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Biomedical subjects

D Higgins

Publications and source records attributed to D Higgins.

At least 19 recordsLinked to original sources
PubMed1992

Laminin selectively enhances axonal growth and accelerates the development of polarity by hippocampal neurons in culture.

We have examined the effects of laminin on the morphological development of embryonic rat hippocampal neurons maintained in tissue culture. Forty-eight hours after plating, neurons grown on a polylysine-coated substrate had become polarized, typically having one long axon and 4 or 5 minor processes. Adsorption of laminin to the substrate did not cause changes in the number of axons extended by hippocampal neurons but did cause significant increases in the length of the axonal plexus and in axonal branching. In contrast to its effects on axons, laminin did not influence the number, length, or branching of the minor processes that eventually become dendrites or the morphology of definite dendrites as assessed after 7 days in culture. In addition to selectively enhancing axonal growth, laminin greatly increased the rate of polarization of hippocampal neurons such that most became polarized within 18 h. Analysis of the time course of laminin's effects revealed that the acceleration of polarization was not associated with a change in the time of initial process formation, but rather with a selective stimulation of the growth of the longest process at all times from the 12th through the 48th h in vitro. These data suggest that even though the basic shape of hippocampal neurons may be intrinsically programmed, critical aspects of their morphological development may be modulated by extracellular matrix molecules such as laminin.

Animals↗
PubMed1992

Thrombospondin promotes process outgrowth in neurons from the peripheral and central nervous systems.

Thrombospondin (TSP) is a prominent constituent of the extracellular matrix of the developing nervous system. We have examined the effects of TSP on the morphological differentiation of neurons. In short-term cultures (less than or equal to 24 hr) of embryonic rat sympathetic neurons, TSP stimulated neurite outgrowth, causing significant increase in the number of processes and their length. Similar effects were observed in cultures of rat dorsal root ganglion, hippocampal, and cerebral cortical neurons. Moreover, in cultures of central neurons, TSP was more effective than laminin in enhancing process extension. Analysis of long-term (5-7 days) cultures of sympathetic neurons indicated that processes formed in the presence of TSP had the cytochemical characteristics of axons. Thus, TSP can influence neuronal development by selectively enhancing axonal growth. The neurite-promoting region of the molecule was identified using a panel of monoclonal antibodies targeted to different regions of the protein. Process outgrowth could be totally inhibited with antibody A4.1, which recognizes the stalk region of TSP. These data suggest that the neurite-promoting activity is localized to a single region of the TSP molecule.

Animals↗
PubMed1992

OBSTRUCT: a program to obtain largest cliques from a protein sequence set according to structural resolution and sequence similarity.

A program OBSTRUCT has been developed to obtain the largest possible subset according to specific constraints from a set of protein sequences whose tertiary structures have been determined crystallographically. The user can request a range in sequence similarity level and/or structural resolution. The program optionally includes sequences with known three-dimensional folds elicited from NMR data.

Protein Conformation↗
PubMed1992

Effects of isoflurane anaesthesia on the median nerve somatosensory evoked potential in children.

Evoked potentials are used to determine the integrity of neural pathways during neurosurgical and orthopaedic procedures, but the extent to which they may be altered by anaesthetic agents has not been studied systematically in children. In this study we have recorded median nerve somatosensory evoked potentials (mnSSEP) in children during isoflurane anaesthesia to determine if there are changes similar to those seen in adults. We studied 10 patients using standardized anaesthetic and clinical neurophysiological techniques. Control mnSSEP were obtained with 70% nitrous oxide in oxygen and isoflurane was then administered at 0.25, 0.50 and 0.75 MAC. The latencies and amplitudes of the mnSSEP were subjected to repeated measures analysis of the variance (ANOVA) and linear regression. There were statistically significant increases in N20, P22 latencies and central conduction time (P < 0.001) and reductions in amplitude of the N20-P22 complex (P < 0.03) with increasing end-tidal isoflurane concentrations. These results are similar to the findings in adults.

Anesthesia, Inhalation↗
PubMed1992

Sequential measurement of the median nerve somatosensory evoked potential during isoflurane anaesthesia in children.

We have used sequential measurements of median nerve somatosensory evoked potentials (mnSSEP) in 10 children to estimate the equilibration time of an inhalation anaesthetic agent between alveolar gas, arterial blood and brain. MnSSEP were obtained sequentially every 90-180 s. After control measurements in the absence of isoflurane, the end-tidal concentration was increased stepwise (0.25, 0.5 and 0.75 MAC). Each isoflurane concentration was maintained for 15 min. The point at which the N20 latency reached stability was determined; the mean time between reaching a stable end-tidal isoflurane concentration and this point varied between 5 min 16 s and 7 min 37 s. This technique may be useful in circumstances in which a "steady state" of anaesthesia is important, such as in the determination of MAC or during intraoperative monitoring of evoked potentials.

Anesthesia, Inhalation↗
PubMed1991

Mesothelioma among employees with likely contact with in-place asbestos-containing building materials.

The occurrence of mesothelioma is a sentinel event in occupational and environmental disease. A mesothelioma surveillance system was established utilizing existing computerized Wisconsin vital statistics data maintained since 1959 and a Cancer Reporting System (CRS) established in 1978. Review of the death certificate listing of usual occupation and industry from 487 mesothelioma deaths in Wisconsin from 1959 to 1989 led to the investigation of 41 persons with likely exposure to inplace asbestos-containing building materials (ACBM): 12 school teachers, 10 school maintenance employees, 7 public building maintenance workers, 5 private building maintenance workers, and 7 commercial and factory workers performing maintenance activities. For 10 (34%) of the 29 maintenance workers the only source of asbestos exposure identified was their maintenance work. For five (17%) histories indicated some prior employment in occupations and industries with probable asbestos exposures. Opportunities for indirect occupational exposure were identified for ten who had been employed in the residential construction industry. One maintenance worker was exposed to asbestos in the household and another had neighborhood exposure. For 9 (75%) of the school teachers, the only identifiable potential source of asbestos exposure was derived from in-place ACBM in schools. One teacher had spent a season in the merchant marine aboard an iron ore-hauling ship and 2 had worked in the residential construction industry. Two of the teachers were sisters, and in two instances, two teachers had taught in the same school facility. We conclude that individuals occupationally exposed to in-place ACBM are at risk for the subsequent development of mesothelioma.

Adult↗
PubMed1991

Protein synthesis is required for the initiation of dendritic growth in embryonic rat sympathetic neurons in vitro.

We have utilized an experimental paradigm which allows the manipulation of dendritic growth in sympathetic neurons in culture to examine the effects of inhibitors of protein synthesis and RNA synthesis on the development of dendrites. Embryonic rat sympathetic neurons extend only axons when they are grown in serum-free medium on a polylysine substrate. The addition of an extract of basement membrane proteins (BME) to this culture system elicits dendritic growth within 48 h. Both cycloheximide and actinomycin-D inhibited BME-induced dendritic growth in greater than 80% of the neuronal population and reduced the number of dendrites extended by greater than or equal to 97%. In contrast, cycloheximide was found to have minimal effects on axonal growth in short-term (less than or equal to 18 h) cultures as measured with respect to the percentage of the population with axons and the number of axons per neuron. However, this inhibitor did significantly reduce (84%) the length of the axonal plexus extended. These results indicate that dendritic and axonal growth in sympathetic neurons are differentially dependent on protein synthesis such that the formation of dendrites requires protein synthesis whereas the initiation, but not the elongation, of axons is relatively independent of protein synthesis.

Animals↗
PubMed1991

Colorimetric end-tidal carbon dioxide monitoring during transfer of intubated children.

We report the use of a cheap, pocket-sized colorimeter to assess the end-tidal carbon dioxide concentration during transfer of intubated children. The device provided breath by breath confirmation of tracheal tube placement and identified one episode of reduced pulmonary perfusion. We would advocate the use of this detector to provide early warning of tracheal tube displacement during the transfer of children weighing more than 15 kg.

Body Weight↗
PubMed1991

The NC1 domain of type IV collagen promotes axonal growth in sympathetic neurons through interaction with the alpha 1 beta 1 integrin.

We have examined the effects of collagen IV on the morphological development of embryonic rat sympathetic neurons in vitro. In short-term (less than or equal to 24 h) culture, collagen IV accelerated process outgrowth, causing increases in the number of neurites and total neuritic length. Analysis of proteolytic fragments of collagen IV indicated that the NC1 domain was nearly as active as the intact molecule in stimulating process outgrowth; in contrast, the 7S domain and triple helix-rich fragments of collagen IV were inactive. Moreover, anti-NC1 antiserum inhibited neuritic outgrowth on collagen IV by 79%. In long-term (up to 28 d) cultures, neurons chronically exposed to collagen IV maintained a single axon but failed to form dendrites. Thus, the NC1 domain of collagen IV can alter neuronal development by selectively stimulating axonal growth. Comparison of collagen IV's effects to those of laminin revealed that these molecules exert quantitatively different effects on the rate of initial axon growth and the number of axons extended by sympathetic neurons. Moreover, neuritic outgrowth on collagen IV, but not laminin, was blocked by cycloheximide. We also observed differences in the receptors mediating the neurite-promoting activity of these proteins. Two different antisera that recognize beta 1 integrins each blocked neuritic outgrowth on both collagen IV and laminin; however, an mAb (3A3) specific for the alpha 1 beta 1 integrin inhibited collagen IV but not laminin-induced process growth in cultures of both sympathetic and dorsal root neurons. These data suggest that immunologically distinct integrins mediate the response of peripheral neurons to collagen IV and laminin.

Animals↗
PubMed1990

Structural requirements for inhibitors of poly(ADP-ribose) polymerase.

The purpose of this study was to examine the structure/activity relationships of a series of substituted benzamides as poly(ADP-ribose) polymerase inhibitors. The experimental approach has involved the use of in vitro and in vivo assays in order to gather information either on the intrinsic activity of the benzamides or on the effect of various pharmacodynamic parameters on the activity in vivo. Although some discrepancies between the data obtained in vivo and in vitro were found in this study, results seem to indicate that most powerful inhibitors were characterized by acylation of the -NH2 function in the 3 position or by substitution in this same position with hydroxy or methoxy groups. The best inhibitors were not cytotoxic under these experimental conditions. Computed calculations of molecular electrostatic potential of these molecules were also performed and a good correlation was found between the similarity index and the experimental inhibitory activity.

Benzamides↗
PubMed1990

Distinct spatial localization of specific mRNAs in cultured sympathetic neurons.

We examined the subcellular distribution of specific mRNAs in cultured sympathetic neurons. Under appropriate conditions, sympathetic neurons extend both axons and dendrites that are distinguishable by light microscopic and immunocytochemical criteria. In situ hybridization revealed a differential localization of mRNA within dendrites. mRNA encoding MAP2 was abundant in cell bodies and distributed nonhomogeneously throughout the dendritic compartment, but was not detected in axons. In contrast, mRNAs encoding GAP-43 and alpha-tubulin were restricted to the cell body and largely excluded from dendrites as well as axons. Detergent extraction revealed that most dendrite-associated mRNA encoding MAP2 was associated with the Triton X-100 insoluble fraction of the cell. The subset of mRNAs present in the dendritic compartment may encode proteins involved in the morphogenesis and remodeling of dendrites.

Animals↗