Biomedical subjects

Kevin R Smith

Publications and source records attributed to Kevin R Smith.

13 recordsLinked to original sources

PubMed2006

Acute pulmonary and systemic effects of inhaled coal fly ash in rats: comparison to ambient environmental particles.

Although primary particle emissions of ash from coal-fired power plants are well controlled, coal fly ash (CFA) can still remain a significant fraction of the overall particle exposure for some plant workers and highly impacted communities. The effect of CFA on pulmonary and systemic inflammation and injury was measured in male Sprague-Dawley rats exposed to filtered air or CFA for 4 h/day for 3 days. The average concentration of CFA particulate matter less than 2.5 microm (PM(2.5)) was 1400 microg/m(3), of which 600 microg/m(3) was PM(1). Animals were examined 18 and 36 h postexposure. Chemical analysis of CFA detected silicon, calcium, aluminum, and iron as major components. Total number of neutrophils in bronchoalveolar lavage fluid (BALF) following exposure to CFA was significantly increased along with significantly elevated blood neutrophils. Exposure to CFA caused slight increases in macrophage inflammatory protein-2, and marked increases in transferrin in BALF. Interleukin-1beta and total antioxidant potential in lung tissues were also increased in rats exposed to CFA. Histological examination of lung tissue demonstrated focal alveolar septal thickening and increased cellularity in select alveoli immediately beyond terminal bronchioles. These responses are consistent with the ability of CFA to induce mild neutrophilic inflammation in the lung and blood following short-term exposure at levels that could be occupationally relevant. However, when comparing the effects of CFA with those of concentrated ambient particles, CFA does not appear to have greater potency to cause pulmonary alterations. This study furthers our understanding of possible mechanisms by which specific sources of particulate air pollution affect human health.

Air Pollutants↗

PubMed2005

Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor.

Changes in the lungs due to smoking include inflammation, epithelial damage, and remodeling of the airways. Airway inflammation is likely to play a critical role in the genesis and progression of tobacco smoke-induced airway disease. Soluble epoxide hydrolase (sEH) is involved in the metabolism of endogenous chemical mediators that play an important role in inflammation. Epoxyeicosatrienoic acids (EETs) have demonstrated antiinflammatory properties, and hydrolysis of these epoxides by sEH is known to diminish this activity. To examine whether acute tobacco smoke-induced inflammation could be reduced by a sEH inhibitor, 12-(3-adamantane-1-yl-ureido)-dodecanoic acid n-butyl ester was given by daily s.c. injection to spontaneously hypertensive rats exposed to filtered air or tobacco smoke for a period of 3 days (6 h/day). Acute exposure to tobacco smoke significantly increased by 3.2-fold (P <0.05) the number of cells recovered by bronchoalveolar lavage. The sEH inhibitor significantly decreased total bronchoalveolar lavage cell number by 37% in tobacco smoke-exposed rats with significant reductions noted in neutrophils, alveolar macrophages, and lymphocytes. A combination of sEH inhibitor and EETs was more significant in its ability to further reduce tobacco smoke-induced inflammation compared with the sEH inhibitor alone. The sEH inhibitor led to a shift in some plasma epoxides and diols that are consistent with the hypothetical action of these compounds. We conclude that an sEH inhibitor, in the presence or absence of EETs, can attenuate, in part, inflammation associated with acute exposure to tobacco smoke.

Animals↗

PubMed2004

Human cortical auditory motion areas are not motion selective.

The existence of a specialized mechanism supporting auditory motion processing in humans is a matter of debate in the psychophysical literature. Recent functional neuroimaging data appear to have resolved the debate in favor of a specialized motion system in that several studies have found cortical regions that seem to be motion selective. While all these studies contrast some form of moving auditory stimulation with a stationary stimulus, none have adequately controlled for the possibility that these areas are simply computing sound-source location and not motion per se: a moving stimulus varies in spatial location as well as motion, and so a system computing spatial location (and not motion) would be activated in response to both a moving and stationary sound source. To control for this possibility, ten subjects were scanned while listening to moving stimuli and while listening to stationary stimuli that varied randomly in spatial location. Consistent with previous imaging studies, we found that a motion stimulus when contrasted with rest (scanner noise) activated STG/planum temporale (bilaterally) and right parietal lobe. However, stationary stimuli presented at varying locations activated these regions equally well, arguing against the existence of specialized motion-processing areas in human cortex.

Acoustic Stimulation↗

PubMed2004

Gene Therapy: The Potential Applicability of Gene Transfer Technology to the Human Germline.

The theoretical possibility of applying gene transfer methodologies to the human germline is explored. Transgenic methods for genetically manipulating embryos may in principle be applied to humans. In particular, microinjection of retroviral vector appears to hold the greatest promise, with transgenic primates already obtained from this approach. Sperm-mediated gene transfer offers potentially the easiest route to the human germline, however the requisite methodology is presently underdeveloped. Nuclear transfer (cloning) offers an alternative approach to germline genetic modification, however there are major health concerns associated with current nuclear transfer methods. It is concluded that human germline gene therapy remains for all practical purposes a future possibility that must await significant and important advances in gene transfer technology.

Journal Article↗

PubMed2003

Word length modulates neural activity in auditory cortex during covert object naming.

Several lines of evidence show that posterior portions of left auditory cortex participate in aspects of speech production. A current hypothesis is that these regions play a specific role in processing phonological codes. We used event-related fMRI to test this hypothesis. Subjects covertly named objects that had names varying in length from one to four syllables. Behavioral data, both in previous work and in the present study, show an increase in naming reaction time as words get longer, reflecting the increase in phonological load. If left posterior auditory areas participate in phonological aspects of production, word length should modulate neural activity in this region. Object naming activated the left planum temporale in each subject, confirming previous findings of auditory cortex involvement in speech production. The timecourse of activation in this region showed a length effect, consistent with its hypothesized role in phonological processing. Similar effects were also observed in premotor cortex, but not in occipital-temporal cortex, which presumably supports visual processing of the pictures to be named.

Auditory Cortex↗

PubMed2003

Airborne particles of the california central valley alter the lungs of healthy adult rats.

Epidemiologic studies have shown that airborne particulate matter (PM) with a mass median aerodynamic diameter < 10 microm (PM10) is associated with an increase in respiratory-related disease. However, there is a growing consensus that particles < 2.5 microm (PM2.5), including many in the ultrafine (< 0.1 microm) size range, may elicit greater adverse effects. PM is a complex mixture of organic and inorganic compounds; however, those components or properties responsible for biologic effects on the respiratory system have yet to be determined. During the fall and winter of 2000-2001, healthy adult Sprague-Dawley rats were exposed in six separate experiments to filtered air or combined fine (PM2.5) and ultrafine portions of ambient PM in Fresno, California, enhanced approximately 20-fold above outdoor levels. The intent of these studies was to determine if concentrated fine/ultrafine fractions of PM are cytotoxic and/or proinflammatory in the lungs of healthy adult rats. Exposures were for 4 hr/day for 3 consecutive days. The mean mass concentration of particles ranged from 190 to 847 microg/m3. PM was enriched primarily with ammonium nitrate, organic and elemental carbon, and metals. Viability of cells recovered by bronchoalveolar lavage (BAL) from rats exposed to concentrated PM was significantly decreased during 4 of 6 weeks, compared with rats exposed to filtered air (p< 0.05). Total numbers of BAL cells were increased during 1 week, and neutrophil numbers were increased during 2 weeks. These observations strongly suggest exposure to enhanced concentrations of ambient fine/ultrafine particles in Fresno is associated with mild, but significant, cellular effects in the lungs of healthy adult rats.

Air Pollutants↗

PubMed2002

Inhibition of tobacco smoke-induced lung inflammation by a catalytic antioxidant.

Cigarette smokers experience airway inflammation and epithelial damage, the mechanisms of which are unknown. One potential cause may be free radicals either in tobacco smoke or produced during persistent inflammation. Inflammation may also be a driving force to cause airway epithelium to undergo changes leading to squamous cell metaplasia. To test whether tobacco smoke-induced inflammation could be reduced by a catalytic antioxidant, manganese(III)meso-tetrakis(N,N'-diethyl-1,3-imidazolium-2-yl) porphyrin (AEOL 10150) was given by intratracheal instillation to rats exposed to filtered air or tobacco smoke. Exposure to tobacco smoke for 2 d or 8 weeks (6 h/d, 3 d/week) significantly increased the number of cells recovered by bronchoalveolar lavage (BAL). AEOL 10150 significantly decreased BAL cell number in tobacco smoke-treated rats. Significant reductions in neutrophils were noted at 2 d and macrophages at 8 weeks. Lymphocytes were significantly reduced by AEOL 10150 at both time points. Squamous cell metaplasia following 8 weeks of tobacco smoke exposure was 12% of the total airway epithelial area in animals exposed to tobacco smoke without AEOL 10150, compared with 2% in animals exposed to tobacco smoke, but treated with AEOL 10150 (p <.05). We conclude that a synthetic catalytic antioxidant decreased the adverse effects of exposure to tobacco smoke.

Animals↗

PubMed2002

Gene transfer in higher animals: theoretical considerations and key concepts.

Gene transfer technology provides the ability to genetically manipulate the cells of higher animals. Gene transfer permits both germline and somatic alterations. Such genetic manipulation is the basis for animal transgenesis goals and gene therapy attempts. Improvements in gene transfer are required in terms of transgene design to permit gene targeting, and in terms of transfection approaches to allow improved transgene uptake efficiencies.

Animals↗

PubMed2002

A zwitterionic viologen disulfonate-hydroquinone charge-transfer crystal: 2,2'-(4,4'-bipyridinium-1,1'-diyl)di(ethanesulfonate)-hydroquinone (1/2).

The structure of the title compound, C(14)H(16)N(2)O(6)S(2).2C(6)H(6)O(2), consists of 2,2'-(4,4'-bipyridinium-1,1'-diyl)di(ethanesulfonate) molecules (with crystallographically imposed twofold symmetry) that are hydrogen bonded to each other, as well as to hydroquinone molecules, in a complex three-dimensional motif. The orange color of the crystals is indicative of the donor-acceptor interaction between the electron-rich hydroquinone pi-donor and the electron-deficient bipyridinium pi-acceptor. The dihedral angle between the bipyridyl planes is 38.31 (11) degrees. The distance from the centroid of one of the hydroquinone molecules to the center of the bipyridinium group is 3.653 (3) A, which is within the range typically observed for molecular complexes exhibiting charge-transfer characteristics.

Journal Article↗

PubMed2002

The role of sperm-mediated gene transfer in genome mutation and evolution.

Contradictory evidence surrounds the claim that sperm cells are able to introduce exogenous DNA into the oocyte at the time of fertilisation. Although strong natural barriers exist against sperm-mediated gene transfer, such barriers are unlikely to be absolutely inviolable. If sperm cells can act as vectors for exogenous DNA, it follows that the genome of sexually reproducing animals may be subject to alteration by exogenous DNA sequences carried by sperm cells. At present there are insufficient data to permit quantification of the rate of sperm-mediated gene transfer. The implications of sperm-mediated gene transfer are significant and include evolutionary effects on the mammalian genome and pathologies in humans from de novo mutations. Despite the absence of firm data, geneticists would be wise to be vigilant to the potential consequences of sperm-mediated gene transfer.

Animals↗

PubMed2002

Animal genetic manipulation--a utilitarian response.

I examine the process and outcomes of animal genetic manipulation ('transgenesis') with reference to its morally salient features. I consider several objections to transgenesis. I examine and reject the alleged intrinsic wrongness of 'deliberate genetic sequence alteration,' as I do the notion that transgenesis may lead to human genetic manipulation. I examine the alleged wrongness of killing inherent in transgenesis, and suggest that the concept of 'replaceability' successfully justifies such killing, although not for entities deemed to possess 'personhood.' I examine 'significant suffering' associated with transgenesis and propose the radical conclusion that, although it would be wrong to prohibit animal genetic manipulation per se, utilitarians ought to support a 'default prohibition' on transgenic experiments that entail significant suffering.

Animals↗

PubMed2002

Particle characteristics responsible for effects on human lung epithelial cells.

Some recent epidemiologic investigations have shown an association between increased incidence of respiratory symptoms and exposure to low levels of particulate matter (PM*) less than 10 microm or less than 2.5 microm in aerodynamic diameter (PM10 and PM2.5, respectively). If particulates are causally involved with respiratory symptoms, it is important to understand which components may be responsible. However, increasing evidence suggests that transition metals present in particles, especially iron, generate reactive oxygen species (ROS) that may be involved in producing some of the observed respiratory symptoms. The hypothesis for this study is twofold: bioavailable transition metals from inhaled airborne particulates catalyze redox reactions in human lung epithelial cells, leading to oxidative stress and increased production of mediators of pulmonary inflammation: and the size, transition metal content, and mineral speciation of particulates affect their ability to cause these effects. This work focused on the relation between physical characteristics of particles (eg, size, bioavailable transition metal content, and mineral speciation) and their ability to generate hydroxyl radicals in cell-free systems and to cause oxidative stress, which results in the synthesis of mediators of pulmonary inflammation in cultured human lung epithelial cells. These relations were studied by comparing size-fractionated, chemically characterized coal fly ash (CFA) produced by combustion of three different coals to obtain milligram quantities of ash. One transition metal, iron, was studied specifically because it is by far the predominant transition metal in CFA. In addition, smaller quantities of particles from gasoline engines, diesel engines, and ambient air were studied. Phosphate buffer soluble fractions from particles from all sources were capable of generating ROS, as measured by production of malondialdehyde (MDA) from 2-deoxyribose. This activity was inhibited over 90% for all particles by the metal chelator N-[5-[3-[(5-aminopentyl)hydroxycarbamoyl]propionamidol-pentyl]-3-[[5-(N-hydroxyacetamido)pentyl]carbamoyl]propionohydroxamic acid (desferrioxamine B, or DF), strongly suggesting that transition metal(s), probably iron, were responsible. Particles from coal or gasoline combustion had greater ability to produce ROS than particles from diesel combustion. Iron was mobilized by citrate (at pH 7.5) from particles of all sources tested; gasoline combustion particles were the only particles not analyzed for iron mobilization because there were not enough particles for the iron mobilization assay. CFA particles were size-fractioned; the amount of iron mobilized by citrate was inversely related to the size of particles and also depended on the source of coal. Iron from the CFA particles was responsible for inducing the iron-storage protein ferritin in cultured human lung epithelial cells (A549 cells). The amount of iron mobilized by citrate was directly proportional to the amount of ferritin induced in the A549 cells. Iron from the CFA was also responsible for inducing the inflammatory mediator interleukin (IL) 8 in A549 cells. Iron existed in several species in the fly ash, but the bioavailable iron was associated with the glassy aluminosilicate fraction, which caused ferritin and IL-8 to be induced in the A549 cells. In crustal dust, another component of urban particulates, iron was associated with oxides and clay but not with aluminosilicates. The crustal dust contained almost no iron that could be mobilized by citrate. Iron could be mobilized from diesel combustion particulates, but at a much lower level than for all other combustion particles. Samples of ambient PM2.5 collected in Salt Lake City over 5-day periods during one month varied widely in the amount of iron that could be mobilized. If bioavailable transition metals (eg, iron) are related to the specific biological responses outlined here, then the potential exists to develop in vitro assays to determine whether particulates of unknown composition and origin can cause effects similar to those observed in this study.

Air Pollutants↗

PubMedDate not supplied

Gene therapy: theoretical and bioethical concepts.

Gene therapy holds great promise. Somatic gene therapy has the potential to treat a wide range of disorders, including inherited conditions, cancers, and infectious diseases. Early progress has already been made in the treatment of a range of disorders. Ethical issues surrounding somatic gene therapy are primarily those concerned with safety. Germline gene therapy is theoretically possible but raises serious ethical concerns concerning future generations.

Adenoviridae↗