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Biomedical subjects

J Millard

Publications and source records attributed to J Millard.

At least 19 recordsLinked to original sources
PubMed2003

Expression of cysteine dioxygenase (EC 1.13.11.20) and sulfite oxidase in the human lung: a potential role for sulfate production in the protection from airborne xenobiotica.

AIMS: The lung is one of the major sites of phase I cytochrome P450 enzyme and phase II sulfotransferase expression, which together are thought to act as an enzymic barrier against the unimpeded transfer of airborne xenobiotics into the lung parenchyma and systemic circulation. Sulfate for conjugation is produced primarily from the oxidation of cysteine, begun by cysteine dioxygenase (CDO), and completed with the conversion of sulfite to sulfate via sulfite oxidase (SO). Little is known about the site of expression of these two enzymes in the alveoli of the human lung. METHODS: Antibodies and oligonucleotide probes raised against both CDO and SO were used for immunohistochemistry and in situ hybridisation, respectively, to investigate the expression of CDO and SO in human lung alveoli. RESULTS: CDO and SO were expressed in alveolar epithelial cells, which is also the site of expression of cytochrome P450 1B1. CONCLUSIONS: These results demonstrate that the two key enzymes in sulfate production are expressed in the same locale as phase I and phase II enzymes, and that these two enzymes may be involved in the production of sulfate for the maintenance of a metabolic barrier against the entry of airborne xenobiotics and the synthesis of important structural proteins and proteoglycans.

Air Pollutants↗
PubMed2001

A phase II trial of dual protease inhibitor therapy: amprenavir in combination with indinavir, nelfinavir, or saquinavir.

This study evaluated dual protease inhibitor (PI) regimens containing amprenavir (APV) in PI-naive, HIV-1-infected patients over 48 weeks. Patients were randomized to 800-mg APV combined with 800-mg indinavir (IDV), 750-mg nelfinavir (NFV), or 800-mg saquinavir-soft gel capsule (SGV-SGC), all three times daily without nucleoside reverse transcriptase inhibitors, or APV given alone for 3 weeks and then with 150-mg lamivudine (3TC) and 300-mg zidovudine (ZDV), twice daily. Dual PI therapy demonstrated substantial antiviral activity and was generally safe and well tolerated. Eight patients had virologic failure; 5 were receiving dual PI therapy and 3 were in the APV/3TC/ZDV arm. The protease I50V mutation characteristic of APV resistance was not observed, although other key PI mutations were selected in 4 patients failing therapy, 2 of whom had PI resistance at baseline.

Adult↗
PubMed2001

A dose-ranging study to evaluate the antiretroviral activity and safety of amprenavir alone and in combination with abacavir in HIV-infected adults with limited antiretroviral experience.

OBJECTIVE: To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults. DESIGN: Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial. METHODS: Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively. RESULTS: At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy. CONCLUSIONS: The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

Administration, Oral↗
PubMed2000

Safety profile and tolerability of amprenavir in the treatment of adult and pediatric patients with HIV infection.

BACKGROUND: Amprenavir (APV) is a new HIV-I protease inhibitor used in combination with other antiretroviral agents for the treatment of HIV-1 infection. OBJECTIVE: The aim of this study was to assess the safety profile and tolerability of APV. METHODS: A review of data from 358 adults enrolled in 2 phase III, randomized, 48-week, controlled studies and from 268 children enrolled in 1 phase II and 1 phase III study was conducted. The adult data were collected between February 25, 1997, and April 1, 1999. Data were collected in children from September 10, 1997, to January 15, 1999; these data were collected before completion of either study. Adults and children who had and had not been treated previously with antiretroviral agents were enrolled. In these studies, APV was used in combination with 2 nucleoside reverse transcriptase inhibitors. RESULTS: The most common drug-related adverse events in patients receiving APV were gastrointestinal events and oral/perioral paresthesia. The majority of adverse events were mild or moderate in intensity, early in onset, and transient. Nausea (27/358 patients, 8%), vomiting (15/358, 4%), rash (11/358, 3%), and diarrhea/loose stools (9/358, 3%) were the most common adverse events associated with treatment discontinuation. Severe laboratory abnormalities possibly related to APV were rare. In children, the nature and frequency of adverse events were similar to those in adults. Metabolic complications were infrequent in APV studies to date; symptoms related to fat redistribution were reported in <3% of patients treated with APV. Lipid or glucose laboratory abnormalities were reported with similar frequency in the APV and control groups in both studies in adults. CONCLUSIONS: In the clinical trials reviewed, APV was generally well tolerated when administered with other antiretroviral agents in adult and pediatric patients with HIV infection.

Adolescent↗
PubMed2000

In vivo assessment of trabecular bone structure using fractal analysis of distal radius radiographs.

Our purpose in this study was (i) to measure trabecular bone structure using fractal analysis of distal radius radiographs in subjects with and without osteoporotic hip fractures, and (ii) to compare these measures with bone mineral density (BMD) as well as with measures of trabecular bone structure derived from high resolution magnetic resonance (MR) images. Distal radius radiographs were obtained using semi-industrial films (55 kVp, 400 mAs) in 30 postmenopausal patients, who had suffered osteoporotic hip fractures (74.8+/-8.2 years) in the last 24 months and 27 postmenopausal age-matched (74.6+/-6.6 yr) normal volunteers. Radiographs were digitized at 50 microm. A Fourier power spectrum-based fractal dimension (FD) characterizing the trabecular pattern was measured in a region of interest proximal to the joint line. The fractal dimension was calculated over two spatial frequency (f) ranges: FD1 was calculated over 0.5<log(f)<l.0, FD2 over the higher range 1.0<log(f)<1.5. Trabecular BMD in the radius was obtained using peripheral quantitative computed tomography (pQCT) (Stratec GmbH, Germany). In addition BMD of the proximal femur was determined using dual x-ray absorptiometry (DXA) (QDR 2000, Hologic, MA). In a subset of patients (16 controls and 18 with hip fractures), high resolution MR imaging of the distal radius (spatial resolution of 156 x 156 x 500 microm) was used to obtain measures analogous to bone histomorphometry. There were significant differences (p<0.05) between the fracture and nonfracture groups in the total femur BMD (13%), trabecular BMD in the distal radius (4%), and the fractal dimension in the radiographs (FD2) (3%). The correlations between FD2 and the total femur BMD as well as trabecular bone BMD in the distal radius were -0.48 (p<0.006) and -0.22 (p<0.33); respectively; FD1 increased with BMD and showed lower correlations. FD2 showed good correlations with App. Tb.N (-0.71) and App. Tb.Sp (0.69) (p<0.01), moderate correlation with App BV/TV (-0.53) (p<0.05), and no significant correlation with App. Tb.Th. The correlations between structural measures and FD1 showed the inverse trend and were typically lower. The odds ratios for a hip fracture were 2.44 for total femur BMD, 1.5 for trabecular BMD (radius), and 1.5 for FD2, respectively. In summary, the fractal measures derived from radiographs of the radius show differences between subjects with and without hip fractures, the predictive power of measures in the distal radius are comparable to radial trabecular BMD but lower than that of total hip BMD.

Aged↗
PubMed1999

Formulation and in vivo evaluation of ocular insert containing phenylephrine and tropicamide.

A Gelfoam based ocular device containing 1.7 mg of phenylephrine and 0.6 mg of tropicamide was formulated and evaluated for pupillary dilation in rabbits. The manufacturing procedure is fairly simple and the required excipients are inexpensive. The in vivo results show that the mydriatic response produced by the proposed device is larger and longer lasting than that produced by eyedrops with an equivalent amount of phenylephrine and tropicamide. The results reported in this study, along with those of previous studies, imply that Gelfoam(R) is a versatile drug carrier for either local or systemic drug delivery via the ophthalmic route.

Animals↗
PubMed1999

Closed contour edge detection of blood vessel lumen and outer wall boundaries in black-blood MR images.

Quantitative measurements of the blood vessel wall area may provide useful information of atherosclerotic plaque burden, progression and/or regression. Magnetic resonance imaging is a promising technique for identifying both luminal and outer wall boundaries of the human blood vessels. Currently these boundaries are primarily defined manually, a process viewed as labor intensive and subject to significant operator bias. Fully automated post-processing techniques used for identifying the lumen and wall boundaries, on the other hand, are also problematic due to the complexity of signal features in the vicinity of the blood vessels. The goals of this study were to develop a robust, automated closed contour edge detection algorithm, apply this algorithm to high resolution human carotid artery images, and assess its accuracy, and reproducibility. Our algorithm has proven to be sensitive to various contrast situations and is reasonably accurate and highly reproducible.

Algorithms↗
PubMed1999

Fractal analysis of radiographs: assessment of trabecular bone structure and prediction of elastic modulus and strength.

The purpose of this study was to determine whether fractal dimension of radiographs provide measures of trabecular bone structure which correlate with bone mineral density (BMD) and bone biomechanics, and whether these relationships depend on the technique used to calculate the fractal dimension. Eighty seven cubic specimen of human trabecular bone were obtained from the vertebrae and femur. The cubes were radiographed along all three orientations--superior-inferior (SI), medial-lateral (ML), and anterior-posterior (AP), digitized, corrected for background variations, and fractal based techniques were applied to quantify trabecular structure. Three different techniques namely, semivariance, surface area, and power spectral methods were used. The specimens were tested in compression along three orientations and the Young's modulus (YM) was determined. Compressive strength was measured along the SI direction. Quantitative computed tomography was used to measure trabecular BMD. High-resolution magnetic-resonance images were used to obtain three-dimensional measures of trabecular architecture such as the apparent bone volume fraction, trabecular thickness, spacing, and number. The measures of trabecular structure computed in the different directions showed significant differences (p<0.05). The correlation between BMD, YM, strength, and the fractal dimension were direction and technique dependent. The trends of variation of the fractal dimension with BMD and biomechanical properties also depended on the technique and the range of resolutions over which the data was analyzed. The fractal dimension showed varying trends with bone mineral density changes, and these trends also depended on the range of frequencies over which the fractal dimension was measured. For example, using the power spectral method the fractal dimension increased with BMD when computed over a lower range of spatial frequencies and decreased for higher ranges. However, for the surface area technique the fractal dimension increased with increasing BMD. Fractal measures showed better correlation with trabecular spacing and number, compared to trabecular thickness. In a multivariate regression model inclusion of some of the fractal measures in addition to BMD improved the prediction of strength and elastic modulus. Thus, fractal based texture analysis of radiographs are technique dependent, but may be used to quantify trabecular structure and have a potentially valuable impact in the study of osteoporosis.

Biomechanical Phenomena↗
PubMed1998

Power spectral analysis of vertebral trabecular bone structure from radiographs: orientation dependence and correlation with bone mineral density and mechanical properties.

Trabecular bone structure and bone density contribute to the strength of bone and are potentially important in the study of osteoporosis. Fourier transforms of the textural patterns in radiographs of trabecular bone have previously been used for the measurement of trabecular bone structure in subjects, however, the relationship between these measures and biomechanical properties of bone have not previously been established. In this study radiographs were acquired of 28 cubic specimens of spinal trabecular bone along each of the three anatomic axes: cranio-caudal or superior-inferior (SI), medial-lateral (ML), and anterior-posterior (AP). The radiographs were digitized, background corrected, and uniformly aligned. The Fast Fourier transform (FFT) was performed on a region comprised solely of trabecular bone for each image. The zero (DC), first (FMO), and second moments (SMO) of the Fourier power spectrum and the fractal dimension (FD) as determined from the Fourier power spectrum were correlated with stereology measures, with bone mineral density (BMD) as well as with measured biomechanical properties [Young's elastic modulus (YM) and ultimate strength] of the cubes. The results show that the power spectra-based measures, when compared with structural parameters determined using 3D stereology, show good correlations with bone volume fraction, trabecular spacing, thickness, and number. These power spectral measures showed fair to good correlations with BMD and the biomechanical properties. Moreover, the correlations between the power spectral measures of trabecular structure and the BMD, YM, and stereology measures of structure depend on the orientation of the radiographic image. Specifically, these were significant differences in the measured biomechanical properties and the power spectral measures of the trabecular structure between the SI and ML and the SI and AP directions. In addition, depending on the spatial frequency range for analysis, the fractal dimension showed opposite trends with changes in BMD and biomechanical properties. Multivariate regression models showed the correlation coefficients increasing with the inclusion of some of the power spectral measures, suggesting that FFT-based texture analysis may play a potential role in studies of osteoporosis.

Biomechanical Phenomena↗
PubMed1997

Absence of bradycardic response to apnea and hypoxia in heart transplant recipients with obstructive sleep apnea.

In patients with obstructive sleep apnea, the vagal stimulation caused by inspiration against the upper airway obstruction results in sinus bradycardia during the apnea followed by a reflex tachycardia at apnea termination. We report on five heart transplant recipients with obstructive sleep apnea who demonstrated no change in baseline heart rate in spite of marked hemoglobin oxygen desaturation, presumably on account of parasympathetic denervation of the allograft. Heart transplant recipients with obstructive sleep apnea may be at an increased risk of development of potentially fatal ventricular arrhythmias if the allograft is unable to respond appropriately to hypoxia. Should cardiac parasympathetic reinnervation occur, prospective polysomnography may be a marker for this process in these patients.

Bradycardia↗
PubMed1997

Sexual healing.

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Adult↗
PubMed1996

In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents.

141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.08 microM against HIV-1 (strain IIIB) and a mean IC50 of 0.012 microM against six HIV clinical isolates. 141W94 was synergistic on the basis of isobologram analysis with each of the following reverse transcriptase inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl, 141W94 was also synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human alpha 1-acid glycoprotein was relatively weak (Kd = 4 microM) and the off-rate for the drug is very fast (> or = 100 s-1). Only a 2-fold reduction of in vitro antiviral activity was observed in the presence of 45% human plasma. No serious drug associated adverse experiences were reported in a Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 141W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.

Carbamates↗
PubMed1995

Effect of demand frequency on lockout period. The Abbott Provider 5500 Patient-Controlled Analgesia machine.

An Abbott Provider 5500 Patient Controlled Analgesia machine was noticed to have developed a prolonged lockout period when frequent analgesic demands were being made. This study tested five other machines and demonstrated that the duration of the lockout period was influenced by the frequency of analgesic demands. This finding could have clinical implications and we recommend that the duration of the lockout period should be specifically examined during the testing of patient-controlled machines.

Analgesia, Patient-Controlled↗