Biomedical subjects

J C Mitchell

Publications and source records attributed to J C Mitchell.

At least 19 recordsLinked to original sources

PubMed2004

The role of the locus coeruleus in corticotropin-releasing hormone and stress-induced suppression of pulsatile luteinizing hormone secretion in the female rat.

Despite a wealth of evidence for CRH mediating stress-induced suppression of the hypothalamic GnRH pulse generator, and hence reproductive dysfunction, the site and mechanism of action remains elusive. The locus coeruleus (LC), a prominent noradrenergic brain stem nucleus, is innervated by CRH neurons, mediates several behavioral stress responses, and is implicated in the control of pulsatile LH secretion. The aim of this study was to test the hypothesis that LC CRH has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats with 17beta-estradiol or oil-filled s.c. capsules were implanted with bilateral LC and i.v. cannulae. Central administration of CRH (10 ng to 1 microg) resulted in a dose-dependent suppression of LH pulses, which was reversed by a CRH receptor antagonist (alpha-helical CRF(9-41), 1 microg). The induction of c-fos expression in glutamic acid decarboxylase67 immunostained neurons in the preoptic area suggests activation of the secretion of gamma-aminobutyric acid in response to intracoerulear administration of CRH; 17beta-estradiol further increased the percentage of glutamic acid decarboxylase67-positive neurons that expressed fos and augmented suppression of LH pulses. Furthermore, intracoerulear administration of alpha-helical CRF(9-41) completely blocked restraint stress-induced suppression of LH pulses, without affecting the inhibitory response to hypoglycemia. These results suggest that CRH innervation of the LC may play a pivotal, but differential, role in the normal physiological response of stress-induced suppression of the GnRH pulse generator and hence the reproductive system.

Animals↗

PubMed2004

Thermodynamic considerations of microgel swelling behavior.

A simple but novel thermodynamic model is presented, based upon van't Hoff analysis, for the reversible swelling behavior of colloidal microgels. The swelling, as a function of temperature, of poly(N-isopropylacrylamide/N,N'-methylenebisacrylamide) as well as poly(N-isopropylacrylamide/vinylpyridine/N,N'-methylenebisacrylamide) and poly(N-isopropylacrylamide/acrylic acid/N,N'-methylenebisacrylamide) microgel dispersions in H2O and D2O has been studied by photon correlation spectroscopy (PCS). PCS data was used to obtain the hydrodynamic diameter and hence the volume of the microgels (before and after reconstitution following freeze-drying) as a function of temperature. The choice of standard reference states, for analyzing the data attained, is discussed, and the one selected is that of the volume of the microgels at 333 K in H2O. For all microgels examined the volume, at this temperature, is shown to be independent of solvent (H2O, D2O). The derived data has allowed the exploration of a novel thermodynamic approach to the study of the swelling behavior of the microgels. The constant volume, at 333 K, for each of the polymer systems constituting the microgels is suggested to be an intrinsic property of the polymers themselves.

Journal Article↗

PubMed2004

Differential effects of repeated restraint stress on pulsatile lutenizing hormone secretion in female Fischer, Lewis and Wistar rats.

Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis and can suppress pulsatile luteinizing hormone (LH) secretion, resulting in reproductive dysfunction. The histocompatible inbred Fischer and Lewis rat strains exhibit marked phenotypic differences in the activity of the HPA axis, the former being more reactive. Using Fischer, Lewis and Wistar rats, we assessed effects of repeated restraint stress on pulsatile LH secretion. Adult rats were ovariectomized and fitted with cardiac catheters. Blood samples were collected at 5-min intervals for 3-5 h for detection of LH. Less frequent samples were collected for corticosterone measurement. After 2 h, rats were restrained for 60 min. The same regimen was repeated four times at 6-day intervals. The mean peak corticosterone levels achieved during the first restraint in Fischer rats were significantly higher than those in Lewis and Wistar rats. By the time of the fourth episode of restraint, there had been some adaptation of the corticosterone response in the Fischer, but not in the Lewis or Wistar rats. LH pulses were interrupted during the 1st restraint in all experimental groups, although only Fischer rats showed suppression of LH pulses during the subsequent 2-h postrestraint period. During the fourth restraint, LH pulse frequency was still reduced in Wistar, but not in Fischer and Lewis rats, both of which showed a complete habituation. These results suggest that differential control mechanisms underlie the response of the HPA and HPG axes to repeated restraint stress.

Adaptation, Physiological↗

PubMed2003

DNA fuel for free-running nanomachines.

We describe kinetic control of DNA hybridization: loop complexes are used to inhibit the hybridization of complementary oligonucleotides; rationally designed DNA catalysts are shown to be effective in promoting their hybridization. This is the basis of a strategy for using DNA as a fuel to drive free-running artificial molecular machines.

Base Sequence↗

PubMed2003

The effect of oestradiol and progesterone on hypoglycaemic stress-induced suppression of pulsatile luteinizing hormone release and on corticotropin-releasing hormone mRNA expression in the rat.

Corticotropin-releasing hormone (CRH) is implicated in the suppression of pulsatile luteinizing hormone (LH) secretion by a variety of stressful stimuli; 17beta-oestradiol (E2) has been shown to modulate this inhibitory response. The present study in ovariectomized (OVX) rats was designed to investigate the effect of E2 and progesterone (P4) on hypoglycaemic stress-induced changes in pulsatile LH secretion and on the associated changes in both central and peripheral components of the hypothalamic-pituitary-adrenal axis. E2 enhanced the hypoglycaemic stress-induced suppression of LH pulses; P4 in addition to E2 further potentiated the inhibitory response. The rise in plasma corticosterone following insulin-induced hypoglycaemia (IIH) was highest in the E2 + P4 group. Nevertheless, when such levels were achieved by administration of corticosterone, the occurrence of LH pulses was completely unaffected, irrespective of ovarian steroid milieu. E2 and E2 + P4 up-regulated basal CRH mRNA expression in the paraventricular nucleus (PVN) as measured by in situ hybridization; this signal was also increased in the medial preoptic nucleus (MPN) following E2. IIH resulted in a rise in CRH mRNA in the PVN, but not in the MPN; this rise may reflect a more significant role for the PVN in the present context. Changes in neuropeptide mRNA expression may signal changes in neuronal activity; nevertheless, the profound differences in LH pulse suppression in OVX, E2 and E2 + P4 rats following IIH were not reflected in the concurrent changes in CRH mRNA in the PVN. The results suggest that while corticosterone has no acute effect on LH pulses in the rat, the up-regulation by ovarian steroids of basal CRH mRNA in the PVN and/or MPN may contribute to the central regulation of these pulses in response to stress.

Adrenocorticotropic Hormone↗

PubMed2002

Fatigue studies of high-palladium dental casting alloys: Part I. Fatigue limits and fracture characteristics.

The fatigue limits and fracture characteristics for a Pd-Cu-Ga alloy and a Pd-Ga alloy were studied. The alloys were cast into tensile test bars with gauge diameter of 3 mm and gauge length of 15 mm, and the surfaces of the castings were neither air-abraded nor polished after removal from the investment. Specimens were prepared from all-new metal (not previously melted), a combination of 50% new metal and 50% old metal (previously melted one time) and 100% old metal. The cast bars were subjected to heat treatment simulating the complete firing cycles for dental porcelain, and fatigued in air at room temperature under uniaxial tension-compression stress at 10 Hz and a ratio of tensile stress amplitude to compressive stress amplitude (R-ratio) of -1. The alloy microstructures and fracture surfaces were examined with a scanning electron microscope (SEM). Results showed that the fatigue limits at 2 x 10(6)cycles of the Pd-Cu-Ga and Pd-Ga alloys were approximately 0.20 and 0.15 of their 0.1% yield strength (YS) in tension, respectively. The fatigue resistance for specimens from both alloys containing 50% old metal and 50% new metal was comparable to that of specimens containing all-new metal, although this decreased dramatically for Pd-Cu-Ga alloy specimens containing all-old metal. The fatigue resistance of the Pd-Cu-Ga alloy subjected to heat treatment simulating the porcelain firing cycles was not adversely affected by remnants of the original as-cast dendritic microstructure that remained in the relatively large test specimens. A longer heat treatment than recommended by the manufacturer for the porcelain firing cycles is needed to completely eliminate the as-cast dendritic structure in these specimens. The Pd-Cu-Ga alloy exhibited superior fatigue resistance to the Pd-Ga alloy, which has an equiaxed-grain microstructure and lower yield strength.

Journal Article↗

PubMed2001

UV-spectrophotometry study of membrane transport processes with a novel diffusion cell.

A novel diffusion cell has been constructed which allows study of membrane diffusion processes without the need for sampling of the receiver compartment, that is highly sensitive and, being based around a diode array spectrophotometer also allows for continuous, real-time recording of multi-species concentration changes in the receiving compartment. The system is controlled to operate isothermally (via a Peltier control system) at temperatures between 15 and 85 degrees C. To examine the performance of this novel design, the transfer of tetracaine from a preparation in PEG 400 (20% tetracaine in PEG 400) has been studied. The results have been used to determine flux, lag time and related parameters. The performance of the novel cell is compared with results from traditional Franz cell diffusion studies.

Algorithms↗

PubMed2001

The stability of benzoyl peroxide by isothermal microcalorimetry.

Isothermal microcalorimetry may be used to determine kinetic and thermodynamic parameters for chemical reactions. This paper reports rate constants, determined as a function of temperature, and the activation enthalpy for the degradation of solid benzoyl peroxide as determined by isothermal microcalorimetry. Studies were conducted on aqueous suspension phase, solid benzoyl peroxide. In addition, supporting evidence is cited from work carried out in this laboratory on the solution phase degradation of benzoyl peroxide using UV-visible spectrophotometry. The activation energy obtained by microcalorimetry was E(a)=137.8+/-6.6 kJ mol(-1) and the activation energy obtained from UV-visible spectrophotometry was E(a)=112.7+/-4.2 kJ mol(-1).

Benzoyl Peroxide↗

PubMed2001

The stability of benzoyl peroxide formulations determined from isothermal microcalorimetric studies.

Recent developments in the analysis of microcalorimetric data output allow the possibility of determining both thermodynamic and kinetic parameters for complex reaction systems. Such experiments routinely take around 50 h, hence qualifying for the description rapid. The methods have earlier been applied to a study of the stability of benzoyl peroxide itself in aqueous suspension. This paper reports the results of isothermal microcalorimetric study of the stability of benzoyl peroxide in the presence of a wide range of excipients and in formulated materials. The results are shown to assist in formulation design, are achieved rapidly and are derived from direct experimental study of the complex systems themselves. That is, no ancillary information is required nor are the studies invasive or destructive.

Benzoyl Peroxide↗

PubMed2001

Rapid atomic density methods for molecular shape characterization.

Two methods for rapid characterization of molecular shape are presented. Both techniques are based on the density of atoms near the molecular surface. The Fast Atomic Density Evaluation (FADE) algorithm uses fast Fourier transforms to quickly estimate densities. The Pairwise Atomic Density Reverse Engineering (PADRE) method derives modified density measures from the relationship between atomic density and total potentials. While many shape-characterization techniques define shape relative to a surface, the descriptors returned by FADE and PADRE can measure local geometry from points within the three-dimensional space surrounding a molecule. The methods can be used to find crevices and protrusions near the surface of a molecule and to test shape complementarity at the interface between docking molecules.

Algorithms↗

PubMed2001

X-ray diffraction characterization of dental gold alloy-ceramic interfaces.

X-ray diffraction (XRD) was employed to study dental alloy-ceramic interfaces. A Au-Pd-In alloy, which requires oxidation before porcelain firing, and a Au-Pt-Pd-In alloy, which does not require oxidation before porcelain firing, were selected in this study. Alloy specimens were centrifugally cast. Specimen surfaces were metallographically polished through 0.05 microm Al2O3 slurries. A thin layer (< 50 microm) of a dental opaque porcelain was fired on the alloy surfaces with and without initial oxidation. XRD was conducted at room temperature on four types of alloy specimens: polished, oxidized, porcelain fired after alloy oxidation, and porcelain fired without initial alloy oxidation. XRD was also performed on fired opaque porcelain without an alloy substrate. The detection of prominent gold solid solution peaks from alloy-ceramic specimens indicated that the incident X-ray beam reached the alloy-ceramic interface. In2O3 and beta-Ga2O3 were identified on the oxidized Au-Pd-In alloy, while In2O3 and SnO2 were detected on the oxidized Au-Pt-Pd-In alloy. Preferred orientation was observed for all the oxides formed on the alloys. Minimum lattice parameter changes (<1%) for the gold solid solutions were observed for both alloys before and after oxidation and porcelain firing. Leucite (KAlSi2O6, TiO2, ZrO2 and SnO2 were detected on the fired opaque porcelain. For both alloys, no additional oxides were identified at the metal-ceramic interfaces beyond those present in the oxidized alloys and the opaque porcelain. Similar results were obtained from alloy-ceramic interfaces where there was no prior alloy oxidation. The results indicate the critical role of alloy surface oxides in metal-ceramic bonding and support the chemical bonding mechanism for porcelain adherence.

Journal Article↗

PubMed2001

A microcalorimetric comparison of the anti-Streptococcus mutans efficacy of plant extracts and antimicrobial agents in oral hygiene formulations.

AIMS: This study aimed to evaluate the efficacy of 'natural' putative antimicrobial agents against Streptococcus mutans and to compare these with synthetic agents using the flow microcalorimeter. Streptococcus mutans is one of the oral pathogens responsible for dental caries. METHODS AND RESULTS: Traditional microbiological techniques are invasive and destructive unlike flow microcalorimetry. This rapid technique was used to continuously monitor the power output (bioactivity) of Strep. mutans with reproducibility, precision and accuracy. The antibacterial agents found in oral hygiene products and all the natural agents tested showed anti-Strep. mutans ability. CONCLUSION: In this study microcalorimetry identified agents that had a biological effect and quantified the rate of kill achieved enabling four broad categories of antimicrobial agent to be defined. SIGNIFICANCE AND IMPACT OF THE STUDY: Microcalorimetric data are a better indication of antimicrobial efficacy than merely determining concentrations at which an antimicrobial agent is bacteriostatic or bactericidal.

Anti-Bacterial Agents↗

PubMed2001

Protein docking using continuum electrostatics and geometric fit.

The computer program DOT quickly finds low-energy docked structures for two proteins by performing a systematic search over six degrees of freedom. A novel feature of DOT is its energy function, which is the sum of both a Poisson-Boltzmann electrostatic energy and a van der Waals energy, each represented as a grid-based correlation function. DOT evaluates the energy of interaction for many orientations of the moving molecule and maintains separate lists scored by either the electrostatic energy, the van der Waals energy or the composite sum of both. The free energy is obtained by summing the Boltzmann factor over all rotations at each grid point. Three important findings are presented. First, for a wide variety of protein-protein interactions, the composite-energy function is shown to produce larger clusters of correct answers than found by scoring with either van der Waals energy (geometric fit) or electrostatic energy alone. Second, free-energy clusters are demonstrated to be indicators of binding sites. Third, the contributions of electrostatic and attractive van der Waals energies to the total energy term appropriately reflect the nature of the various types of protein-protein interactions studied.

Computer Simulation↗

PubMed2000

Comparison of mechanical properties for equiaxed fine-grained and dendritic high-palladium alloys.

Two Pd-Cu-Ga alloys and a Pd-Ga alloy were selected for study. Bars of each alloy were tested in tension for the as-cast and simulated porcelain-firing conditions, and values of mechanical properties were measured. Fracture surfaces and microstructures of axially sectioned fracture specimens were observed with the SEM. The two Pd-Cu-Ga alloys exhibited similar mechanical properties. The Pd-Ga alloy had lower strength and higher percentage elongation. Heat treatment simulating porcelain firing cycles decreased the strength of both Pd-Cu-Ga alloys and increased their ductility. However, this heat treatment did not significantly affect the mechanical properties of the Pd-Ga alloy. All three high-palladium alloys had the same modulus of elasticity. The amount of overall porosity was relatively minimal (< 1%) and not significantly different among the three alloys. However, porosity was a significant factor for UTS of one Pd-Cu-Ga alloy and the Pd-Ga alloy.

Journal Article↗

PubMed1999

Pharmaceutical microcalorimetry: applications to long-term stability studies.

Calorimetry has been a mainstay of stability analyses for some time in the form of differential scanning microcalorimetry (DSC). This technique exploits high (relatively) temperature studies of pure materials and of formulations to accelerate any degradation or interactions. The behaviour of the material at storage or ambient conditions is then estimated via extrapolation from the Arrhenius equation. Recent developments in isothermal microcalorimetry allow the direct determination of both kinetic and thermodynamic parameters for long, slow reactions from studies conducted at appropriate temperatures and under designated environmental control (pH, pO2, RH etc.). This review introduces the kinetic analysis of microcalorimetric data and, through selected examples, shows applications of the method.

Calorimetry↗

PubMed1999

A rare fracture-dislocation of the hip in a gymnast and review of the literature.

Posterior fracture-dislocation of the hip is an uncommon injury in athletics and leisure activities. It is more commonly seen in high energy motor vehicle accidents and occasionally in high energy sporting activities. A rare case is reported of posterior fracture-dislocation of the hip joint that occurred in a young athlete during gymnastics. This unusual mechanism of injury illustrates the great forces sustained by the hip joint of gymnasts. Early reduction and operative treatment led to a congruent and stable hip joint. After rehabilitation, she returned to light sporting activities after six months.

Acetabulum↗

PubMed1996

Determination of receptor-bound drug conformations by QSAR using flexible fitting to derive a molecular similarity index.

Results are presented for a QSAR analysis of bisamidines, using a similarity index as descriptor. The method allows for differences in conformation of bisamidines at the receptor site to be taken into consideration. In particular, it has been suggested by others that pentamidine binds in the minor groove of DNA in a so-called isohelical conformation, and our QSAR supports this suggestion. The molecular similarity index for comparison of molecules can be used as a parameter for correlating and hence rationalising the activity as well as suggesting the design of bioactive molecules. The studied compounds had been evaluated for potency against Leishmania mexicana amazonensis, and this potency was used as a dependent variable in a series of QSAR analyses. For the calculation of similarity indexes, each analogue was in turn superimposed on a chosen lead compound in a reference conformation, either extended or isohelical, maximising overlap and hence similarity by flexible fitting.

Animals↗

PubMed1996

Does selective vagotomy affect conditioned flavor-nutrient preferences in rats?

We investigated the effects of selective vagotomy on the learning of conditioned flavor preferences associated with intragastric Polycose infusion. Normal control, hepatic branch vagotomized, and gastric vagotomized rats implanted with gastric catheters received a flavor (CS+) paired with intragastric Polycose infusion, and on alternate days, a different flavor (CS-) paired with intragastric water infusion. After training, rats were given a two-bottle extinction test for 12 days. The results show that normal control and hepatic branch vagotomized rats had a significant CS+ flavor preference during extinction testing, whereas the gastric vagotomized rats showed no preference. This result indicates that the hepatic branch of the vagus does not play a solitary role in learned flavor-nutrient preferences using Polycose. However, the gastric vagal branches may be involved in the preference learning.

Animals↗