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Biomedical subjects

P O'Hara

Publications and source records attributed to P O'Hara.

At least 19 recordsLinked to original sources
PubMed2006

The illegal introduction of rabbit haemorrhagic disease virus in New Zealand.

In 1997, a group of pastoral farmers, frustrated by governmental and official responses to their problems of rabbit control, introduced and spread the rabbit haemorrhagic disease virus in a clandestine operation that succeeded in distributing infection over a large area of the South Island before the disease was detected by government officials. The government concluded that eradication was not technically or economically feasible and the disease was accepted as being endemic. The episode highlighted the inadequate decision-making environment that existed at the time, now improved by the passage of the Hazardous Substances and New Organisms Act. It also highlights the importance of having a comprehensive biosecurity detection and response capability, including the ability to conduct prompt risk assessments, since preventing entry of biological agents may be difficult to achieve in the face of a determined adversary.

Animals↗
PubMed2001

Cloning and characterization of a human orphan family C G-protein coupled receptor GPRC5D.

Recently three orphan G-protein coupled receptors, RAIG1, GPRC5B and GPRC5C, with homology to members of family C (metabotropic glutamate receptor-like) have been identified. Using the protein sequences of these receptors as queries we identified overlapping expressed sequence tags which were predicted to encode an additional subtype. The full length coding regions of mouse mGprc5d and human GPRC5D were cloned and shown to contain predicted open reading frames of 300 and 345 amino acids, respectively. GPRC5D has seven putative transmembrane segments and is expressed in the cell membrane. The four human receptor subtypes, which we assign to group 5 of family C GPCRs, show 31-42% amino acid sequence identity to each other and 20-25% sequence identity to the transmembrane domains of metabotropic glutamate receptor subtypes 2 and 3 and other family C members. In contrast to the remaining family C members, the group 5 receptors have short amino terminal domains of some 30-50 amino acids. GPRC5D was shown to be clustered with RAIG1 on chromosome 12p13.3 and like RAIG1 and GPRC5B to consist of three exons, the first exon being the largest containing all seven transmembrane segments. GPRC5D mRNA is widely expressed in the peripheral system but all four receptors show distinct expression patterns. Interestingly, mRNA levels of all four group 5 receptors were found in medium to high levels in the kidney, pancreas and prostate and in low to medium levels in the colon and the small intestine, whereas other organs only express a subset of the genes. In an attempt to delineate the signal transduction pathway(s) of the orphan receptors, a series of chimeric receptors containing the amino terminal domain of the calcium sensing receptor or metabotropic glutamate receptor subtype 1, and the seven transmembrane domain of the orphan receptors were constructed and tested in binding and functional assays.

Amino Acid Sequence↗
PubMed2001

Fatty acid synthesis in developing leaves of Brassica napus in relation to leaf growth and changes in activity of 3-oxoacyl-ACP reductase.

In young expanding leaves of Brassica napus, the demand for fatty acids is met by de novo biosynthesis of fatty acid synthase components, as demonstrated by 3-oxoacyl-ACP reductase. Using a novel radio-chemical assay for 3-oxoacyl-ACP reductase and specific antibodies, we have demonstrated a direct relationship between the increase in activity and synthesis of polypeptide. The maximum rate of fatty acid synthesis was between 4 and 7 days post-emergence, but slowed after this point even though 3-oxoacyl-ACP reductase activity was high. Leaf area continued to expand in a linear fashion after reductions in both enzyme activity and the rate of fatty acid synthesis.

3-Oxoacyl-(Acyl-Carrier-Protein) Reductase↗
PubMed2001

Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model.

PURPOSE: Targeted delivery of rifampicin loaded microspheres to the alveolar macrophage, the host cell for Mycobacterium tuberculosis (MTB), may be an effective targeted approach to pulmonary tuberculosis therapy. A guinea pig infection model has been adopted as a post-treatment screening method for antimicrobial effect. Insufflation and nebulization methods of drug delivery were evaluated. METHODS: Rifampicin alone (RIF, 1.03-1.72 mg/kg), within poly(lactide-co-glycolide) microspheres (R-PLGA, equivalent to 1.03-1.72 mg/kg) or polymer microparticles alone (PLGA) were administered by insufflation or nebulization, 24 h before bacterial aerosol exposure. Animals were infected with an aerosol containing a small number (2 x 10(5) cfu/mL) of virulent H37Rv strain of MTB. Lung and spleen tissue samples were collected 28 days after infection for quantitative bacteriology and histopathological analysis. RESULTS: There was a dose-effect relationship between insufflated R-PLGA and burden of bacteria in the lungs. In addition, guinea pigs treated with R-PLGA had a significantly smaller number of viable bacteria (P < 0.05), reduced inflammation and lung damage than lactose or saline control, PLGA or RIF treated animals. CONCLUSIONS: These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB.

Administration, Inhalation↗
PubMed2001

Airways delivery of rifampicin microparticles for the treatment of tuberculosis.

A Mycobacterium tuberculosis (H37Rv)-infected guinea pig model was used to screen for targeted delivery to the lungs by insufflation (with lactose excipient) or nebulization, of either rifampicin alone, rifampicin within poly(lactide-co-glycolide) microspheres (R-PLGA) or polymer microparticles alone (PLGA). Animals treated with single and double doses of R-PLGA microspheres exhibited significantly reduced numbers of viable bacteria, inflammation and lung damage compared with lactose-, PLGA- or rifampicin-treated animals 28 days post-infection (P < 0.05). Two doses of R-PLGA resulted in reduced splenic enlargement. These studies support the potential of R-PLGA delivered to the lung to treat pulmonary tuberculosis.

Animals↗
PubMed2001

Variation in health and risk behavior among youth living with HIV.

Lifetime and current health practices and risk behaviors were examined among 350 youth living with HIV (YLH) aged 14-23 years from four AIDS epicenters (72.6% male; 26.2% African American, 36.9% Latino). YLH were relatively healthy (M CD4 cells = 499), had used substantial health care and were satisfied with the care. YLH's sexual and substance-use histories indicated substantial HIV related risk acts: the median number of lifetime partners was 25 with only 8% using condoms consistently; 14.9% had injected drugs, and 61.2% had used hard drugs. Compared with females, males had more lifetime and recent sexual partners and had used more drugs. Youth who were recently sexually active (81.3%) had multiple partners. Most of the sexually active YLH used condoms consistently (81.6%). YLH who were symptomatic or had an AIDS diagnosis were likely to have recently had more seropositive sexual partners than the asymptomatic youth. Youth disclosed their serostatus to about half of their sexual partners (53.9%). YLH with AIDS used fewer hard drugs than those without an AIDS diagnosis. Health and risk behaviors of the YLH varied significantly based on their disease stage, gender, and ethnicity, suggesting the need for tailoring interventions for subgroups of YLH.

Adolescent↗
PubMed2000

Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: manufacture and characterization.

PURPOSE: Particles with aerodynamic diameters of 1-5 microm deposit in the periphery of the lungs and are phagocytized by alveolar macrophages, the primary site of Mycobacterium tuberculosis infection. Aerosols of biodegradable polymeric microspheres containing antitubercular agents may be delivered to the lungs to improve the treatment of tuberculosis. METHODS: Poly(lactide-co-glycolide) (PLGA) microspheres containing rifampicin were prepared using solvent evaporation and spray drying methods. The solvent evaporation process was optimized using factorial experimental design and surface response methodology. The morphology, particle size, drug loading, and dissolution of microspheres was evaluated. RESULTS: The spray dried rifampicin loaded PLGA microparticles were shriveled, unlike the spherical particles produced by solvent evaporation. Drug loadings of 20% and 30% were achieved for solvent evaporation and spray dried products, respectively. The particles prepared by solvent evaporation and spray drying had 3.45 microm and 2.76 microm median diameters by volume, respectively. CONCLUSIONS: Respirable rifampicin loaded PLGA microspheres were produced by both solvent evaporation and spray drying methods. These particles are being evaluated in an animal model of tuberculosis.

Antibiotics, Antitubercular↗
PubMed2000

Analysis of risk factors for myocardial infarction and cardiac mortality after major vascular surgery.

BACKGROUND: Patients undergoing vascular surgical procedures are at high risk for perioperative myocardial infarction (PMI). This study was undertaken to identify predictors of PMI and in-hospital death in major vascular surgical patients. METHODS: From the Vascular Surgery Registry (6,948 operations from January 1989 through June 1997) the authors identified 107 patients in whom PMI developed during the same hospital stay. Case-control patients (patients without PMI) were matched at a 1x:x1 ratio with index cases according to the type of surgery, gender, patient age, and year of surgery. The authors analyzed data regarding preoperative cardiac disease and surgical and anesthetic factors to study association with PMI and cardiac death. RESULTS: By using univariable analysis the authors identified the following predictors of PMI: valvular disease (P = 0.007), previous congestive heart failure (P = 0.04), emergency surgery (P = 0.02), general anesthesia (P = 0.03), preoperative history of coronary artery disease (P = 0.001), preoperative treatment with beta-blockers (P = 0.003), lower preoperative (P = 0.03) and postoperative (P = 0.002) hemoglobin concentrations, increased bleeding rate (as assessed from increased cell salvage; P = 0.025), and lower ejection fraction (P = 0.02). Of the 107 patients with PMI, 20.6% died of cardiac cause during the same hospital stay. The following factors increased the odds ratios for cardiac death: age (P = 0.001), recent congestive heart failure (P = 0.01), type of surgery (P = 0.04), emergency surgery (P = 0.02), lower intraoperative diastolic blood pressure (P = 0.001), new intraoperative ST-T changes (P = 0.01), and increased intraoperative use of blood (P = 0.005). Patients who underwent coronary artery bypass grafting, even more than 12 months before index surgery, had a 79% reduction in risk of death if they had PMI (P = 0.01). Multivariable analysis revealed preoperative definitive diagnosis of coronary artery disease (P = 0.001) and significant valvular disease (P = 0.03) were associated with increased risk of PMI. Congestive heart failure less than 1 yr before index vascular surgery (P = 0. 0002) and increased intraoperative use of blood (P = 0.007) were associated with cardiac death. The history of coronary artery bypass grafting reduced the risk of cardiac death (P = 0.04) in patients with PMI. CONCLUSIONS: The in-hospital cardiac mortality rate is high for patients who undergo vascular surgery and experience clinically significant PMI. Stress of surgery (increased intraoperative bleeding and aortic, peripheral vascular, and emergency surgery), poor preoperative cardiac functional status (congestive heart failure, lower ejection fraction, diagnosis of coronary artery disease), and preoperative history of coronary artery bypass grafting are the factors that determine perioperative cardiac morbidity and mortality rates.

Analysis of Variance↗
PubMed1999

The agonist-binding domain of the calcium-sensing receptor is located at the amino-terminal domain.

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that displays 19-25% sequence identity to the gamma-aminobutyric acid type B (GABAB) and metabotropic glutamate (mGlu) receptors. All three groups of receptors have a large amino-terminal domain (ATD), which for the mGlu receptors has been shown to bind the endogenous agonist. To investigate whether the agonist-binding domain of the CaR also is located in the ATD, we constructed a chimeric receptor named Ca/1a consisting of the ATD of CaR and the seven transmembrane region and C terminus of mGlu1a. The Ca/1a receptor stimulated inositol phosphate production when exposed to the cationic agonists Ca2+, Mg2+, and Ba2+ in transiently transfected tsA cells (a transformed HEK 293 cell line). The pharmacological profile of Ca/1a (EC50 values of 3.3, 2.6, and 3.9 mM for these cations, respectively) was very similar to that of the wild-type CaR (EC50 values of 3.2, 4.7, and 4.1 mM, respectively). For the mGlu1a receptor, it has been shown that Ser-165 and Thr-188, which are located in the ATD, are involved in the agonist binding. An alignment of CaR with the mGlu receptors showed that these two amino acid residues have been conserved in CaR as Ser-147 and Ser-170, respectively. Each of these residues was mutated to alanines and tested pharmacologically using the endogenous agonist Ca2+. CaR-S147A showed an impaired function as compared with wild-type CaR both with respect to potency of Ca2+ (4-fold increase in EC50) and maximal response (79% of wild-type response). CaR-S170A showed no significant response to Ca2+ even at 50 mM concentration. In contrast, each of the two adjacent mutations, S169A and S171A, resulted in pharmacological profiles almost identical to that of the wild-type receptor. These data demonstrate that Ser-170 and to some extent Ser-147 are involved in the Ca2+ activation of the CaR, and taken together, our results reveal a close resemblance of the activation mechanism between the CaR and the mGlu receptors.

Amino Acid Sequence↗
PubMed1999

Substance use and its relationship to depression, anxiety, and isolation among youth living with HIV.

Reductions from lifetime to recent levels of substance use, the time since HIV diagnosis, physical health symptoms, CD4 counts, emotional distress, and social supports were examined among 227 (20% female; 22% African American, 27% Anglo, 35% Latino) youth living with HIV (YLH) ages 13 to 24 years. Substance use pervaded the lives of these youth. Male YLH had used more drugs., more often, and for longer periods than women. However, there had been major reductions in use. Being male, having high emotional distress, and having fewer negative social supports were significantly associated with greater reductions in substance use. There was a trend for the length of time that an individual was seropositive being associated with reductions in substance use. The counterintuitive findings suggest that there must be a re-examination of the role of the social support networks of youth living with HIV, as well as the ways in which emotional distress interacts with risk behaviors.

Journal Article↗
PubMed1998

Early and late weight gain following smoking cessation in the Lung Health Study.

The authors examine weight gains associated with smoking cessation in the Lung Health Study (1986-1994) over a 5-year follow-up period. A cohort of 5,887 male and female smokers in the United States and Canada, aged 35-60 years, were randomized to either smoking intervention or usual care. Among participants who achieved sustained quitting for 5 years, women gained a mean of 5.2 (standard error, 5.0) kg in year 1 and a mean of 3.4 (standard error, 5.5) kg in years 1-5. Men gained a mean of 4.9 (standard error, 4.9) kg in year 1 and a mean of 2.6 (standard error, 5.8) kg in years 1-5. In regression analyses, smoking-change variables were the most potent predictors of weight change. Participants going from smoking to quit-smoking in a given year had mean weight gains of 2.95 kg/year (3.61%) in men and 3.09 kg/year (4.69%) in women. Over 5 years, 33% of sustained quitters gained > or = 10 kg compared with 6% of continuing smokers. Also among sustained quitters, 7.6% of men and 19.1% of women gained > or = 20% of baseline weight; 60% of the gain occurred in year 1, although significant weight gains continued through year 5. The average gains and the high proportions of sustained and intermittent quitters who gained excessive weight suggest the need for more effective early interventions that address both smoking cessation and weight control.

Adult↗
PubMed1998

Comparison of the performance of normal individuals and survivors of traumatic brain injury on repeat administrations of the Wisconsin Card Sorting Test.

Repeat administrations of the Wisconsin Card Sorting Test (WCST) are a common clinical practice to assess changes in cognitive functions of individuals recovering from traumatic brain injury (TBI). Yet, little is even known about the performance of healthy individuals on repeat administrations of the test. The present study compared the effects of repeat administration of the WCST in normal individuals and survivors of traumatic brain injury. Normal participants were administered the WCST twice, with a 5-month interval between testings and the findings were compared to the data from patients with TBI tested twice. Normal controls only modestly improved their performance on repeat testing. In contrast, using a reliability of change (RC) index, TBI survivors demonstrated clinically meaningful gains in performance.

Adult↗
PubMed1998

Effect of weight gain on pulmonary function after smoking cessation in the Lung Health Study.

The objective of this study was to determine if the weight gain that accompanies smoking cessation is independently associated with reductions in FEV1 and FVC, using a multicenter randomized intervention trial of smoking cessation in 10 communities in the United States and Canada. Enrollees were currently smoking women and men 35 to 60 yr of age with mild-to-moderate airway obstruction. Participants were randomized to one of three study groups: an intensive smoking cessation program with an inhaled bronchodilator (or a placebo), and usual care. Changes in absolute and percent predicted FEV1 and FVC between baseline and fifth annual follow-up visit were monitored in relation to changes in body weight during the interval. At the baseline examination, percent predicted FEV1 was maximal at 90 to 100% ideal body weight (IBW) and was lower as body weight deviated from this range. The FVC decreased linearly when IBW exceeded 100%. Weight gain was greatest during the first 12 mo after smoking cessation. Weight gain was associated with lower fifth-year FEV1 and FVC in all smoking categories: continuous smokers, intermittent smokers, and sustained quitters. The FVC was affected by weight gain more than was the FEV1, and the FEV1 was affected by smoking cessation more than FVC. Men showed more impairment of FVC with weight gain than did women, possibly because of differential patterns of fat deposition. In sustained quitters, after adjustment for baseline factors, the estimated reduction of FVC was 17.4 ml/kg weight gain for men and 10.6 ml/kg for women. The estimated loss of FEV1 was 11.1 ml/kg weight gain for men and 5.6 ml/kg for women. Lung function after smoking cessation is significantly influenced by weight gain and affects men more than women. The deleterious effects of weight gain are small, however, in comparison with the beneficial effects of smoking cessation.

Adipose Tissue↗
PubMed1998

Influence of alcohol and drug use on AIDS risk behavior among youth in dropout prevention.

Youth enrolled in dropout prevention and alternative school programs engage in a number of high risk behaviors in greater numbers than those in traditional school settings [1, 2]. However, data on alcohol and drug use influences and risky sexual behavior are often not collected or reported among these youth due to small enrollments and rapid turnover. In this study alcohol and drug use and sexual behaviors were surveyed among 212 youth in dropout prevention. A risk profile score for HIV/AIDS was developed and the contribution of alcohol and drug use to HIV/AIDS risk was determined. Results showed that use of alcohol and drugs and age of sexual initiation were significantly associated with a high risk profile score. Of sexually active youth, 28 percent reported using alcohol or drugs prior to having sexual intercourse and more than half reported not using condoms during their last sexual experience. Males were more likely than females to use alcohol and drugs before having sex, and were more likely to have had sex with two or more partners. Findings from this study suggest that among youth in dropout prevention, the association of alcohol and drug use to HIV/AIDS risk is significant and that prevention programs need to target alcohol and drug use as important influences on risky sexual behavior.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Cloning and characterization of a metabotropic glutamate receptor, mGluR4b.

An alternative spliced variant of metabotropic glutamate receptor subtype mGluR4a, termed mGluR4b was isolated from a rat cDNA library. Subtype mGluR4b was identical to the previously described mGluR4a, except for the last 64 amino acids in the C-terminal region in which were replaced by 135 new amino acids in mGluR4b. Recombinant baculoviruses coding for mGluR4a and mGluR4b were expressed in Spodoptera frugiperda, Sf-9, insect cells and characterized pharmacologically by measuring [3H]-L-2-amino-4-phosphonobutyrate ([3H]-L-AP4) binding and second messenger formation. [3H]-L-AP4 binding to membranes prepared from Sf-9 cells expressing mGluR4a and mGluR4b revealed respective affinities (Kd) of 480 and 360 nM and maximal binding densities (Bmax) of 4.2 and 0.8 pmol/mg protein. The ligand selectivity of mGluR4a and mGluR4b was similar: L-AP4 > L-serine-O-phosphate > L-glutamate > L-2-amino 2-methyl-4-phosphonobutyrate > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate > or = quisqualate. A decrease in the affinity of [3H]-L-AP4 was observed in the presence of 0.1 mM guanosine 5'-O-(3-thio)trisphosphate-gamma-S, indicating that mGluR4a and mGluR4b were functionally coupled to G-proteins in Sf-9 cells. Agonists of mGluR4 caused a minor decrease in forskolin-induced cAMP formation in Sf-9 cells expressing either mGluR4a or mGluR4b, suggesting that both receptors are coupled to adenylate cyclase in an inhibitory manner. Thus, mGluR4a and mGluR4b share a common signal transduction pathway and pharmacology when expressed in Sf-9 insect cells.

Amino Acid Sequence↗
PubMed1997

HIV prevention among Zambian adolescents: developing a value utilization/norm change model.

Peer-led interventions are effective in reducing risk for HIV among adolescents. A pre-intervention study was conducted to determine how to successfully carry out a possible future intervention to reduce HIV risk among adolescents in urban Zambia. Ethnographic and sexual data were collected on 276 males and females both attending and not attending secondary school during a 14-month period in 1992-1993. Additionally, several focus groups were conducted. This paper reviews the cultural background of Zambian adolescents and presents an overview of the study results. Among the findings, it was learned that most of the male and female adolescents (average age of 17) are sexually active, very few routinely use condoms, less than half of sexually active adolescents have ever used a condom, AIDS is omnipresent in Zambia, the threat of HIV infection is a very real concern for most of the adolescents, there is a strong desire to protect themselves from HIV infection during sex (but condoms are often seen as ineffective and other forms of safer sex are not discussed), nearly all of the sexually active females and some of the males have received money or gifts for sex, and some of the out-of-school females are engaging in very risky sex (e.g., unprotected anal intercourse, and anilingus) with adult men. The ethnographic data, including a brief trial risk reduction workshop, suggests that the core values and social norms of the adolescents may shape behavioral change. A value utilization/norm change (VUNC) model is developed, which is intended to provide a conceptual framework for understanding how to utilize selected core values of the adolescents to strengthen or alter norms within the social networks in order to elicit desired HIV risk reduction.

Adolescent↗