not significantly different for either cloning efficiency or mutant frequency (MF); inclusion of both sets of controls in the analysis increased the ability to detect a Chernobyl exposure effect in the liquidators. After adjusting for age and smoking, the results revealed no significant difference in cloning efficiency of Chernobyl liquidators relative to Russian controls but a significant, 24% increase in liquidator HPRT mutant frequency over Russian controls (90% confidence interval was 7% to 45% increase). The analytical method also accounted for differences in precision of the individual estimates of log CE and log MF and accommodated for outliers. The increase in HPRT mutant frequency of liquidators is an attribute of the exposed population as a whole rather than of individuals. These results demonstrate that, under appropriate circumstances, the HPRT specific locus mutation assay of peripheral blood lymphocytes can be used to detect a semi-acute, low dose radiation exposure of a population, even 6 to 10 years after the exposure.

Adult↗
PubMed1998

The accumulation of chromosome aberrations and Dlb-1 mutations in mice with highly fractionated exposure to gamma radiation.

The dichotomy between the doses at which experimental measurements of genetic effects can be made and the doses to which people are exposed is often different by two or more orders of magnitude. This presents a significant problem when determining the effects of low doses of radiation or chemicals. The solution has usually involved extrapolating the data by curve-fitting or by applying theoretical considerations. Both approaches are unsatisfactory due to uncertainties of the assumptions used in each process. The alternative solution has been to increase the sample size enormously at the lower doses. This is impractical beyond a certain point due to the variation in the spontaneous frequency and the need to quadruple the sample size for a doubling of precision. The development of new methods for measuring stable genetic effects, however, permits a simple and effective approach to this problem: if the genetic events being detected have no effect on survival, i.e., are selectively neutral, then the effects of multiple independent treatments will be additive. If the independent treatments are identical, then the effect of each is easily calculated by dividing the total effect by the number of treatments. Here we report a limited test of this approach using mice. Chromosome aberrations induced in lymphocytes and Dlb-1 mutations induced in the small intestine were measured after daily doses of 0.64, 1.85 or 5.5 cGy 137Cs gamma rays administered for 21, 42 or 63 days. The dose response curve for chromosome translocations obtained in this way, combined with the data from single larger acute doses, shows no evidence for a threshold over a 500-fold dose range. Dlb-1 mutations were increased at each dose and time but the results do not permit reliable extrapolations. The results suggest that translocations might be useful for quantifying the effect of doses below 0.05 cGy and that the effect of dose rate and dose fractionation at much lower doses than reported here could be investigated.

Animals↗
PubMed1998

Persistence of radiation-induced translocations in human peripheral blood determined by chromosome painting.

We have investigated the persistence of translocations and other types of chromosome damage with time using human peripheral blood acutely exposed in vitro to 137Cs gamma rays at doses ranging from 0.5 to 4 Gy. Freshly drawn blood from one donor was irradiated and metaphase chromosomes were prepared 2 to 7 days after exposure. Chromosomes 1, 2 and 4 were painted red-orange and chromosomes 3, 5 and 6 were painted green by fluorescence in situ hybridization (FISH) using "semi-directly" labeled whole-chromosome painting probes. This type of labeling combines direct and indirect labeling and showed significant advantages over both these other methods. All types of structural chromosome aberrations were classified by the Protocol for Aberration Identification and Nomenclature Terminology (PAINT) system. The yields of dicentric chromosomes, acentric fragments and ring chromosomes diminished with time as expected. Translocations exhibited greater persistence but showed a clear and statistically significant reduction in frequency at all doses. The mathematical model suggested that the translocation frequencies would reach a plateau of approximately 4, 15, 51, 106 and 179 translocations per 100 cell equivalents after irradiation with 0.5, 1, 2, 3 and 4 Gy, respectively. When translocations were classified by the conventional system, an analysis of the distribution of translocations and dicentrics per cell indicated that both types of exchanges were Poisson-distributed 48 h postirradiation. However, cells bearing translocations have a higher possibility of having dicentrics than cells without translocations. These findings suggest that dicentrics may contribute to a decline of translocation frequencies with time, and that some translocations are not completely persistent. The results obtained here using human blood exposed in vitro may influence the use of translocations as a retrospective biodosimeter of exposure to ionizing radiation in humans.

Cells, Cultured↗
PubMed1998

Covalent binding of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline to albumin and hemoglobin at environmentally relevant doses. Comparison of human subjects and F344 rats.

Covalent binding of the food-borne heterocyclic amine 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to albumin and hemoglobin (Hb), 3.5-6.0 hr after oral administration of a single dose of either 21.3 or 228.0 microg of [14C]MeIQx (304 and 3257 ng/kg of body weight, respectively, based on a 70-kg subject weight), was studied in human volunteers using accelerator mass spectrometry. Human protein adduct levels were compared with data obtained for male F344 rats 4.5 hr after oral administration of 0.94-11,420 ng/kg of body weight [14C]MeIQx. Dose-dependent levels of MeIQx-albumin and MeIQx-Hb adducts were detected in both humans and rats. In each case, the regression coefficient (slope) of the dose-response curve was approximately 1. The highest levels of adduct formation per unit dose of MeIQx occurred with human albumin, followed by rat albumin, human Hb, and rat Hb (in that order). Although the human subjects were elderly and underwent colon resection surgery during the study period, the results indicate that formation of albumin and Hb adducts is dose dependent and that a trend exists for higher adduct levels per unit dose in humans, compared with F344 rats. Furthermore, MeIQx-albumin adducts are likely to provide a more sensitive marker of exposure to MeIQx than are MeIQx-Hb adducts.

Adult↗
PubMed1997

The limits of random fingerprinting.

Various random fingerprinting methods are sometimes used to detect overlap between pairs of clones as a first step toward producing a minimal tiling path of clones for subsequent mapping and sequencing efforts. This paper evaluates and compares various statistical procedures for detecting pairwise overlap between clones when the fingerprints arise from any random process meeting simple, plausible assumptions about the relationship between overlap and the resulting fingerprint. Examples of such random processes include, but are not limited to, large-scale hybridization procedures designed to prepare tiling paths of clones for subsequent large-scale genomic sequencing. Our goals are to assess how well random fingerprinting can possibly detect overlap, to assess the effects of inevitable fingerprinting errors on statistical detection, to determine how one can make the best use of the data random fingerprinting provides, and to evaluate how well simple, heuristic techniques for overlap detection compare to more complex, likelihood-based approaches. The paper provides a quantitative assessment of the ability of any random fingerprinting procedure to detect various proportions of clonal overlap and shows the extent to which a small amount of experimental error will vitiate the performance of such techniques. The paper outlines a simple approximation method for constructing Bayesian overlap detectors, while concluding that detectors constructed from linear combinations of fingerprint data can be designed that will perform nearly as well as more complex, likelihood-based approaches.

DNA Fingerprinting↗
PubMed1995

A 30-Mb metric fluorescence in situ hybridization map of human chromosome 19q.

A high-resolution metric physical map of chromosome 19q has been constructed by fluorescence in situ hybridization. The map locates 136 cosmid reference points that span 30 Mb. The reference points are sequentially ordered from centromere to telomere, and the distance between neighboring cosmids is known from 240 partially overlapping, redundant estimates of genomic distances in kilobases separating pairs of cosmids. The average spacing between cosmid reference points is 220 kb, with over 75% of intervals less than 300 kb. Eighty-four genes and polymorphic markers have been assigned to mapped cosmids. The information on order and genomic distances separating pairs of cosmids, both key elements for building physical maps, has furthered the construction and integration of the genetic and physical maps of chromosome 19.

Chromosome Mapping↗
PubMed1995

Sequence diversity and chromosomal distribution of "young" Alu repeats.

Members of the recently inserted human-specific (HS)/predicted variant (PV) subfamily of Alu elements were sequenced. A number of these Alu elements share greater than 98% sequence identity with the subfamily consensus sequence, and they are flanked by perfect 5' and 3' direct repeats ranging in size from 6 to 15 nucleotides (nt). Based on the low number of random mutations, the estimated average age of these elements was calculated to be 1.5 million years (Myr). All the young Alu subfamily members were restricted to the human genome, as judged by polymerase chain reaction (PCR) amplification of human and non-human primate DNA samples using the unique flanking sequences specific for each Alu element. The chromosomal locations of several Alu elements belonging to the young subfamilies, designated as HS/PV and Sb2, were determined by PCR amplification of DNA samples from human/rodent somatic cell hybrid panels. A statistical analysis of the chromosomal distribution pattern showed that the recently inserted Alu elements appear to integrate randomly in the human genome.

Animals↗
PubMed1994

Predicting progress in directed mapping projects.

Several recent mapping efforts have used so-called "directed" approaches to construct their maps. However, most, but not all, published methods for modeling the progress in physical mapping projects have been focused on random approaches, such as bottom-up fingerprinting and STS-content mapping. In addition, those few efforts that did model directed approaches used methods that required assuming that all insert lengths were the same. This assumption is unnecessary. Using properties of stationary processes, one can derive simple asymptotic formulas that apply equally to constant and variable clone lengths. Also, in the case of constant clone lengths, these results are equivalent to, and extend, those published results for directed mapping derived by other methods. Simulations show that these methods provide estimates well within the limits of uncertainty inherent in any mapping project.

Chromosome Mapping↗
PubMed1994

Human chromosome 19p: a fluorescence in situ hybridization map with genomic distance estimates for 79 intervals spanning 20 Mb.

A physical map of human chromosome 19p has been constructed by fluorescence in situ hybridization of cosmids to metaphase chromosomes and sperm pronuclear interphases. The map spans approximately 20 Mb and was generated with 141 multiple, partially overlapping estimates of genomic distances for 79 intervals separating 80 sequentially ordered cosmid reference points. The average distance separating pairs of cosmids was 250 kb, with a range from 50 to 700 kb; 75% of the intervals were estimated to be less than or equal to 300 kb and only 8 intervals were between 500 and 700 kb. Cosmids positive for 33 genes or gene families and 5 polymorphic markers were included among the mapped elements. The fluorescence in situ hybridization map will be useful for furthering the integration of the physical and genetic maps of 19p and for placing newly identified markers within a few hundred kb of their neighbors.

Analysis of Variance↗
PubMed1988

Altered angiotensin II sensitivity of neurons in the organum vasculosum lamina terminalis region of the spontaneously hypertensive rat.

Using in vitro hypothalamic brain slices, differences in angiotensin II (AII) sensitivity of neurons in the organum vasculosum lamina terminalis (OVLT) region were compared between spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). AII, the AII competitive antagonist saralasin, and L-glutamate were micropressure-applied onto OVLT neurons. AII excitation of SHR neurons was blocked or antagonized by simultaneous application of saralasin, evoked at significantly lower thresholds and displayed exaggerated periods of postactivity compared to OVLT neurons in preparations taken from WKY controls. Neuronal responses to L-glutamate were similar between the two rat strains. Differences in neuronal sensitivity to AII may be causally linked to hypertension in SHR.

Angiotensin II↗
PubMed1988

Development of angiotensin II-sensitive OVLT neurons in SHR and WKY rats.

Angiotensin II (AII) sensitivity of neurons in the region of the organum vasculosum laminae terminalis (OVLT) was examined electrophysiologically using in vitro hypothalamic brain slices taken from 4-, 9- and 14-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Micropressure application of AII, its competitive antagonist saralasin, and L-glutamate revealed that neurons in this region of SHR were significantly more sensitive to AII than cells in age-matched WKY preparations. Neuronal sensitivity to L-glutamate was similar between SHR and WKY rats at all ages. Following electrophysiological study, hypothalamic and cortical brain slices were assayed for 125I-labelled AII binding. AII receptor binding in the hypothalamic slices from SHR was elevated significantly above binding in WKY hypothalamic slices at 4, 9, and 14 weeks of age. In contrast, AII binding in cortical slices taken from SHR and WKY rats was similar. These data suggest that altered neuronal AII-sensitivity is not a consequence of hypertension development in SHR and may contribute to its development.

Action Potentials↗
PubMed1988

Effects of fasting and refeeding on blood pressure are determined by nutritional state, not by body weight change.

It is commonly assumed that caloric restriction is effective in lowering blood pressure because of the accompanying weight loss and reversal of obesity. However, clinical trials of caloric restriction reporting the greatest falls in blood pressure were those that produced the most rapid weight loss on diets allowing the fewest calories, but the amount of weight loss was unrelated to antihypertensive effect. In obese rats undergoing a supplemented fast, blood pressure fell almost immediately but then stabilized despite continuing weight loss. The depressor effect of fasting was reversed within 2 days of refeeding. Body weight change was no longer correlated with blood pressure change after nutritional state was controlled for. Nutritional state (fed, fasted, refed), but not body weight, has important effects on blood pressure.

Animals↗
PubMed1988

Refeeding hypertension in dietary obesity.

A novel model of nutritionally induced hypertension in the rat is described. Dietary obesity was produced by providing sweet milk in addition to regular chow, which elicited a 52% increase in caloric intake. Despite 54% greater body weight gain and 139% heavier retroperitoneal fat pads, 120 days of overfeeding failed to increase systolic pressure in the conscious state (125 +/- 8 vs. 121 +/- 4 mmHg in chow-fed controls) or mean arterial pressure under urethan anesthesia (71 +/- 4 vs. 63 +/- 3 mmHg). In contrast, mild hypertension developed in intermittantly fasted obese animals (a 21-mmHg increase in systolic blood pressure measured in the conscious state and a 16-mmHg increase in mean arterial pressure under anesthesia relative to chow-fed controls). The first 4-day supplemented fast was initiated 4 wk after the introduction of sweet milk, when the animals were 47 g overweight relative to chow-fed controls. Thereafter, 4 days of starvation were alternated with 2 wk of refeeding for a total of 4 cycles. A rapid fall in systolic blood pressure (12 +/- 2 mmHg at 2 days) accompanied the onset of supplemented fasting and was maintained thereafter (2.7 +/- 2.6 mmHg further decrease during the latter half of the fast). With refeeding, blood pressure rose precipitously (13 +/- 3 mmHg in the 1st 2 days), despite poststarvation anorexia. Blood pressure tended to rise slightly over the remainder of the realimentation period (5.2 +/- 2.8 mmHg). After the 4th supplemented fast, hypertension was sustained during 30 days of refeeding. Cumulative caloric intake in starved-refed rats fell within 2% of that in chow-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Cardiovascular function is altered by picomole injections of glutamate into rat medulla.

Local neural circuitry in the nucleus tractus solitarius (NTS) involved in cardiovascular control was studied by injecting nanoliter volumes of excitatory amino acids into the structure. Experiments were performed on urethane-anesthetized, artificially ventilated rats. Multibarrel micropipettes were used for pressure ejection of drugs or a dye for marking ejection sites. Ejected volumes, ranging from 200 pl to 25 nl, were directly monitored for every injection. Injections of as little as 200 fmol of L-glutamate in 200 pl into the medial and lateral NTS region rostral to the obex elicited marked, site-specific decreases in arterial pressure and heart rate. The majority of these responses were eliminated by blockade of parasympathetic and sympathetic neural outflow. At sites caudal to obex, in the commissural region of the NTS, L-glutamate injections produced marked elevations in heart rate and arterial pressure which were sympathetically mediated. Responses to L-glutamate were attenuated by concurrent injection of glutamic acid diethyl ester and DL-2-amino-4-phosphonobutyrate, or lidocaine. These results indicate a heterogeneity in the spatial organization of brain-stem circuitry underlying cardiovascular control that has not been previously described.

Animals↗
PubMed1987

Inhibition of renal sympathetic nervous activity by area postrema stimulation in rabbits.

This study investigated the effect of chemical and electrical stimulation of the area postrema on renal sympathetic nerve activity (RSNA), arterial pressure, and heart rate in urethan-anesthetized rabbits. Electrical stimulation of the area postrema at 2, 5, 10, 20, 40, and 80 Hz using constant currents of 7.5, 15, and 30 microA (pulse duration = 0.3 ms, train duration = 5 s) produced progressive decreases in RSNA and heart rate, with no consistent change in arterial pressure. To control for electrical activation of fibers of passage in or near the area postrema, L-glutamate was injected into the area postrema using glass micropipettes. Micropressure injection of L-glutamate (10 mM) in volumes of 5-10 nl produced rapid decreases in RSNA averaging 27 +/- 5% (P less than 0.05) accompanied by a small bradycardia. The effects of electrical stimulation of the area postrema, but not the adjacent nucleus tractus solitarius, were totally eliminated by micropressure injection of kainic acid (40 ng in 40 nl) into the area postrema. During continuous electrical stimulation of the area postrema using parameters that produced small decrements in RSNA and heart rate, the slope of the line relating baroreflex inhibition of RSNA to increases in arterial pressure during graded infusions of phenylephrine was significantly enhanced (-6.77 +/- 1.30 vs. -3.81 +/- 0.66% RSNA/mmHg). These data are consistent with the hypothesis that activation of neurons in the area postrema results in an inhibition of RSNA. Furthermore, stimulation of the area postrema augments baroreflex inhibition of RSNA during increases in arterial pressure with phenylephrine.

Animals↗