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Biomedical subjects

A M Davis

Publications and source records attributed to A M Davis.

At least 19 recordsLinked to original sources
PubMed2007

Maternal diet composition alters serum steroid and free fatty acid concentrations and vaginal pH in mice.

We examined the effects of three maternal diets (very high fat (VHF), low fat (LF), and control (Purina 5015)) on serum steroids, free fatty acids (FFA), and vaginal pH in National Institutes of Health Swiss mice. Females were fed (VHF, n = 33; LF, n = 33; 5015, n = 48) from 4 to 16 weeks of age. Following breeding, female serum was collected at 0.5 (pre-implantation, early diestrus) or 8.5 (post-implantation, mid-diestrus) days post-coitus (dpc). The serum concentrations of 17beta-estradiol, testosterone, progesterone, and FFA were analyzed at both collection points, and vaginal pH at 0.5 dpc. Striking differences in steroids and FFA were observed at 0.5 dpc among the groups. Estradiol was higher in the VHF (14.1 +/- 3.0 pg/ml), compared with LF mice (5.2 +/- 2.3 pg/ml; P< or = 0.05). In contrast, 0.5 dpc testosterone was lower in the VHF (10.5 +/- 3.0 pg/ml) versus the LF group (32.7 +/- 8.4 pg/ml; P< or = 0.05). At 8.5 dpc, progesterone was higher in the VHF (89.6 +/- 6.7 ng/ml) versus the 5015 group (60.1 +/- 4.9 ng/ml; P< or = 0.05). VHF mice had higher FFA concentrations at 0.5 dpc (1.0 +/- 0.2 mmol/l) than LF and control mice (0.5 +/- 0.1 and 0.6 +/- 0.1 mmol/l respectively; P< or = 0.05). At 8.5 dpc, VHF females had higher serum FFA (0.8 +/- 0.1 mmol/l) than LF and control females (0.4 +/- 0.1 and 0.6 +/- 0.1 mmol/l; P< or = 0.05). Mean vaginal pH of VHF females (6.41 +/- 0.09) was lower than 5015 females (6.76 +/- 0.10; P< or = 0.05). These diet-induced alterations in serum steroid and FFA concentrations might affect several reproductive processes, including preferential fertilization by one class of sperm over the other and sex bias in pre- and post-implantational embryonic development.

Animals↗
PubMed2006

Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT.

INTRODUCTION: Regulatory and competitive pressure to reduce the QT interval prolongation risk of potential new drugs has led to focus on methods to test for inhibition of the human ether-a-go-go-related gene (hERG)-encoded K+ channel, the primary molecular target underlying this safety issue. Here we describe the validation of a method that combines medium-throughput with direct assessment of channel function. METHODS: The electrophysiological and pharmacological properties of hERG were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks HT). A pharmacological comparison was also made between IonWorks HT and an indirect assay (Rb+ efflux). RESULTS: Basic electrophysiological properties of hERG were similar whether recorded conventionally (HEK cells) or using IonWorks HT (CHO cells): for example, tail current V1/2 -12.1+/-5.0 mV (32) for conventional and -9.5+/-6.0 mV (46) for IonWorks HT (mean+/-S.D. (n)). A key finding was that as the number of cells per well was increased in IonWorks HT, the potency reported for a given compound decreased. Using the lowest possible cell concentration (250,000 cells/ml) and 89 compounds spanning a broad potency range, the pIC50 values from IonWorks HT (CHO-hERG) were found to correlate well with those obtained using conventional methodology (HEK-hERG)(r=0.90; p<0.001). Further validation using CHO-hERG cells with both methods confirmed the correlation (r=0.94; p<0.001). In contrast, a comparison of IonWorks HT and Rb+ efflux data with 649 compounds using CHO-hERG cells showed that the indirect assay consistently reported compounds as being, on average, 6-fold less potent, though the differences varied depending on chemical series. DISCUSSION: The main finding of this work is that providing a relatively low cell concentration is used in IonWorks HT, the potency information generated correlates well with that determined using conventional electrophysiology. The effect on potency of increasing cell concentration may relate to a reduced free concentration of test compound owing to partitioning into cell membranes. In summary, the IonWorks HT hERG assay can generate pIC50 values based on a direct assessment of channel function in a timeframe short enough to influence chemical design.

Animals↗
PubMed2005

Scrapie infection alters the distribution of plasma metabolites in diseased Cheviot sheep indicating a change in energy metabolism.

Nuclear magnetic resonance (NMR) spectroscopy has been used to profile the metabolic status of plasma from; sheep showing clinical signs of scrapie, those known to be infected with scrapie but yet to show clinical signs, and control animals. The NMR measurements have shown that energy metabolism in scrapie infected animals is altered before the onset of clinical symptoms. These metabolic changes may provide the foundation for a pre-clinical diagnostic test for scrapie in sheep.

Animals↗
PubMed2004

The influence of anatomic location on functional outcome in lower-extremity soft-tissue sarcoma.

BACKGROUND: The purpose of this study was to explore the relationship between the anatomical location of lower-extremity soft-tissue sarcoma and functional outcome. METHODS: Function was evaluated with the Musculoskeletal Tumor Society (MSTS 1993) score and Toronto Extremity Salvage Score (TESS); 207 patients (median age, 54 years) were eligible. The median maximum tumor diameter was 8.0 cm; 58 tumors were superficial and 149 were deep. Nine locations based on anatomical compartments were defined: 6 tumors were in the groin/femoral triangle; 8, the buttock; 52, the anterior thigh; 22, the medial thigh; 20, the posterior thigh; 10, the popliteal fossa; 13, the posterior calf; 11, the anterolateral leg; and 7, the foot or ankle. RESULTS: Treatment of superficial tumors did not lead to significant changes in MSTS score (mean, 90.6% preoperatively vs. 93.0% postoperatively; P =.566) or TESS (mean, 86.4% preoperatively vs. 90.9% postoperatively; P =.059). Treatment of deep tumors lead to significant reductions in MSTS score and TESS (mean MSTS, 86.9% preoperatively vs. 83.0% postoperatively; P =.001; and mean TESS, 83.0% preoperatively vs. 79.4% postoperatively; P =.015). Anatomical location was not a significant predictor of aggregated MSTS and TESS evaluations. Exploratory analysis showed variation in MSTS pain and gait handicap or limp items and TESS dressing, sitting, bending, and bathing items by anatomical location. CONCLUSIONS: The treatment of superficial tumors does not lead to significant changes in MSTS score or TESS. Anatomical location is not a significant predictor of aggregated MSTS and TESS evaluations. However, there is variation in MSTS and TESS item scores across anatomical locations.

Activities of Daily Living↗
PubMed2003

Rasch analysis of the Western Ontario McMaster (WOMAC) Osteoarthritis Index: results from community and arthroplasty samples.

BACKGROUND AND OBJECTIVE: This study is based on secondary analysis of Western Ontario McMaster Osteoarthritis Index (WOMAC) data from a community sample over 55 years and total hip or knee arthroplasty samples presurgery and 1-year postoperative. METHODS: The WOMAC data were evaluated by Rasch analysis. Data were considered to fit the Rasch mathematical model for the pain and physical dimensions of the WOMAC if unidimensionality was confirmed by principle component analysis of the subscale and the residuals from the Rasch analysis, infit and outfit statistics were in the range of 0.80 to 1.20; if there was no differential item functioning based on gender or hip vs. knee subjects; and, if there was stability of the item logits across the three data samples. RESULTS: A three-item pain dimension (excluding night pain and pain on standing) and a 14-item physical dimension (excluding heavy domestic duties, getting in and out of the bath and getting on and off the toilet) fit the Rasch model based on these criteria. CONCLUSION: In evaluating existing health status questionnaires using Rasch methodology, it is important to evaluate relevant patient samples and longitudinal data when the measure is intended to evaluate change in status. By these criteria, a modified WOMAC questionnaire fits the Rasch model and has interval-level scaling properties.

Aged↗
PubMed2003

Long term somatic growth after repair of tetralogy of Fallot: evidence for restoration of genetic growth potential.

OBJECTIVE: To compare actual with predicted long term growth after early repair of tetralogy of Fallot (TOF). DESIGN: Serial preoperative and postoperative anthropometric data were converted with z scores. The presence of restrictive physiology was assessed by echocardiography. PATIENTS: 45 otherwise healthy patients who underwent repair at median age 1.6 years (range 0.2-4.9) were studied. Predicted height was determined from mid-parental height corrected for sex. RESULTS: Mean (SD) weight and height z scores at the time of surgery were significantly depressed (-1.04 (0.82) and -0.93 (0.95), respectively; p < 0.0001 for both). At latest follow up at a median age of 14.2 years (range 11-20.5), mean weight and height z scores were 0.16 (1.1) and -0.05 (0.81) (p = 0.32 and p = 0.41, respectively). The improvement between surgical and late weight and height z scores was significant (p < 0.0001 for each comparison). Catch up growth was largely complete within two years. Age at correction, duration of follow up, and prior surgical procedures were unrelated to growth. Mean current height z scores were similar to those predicted by mid-parental height. Patients with restrictive right ventricular physiology (n = 24) had a significantly greater late z score for weight (0.49 v -0.34; p = 0.01), with a similar trend for height. Low birth weight patients experienced comparable catch up growth but remained shorter than patients with normal birth weight (mean height z score -0.64 v 0.06; p = 0.03). CONCLUSIONS: Early repair of TOF results in significant acceleration of weight and height, with normalisation of long term growth and fulfilment of genetic growth potential.

Adolescent↗
PubMed2002

Short-lived nuclides in hibonite grains from Murchison: evidence for solar system evolution.

Records of now-extinct short-lived nuclides in meteorites provide information about the formation and evolution of the solar system. We have found excess 10B that we attribute to the decay of short-lived 10Be (half-life 1.5 million years) in hibonite grains from the Murchison meteorite. The grains show no evidence of decay of two other short-lived nuclides-26Al (half-life 700,000 years) and 41Ca (half-life 100,000 years)-that may be present in early solar system solids. One plausible source of the observed 10Be is energetic particle irradiation of material in the solar nebula. An effective irradiation dose of approximately 2 x 10(18) protons per square centimeter with a kinetic energy of >/=10 megaelectronvolts per atomic mass unit can explain our measurements. The presence of 10Be, coupled with the absence of 41Ca and 26Al, may rule out energetic particle irradiation as the primary source of 41Ca and 26Al present in some early solar system solids and strengthens the case of a stellar source for 41Ca and 26Al.

Journal Article↗
PubMed2002

Function and health status outcomes in a randomized trial comparing preoperative and postoperative radiotherapy in extremity soft tissue sarcoma.

PURPOSE: Morbidity associated with wound complications may translate into disability and quality-of-life disadvantages for patients treated with radiotherapy (RT) for soft tissue sarcoma (STS) of the extremities. Functional outcome and health status of extremity STS patients randomized in a phase III trial comparing preoperative versus postoperative RT is described. PATIENTS AND METHODS: One hundred ninety patients with extremity STS were randomized after stratification by tumor size dichotomized at 10 cm. Function and quality of life were measured by the Musculoskeletal Tumor Society Rating Scale (MSTS), the Toronto Extremity Salvage Score (TESS), and the Short Form-36 (SF-36) at randomization, 6 weeks, and 3, 6, 12, and 24 months after surgery. RESULTS: One hundred eighty-five patients had function data. Patients treated with postoperative RT had better function with higher MSTS (25.8 v 21.3, P <.01), TESS (69.8 v 60.6, P =.01), and SF-36 bodily pain (67.7 v 58.5, P =.03) scores at 6 weeks after surgery. There were no differences at later time points. Scores on the physical function, role-physical, and general health subscales of the SF-36 were significantly lower than Canadian normative data at all time points. After treatment arm was controlled for, MSTS change scores were predicted by a lower-extremity tumor, a large resection specimen, and motor nerve sacrifice; TESS change scores were predicted by lower-extremity tumor and prior incomplete excision. When wound complication was included in the model, patients with complications had lower MSTS and TESS scores in the first 2 years after treatment. CONCLUSION: The timing of RT has minimal impact on the function of STS patients in the first year after surgery. Tumor characteristics and wound complications have a detrimental effect on patient function.

Adult↗
PubMed2001

Developmental sex differences in glutamic acid decarboxylase (GAD(65)) and the housekeeping gene, GAPDH.

Previous work has demonstrated that the GABAergic system is involved in sexual differentiation of the rodent hypothalamus. The present study was designed to further examine this involvement by investigating developmental sex differences in GAD(65) protein levels in hypothalamic and extrahypothalamic brain regions known to be sexually dimorphic in adulthood. Brain nuclei were micro-dissected and GAD(65) protein levels were quantified using western immunoblotting. Sex differences in levels of GAD(65) were found in the dorsomedial nucleus and preoptic area of the hypothalamus and also the medial amygdaloid nucleus and CA1 subfield of the hippocampus. Unexpectedly, there were sex differences in protein levels of the housekeeping gene, GAPDH, cautioning against the use of GAPDH for standardizing protein samples during western immunoblotting.

Aging↗
PubMed2001

CNS region-specific oxytocin receptor expression: importance in regulation of anxiety and sex behavior.

The oxytocin receptor (OTR) is differentially expressed in the CNS. Because there are multiple mechanisms by which the OTR can be transcriptionally induced, we hypothesized that differences in OTR expression may be explained by activation of distinct signal transduction pathways and may be critical for the control of anxiety and sex behaviors. To determine the regulation and functional significance of this expression, we infused female rats with modifiers of protein kinases before assaying for behavior and oxytocin receptor binding. In the ventromedial nucleus of the hypothalamus (VMH), estrogen-dependent induction of oxytocin receptors required protein kinase C activation, and oxytocin infused here promoted female sex behavior but had no effect on anxiety. In contrast, dopamine controlled tonic oxytocin receptor expression in the central nucleus of the amygdala (cAmyg) through activation of protein kinase A, and oxytocin infused here was anxiolytic but had no effect on female sex behavior. Therefore, we have identified brain region-specific regulation of the OTR in the VMH and cAmyg. Distinct signal transduction pathways regulating receptor expression and binding in each brain region may mediate in part the ability of oxytocin to exert these differential behavioral effects.

Animals↗
PubMed2001

Attenuation of hyperalgesia by LY235959, a competitive N-methyl-D-aspartate receptor antagonist.

N-methyl-D-aspartate (NMDA) receptor antagonists may be of value in the management of hyperalgesia. LY235959, a competitive NMDA receptor antagonist, at doses of 0.001 and 0.003 nmol, intrathecally (i.t.) blocked the hyperalgesia induced by 11.1 nmol of NMDA in rats prepared with a chronic i.t. cannula. However, LY235959 does not block the hyperalgesia produced by kainic acid (a non-NMDA glutamate receptor agonist) providing evidence of its selectivity for the NMDA receptor. Using the formalin nociceptive test, 0.001 nmol LY235959 (i.t.) significantly reduced the number of Phase 2 flinches by about 80%. LY235959 can also reduce the flinching in Phase 2 by 30% when given subcutaneously (s.c.) at the lowest dose which does not produce motor deficits (20 mmol/kg). Thus, LY235959 (i.t. or s.c.) has NMDA receptor antagonist activity as defined by its ability to prevent hyperalgesia and formalin-induced central sensitization. Moreover, it is a much more potent antihyperalgesic after i.t. as compared to s.c. administration.

Animals↗
PubMed2001

Comparison of two methods of reconstruction for primary malignant tumors at the knee: a sequential cohort study.

BACKGROUND AND OBJECTIVES: The purpose of this study was to compare the complications and functional outcome associated with the use of an irradiated allograft-implant composite or a bone-ingrowth modular tumor prosthesis for replacement of the knee joint after resection of a bone sarcoma from the distal femur or proximal tibia. METHODS: Eleven patients initially received an allograft reconstruction, followed by 64 treated with a tumor prosthesis. The primary analysis concerned reconstructive failure, defined by the requirement for removal of the original construct. Functional outcome was assessed by using the 1987 Musculoskeletal Tumor Society rating system. RESULTS: Reconstructive failure occurred in 6 of 11 (55%) allograft constructs compared with 10 of 64 (16%) tumor prostheses (P = 0.009). Failures were due to infection (2 of 11 allografts versus 4 of 64 prostheses; P = 0.2) or mechanical complications (4 of 11 allograft fractures versus 5 of 64 broken prosthetic stems and 1 aseptically loose prosthesis; P = 0.03). The limb salvage rate was 95% (61 of 64) for patients with a tumor prosthesis compared with 64% (7 of 11) for those with an allograft (P = 0.007). Patients with a tumor prosthesis had a better functional outcome with a mean score of 75% compared with 57% for those with an allograft reconstruction (P = 0.006). CONCLUSIONS: This comparative study suggests that limb salvage surgery at the knee has a better and more predictable outcome with a tumor prosthesis than with an allograft-implant reconstruction.

Adolescent↗
PubMed2001

GABA influences the development of the ventromedial nucleus of the hypothalamus.

The region that becomes the ventromedial nucleus of the hypothalamus (VMH) is surrounded by cells and fibers containing immunoreactive gamma-aminobutyric acid (GABA) by embryonic day 13 (E13), several days before the nucleus emerges in Nissl stains. As GABA plays many roles during neural development, we hypothesized that it influences VMH development, perhaps by providing boundary information for migrating neurons. To test this hypothesis we examined the VMH in embryonic mice in which the beta3 subunit of the GABA(A)-receptor, a receptor subunit that is normally highly expressed in this nucleus, was disrupted by gene targeting. In beta3 -/- embryos the VMH was significantly larger, and the distribution of cells containing immunoreactive estrogen receptor-alpha was expanded compared to controls. Using in vitro brain slices from wild-type C57BL/6J mice killed at E15 we found that treatment with the GABA(A) antagonist bicuculline increased the number of cells migrating per video field analyzed in the VMH. In addition, treatment with either bicuculline or the GABA(A) agonist muscimol altered the orientation of cell migration in particular regions of this nucleus. These data suggest that GABA is important for the organization of cells during VMH formation.

Animals↗
PubMed2001

Magnetic properties and heavy-metal contents of contaminated seabed sediments of Penny's Bay, Hong Kong.

Magnetic properties and heavy-metal concentrations of vibrocore samples were found to be potential indicators of shipping contamination in seabed sediments in Hong Kong Harbour. Geochemical results of 74 vibrocores located off Penny's Bay on Lantau Island revealed an enrichment of heavy metals in the upper 1-2 m of the cores within the eastern part of the study site. Whole-core magnetic susceptibility measurements also showed a greater concentration of magnetic particles in the surficial layer of these cores. A significant correlation exists between the magnetic susceptibility and the concentrations of Pb, Zn and Cu, as well as the Tomlinson pollution load index (PLI). The proximity of these cores to a major navigation fairway and an anchorage site suggests probable contamination of the surficial seabed sediments by shipping-related wastes. A study of the magnetic properties of one of the cores, VT60, revealed a difference in the magnetic properties between the contaminated and the uncontaminated sediments. Samples from the contaminated zone exhibited relatively stronger magnetic remanence and susceptibility. The two groups of samples also formed distinct trends on the hysteresis ratios plot. A level of unusually high magnetic susceptibility within the contaminated zone was attributable to the presence of strongly magnetized granules, which were probably refuse from shipping-related activities. Geochemical and magnetic results were also conducted on samples of different size-fractions from this core. The < 63 microns fraction was found to contain a relatively higher magnetic susceptibility and greater heavy-metal content.

Environmental Monitoring↗