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Biomedical subjects

T J O'Neill

Publications and source records attributed to T J O'Neill.

At least 19 recordsLinked to original sources
PubMed2001

Estimating cohort health expectancies from cross-sectional surveys of disability.

A life history can be regarded as a random process that evolves with age through various states of health before terminating with absorption into the state of death. Health expectancies are the occupation times of the non-absorbing states and their estimation is of interest. A continuing major problem has been the lack of satisfactory longitudinal data on which to base estimates and as a result standard inferential techniques may not be relevant. Supposing only cross-sectional data available, we propose a method that is generally applicable and first estimates a logistic parametrization of the probabilities of the various states. A large sample approximation is obtained for the distribution of age specific log (odds). Parameters are estimated by weighted least squares, and this in turn leads to estimates of cohort health expectancies. A result of Liang and Zeger is used to find standard errors. The method is illustrated by application to Australian data from the health surveys of 1981, 1988 and 1993.

Aged↗
PubMed2001

Convergence criteria for scattering models of ultrasonic wave propagation in suspensions of particles.

Scattering models used to simulate the attenuation and phase velocity of an ultrasonic wave propagating through a suspension of particles involve the summation of an infinite series of partial waves. The accuracy of computation is influenced by the number of terms included in the harmonic series, and the number of terms required depends upon the scatterer size compared with wavelength. It is shown that the errors in modelled attenuation and phase velocity resulting from premature truncation can be significant when modelling higher values of particle diameter-frequency product. A useful and simple heuristic is presented, in which the number of terms in the summation of the infinite series needed for satisfactory convergence to a final value is a function of the particle diameter-frequency product and of the compressive wave velocity in the continuous phase.

Journal Article↗
PubMed2001

Identification of G protein-coupled, inward rectifier potassium channel gene products from the rat anterior pituitary gland.

Dopamine (DA) is a physiological regulator of PRL secretion, exerting tonic inhibitory control. DA activates an inward rectifier K(+) (IRK) channel in rat lactotropes, causing membrane hyperpolarization and inhibition of Ca(2+)-dependent action potentials. Both the activation of this effector K(+) channel and the inhibition of PRL release are mediated by D(2)-type receptor activation and pertussis toxin- sensitive G proteins. To study the molecular basis of this physiologically relevant channel, a homology-based PCR approach was employed to identify members of the IRK channel family expressed in the anterior pituitary gland. Nondegenerate primers corresponding to regions specific for IRK channels known to be G protein activated (GIRKs; gene subfamily Kir 3.0) were synthesized and used in the PCR with reverse transcribed female rat anterior pituitary messenger RNA as the template. PCR products of predicted sizes for Kir 3.1, 3.2, and 3.4 were consistently observed by ethidium bromide staining after 16 amplification cycles. The identities of the products were confirmed by subcloning and sequencing. Expression of each of these gene products in anterior pituitary was confirmed by Northern blot analysis. Functional analysis of the GIRK proteins was performed in the heterologous expression system, Xenopus laevis oocytes. Macroscopic K(+) currents were examined in oocytes injected with different combinations of Kir 3.0 complementary RNA (cRNA) and G protein subunit (beta(1)gamma(2)) cRNA. The current-voltage relationships demonstrated strong inward rectification for each individual and pairwise combination of GIRK channel subunits. Oocytes coinjected with any pair of GIRK subunit cRNA exhibited significantly larger inward K(+) currents than oocytes injected with only one GIRK channel subtype. Ligand-dependent activation of only one of the GIRK combinations (GIRK1 and GIRK4) was observed when channel subunits were coexpressed with the D(2) receptor in Xenopus oocytes. Dose-response data fit to a Michaelis-Menten equation gave an apparent K(d) similar to that for DA binding in anterior pituitary tissue. GIRK1 and GIRK4 proteins were coimmunoprecipitated from anterior pituitary lysates, confirming the presence of native GIRK1/GIRK4 oligomers in this tissue. These data indicate that GIRK1 and GIRK4 are excellent candidate subunits for the D(2)-activated, G protein-gated channel in pituitary lactotropes, where they play a critical role in excitation-secretion coupling.

Animals↗
PubMed2000

Synthesis of conformationally constrained 5,6,7, 8-Tetrahydroimidazo[1,5-a]pyridine inhibitors of farnesyltransferase.

[reaction: see text] Synthesis of the 8-amino-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring system was accomplished by intramolecular cyclization of an iminium ion, derived from condensation of an amine and a substituted gamma-(1-imidazolyl)butyraldehyde. The reaction was used to produce conformationally restricted farnesyltransferase inhibitor analogues which exhibit improved in vivo metabolic stability.

Administration, Oral↗
PubMed2000

Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults.

PRO 542 (CD4-IgG2) is a recombinant antibody-like fusion protein wherein the Fv portions of both the heavy and light chains of human IgG2 have been replaced with the D1D2 domains of human CD4. Unlike monovalent and divalent CD4-based proteins, tetravalent PRO 542 potently neutralizes diverse primary human immunodeficiency virus (HIV) type 1 isolates. In this phase 1 study, the first evaluation of this compound in humans, HIV-infected adults were treated with a single intravenous infusion of PRO 542 at doses of 0.2-10 mg/kg. PRO 542 was well tolerated, and no dose-limiting toxicities were identified. Area under the concentration-time curve, and peak serum concentrations increased linearly with dose, and a terminal serum half-life of 3-4 days was observed. No patient developed antibodies to PRO 542. Preliminary evidence of antiviral activity was observed as reductions in both plasma HIV RNA and plasma viremia. Sustained antiviral effects may be achieved with repeat dosing with PRO 542.

Anti-HIV Agents↗
PubMed2000

Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.

For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Although these data support the further development of FTIs, it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers. Moreover, Ki-RasB binds more tightly to FPTase than either Ha- or N-Ras, and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing. Given the unique biochemical and biological features of Ki-RasB, it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein. We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V) under the control of the MMTV enhancer/promoter. The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detected in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity. Although FPTase activity was inhibited in tumors from the treated mice, unprocessed Ki-RasB was not detected. These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model, Ki-Ras may not be the sole mediator of the biological effects of the FTI.

Alkyl and Aryl Transferases↗
PubMed2000

The analysis of group truncated binary data with random effects: injury severity in motor vehicle accidents.

The analysis of group truncated binary data has been previously considered by O'Neill and Barry (1995b, Biometrics 51, 533-541), where the analysis assumed that responses within each group were independent. In this paper, we consider the analysis of such data when there is group-level heterogeneity. A generalized linear mixed model is hypothesized to model the response and maximum likelihood estimates are derived for the truncated case. A score test is derived to test for heterogeneity. Finally, the method is applied to a set of traffic accident data.

Accidents, Traffic↗
PubMed2000

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen.

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O(2) (HBO(2)) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O(2) exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor (N(omega)-nitro-L-arginine methyl ester), L-arginine, NO donors, or the N-methyl-D-aspartate receptor inhibitor MK-801. After 30 min of O(2) exposure at 3 and 4 ATA, rCBF decreased by 26-39% and by 37-43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N(omega)-nitro-L-arginine methyl ester and exposed to HBO(2) at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO(2) at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO(2) exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO(2), but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.

Animals↗
PubMed1999

Alternative splicing, gene localization, and binding of SH2-B to the insulin receptor kinase domain.

The SH2-B protein is an SH2-domain-containing molecule that interacts with a number of phosphorylated kinase and receptor molecules including the insulin receptor. Two isoforms of the SH2-B have been identified and have been proposed to arise through alternate splicing. Here we have identified a third isoform of the SH2-B protein, SH2-Bgamma, that interacts specifically with the insulin receptor. This interaction required phosphorylation of residue Y1146 in the triple tyrosine motif within the activation loop of the IR kinase and is one of only two signaling molecules shown to interact directly with this residue of the insulin receptor kinase domain. The intron/exon structure of the SH2-B gene was determined. Alternate splice sites utilized to generate the different isoforms of the SH2-B protein were identified in the 3' end of the SH2-B gene immediately downstream of the exon encoding the core of the SH2 domain. Additionally, the chromosomal location of the SH2-B gene was determined to be the distal arm of mouse Chromosome (Chr) 7 in a region linked to obesity in mice.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The effectiveness of air bags.

Previous research has shown that the installation of air bags in vehicles significantly reduces crash related deaths, but these analyses have used statistical techniques which have not been capable of controlling for other major determinants of crash survival. This study analysed data from the US FARS database of fatal crashes using conditional logistic regression which is simultaneously able to estimate occupant protection effects for a range of variables. Results of the analysis provided a comparative quantification of both the effect of the air bag as well as other well known determinants of occupant crash survival (age, seat belt use, and gender). When potentially confounding variables were controlled, both the driver and passenger side air bag devices were shown to significantly reduce the probability of death in direct frontal collisions, but the effect size calculated was small compared to the effect of the seat belt. The effect size may also be very small in absolute terms depending on the severity of the crash involved. Given the limited benefit of the air bag, efforts to promote air bags seem particularly difficult to justify in countries such as the United States where the vastly superior occupant protection of the seat belt is under-utilised.

Accident Prevention↗
PubMed1998

A comparison of the patient and surgeon opinion on the long-term aesthetic outcome of reduction mammaplasty.

The aim of this study was to assess the difference in opinion between patients and surgeons regarding the aesthetic outcome of reduction mammaplasty. A total of 34 women, who were more than 1 year post surgery, attended an outpatient clinic to assess their opinion of the aesthetic outcome of their breast reduction. A questionnaire was used to standardise their responses. Photographic slides were taken to record the frontal, left oblique and recumbent view of their torso. These slides were assessed by four consultant plastic surgeons who completed the same questionnaire, and were blinded as to the surgeon and patient. The majority of patients rated the aesthetic outcomes of their surgery significantly higher than the consultants. Scarring was the most frequent cause of dissatisfaction for both surgeons and patients. The consultants considered the scarring following Lejour reduction to be significantly better than that following the inferior mound reduction. The nipple was considered to be too high on the breast by 12% of women but they did not request correction of this. However, consultants thought this was a problem in 27% of cases. The aesthetic outcome of reduction mammaplasty was acceptable to the patients although surgical assessment indicates that there is scope for improvement. The main area of aesthetic dissatisfaction remains the postoperative scarring.

Adult↗
PubMed1998

A farnesyltransferase inhibitor induces tumor regression in transgenic mice harboring multiple oncogenic mutations by mediating alterations in both cell cycle control and apoptosis.

The farnesyltransferase inhibitor L-744,832 selectively blocks the transformed phenotype of cultured cells expressing a mutated H-ras gene and induces dramatic regression of mammary and salivary carcinomas in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice. To better understand how the farnesyltransferase inhibitors might be used in the treatment of human tumors, we have further explored the mechanisms by which L-744,832 induces tumor regression in a variety of transgenic mouse tumor models. We assessed whether L-744,832 induces apoptosis or alterations in cell cycle distribution and found that the tumor regression in MMTV-v-Ha-ras mice could be attributed entirely to elevation of apoptosis levels. In contrast, treatment with doxorubicin, which induces apoptosis in many tumor types, had a minimal effect on apoptosis in these tumors and resulted in a less dramatic tumor response. To determine whether functional p53 is required for L-744,832-induced apoptosis and the resultant tumor regression, MMTV-v-Ha-ras mice were interbred with p53(-/-) mice. Tumors in ras/p53(-/-) mice treated with L-744,832 regressed as efficiently as MMTV-v-Ha-ras tumors, although this response was found to be mediated by both the induction of apoptosis and an increase in G1 with a corresponding decrease in the S-phase fraction. MMTV-v-Ha-ras mice were also interbred with MMTV-c-myc mice to determine whether ras/myc tumors, which possess high levels of spontaneous apoptosis, have the potential to regress through a further increase in apoptosis levels. The ras/myc tumors were found to respond nearly as efficiently to L-744,832 treatment as the MMTV-v-Ha-ras tumors, although no induction of apoptosis was observed. Rather, the tumor regression in the ras/myc mice was found to be mediated by a large reduction in the S-phase fraction. In contrast, treatment of transgenic mice harboring an activated MMTV-c-neu gene did not result in tumor regression. These results demonstrate that a farnesyltransferase inhibitor can induce regression of v-Ha-ras-bearing tumors by multiple mechanisms, including the activation of a suppressed apoptotic pathway, which is largely p53 independent, or by cell cycle alterations, depending upon the presence of various other oncogenic genetic alterations.

Alkyl and Aryl Transferases↗
PubMed1998

Diclofenac analgesia following cleft palate surgery.

OBJECTIVE: This prospective study looked at the postoperative hemorrhage risk associated with the use of diclofenac following cleft palate repair. PATIENTS: Twenty consecutive children (6 months to 9 years of age) requiring repair of the hard or soft palate were included. DESIGN AND METHODS: Single per rectum doses of diclofenac were given at 1 mg/kg following cleft palate repair, with additional doses every 12 hours. RESULTS AND CONCLUSIONS: The use of the nonsteroidal anti-inflammatory drug, diclofenac, for postoperative analgesia is well established for many types of surgery. The authors find that twice daily diclofenac rectal suppositories provide very good analgesia postcleft palate repair. This, combined with supplemental oral paracetamol, obviates the need for opiates, resulting in alert infants who feed well and are suitable for early discharge.

Acetaminophen↗
PubMed1998

Measurement of cerebral blood flow in rats and mice by hydrogen clearance during hyperbaric oxygen exposure.

The hydrogen (H2) clearance method was adapted for the measurement of regional cerebral blood flow (rCBF) in anesthetized rats and mice during hyperbaric oxygen (HBO2) exposure. Polarographic platinum electrodes 0.1 mm in diameter were used to record H2 clearance curves from the parietal cortex (PC), substantia nigra (SN), and caudate putamen nucleus (CPN) after inhalation of 2.5% H2 in air. The system for H2 breathing under hyperbaric conditions was designed for remote operation from outside the chamber. The rCBF values (measured every 10 min) were calculated from the H2 clearance curves using the initial slope method. During air breathing control, rCBF values were similar to values reported using other methods. Considering all control rats together, blood flow (ml.100 g-1.min-1) was 89 +/- 3.6 in the SN, 78 +/- 4.7 in the CPN, and 76 +/- 6.7 in the PC. Blood flow (ml.100 g-1.min-1) for air-breathing mice was 108 +/- 11.4 in the SN and 74 +/- 8.8 in the CPN. During HBO2 exposure to 3 atm abs, rCBF in rats fell within 30 min by 26-39% (P < 0.05) and by 27-29% in mice (P < 0.05). HBO2 exposure to 4 atm abs induced maximal rCBF decreases in rats within 60 min by 37% (P < 0.01) in the SN and by 47% (P < 0.01) in the CPN. Breathing CO2 during HBO2 exposure to 4 atm abs reversed the vasoconstriction and led to a rCBF increase of 80-96% in rats. The H2 clearance method seems to be an accurate and sensitive technique for the repeated measurement of local CBF under hyperbaric conditions.

Animals↗