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Biomedical subjects

S S Smith

Publications and source records attributed to S S Smith.

At least 55 records · Page 3Linked to original sources
PubMed1998

Estrous hormones enhance coupled, rhythmic olivary discharge in correlation with facilitated limb stepping.

Synchronized oscillatory behaviour of neurons within the dorsal accessory olive of the rat were monitored across spontaneous changes in rapid, co-ordinated limb movements associated with the estrous (hormone) and circadian cycles as well as following local administration of estradiol. Facilitation of rapid alterations in limb movement is observed following increases in circulating estradiol and progesterone on the night of behavioural estrus, as assessed by the ability of a rat to maintain a consistent position on a treadmill in response to variable changes in acceleration. Synchronized olivary activity was determined using chronically implanted bundles of microwires (50 microns diameter) to record from as many as 23 individual olivary neurons simultaneously across several four to five day estrous cycles, and in some cases after injection of the estrous hormones, estradiol and/or progesterone, either by systemic or local administration. Rats were tested during non-movement, constant speed locomotion or using a variable acceleration paradigm. Olivary oscillations were most commonly observed during treadmill locomotion with variable changes in acceleration. Local administration of estradiol, in combination with systemic progesterone administration, enhanced rhythmic olivary oscillations during this paradigm. At this time, at least a six-fold increase in the size of the coupled cluster of rhythmically discharging olivary neurons was observed compared with values obtained on diestrus, a low hormone state. Similar facilitating effects on olivary oscillations were observed on estrus, or following systemic injection of both estrous hormones. Administration of either steroid alone was not as effective. During the dark phase of the light:dark cycle, the oscillatory behaviour of these neurons was enhanced more than five-fold than during the light phase, and coupling diameter was maximal on the night of behavioural estrus. The synchronized oscillatory discharge of neurons within the olive is a putative timing mechanism which may underlie hormone-associated facilitation of rapid limb movements. The results from the present study provide evidence that both hormonal and circadian factors can enhance olivary rhythmicity in association with behavioural rhythmicity.

Acceleration↗
PubMed1998

Step cycle-related oscillatory properties of inferior olivary neurons recorded in ensembles.

This study was conducted to characterize patterns of discharge from the dorsal accessory olive during different behavioural states. To accomplish this goal, adult rats were chronically implanted with arrays of microwires (25-50 microns) to record from as many as 23 neurons from the dorsal accessory olive bilaterally during locomotor paradigms or at rest. Olivary neurons discharged sporadically at low firing frequencies (1-5 Hz) when the rat was at rest. However, during locomotor paradigms involving constant speed treadmill locomotion, olivary neurons discharged rhythmically at frequencies which closely matched step cycle frequencies. The rhythmic nature of olivary discharge was maintained even during brief periods of inconsistent gait. During treadmill locomotion utilizing variable acceleration/deceleration paradigms olivary neurons discharged at 3 Hz frequencies. Electrical stimulation of peripheral afferents resulted in rhythmic discharge of olivary neurons at frequencies harmonic with the rate of stimulation. These data suggest that oscillatory patterns of discharge exhibited by the inferior olivary nucleus are only seen during rhythmic behavioral tasks or stimulation paradigms. Further, the dissociation between the rhythmic nature of the task and the continued oscillation suggests that oscillatory activity of the inferior olive may be due both to an intrinsic rhythm as well as related to ongoing sensorimotor input.

Animals↗
PubMed1998

Differential white cell count after two bouts of downhill running.

The purpose of this study was to compare blood markers associated with eccentrically biased exercise and muscle damage, after two bouts of downhill running. Nine active, untrained males performed 2 x 45 min bouts of downhill running (-0.16 radians), at a speed that would elicit 70% of each subjects VO2max, on a level grade; runs were spaced 14d apart (RUN1, RUN2). Blood samples were obtained before, after, and every hour for 12 h after exercise, as well as every 24 h for 5 d, to assess numbers of circulating neutrophils, monocytes, and lymphocytes, serum cortisol, creatine kinase (CK); subjective sensations of delayed onset muscle soreness (DOMS) were monitored. To control for diurnal variation, two weeks prior to the RUN1, subjects had blood draws performed at the same time as would occur after exercise, but did no exercise (CONTROL). During the 5 d after exercise, DOMS and CK were significantly greater (p < 0.05) after RUN1 compared to RUN2 and CONTROL. During the 12 h after RUN1 and RUN2, neutrophils showed similar responses compared to CONTROL. However, neutrophils were significantly elevated at 96 h after RUN1 and 24 h after RUN2. Monocytes were significantly elevated during 5-11 h after RUN1 and RUN2, compared to CONTROL. Cortisol showed a similar significant diurnal decrease for all three conditions during the 12 h following exercise. The significantly lower levels of CK and DOMS seen after RUN2, compared with the initial run is consistent with the literature. The similar changes in neutrophils and monocytes during the 12 h following RUN1 and RUN2, followed by disparate responses over the subsequent 5 d, requires further investigation.

Adult↗
PubMed1998

Does over-the-counter nicotine replacement therapy improve smokers' life expectancy?

OBJECTIVE: To determine the public health benefits of making nicotine replacement therapy available without prescription, in terms of number of quitters and life expectancy. DESIGN: A decision-analytic model was developed to compare the policy of over-the-counter (OTC) availability of nicotine replacement therapy with that of prescription ([symbol: see text]) availability for the adult smoking population in the United States. MAIN OUTCOME MEASURES: Long-term (six-month) quit rates, life expectancy, and smoking attributable mortality (SAM) rates. RESULTS: OTC availability of nicotine replacement therapy would result in 91,151 additional successful quitters over a six-month period, and a cumulative total of approximately 1.7 million additional quitters over 25 years. All-cause SAM would decrease by 348 deaths per year and 2940 deaths per year at six months and five years, respectively. Relative to [symbol: see text] nicotine replacement therapy availability, OTC availability would result in an average gain in life expectancy across the entire adult smoking population of 0.196 years per smoker. In sensitivity analyses, the benefits of OTC availability were evident across a wide range of changes in baseline parameters. CONCLUSIONS: Compared with [symbol: see text] availability of nicotine replacement therapy, OTC availability would result in more successful quitters, fewer smoking-attributable deaths, and increased life expectancy for current smokers.

Adult↗
PubMed1998

Stalling of DNA methyltransferase in chromosome stability and chromosome remodelling (Review).

As a consequence of their mechanism of action, DNA (cytosine-5) methyltransferases from both prokaryotes and eukaryotes necessarily recognize mispaired bases in unusual DNA structures as catalytic transition-state analogs. A review of the available data suggests that the enzymes are designed to stall at these sites because they are unable to release substrates or products that are fixed in a conformation resembling the transition state. The enzymes can operate by a two-step process in which they first methylate extrahelical cytosines satisfying their recognition requirements and subsequently stall at the site of methylation. On RNA and DNA RNA hybrids they may operate by a similar one-step process in which they stall at transition-state analogs without methylating cytosine moieties. These natural capacities suggest that the enzymes may physically participate in stable nucleoprotein assemblies formed as components of normal chromatin structure or as intermediates in the repair of unusual structures. The methyltransferases, themselves, may physically participate in chromosome remodelling as part of a mechanism of inactivation or imprinting by stabilizing RNA DNA hybrids or RNA RNA secondary structure involving cis-acting untranslated RNAs like the product of the Xist gene. Methyl-transferase may physically participate in the repair of certain unusual structures by serving as a nucleation point. The affinity for secondary structure in nucleic acids may account for the spreading of DNA methylation patterns. Titration of host methyltransferase by RNA DNA hybrids and RNA secondary structure formed during retroviral replication in certain tumorigenic retroviruses, like MMTV, may account for global hypomethylation observed in retrovirally transformed cells. In a similar fashion, titration of methyltransferase by secondary structures associated with chromosome instability may account for global hypomethylation observed in association with local hypermethylation in tumorigenesis.

Animals↗
PubMed1997

Stalling of human methyltransferase at single-strand conformers from the Huntington's locus.

We describe evidence for a sequence of events in which the Human DNA(cytosine-5)methyl-transferase first methylates spontaneous single-stranded conformers (SSCs) and then stalls at the methylated site to produce a complex with the conformationally unusual DNA. This property of the enzyme is a result of its ability to respond to a general loss of symmetry at its CG recognition site. The data suggest that DNA methyltransferase, itself, may physically participate in biological processes that distinguish between DNA that is in the normal Watson-Crick paired conformation and DNA that is conformationally unusual (e.g. a hairpin loop or misassembled replication intermediate). The in vitro methylation of spontaneous SSCs from the Huntington's locus illustrates the phenomenon.

Amino Acid Sequence↗
PubMed1997

Nucleoprotein-based nanoscale assembly.

A system for addressing in the construction of macromolecular assemblies can be based on the biospecificity of DNA (cytosine-5) methyltransferases and the capacity of these enzymes to form abortive covalent complexes at targeted 5-fluorocytosine residues in DNA. Using this system, macromolecular assemblies have been created using two representative methyltransferases: M-HhaI and M x MspI. When 5-fluorocytosine (F) is placed at the targeted cytosine in each recognition sequence in a synthetic oligodeoxynucleotide (GFGC for M x HhaI or FCGG for M x MspI), we show that the first recognition sequence becomes an address for M x HhaI, while the second sequence becomes an address for M x MspI. A chimeric enzyme containing a dodecapeptide antigen linked to the C terminus of M-HhaI retained its recognition specificity. That specificity served to address the linked peptide to the GFGC recognition site in DNA. With this assembly system components can be placed in a preselected order on the DNA helix. Axial spacing for adjacent addresses can be guided by the observed kinetic footprint of each methyltransferase. Axial rotation of the addressable protein can be guided by the screw axis of the DNA helix. The system has significant potential in the general construction of macromolecular assemblies. We anticipate that these assemblies will be useful in the construction of regular protein arrays for structural analysis, in the construction of protein-DNA systems as models of chromatin and the synaptonemal complex, and in the construction of macromolecular devices.

Base Sequence↗
PubMed1997

Approach and avoidance motivation in psychopathic criminal offenders during passive avoidance.

The authors evaluated competing theories that attribute psychopathic individuals' poor passive avoidance to a strong activating system, a weak inhibitory system, or poor modulation of behavioral activation when inhibitory cues appear. In Study 1, the continuous motor task involved a reward phase to elicit the activating system followed by a passive avoidance phase. Study 2 tested the generality of the theories by using an active avoidance phase to elicit the activating system. Heart rate and response speed results from Study 1 best supported the strong activating system and poor response modulation models in low-anxiety psychopathic offenders. Study 2 results did not clearly support any of the models. Further research is needed to determine if excessive activation by reward and poor response modulation are associated with passive avoidance deficits and other characteristics of low-anxiety psychopathic offenders.

Adult↗
PubMed1997

Neuropsychological function in restrained versus unrestrained motor vehicle occupants who suffer closed head injury.

It is known that using seatbelts reduces the incidence and severity of closed head injury (CHI) from motor vehicle crashes. One would expect unrestrained occupants in motor vehicle crashes to suffer more severe CHIs than restrained occupants, as reflected by Glasgow Coma Scale (GCS) scores. One might also expect an increased risk of focal injury due to contact forces in unrestrained occupants. The purpose of this study was to test the hypothesis that failure to use seatbelts results in increased severity of neuropsychological sequelae, even with GCS controlled. We also examined the impact of demographic variables on seatbelt use. Subjects included patients admitted to a hospital trauma service who were suspected of having suffered CHI. All patients completed neuropsychological testing, which was entered into a data base along with demographic and clinical information. People who had documented use of seatbelt restraints were compared with those who were unrestrained. Results confirmed that certain demographic variables are associated with the use of seatbelts. Results also suggested that failure to use seatbelt restraints is associated with more severe impairment on tests that are sensitive to frontal lobe dysfunction.

Adolescent↗
PubMed1997

CFTR activation: additive effects of stimulatory and inhibitory phosphorylation sites in the R domain.

To investigate the functional significance of individual consensus phosphorylation sites within the R domain of cystic fibrosis transmembrane conductance regulator (CFTR), serines were eliminated by substituting them with alanine. Included in this analysis were serine-660, -670, -686, -700, -712, -737, -768, -795, and -813, which lie within protein kinase A consensus sequences, and serine-641, which does not. Elimination of single potential phosphorylation sites altered the sensitivity of CFTR (expressed in Xenopus oocytes) to activating conditions in a manner that was highly site dependent. Substitution at serine-660, -670, -700, -795, or -813 significantly increased the half-maximal activation constant (KA) for activation by 3-isobutyl-1-methylxanthine, which is consistent with the hypothesis that phosphorylation at any of these sites promotes CFTR activation. The effect of substitution at serine-813 was significantly greater than at the other sites. In contrast, alanine substitution at serine-737 or -768 actually decreased the KA for activation, suggesting that phosphorylation at either of these sites is inhibitory. Substitution at serine-641, -686, and -712 had no significant effect on activation sensitivity. The effects of multiple serine to alanine substitutions were consistent with the notion that phosphorylation at individual sites produced roughly additive effects, suggesting that the effect produced by phosphorylation of any one serine was not dependent on the phosphorylation state of other serines. These results are consistent with the notion that, although none of the phosphorylation sites studied here are absolutely necessary for activation of CFTR, individual sites contribute differently to the gating of the channel.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Cerebellar nitric oxide synthase is expressed within granule cell patches innervated by specific mossy fiber terminals: a developmental profile.

The nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) staining technique was utilized as a marker of nitric oxide synthase (NOS) to map NOS expression in developing and adult rat cerebellum. NADPH-d-positive cells were first visualized in the cerebellar cortex at postnatal day 5 (PND5) which increased to peak levels by PND30 when they began to exhibit a patch-like organization. In order to determine the relationship of the NADPH-d staining pattern with mossy fiber innervation, mossy fiber projections were traced using cholera toxin B subunit or biocytin injected into the lateral reticular nuclei (LRtN) or pontine nuclei (PtN), respectively. Double staining revealed that the clustered mossy fiber terminals projecting from the ventrorostral LRtN and caudal PtN were well matched with NADPH-d-stained patches. This patch-like localization of NOS matched with specific mossy fiber terminals in adult cerebellum implicates these NOS patches as defining distinct anatomical zones.

Afferent Pathways↗
PubMed1997

Intracellular ion concentrations and their maintenance by Na+/K(+)-ATPase in preimplantation mouse embryos.

We have measured the amounts of Na+, K+ and C- in preimplantation mouse embryos (1-cell, 2-cell and morula) using electron probe X-ray microanalysis. The levels of these ions do not vary much over this period, and are approximately the same as those found in other mammalian cells, contrary to previous reports. We have confirmed that preimplantation embryos exhibit Na+/K(+)-ATPase activity at all stages examined, and have shown that the ATPase maintains high K+/Na+ ratios (12-16) in all these embryonic stages, comparable to those seen in other healthy cells; this is in contrast to the low ratios reported in earlier work. Inhibition of the Na+/K(+)-ATPase results in the slow exchange of intracellular K+ for extracellular Na+ (half-time approximately 5 h), indicating that Na+/K(+)-ATPase activity maintains steep Na+ and K+ gradients in preimplantation mouse embryos as it does in most other cells.

Amiloride↗
PubMed1996

Stoichiometry of subunits and heme content of hemoglobin from the earthworm Lumbricus terrestris.

The extracellular hemoglobin (Hb) of the earthworm, Lumbricus terrestris, has four major O2-binding chains, a, b, c (forming a disulfide-linked trimer), and d ("monomer"). Additional structural chains, "linkers," are required for the assembly of the approximately 200-polypeptide molecule. The proportion of linker chains had been reported to be one-third of the total mass on the basis of densitometry of Coomassie Blue-stained SDS-gels. Reverse-phase high performance liquid chromatography (HPLC), however, gave 16.3% linkers on the basis of both 220-nm absorbance and amino acid analysis (Ownby, D. W., Zhu, H., Schneider, K., Beavis, R. C., Chait, B. C., and Riggs, A. F. (1993) J. Biol. Chem. 268, 13539-13547). The subunit proportions have now been redetermined by SDS capillary electrophoresis as a test of the HPLC results. The electrophoresis, monitored at 214 nm, avoided the use of Coomassie Blue and provided results identical with those obtained by HPLC. Capillary electrophoresis monitored at both 214 and 415 nm was used to show that linker chains do not bind heme. Heme content has been found to be 2.9% by determination of hemin, amino acid analysis and dry weight. Measurement of the rate of hemin loss from oxidized L. terrestris Hb shows that high rates of loss can account for values of heme content significantly below 2.9% (or 0.26% iron).

Animals↗
PubMed1996

The estrous cycle and the olivo-cerebellar circuit. I. Contrast enhancement of sensorimotor-correlated cerebellar discharge.

Neuromodulation of Purkinje (Pnj) cell responses by monoamines and estrous hormones is well characterized in the cerebellum at the cellular level, but not at the level of neuronal circuits in the awake behaving animal. In the present study, simultaneous recordings of up to 16 single neurons from within the olivo-cerebellar circuit were obtained through chronically implanted microwire electrode bundles: arrays of Pnj cell like neurons (Pnj cln) in the paravermal cerebellum and neurons within the afferent source of its climbing fiber input, the rostral dorsal accessory olive (rDAO), were recorded simultaneously across 3-20 consecutive estrous cycles during constant or variable speed treadmill locomotion performance tasks. Over 90% of Pnj cln recorded during treadmill locomotion exhibited significant increases (80%) or decreases (10%) in activity correlated with the stance phase of locomotion. In contrast, cells from the rDAO increased activity during speed changes or when the rat failed to maintain the treadmill speed (position slip). On the night of behavioral estrus, which is triggered by elevations in circulating levels of 17 beta-estradiol and progesterone, the magnitude of both increases and decreases in stance-correlated Pnj cln activity increased by 85-115%. These results are consistent with our previous findings that 17 beta-estradiol and progesterone enhance excitatory and inhibitory responses of single Pnj cells to locally applied glutamate and GABA, respectively. This dual enhancement of both excitatory and inhibitory effects, apparently paradoxical at the cellular level, produced a marked heightening of the contrast of the neural population "signal" at the neuronal ensemble level. Furthermore, the stance-correlated discharge of Pnj cln during estrus preceded that during diestrus by approximately 120 ms. Frame-by-frame video analysis also suggested that the swing phase of the step cycle was shortened on estrus compared with diestrus (low hormone state). In addition, rDAO discharge correlated with speed change or position slip was also significantly increased (P < 0.05) on the night of behavioral estrus versus diestrus. Thus, estrus was associated with changes in both the amplitude and the timing of Pnj cln and rDAO discharge correlated with specific behavioral events. These estrous-associated changes in Pnj cell activity were well correlated (r = 0.84) with faster responses to random changes in treadmill speed, a motor performance task. Together, these findings suggest that the increases in the contrast of stance-correlated Phj cln discharge observed following peak circulating levels of sex steroid hormones are associated with improved motor performance on a randomly moving treadmill.

Animals↗
PubMed1996

The estrous cycle and the olivo-cerebellar circuit. II. Enhanced selective sensory gating of responses from the rostral dorsal accessory olive.

This study demonstrates that gating of responses of the rostral dorsal accessory olive (rDAO) to somatosensory stimulation varies across the estrous hormone cycle of the rat. The rDAO has been suggested as an "error" or event signal generator for the cerebellar cortex. Selective sensory gating of input to this structure may underlie this error signalling function. In the present study, as many as 23 single neurons were recorded simultaneously from either the forepaw or the snout areas of the rDAO. Responses of these neurons to electrical stimulation of peripheral afferents were determined during active movement or non-movement conditions. These results were then compared across the estrous cycle or after administration of the estrous hormones 17 beta-estradiol (E2) and/or progesterone (P) to rats on diestrus or following E2 priming. Elevations in circulating estrous hormones produced greater excitatory responses of rDAO neurons to stimulation during non-movement, and, conversely, enhanced inhibition of rDAO activity during active movement of the stimulated peripheral area compared with control diestrous conditions, suggesting that selective gating processes to the rDAO are enhanced by estrous hormones. The results of this study suggest that the night of behavioral estrus is associated with enhanced selective sensory gating processes associated with improved detection and processing of error signals.

Animals↗
PubMed1996

Characterization of tobacco withdrawal symptoms: transdermal nicotine reduces hunger and weight gain.

The accurate assessment of both tobacco withdrawal and the impact of the nicotine patch on withdrawal may be compromised by attrition of subjects, or by subjects smoking during withdrawal. To reduce these occurrences, 211 participants were provided with intensive cessation counseling while trying to quit smoking with either nicotine (21 mg) or placebo transdermal patches. Subject attrition was low, with 80.5% of participants continuing through the 5-week study period. Abstinence rates were also high over this period (75% and 61% in active and placebo groups, respectively). In this multisite, double-blind trial, withdrawal severity was assessed using a nine-item daily self-report questionnaire, and abstinence was confirmed via CO monitoring. Abrupt smoking cessation increased multiple tobacco withdrawal symptoms/signs including craving for cigarettes, irritability, anxiety, appetite, sleep disruption, difficulty concentrating, restlessness, depression, and impatience. Treatment with transdermal nicotine reduced craving for cigarettes, anxiety, irritability, and appetite, as well as weight gain (1.85 versus 2.88 kg mean gain over 4 weeks in active and placebo groups, respectively).

Administration, Cutaneous↗
PubMed1996

Pediatric great vessel anomalies: initial clinical experience with spiral CT angiography.

PURPOSE: To evaluate the use of spiral computed tomographic (CT) angiography for the diagnosis of pediatric great vessel anomalies. MATERIALS AND METHODS: Techniques used in adult CT angiography were modified to allow imaging of 15 children aged 1 month to 12 years. Two-dimensional axial images and three-dimensional shaded surface display images of the airway and great vessels were generated from volumetric CT data and evaluated prospectively. Findings were correlated with results obtained at surgery (five patients), autopsy (one patient), bronchoscopy (one patient), or other imaging studies (eight patients). RESULTS: In 14 patients, CT angiography accurately demonstrated vessel anomalies, including double or right aortic arch (seven cases), aberrant subclavian artery (six cases), innominate artery compression syndrome (one case), unilateral pulmonary artery agenesis (one case), and pulmonary artery enlargement (three cases). One patient had normal vasculature. CONCLUSION: CT angiography is feasible in children and can be used to delineate abnormal great vessel anatomy.

Angiography↗