Biomedical subjects

J C Smith

Publications and source records attributed to J C Smith.

At least 73 records · Page 4Linked to original sources

PubMed2001

The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer.

Sex hormones appear to play a pivotal role in determining cardiovascular risk. Androgen deprivation therapy for males with prostate cancer results in a hypogonadal state that may have important, but as yet undetermined, effects on the vasculature. We studied the effects of androgen deprivation therapy on large artery stiffness in 22 prostate cancer patients (mean age, 67 +/- 8 yr) over a 6-month period. Arterial stiffness was assessed using pulse-wave analysis, a technique that measures peripheral arterial pressure waveforms and generates corresponding central aortic waveforms. This allows determination of the augmentation of central pressure resulting from wave reflection and the augmentation index, a measure of large artery stiffness. Body compositional changes were assessed using bioelectrical impedance analysis. Fasting lipids, glucose, insulin, testosterone, and estradiol were measured. After a 3-month treatment period, the augmentation index increased from 24 +/- 6% (mean +/- SD) at baseline to 29 +/- 9% (P = 0.003) despite no change in peripheral blood pressure. Timing of wave reflection was reduced from 137 +/- 7 to 129 +/- 10 msec (P = 0.003). Fat mass increased from 20.2 +/- 9.4 to 21.9 +/- 9.6 kg (P = 0.008), whereas lean body mass decreased from 63.2 +/- 6.8 to 61.5 +/- 6.0 kg (P = 0.016). There were no changes in lipids or glucose during treatment. Median serum insulin rose from 11.8 (range, 5.6-49.1) to 15.1 (range, 7.3-83.2) mU/liter at 1 month (P = 0.021) and to 19.3 (range, 0-85.0 mU/liter by 3 months (P = 0.020). There was a correlation between the changes in fat mass and insulin concentration over the 3-month period (r = 0.56; P = 0.013). In a subgroup of patients whose treatment was discontinued after 3 months, the augmentation index decreased from 31 +/- 7% at 3 months to 29 +/- 5% by 6 months, in contrast to patients receiving continuing treatment in whom the augmentation index remained elevated at 6 months compared with baseline (P = 0.043). These data indicate that induced hypogonadism in males with prostate cancer results in a rise in the augmentation of central arterial pressure, suggesting large artery stiffening. Adverse body compositional changes associated with rising insulin concentrations suggest reduced insulin sensitivity. These adverse hemodynamic and metabolic effects may increase cardiovascular risk in this patient group.

Adipose Tissue↗

PubMed2001

Determinants of T box protein specificity.

Members of the T box family of transcription factors play important roles in early development. Different members of the family exert different effects and here we show that much of the specificity of the Xenopus T box proteins Xbra, VegT and Eomesodermin resides in the DNA-binding domain, or T box. Binding site selection experiments show that the three proteins bind the same core sequence, but they select paired sites that differ in their orientation and spacing. Lysine 149 of Xbra is conserved in all Brachyury homologues, while the corresponding amino acid in VegT and Eomesodermin is asparagine. Mutation of this amino acid to lysine changes the inductive abilities of VegT and Eomesodermin to resemble that of Xbra.

Amino Acid Sequence↗

PubMed2001

Making mesoderm--upstream and downstream of Xbra.

The mesoderm of the amphibian embryo is formed through an inductive interaction in which cells of the vegetal hemisphere of the embryo act on overlying equatorial cells. My laboratory is studying the Brachyury gene, which plays a key role in this interaction, being both necessary and sufficient for normal mesoderm formation. In this article I describe our attempts to understand how Xenopus Brachyury (Xbra) is activated in the right cells at the right time, and then to understand how Xbra exerts its effects.

Animals↗

PubMed2001

URI and antibiotics.

Explore the source record for details and available documents.

Anti-Bacterial Agents↗

PubMed2001

The effects of high-intensity exercise on a 10-second sprint cycle test.

Nine men (25.11 +/- 1.16 years) performed 3 different test sessions. In the control session, subjects performed a 10-second sprint cycle test and 1 repetition maximum (1RM) in the back squat. The 5-minute test session consisted of 10 x 1 repetition in the parallel back squat exercise at 90% of their 1RM, 5 minutes of rest, and then a 10-second sprint cycle test. The 20-minute test session consisted of the same test protocol as the 5-minute test session except that the subjects rested for 20-minutes prior to the sprint cycle test. Significant differences were found in average power and average power relative to body weight (F = 5.684, p = 0.014, and F = 1.258, p = 0.006, respectively) for the 5-minute test session. The authors conclude that this particular squat protocol could have a potential carry-over effect into improvements in 100-m sprint times when performing the squats 5-minutes prior to performance.

Adult↗

PubMed2000

S100 protein-annexin interactions: a model of the (Anx2-p11)(2) heterotetramer complex.

The (Anx2)(2)(p11)(2) heterotetramer has been implicated in endo- and exocytosis in vivo and in liposome aggregation in vitro. Here we report on the modelling of the heterotetramer complex using docking algorithms. Two types of models are generated-heterotetramer and heterooctamer. On the basis of the agreement between the calculated (X-ray) electron density and the observed projected density from cryo-electron micrographs on the one hand, and calculated energy criteria on the other hand, the heterotetramer models are proposed as the most probable, and one of them is selected as the best model. Analysis of this model at an atomic level suggests that the interaction between the Anx2 core and p11 has an electrostatic character, being stabilised primarily through charged residues.

Algorithms↗

PubMed2000

Ionisation and the effect of absorption enhancers on transport of salicylic acid through silastic rubber and human skin.

PURPOSE: to investigate if salicylic acid (SA)-permeation through excised human skin (HS) and silastic rubber (SR) conforms to the pH-hypothesis and to assess the influence of a range of absorption enhancers on the transport of SA with and without a transmembrane pH-gradient. METHODS: Franz cells were used to study SA permeation from solutions and saturated suspensions. McIlvaine buffers were used to maintain transmembrane pH-gradients. Membrane pretreatment was used to study the action of absorption enhancers. RESULTS: the flux of SA from solutions was dependent upon the vehicle pH and permeant concentration was directly related to the degree of ionisation of the solute. Flux from suspensions was independent of pH, since the level of unionised drug, the predominant diffusing species, was maintained at the intrinsic saturated solubility at all pH values. The observed SA flux enhancement across human skin without a transmembrane pH-gradient was not significantly different from the enhancement with a pH-gradient for all of the absorption enhances used, except for dodecylamine. CONCLUSIONS: the results showed that SA permeation conformed to the p H-partition hypothesis. The evidence from absorption-enhancer pretreatment demonstrated that, under certain conditions, the transdermal penetration enhancement of a number of topical enhancing compounds, including Azone and oleic acid can be explained without recourse to ion-pair phenomena.

Absorption↗

PubMed2000

Pathway for large-scale conformational change in annexin V.

Crystallographic studies have shown that the binding of calcium to domain III of annexin V is accompanied by a large conformational change involving surface exposure of Trp187. Here we examine this conformational transition using computer simulation. It is found that the burial of Trp187 is accompanied by a large increase in conformational strain, compensated by improved protein-protein interaction energies. A low energy pathway for the conformational change is determined using the conjugate peak refinement method [Fischer, S., and Karplus, M. (1992) Chem. Phys. Lett. 194, 252-261] with solvent effects taken into account using nonuniform charge scaling. The pathway obtained is complex, involving >300 dihedral angle transitions and the complete unwinding of one helix. Acidic residues play a key role in the conformational pathway, via a succession of direct hydrogen bonds with the indole ring of Trp187. This finding is discussed in the light of experimentally determined pH, calcium ion and mutational effects on the conformational transition.

Annexin A5↗

PubMed2000

Nitric oxide modulates N-methyl-D-aspartate-evoked serotonin release in the raphe nuclei and frontal cortex of the freely moving rat.

The role of nitric oxide (NO) in N-methyl-D-aspartate (NMDA)-regulated release of 5-hydroxytryptamine (5-HT) in the frontal cortex and raphe nuclei of freely moving rats has been studied using microdialysis with dual probes, one in each region of the same animal. In order to do this the selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 1 mM) and the NO donor S-nitroso-N-penicillamine (SNAP; 500 microM-5 mM) were used. All drugs were infused into the raphe via the dialysis probe. NMDA showed an inverse concentration effect on 5-HT release in the raphe with 25 microM decreasing 5-HT release and 100 microM increasing release. At the same time the converse effect was seen in the frontal cortex. Co-infusion of 7-NI abolished the effect of 100 microM but not 25 microM NMDA. 7-NI given alone decreased raphe 5-HT release with a concomitant increase being seen in the frontal cortex. Low concentrations of SNAP infused into the raphe were found to decrease 5HT release locally but increase release in the frontal cortex. In contrast the highest concentration of SNAP used was found to have the opposite effect in both brain regions. These data suggest that NO plays a role in mediating both basal and NMDA-evoked changes in serotonergic transmission between the raphe and frontal cortex.

Animals↗

PubMed2000

Solvent dependence of dynamic transitions in protein solutions.

A transition as a function of increasing temperature from harmonic to anharmonic dynamics has been observed in globular proteins by using spectroscopic, scattering, and computer simulation techniques. We present here results of a dynamic neutron scattering analysis of the solvent dependence of the picosecond-time scale dynamic transition behavior of solutions of a simple single-subunit enzyme, xylanase. The protein is examined in powder form, in D(2)O, and in four two-component perdeuterated single-phase cryosolvents in which it is active and stable. The scattering profiles of the mixed solvent systems in the absence of protein are also determined. The general features of the dynamic transition behavior of the protein solutions follow those of the solvents. The dynamic transition in all of the mixed cryosolvent-protein systems is much more gradual than in pure D(2)O, consistent with a distribution of energy barriers. The differences between the dynamic behaviors of the various cryosolvent protein solutions themselves are remarkably small. The results are consistent with a picture in which the picosecond-time scale atomic dynamics respond strongly to melting of pure water solvent but are relatively invariant in cryosolvents of differing compositions and melting points.

Calorimetry, Differential Scanning↗

PubMed2000

c-Fos induction in visceral and vestibular nuclei of the rat brain stem by a 9.4 T magnetic field.

Recently, it has been shown that rats placed in a 9.4T static magnetic field for 30 min after drinking a glucose-saccharin solution develop a conditioned taste aversion (CTA) to glucose-saccharin. We sought to identify brain stem regions that are activated by the 9.4 T magnetic field exposure using c-Fos immunohistochemistry. Rats were restrained in a 9.4 T magnet for 30 min; sham-exposed rats were restrained but not exposed to the magnetic field. The magnetic field induced significantly more c-Fos-positive cells than sham treatment in the solitary tract, parabrachial, medial vestibular, prepositus, and supragenualis nuclei. These results suggest that magnetic field exposure causes neural activation in visceral and vestibular nuclei that may promote CTA learning.

Animals↗

PubMed2000

Xwnt11 and the regulation of gastrulation in Xenopus.

The molecular basis of gastrulation is poorly understood. In this paper we address this problem by taking advantage of the observation that the transcription activator Brachyury is essential for gastrulation movements in Xenopus and mouse embryos. We infer from this observation that amongst the target genes of Brachyury are some that are involved in the regulation of gastrulation. In the course of a screen for Brachyury targets we identified Xwnt11. Use of a dominant-negative Xwntll construct confirms that signalling by this class of Wnts is essential for normal gastrulation movements, and further investigation suggests that Xwntll signals not through the canonical Wnt signalling pathway involving GSK-3 and beta-catenin but through another route, which may require small GTPases such as Rho and Rac. Future work will concentrate on elucidating the Xwnt11 signal transduction pathway and on investigating its influence on cell shape and polarity during Xenopus gastrulation.

Animals↗

PubMed2000

Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation.

Vertebrate gastrulation involves the specification and coordinated movement of large populations of cells that give rise to the ectodermal, mesodermal and endodermal germ layers. Although many of the genes involved in the specification of cell identity during this process have been identified, little is known of the genes that coordinate cell movement. Here we show that the zebrafish silberblick (slb) locus encodes Wnt11 and that Slb/Wnt11 activity is required for cells to undergo correct convergent extension movements during gastrulation. In the absence of Slb/Wnt11 function, abnormal extension of axial tissue results in cyclopia and other midline defects in the head. The requirement for Slb/Wnt11 is cell non-autonomous, and our results indicate that the correct extension of axial tissue is at least partly dependent on medio-lateral cell intercalation in paraxial tissue. We also show that the slb phenotype is rescued by a truncated form of Dishevelled that does not signal through the canonical Wnt pathway, suggesting that, as in flies, Wnt signalling might mediate morphogenetic events through a divergent signal transduction cascade. Our results provide genetic and experimental evidence that Wnt activity in lateral tissues has a crucial role in driving the convergent extension movements underlying vertebrate gastrulation.

Animals↗

PubMed2000

Enzyme activity and dynamics: xylanase activity in the absence of fast anharmonic dynamics.

The activity and dynamics of a simple, single subunit enzyme, the xylanase from Thermotoga maritima strain Fj SS3B.1 have been measured under similar conditions, from -70 to +10 degrees C. The internal motions of the enzyme, as evidenced by neutron scattering, undergo a sharp transition within this temperature range; they show no evidence for picosecond-timescale anharmonic behaviour (e.g. local diffusive motions or jumps between alternative conformations) at temperatures below -50 degrees C, whereas these motions are strongly activated at higher temperatures. The activity follows Arrhenius behaviour over the whole of the temperature range investigated, -70 to +10 degrees C. The results indicate that a temperature range exists over which the enzyme rate-limiting step is independent of fast anharmonic dynamics.

Enzyme Activation↗

PubMed2000

Gradual refinement of activin-induced thresholds requires protein synthesis.

Activin induces the expression of different genes in a concentration-dependent manner. In this paper, we show that the initial response of cells to activin, whether assayed in dispersed cells or in a bead-implantation regime in intact animal caps, is to activate expression of both Xbra and goosecoid. However, differential expression of the two genes, with down-regulation of Xbra, occurs very rapidly and certainly within 3 h of the initial phase of expression. This rapid refinement of gene expression can occur in dispersed cells and thus does not require cell-cell interactions. Refinement of gene expression does, however, require protein synthesis but not goosecoid function. Together, our results place the burden of threshold formation not on the initial induction of different genes but on regulatory interactions between the genes once they have been activated.

Activins↗

PubMed2000

Evidence of recall bias in volunteered vs. prompted responses about occupational exposures.

BACKGROUND: Recall bias remains a concern in case-control studies, although few investigations have found evidence of differential recall. This study examined whether differences in occupational exposure reporting occur in volunteered vs. prompted questionnaire responses. METHODS: In a large, population-based, case-control study of a childhood cancer, neuroblastoma, we calculated odds ratios for broad occupational exposure groups on the assumption that in the absence of recall bias, risk estimates for such broad groupings should be close to the null value. RESULTS: Prompted exposures and work activities showed little evidence of differential recall by parents of cases and controls (all OR < 1.2), but case parents were more likely to volunteer information about other exposures or activities (ORs: 1.35-1.71). Case mothers were also more likely than control mothers to report activities involving indirect exposure (OR = 1.41). CONCLUSIONS: These findings suggest that prompted exposure questions are less likely to be subject to recall bias than open-ended questions.

Case-Control Studies↗

PubMed2000

Dynamic simulation of the mouse prion protein.

Conformational flexibility in the prion protein is believed to play a role in prion diseases. Here we examine the dynamic structure of the mouse cellular prion protein using two one-nanosecond molecular dynamics simulations from different initial conditions. The two simulations produce similar results. The overall structure remains close to that determined by nmr spectroscopy, with small deviations arising from loop fluctuation and slight changes in the relative helix positions. The sequence dependence of the fluctuation magnitudes is similar to the variation between the nmr-derived structure solutions. In both simulations, the N-terminal region of the protein forms a short, two-stranded beta-sheet, to which a third strand joins after approximately 100 ps. The additional strand may reflect nucleative properties of the beta-sheet required for disease-related prion conformational change.

Animals↗

PubMed2000

Atomic detail peptide-membrane interactions: molecular dynamics simulation of gramicidin S in a DMPC bilayer.

Molecular dynamics simulations have been performed of the sequence-symmetric cyclic decapeptide antibiotic gramicidin S (GS), in interaction with a hydrated dimyristoylphosphatidylcholine (DMPC) bilayer, and the results compared with a "control" simulation of the system in the absence of GS. Following experimental evidence, the GS was initially set in a single antiparallel beta-sheet conformation with two Type II' beta-turns in an amphiphilic interaction with the membrane. This conformation and position remained in the 6.5 ns simulation. Main-chain dihedrals are on average approximately 26 degrees from those determined by NMR experiment on GS in dimethylsulfoxide (DMSO) solution. Sequence-symmetric main-chain and side-chain dihedral angle pairs converge to within approximately 5 degrees and approximately 10 degrees, respectively. The area per lipid, lipid tail order parameters, and quadrupole spin-lattice relaxation times of the control simulation are mostly in good agreement with corresponding experiments. The GS has little effect on the membrane dipole potential or water permeability. However, it is found to have a disordering effect (in agreement with experiment) and a fluidifying effect on lipids directly interacting with it, and an ordering effect on those not directly interacting.

Anti-Bacterial Agents↗