Genetic polymorphism of trimethylamine N-oxidation.
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Animals↗
Biomedical subjects
R L Smith
Publications and source records attributed to R L Smith.
Nodular mass in the anterior floor of the mouth.
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Aged↗
Development of mature microcystic lesions in the cochlear nuclei of the Mongolian gerbil, Meriones unguiculatus.
Microcystic lesions are a persistent final stage in a neurodegenerative disorder characteristic of the cochlear nuclei of gerbils. When gerbils of various ages raised under known acoustic conditions were examined, the volume density and number of lesions increased with age, however, the affected region was restricted to the posteroventral cochlear nucleus and adjacent portions of the dorsal cochlear nucleus, interstitial nucleus, and posterior anteroventral cochlear nucleus. Lesions were also noted in a separate locus in the auditory nerve trunk associated with the acoustic nerve nucleus. The fusiform and molecular layers of the dorsal cochlear nucleus were spared at all ages observed. The spherical cell region of the arteroventral cochlear nucleus was also largely spared. A good correlation was observed between the cumulative input from the auditory nerve fibers caused by the ambient acoustic environment acting over the life of the animal and the number of lesions in tonotopic subdivisions of the cochlear nuclei. The earliest microcysts formed in regions receiving auditory nerve fibers most strongly stimulated by the ambient noise. Thereafter, short exposures to higher levels of input or long exposures to lower levels of input were quantitatively equivalent in producing microcystic lesions.
Aging↗
Encoding of amplitude modulation in the gerbil cochlear nucleus: I. A hierarchy of enhancement.
The main goal of the present study was to investigate the encoding of a biologically-relevant acoustic feature--amplitude modulation (AM)--in single neurons of the auditory nerve and ventral cochlear nucleus (VCN). In the anesthetized gerbil auditory-nerve fibers and VCN units show strong synchronous responses to low-intensity, low-frequency AM. As frequency increases, the strength of the synchronous response decreases. In the auditory nerve the strength of the synchronous response is substantially less at high intensities than at low intensities and does not change significantly with AM frequency at high intensities. In contrast to the auditory nerve, VCN units show strong responses at high intensities. They have a particular AM frequency to which they are maximally responsive, and this frequency varies from unit to unit. Therefore, VCN units transform their ascending inputs by enhancing the synchronous response to AM. A correlation exists between a unit's ability to encode AM and its responses to simple sounds. Specifically, onset units show the strongest synchronous responses, followed in order by chopper, primarylike-with-notch and primarylike units. This enhancement is greatest at high intensities and can occur up to 90 dB above a unit's threshold. Thus, a hierarchy of enhancement for AM processing exists in the most peripheral nucleus of the central auditory system.
Acoustic Stimulation↗
Encoding of amplitude modulation in the gerbil cochlear nucleus: II. Possible neural mechanisms.
Rapid changes in sound amplitude--amplitude modulation (AM)--comprise an important feature of biologically-relevant sounds, including speech. In the companion paper, a hierarchy of enhancement for AM processing was demonstrated for unit types of the gerbil ventral cochlear nucleus (VCN) [Frisina, et al., Hear. Res. 44, 1990]. In the present report additional neurophysiological findings are presented as an initial test of alternative hypotheses of how VCN unit types amplify or enhance AM information, and how they accomplish this over a wide intensity range. These hypotheses invoke mechanisms such as off-CF excitatory or inhibitory inputs, input from high-threshold auditory-nerve fibers, amplification of residual AM responses of auditory-nerve fibers at high intensities, or post-synaptic cell feedback. From consideration of VCN unit response properties such as onset and steady-state rate-intensity functions, pure-tone tuning, and non-CF responses to AM, it is concluded that: Off-CF excitatory inputs do not play a significant role in VCN AM encoding; Off-CF inhibitory inputs could work in conjunction with one or more of the other proposed mechanisms to account for differential enhancement of AM by VCN neurons.
Action Potentials↗
Topically active carbonic anhydrase inhibitors. 3. Benzofuran- and indole-2-sulfonamides.
Derivatives of benzofuran- and indole-2-sulfonamide were prepared for evaluation as topically active ocular hypotensive agents. These compounds were found to be excellent inhibitors of carbonic anhydrase and to lower intraocular pressure in a rabbit model of ocular hypertension. However, the development of these compounds for clinical use was precluded by the observation that they cause dermal sensitization in guinea pigs. A correlation between electrophilicity, as assessed by in vitro reactivity with reduced glutathione, and dermal sensitization potential was further documented.
Administration, Topical↗
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 6. Trans-6-[2-(substituted-1-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones.
A variety of trans-6-[2-(substituted-1-naphthyl)ethyl(or ethenyl)]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-ones were prepared and, upon conversion to their 3,5-dihydroxy carboxylates, were found to have good inhibitory activity against the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-determining enzyme in cholesterogenesis. The most active compounds are 2,4,6- and 2,4,7-trichloro derivatives and would be expected to display about the same potency as the standard compactin upon resolution.
Chemical Phenomena↗
L-662,583 is a topically effective ocular hypotensive carbonic anhydrase inhibitor in experimental animals.
1. L-662,583 was a potent inhibitor in vitro of purified, human erythrocyte carbonic anhydrase II, possessing an IC50 of 0.7 nM. The IC50 values for MK-927, acetazolamide and methazolamide were 13.0 nM, 10.8 nM and 21.2 nM, respectively. 2. A 1 h pretreatment with one 50 microliters drop of a 0.1% solution of L-662,583 blocked carbonic anhydrase activity in a homogenate of the iris + ciliary body of albino rabbits by 63%. Similar treatment with 0.1% suspensions of acetazolamide and methazolamide elicited inhibitions of 30% and 20%, respectively. This ex vivo model indirectly assesses the ability of an agent to enter the rabbit eye. 3. Concentrations of L-662,583 in the cornea, aqueous humour and iris + ciliary body of albino rabbits were determined by h.p.l.c. at predetermined times after the instillation (one drop of 50 microliters) of a 2% solution of L-662,583. Peak levels for cornea (47.4 micrograms g-1), aqueous humour (4.51 micrograms ml-1) and iris + ciliary body (9.61 micrograms g-1) occurred at 0.5, 2 and 1 h after instillation, respectively. 4. The experimentally elevated intraocular pressure of the right eye of rabbits, induced by prior intraocular injection of alpha-chymotrypsin, was maximally decreased by 4.5 mmHg, 6.2 mmHg and 9.8 mmHg after the instillation (one drop of 50 microliters) of 0.01%, 0.1% and 0.5% solutions of L-662,583, respectively. All three concentrations lowered intraocular pressure at all time points from 1 h up to and including 5 h, the last recorded time point. The unilateral instillation of L-662,583 (0.5%) into the contralateral, left eye failed to lower the elevated intraocular pressure of the untreated, right eye. This finding indicates that the site of action of topically applied L-662,583 in this paradigm is local. The ocular normotensive, albino rabbit was much less susceptible than the ocular hypertensive rabbit to the intraocular pressure lowering effect of topically applied L-662,583, with a 2% solution maximally decreasing intraocular pressure by 2.3 mmHg. 5. Unilateral ocular hypertension was elicited in the right eye of sedated, cynomolgus monkeys by argon laser-induced photocoagulation of the trabecular meshwork. The instillation (one drop of 50 microL) of L-662, 583 (2%) significantly lowered the elevated intraocular pressure of the right eye at all time points from 1 h up to and including 5 h. The maximum decline was 8.3 mmHg at 3 h and this represented a reduction of 23% from the corresponding baseline value of 36.8 mmHg. The intraocular pressure of the hypertensive, right eye was maximally decreased by 4.1 mmHg and 4.8 mmHg after the instillation of 0.5% and 1% solutions of L-662,583, respectively. Like the rabbit, the normotensive eye of cynomolgus monkeys was more resistant than the hypertensive eye to the ocular hypotensive action of L-662, 583, as indicated by the inability of 0.5% and 1% solutions of the agent to lower intraocular pressure. L-662,583 (2%) maximally reduced the intraocular pressure of normotensive monkey eyes by 2.4 mmHg at 2 h. 6. L-662,583 is structurally different from MK-927, a carbonic anhydrase inhibitor that lowers the intraocular pressure of glaucoma patients following the instillation of a 2% solution. These preclinical observations indicate that L-662,583, like MK-927, is a water-soluble carbonic anhydrase inhibitor which, on topical administration, lowers intraocular pressure by virtue of an action confined to within the eye.
Administration, Topical↗
Control of nitrogenase recovery from oxygen inactivation by ammonia in the cyanobacterium Anabaena sp. strain CA (ATCC 33047).
The control of nitrogenase recovery from inactivation by oxygen was studied in Anabaena sp. strain CA (ATCC 33047). Nitrogenase activity (acetylene reduction) in cultures grown in 1% CO2 in air was inhibited by exposure to 1% CO2-99% O2 and allowed to recover in the presence of high oxygen tensions. Cultures exposed to hyperbaric levels of oxygen in the presence of 10 mM NH4NO3 were incapable of regaining nitrogenase activity, whereas control cultures returned to 65 to 80% of their original activity within about 3 h after exposure to high oxygen tension. In contrast to the regulation of heterocyst differentiation and nitrogenase synthesis, recovery from oxygen inactivation in this organism was shown to be under the control of NH4+ rather than NO3-.
Ammonium Chloride↗
Influence of cavosurface configuration and composite resin type on impact fracture resistance of Class IV restorations.
The fracture behaviours of intact maxillary central incisor teeth, and teeth restored by five different composite resins utilising uninstrumented fractured etched margins and bevelled etched margins, were determined by a pendulum impact method. It was established that: 1. Intact teeth fractured in a predictable manner when struck by a pendulum hammer at predetermined points on the labial surfaces close to incisal angles. 2. The impact resistance of teeth with bevelled margin restorations was significantly greater than that of teeth restored using the uninstrumented fractured margins. 3. Differences in impact resistance between intact teeth and teeth restored with bevelled margins were not significant. 4. There was no significant difference in fracture energy between any of the composite resin materials in either the uninstrumented joint or bevelled joint modes. 5. For all restorations placed on uninstrumented margins, the fracture paths were at or near the adhesive interface; no restorations failed cohesively. 6. Fracture paths in the bevelled joint mode were variable, with fracture occurring either entirely in enamel, or entirely in composite resin, or at the interface.
Acrylic Resins↗
Nerve growth factor-dependence of herpes simplex virus latency in peripheral sympathetic and sensory neurons in vitro.
Previously, we reported that nerve growth factor (NGF) is required to maintain herpes simplex virus (HSV) latency in cultures of rat sympathetic neurons (Wilcox and Johnson, 1987, 1988). Here, we extend these results by showing that NGF was also required to maintain HSV latency in cultures of sensory neurons obtained from dorsal root ganglia of rats, monkeys, and humans. The interruption of the neuronal supply of NGF for 1 hr reactivated HSV, indicating that the latent virus was exquisitely sensitive to perturbations in the concentration or binding of NGF. A species-specific monoclonal antibody directed against the human NGF-receptor, which blocks NGF binding, reactivated latent HSV in human, but not rat, sensory neurons. In contrast, a monoclonal antibody against the rat NGF-receptor, which binds the receptor without blocking NGF action, did not produce reactivation. These results indicate that the effects of NGF on HSV latency are mediated via NGF binding to the NGF receptor. In addition, treatments that interfere with specific steps in the transduction of the NGF signal, including treatment with 6-hydroxydopamine and colchicine, reactivated latent HSV. Further, in neurons harboring latent virus, interruption of protein synthesis or RNA transcription for 1 hr resulted in viral reactivation, suggesting that a short-lived factor may be present in neurons which represses viral reactivation.
Animals↗
Adaptation of brain 5HT2 receptors after mianserin treatment: receptor sensitivity, not receptor binding, more accurately correlates with behavior.
This study investigates the possibility that mianserin, a serotonin-2 (5HT2) receptor antagonist, produces a prolonged antagonism of quipazine discrimination, consistent with its prolonged biochemical effects. Rats were trained on a saline-quipazine (1.5 mg/kg) discrimination; following acquisition, the animals were assigned to groups and given injections of 2.0 mg/kg mianserin. Individual groups were tested at 45 min and successive 12-hr intervals for their ability to discriminate 0.75 mg/kg of quipazine, a dose that elicited 75% responding on the quipazine lever. Blockade of the quipazine cue persisted for 48 hr following mianserin administration. The above procedure was replicated using lower doses of mianserin (0.25, 0.10 and 0.05 mg/kg) and two other 5HT2 antagonists, pizotifen and metergoline (2.0 mg/kg), both of which showed similar profiles of extended antagonism. Changes in both receptor density and receptor sensitivity were investigated as possible mechanisms of mianserin's prolonged activity. Analysis of [3H]ketanserin binding revealed that a single 2.0-mg/kg dose of mianserin produced a significant decrease in the number of receptor sites (44%) 24 hr after treatment; however, this loss of sites recovered by 36 hr post-injection and could therefore not account for mianserin's continued antagonism at this and later times. 5HT-mediated phosphoinositide hydrolysis in cerebral cortex slices was used as a measure of 5HT2 receptor sensitivity. Treatment of rats with 2 mg/kg of mianserin caused a marked reduction in the maximum phosphoinositide response to 5HT that persisted for up to 36 hr. Hence, the time course for recovery of 5HT2 receptor sensitivity corresponded more closely to behavioral recovery than did 5HT2 receptor binding.
Animals↗
Soluble mediators of articular cartilage degradation in juvenile rheumatoid arthritis.
Juvenile rheumatoid arthritis (JRA) involves a wide range of joint tissues. Tissue changes include proliferation of synovial cells, alterations in synovial fluid, and degradation of articular cartilage. Synovial cell proliferation results in increased numbers of fibroblasts and lymphocytes. Changes in the synovial fluid include increased content of antibodies, altered complement ratios, increased levels of factors stimulating cartilage-mediated proteoglycan degradation, and decreased levels of insulinlike growth factor I. Levels of cytokine such as interleukin-1 and interleukin-2 vary with cell culture and assay technique. Cartilage degradation is apparent from increased quantities of proteoglycan and glycosaminoglycan in serum and synovial fluid. Type II collagen peptide antibodies are also prevalent in JRA patients. Cartilage degradation appears linked to factors in JRA synovial fluid. Conditioned medium of peripheral blood mononuclear cells from patients with JRA also stimulates increased release of cartilage proteoglycan. Thus, the outcome in JRA likely reflects activities of interacting soluble factors that directly influence cartilage homeostasis.
Arthritis, Juvenile↗
Foveal regions of bird retinas correlate with the aster of the inner nuclear layer.
A radiate specialization, the aster, has been found in whole-mount retinas of birds and is associated to each one of the temporal and nasal fovea, with the one related to the convexiclivate nasal fovea more evident. This radial arrangement extends uniformly in all directions from the foveal pit. Transverse sections of the retina show that this structure is formed by bands of cells and bundles of fibers from the inner nuclear layer.
Animals↗
Growth hormone stimulates insulin-like growth factor I actions on adult articular chondrocytes.
We report effects of adding insulin-like growth factor I (IGF-I) and methionyl human growth hormone (GH), alone or in combination, to adult bovine articular chondrocytes plated at high density. Purified human and synthetic IGF-I stimulated chondrocyte DNA and proteoglycan synthesis. GH had no effect on either process. However, GH added in combination with IGF-I increased proteoglycan, cell-associated proteoglycan, and keratan sulfate synthesis over levels observed with IGF-I alone. IGF-I and GH did not alter the hydrodynamic size of proteoglycans or synthesis of collagen. Our results show that GH and IGF-I act together to stimulate adult chondrocyte extracellular matrix synthesis.
Animals↗
Trimethylaminuria: the detection of carriers using a trimethylamine load test.
A method potentially of value for investigating putative heterozygotes or carriers of trimethylaminuria by using a single oral dose of trimethylamine (TMA) is described. For healthy volunteers under normal dietary condition and following oral challenge with 300 mg and 600 mg TMA-base, over 90% of the urinary TMA was excreted in the form of TMA (93.6 +/- 1.6%). However, at a dose level of 900 mg TMA-base, there was clear evidence of saturation of the N-oxidation reaction as urinary TMA excretion declined to 77.2% (range 74.8-78.9) of the total dose of TMA. By contrast, in pedigree studies based upon propositi with trimethylaminuria, several parents were identified who showed clear evidence of saturation of the N-oxidation of TMA at the 600 mg TMA-base dose level, but not at 300 mg TMA-base or under normal dietary condition. In these individuals, the proportion of urinary TMA as trimethylamine N-oxide (TMAO) declined to (77.3 +/- 1.7%). Accordingly we propose that the oral administration of 600 mg TMA-base and the analysis of the following 0-8-h urine collection may be useful for the investigation of possible carriers of trimethylaminuria.
Administration, Oral↗
Blood pressure during induction and termination of the dorsal immobility response.
Evidence has indicated that afferent baroreceptor input may play a role in the induction of the dorsal and tonic immobility responses, which are behaviorally similar, but involve opposite posture changes upon induction (i.e., upright versus inverted, respectively). Information is lacking on the topography of the blood pressure response during periods of dorsal immobility. The blood pressure response of the adult Wistar rat during induction and termination of dorsal immobility was compared to the blood pressure response during a condition which controlled for posture change. Each animal received two control trials, ten dorsal immobility trials and then two control trials in two successive sessions four and ten days after surgery. A precise second-by-second topographical analysis of the dorsal immobility response revealed a sharp rise in blood pressure at trial onset of 18.4 mmHg, followed by a return below pretrial levels and then subsequent recovery back to pretrial levels by the tenth-trial second. This level was maintained until the last five seconds of immobility when a rapid blood pressure elevation occurred. This terminating elevation correlated highly with the observation of large movement and probably reflected motor activity that eventually culminated in escape from immobility. The vertical posture change of the control condition, on the other hand, resulted in a gradual diminution of blood pressure, which implied that the initial blood pressure elevation during initiation of the dorsal immobility response could not be accounted for simply by posture change.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗