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Biomedical subjects

M Hennessy

Publications and source records attributed to M Hennessy.

At least 19 recordsLinked to original sources
PubMed2006

A primer on the mechanics of P-glycoprotein the multidrug transporter.

P-glycoprotein (P-gp) the multidrug transporter is a well-characterised member of the super-family of ATP-binding cassette (ABC) transporters, and mediates the clearance of xenotoxins against steep concentration gradients at the expense of ATP hydrolysis. The primary function of this protein is to prevent the uptake of toxic compounds from the gut into the body, and to protect vital structures such as the brain, cerebrospinal fluid, testis, foetus and bone marrow against toxins. Although P-gp transports a wide range of compounds, which is advantageous, it can also be a disadvantage and may interfere with the delivery of drugs to target tissues resulting in multidrug resistance. In the present review: (i) we consider our current understanding of the structure of P-glycoprotein, (ii) discuss substrate binding and its coupling to ATPase activity, (iii) provide insight into key features which define P-glycoprotein substrates/inhibitors and the ability to predict potential substrates in silico, (iv) provide an overview of existing models of pump function and (v) present emerging concepts into the regulation of P-glycoprotein expression, with particular reference to multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Adrenoceptor blockade alters plasma gelatinase activity in patients with heart failure and MMP-9 promoter activity in a human cell line (ECV304).

This study assessed the effects of short-term adrenoceptor blockade on plasma matrix metalloproteinase (MMP) activity in patients with heart failure, and the ability of adrenoceptor stimulation to modulate matrix metalloproteinase-9 (MMP-9) promoter activity in vitro. Patients with heart failure received standard therapy or standard therapy plus carvedilol. Plasma MMP activity was determined by zymography and tissue inhibitor (TIMP-1) expression was measured by immunoblotting. MMP-9 promoter activity was assessed in transfected ECV304 cells following exposure to isoprenaline or phenylephrine in the absence or presence of either propranolol or prazosin. In patients with heart failure, carvedilol attenuated the increase in proMMP-9 activity observed at 4 and 12 weeks in non-beta-blocker-treated patients (44.0 +/- 4.9 AU versus 60.8 +/- 6.7 AU; P < 0.05). Although TIMP-1 expression was unaltered, the MMP-9:TIMP-1 ratio was lower in those receiving carvedilol at 4 and 12 weeks (0.54 +/- 0.07 versus 1.04 +/- 0.17; P < 0.05). Isoprenaline transiently increased MMP-9 promoter activity after 4 h exposure (80.6 +/- 14.8-fold; P < 0.001) before returning to baseline. The response to isoprenaline was prevented by propranolol (P < 0.01). Phenylephrine caused a biphasic increase in MMP-9 promoter activity, with the greatest increase occurring at 24 h (23 +/- 3.7-fold) compared to baseline. This response was unaffected by co-incubation with prazosin. In conclusion, treatment with a mixed alpha1/beta-adrenoceptor antagonist attenuates MMP activity and tips the degradative balance to a less degradative phenotype in heart failure patients. Furthermore, adrenoceptor stimulation increases MMP-9 promoter activity, which is inhibited by beta- but not alpha-adrenoceptor blockade. Therefore, mixed adrenoceptor blockade may reduce remodeling in heart failure as a direct consequence of a beta-adrenoceptor-mediated reduction in MMP-9 transcription.

Adrenergic alpha-Antagonists↗
PubMed2006

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals.

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.

Adult↗
PubMed2005

Reduction of paediatric in-patient cardiac arrest and death with a medical emergency team: preliminary results.

AIMS: To determine the impact of a paediatric medical emergency team (MET) on cardiac arrest, mortality, and unplanned admission to intensive care in a paediatric tertiary care hospital. METHODS: Comparison of the retrospective incidence of cardiac arrest and death during 41 months before introduction of a MET service with the prospective incidence of these events during 12 months after its introduction. Comparison of transgression of MET call criteria in patients who arrested and died before and after introduction of MET. RESULTS: Cardiac arrest decreased from 20 among 104 780 admissions (0.19/1000) to 4 among 35 892 admissions (0.11/1000) (risk ratio 1.71, 95% CI 0.59 to 5.01), while death decreased from 13 (0.12/1000) to 2 (0.06/1000) during these periods (risk ratio 2.22, 95% CI 0.50 to 9.87). Unplanned admissions to intensive care increased from 20 (SD 6) to 24 (SD 9) per month. The incidence of transgression of MET call criteria in patients who arrested decreased from 17 to 0 (risk difference 0.16/1000, 95% CI 0.09 to 0.24), and in those who died, decreased from 12 to 0 (risk difference 0.11/1000, 95% CI 0.05 to 0.18) after introduction of MET. CONCLUSIONS: Introduction of a medical emergency team service was coincident with a reduction of cardiac arrest and mortality and a slight increase in admissions to intensive care.

Cardiopulmonary Resuscitation↗
PubMed2001

beta-3 adrenergic agonist restores skeletal muscle insulin responsiveness in Sprague-Dawley rats.

Between 7 and 14 weeks of age, male Sprague-Dawley rats develop a greater than 50% loss in insulin-stimulated glucose transport in skeletal muscle. We treated rats aged 14 weeks with the beta-3 adrenergic agonist CL316,243 (1 mg/kg/day by minipump for 14 days). Treatment resulted in a 56% reduction in visceral fat (P < 0.05). Muscle mass and body weight were unchanged. In strips of soleus muscle isolated from rats treated with CL316,243, basal transport of [(3)H]-2-deoxyglucose (2-DOG) was unchanged (105.8 +/- 7.5 nmol/g/min for vehicle vs 122.0 +/- 8.7 for CL316,243). However, in rats treated with CL316,243, the increase in 2-DOG transport in response to a maximal concentration of insulin was substantially increased (55.5 +/- 13.1 nmol/g/min for vehicle vs 102.4 +/- 13.5 for CL316,243, P < 0.03). CL 316,243 caused no significant changes in fasting glucose, insulin, or free fatty acids. Treatment of soleus muscle strips in vitro with CL316,243 (either 0.1 nM or 1.0 nM for 120 min at 37 degrees C) had no effect either on basal 2-DOG transport or on insulin-stimulated transport. We conclude that the CL316,243 causes a reduction in visceral fat and a reversal of muscle insulin resistance. The effect CL 316,243 on muscle insulin responses appears to be indirect, as it did not occur in vitro.

Adrenergic beta-3 Receptor Agonists↗
PubMed2001

Effect of sildenafil on blood pressure and arterial wave reflection in treated hypertensive men.

As the effects of sildenafil are in part mediated by enhancing the action of nitric oxide and nitrates given acutely markedly reduce early wave reflection, we explored the effects of a single oral dose of sildenafil citrate (50 mg) on blood pressure and arterial wave reflection in treated hypertensive men in a single-blind randomised placebo controlled crossover study. Eight men (aged 57-76 years) with well controlled hypertension and erectile dysfunction and no contraindications to the use of sildenafil, were given either sildenafil 50 mg or placebo orally, with the second drug being given 2 weeks later. Blood pressure and heart rate with an automated digital oscillometric device (Omron) HEM-705 CP) and the augmentation index, a measure of arterial wave reflection in the aorta derived using radial applanation tonometry, were measured before and at 15-min intervals for 2 h thereafter. The extent of individual maximum reductions (mm Hg) from baseline in systolic (24 +/- 10 vs. 6 +/- 8, P < 0.05) and diastolic blood pressure (8 +/- 5 vs. 3 +/- 2, P < 0.05) occurred on the sildenafil study day. On average the brachial blood pressure at 75 min following sildenafil was 17/11 mm less than on the placebo day (P < 0.01). Augmentation index was also reduced significantly at 90 min (P < 0.05) suggesting reduced vascular tone in the arteries. The area under the brachial and aortic blood pressure and augmentation index time curve (by the trapezoidal rule corrected for baseline reading) was significantly lower (P < 0.05) on the sildenafil study day. The study shows that the peripheral vasodilatory effects of sildenafil, possibly related to nitric oxide, are accompanied by a fall in systemic blood pressure and reduced arterial wave reflection.

Aged↗
PubMed2001

Relation of health literacy to gonorrhoea related care.

OBJECTIVE: To assess the relation between health literacy and receipt of a screening test for gonorrhoea in the past year. METHODS: Study design was multisite, cross sectional survey of subjects enrolled from clinics, from community based organisations, and by street intercept. Data were obtained using face to face interview. The dependent variable was self reported receipt of a test for gonorrhoea in the past year. Health literacy was measured by the Rapid Estimate of Adult Literacy in Medicine (REALM), recoded to represent 8th grade or lower reading or 9th grade and higher reading level. Statistical analyses were adjusted to account for selection bias in literacy assessment. RESULTS: 54% of the sample reported at least one gonorrhoea test in the previous year. 65% of the sample read at a 9th grade level or higher. REALM score was moderately correlated with the respondent's years of education. After adjustment for missing REALM data, past suspicion of gonorrhoea, self inspection for gonorrhoea, self efficacy for care seeking, REALM score of 9th grade reading level or higher, and younger age were independently associated with gonorrhoea testing in the previous year. For the average respondent, REALM reading grade level of 9th grade or higher is associated with a 10% increase in the probability of having a gonorrhoea test in the past year. CONCLUSIONS: Low literacy appears to pose a barrier to care for sexually transmitted infections such as gonorrhoea.

Adolescent↗
PubMed2001

Using intervention theory to model factors influencing behavior change. Project RESPECT.

Project RESPECT was a multisite randomized trial comparing three clinic-based interventions' ability to increase condom use and prevent infection with HIV and sexually transmitted diseases. Because Project RESPECT had guiding concepts that determined the content of the sessions, the authors investigated how the intervention operated using these theoretical variables. Growth curve analysis and structural equation modeling estimated the correlation between intentions toward condom use and self-reports of condom use and isolated the treatment effects on mediating variables--attitudes, self-efficacy, and social norms--that predict intentions. The correlations between intentions and behavior exceeded .70 for both genders, justifying the emphasis on intentions. Project RESPECT was effective through changing attitudes and self-efficacy for females in both counseling interventions. For males, only enhanced counseling had significant effects on these two mediator variables.

Analysis of Variance↗
PubMed2000

Are there gender differences in patients presenting with unstable angina?

BACKGROUND: There are limited studies on gender differences in patients with unstable angina. We investigated the influence of gender in these patients in a tertiary referral centre. METHODS AND RESULTS: Three hundred and thirteen consecutive patients (210 men and 103 women) with unstable angina were studied over a 42-month period. Patient characteristics, cardiovascular risk factors and subsequent management including coronary artery bypass graft (CABG) operation and percutaneous transluminal coronary angioplasty (PTCA) were investigated. There was no difference in age [61.6 (11.0) (S.D.) years for men vs. 63.5 (10.5) years for women]. Diabetes mellitus and hypertension were more common in women (diabetes, 11% vs. 23%, P = 0.007; hypertension, 32% vs. 52%; P = 0.001). The number of smokers was greater in men (73% vs. 46%, P = 0.00001). There was no difference in the prevalence of hypercholesterolaemia or in the incidence of previous myocardial infarction, previous history of angina and family history of ischaemic heart disease. The duration of unstable angina before presentation to the referring hospital was similar in both sexes. The use of aspirin, intravenous heparin and antianginal drugs was also comparable in the two genders. The number of coronary arteries involved in men and women appeared similar (one vessel, 22% vs. 27%; two vessels, 26% vs. 21%; three vessels, 52% vs. 52% in men and women, respectively). The proportion of men and women who underwent subsequent revascularisation was also similar (CABG, 31% vs. 33%; PTCA, 42% vs. 40%). The overall in-hospital mortality was higher in women (6.8% vs. 2.8%), but was not statistically significant (P = 0.18). CONCLUSIONS: Gender differences in unstable angina manifest in the preponderance of selected risk factors including diabetes mellitus and hypertension in women and smoking in men. There is no difference in age, the degree of coronary artery involvement and the subsequent management in a tertiary referral centre.

Angina, Unstable↗
PubMed2000

The safety practices of sporting clubs/centres in the city of Hume.

Sports injuries are a significant public health problem in Australia. However, little information is available about community level sports injuries, or about the sports safety policies and practices of community level sports organisations in Australia. The aim of this paper is to present the results of a survey of local clubs and sporting centres in the City of Hume, a local council in Victoria. This is the first reported survey of safety practices of sporting clubs/centres at the community level in Australia. Sixty-four clubs/centres participated in the survey, which involved face-to-face interviews with representatives from the participating clubs/centres. A major finding was that whilst sports bodies perform certain activities typically associated with preventing sports injuries, they often do not have formal policies or written objectives which recognise the safety of their participants as an important goal. The sports safety measures reported to be adopted by the surveyed clubs/centres included use of protective equipment, accredited coaches, sports trainers, encouraging warm-ups, modified rules for juniors and checking of playing areas and facilities for environmental hazards. The provision of first aid services (including personnel and equipment) varied across the sporting clubs/centres. The major barriers towards improving sports safety were reported to be a lack of funds, the media's attitude towards sports injuries and the role of the local council as the owner of sporting facilities. There is also a clear role for researchers to improve the dissemination of key findings from their injury prevention research in a form that can be readily used at the grass roots of sports participation.

Athletic Injuries↗
PubMed2000

Modeling intervention efficacy for high-risk women. The WINGS Project.

This study evaluates the effectiveness of two strategies--communication and condom skills training--for increasing condom-protected sex in a sample of 510 high-risk women ages 17 to 61. Baseline and 3- and 6-month postintervention interview data were gathered in three cities participating in a randomized trial of a six-session, group skill-building intervention. This analysis was conducted for the entire sample and for six subgroups categorized by age, single or multiple partners, and history of childhood sexual abuse. The dependent variable was the odds ratio of protected sex acts at each follow-up. Structural equation modeling was used to estimate effects for two intervention pathways. The pathway through condom skills increased the odds of protected sex for the intervention group (chi 2 difference = 35, df = 2, p < .05) as well as for all subgroups. The pathways through communication were significant for the intervention group (chi 2 difference = 23, df = 3, p < .05) but fully effective only for participants under 30 and participants who reported childhood sexual abuse. The effectiveness of both pathways diminished at 6 months. WINGS demonstrates that condom skills training can increase protected sex for a heterogeneous group of women. Further research needs to examine how such skill training translates into use of condoms by male partners. To increase the duration of intervention effects, booster sessions may need to be incorporated.

Adolescent↗
PubMed1999

Interaction of sildenafil and indinavir when co-administered to HIV-positive patients.

OBJECTIVES: The prevalence of erectile dysfunction in HIV-infected men is estimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the protease inhibitors are both metabolized by, and act as inhibitors of cytochrome P450 3A4, we evaluated the pharmacokinetics of the combination sildenafil plus indinavir in HIV-infected patients. DESIGN AND METHODS: Six patients at steady state in treatment with indinavir participated in the study. On the first day blood samples for indinavir assay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the second study day patients received a single dose of 25 mg of sildenafil in addition to their routine morning medication. Blood samples were taken as described. Separated plasma was stored at -80 degrees C until analysis by high performance liquid chromatography. In a parallel study, the effect of indinavir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolism of sildenafil was assessed. RESULTS: The geometric mean area under the concentration curve for 0-8 h (AUC0-8h) and maximum plasma concentration (Cmax) for indinavir were 19.69 microg/ml h (range, 9.19-31.99 microg/ml h) and 7.02 microg/ml (range, 2.33-16.17 microg/ml), respectively, on the first study day. In the presence of sildenafil, the mean AUC0-8h and Cmax of indinavir were 22.37 microg/ml h [range, 10.08-37.25 microg/ml h; 95% confidence interval (CI) for difference between means, -15 to 13.25) and 9.11 microg/ml (range, 3.41-22.78 microg/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC0-8h and Cmax for sildenafil were 1631 ng/ml h (range, 643-2970 ng/ml h) and 384 ng/ml (range, 209-766 ng/ml) respectively. The AUC for sildenafil was 4.4 times higher than data from historical controls given either 50 mg or 100 mg of sildenafil and dose normalized to 25 mg. Indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 +/- 0.17 microM, mean +/- SD]. CONCLUSIONS: Co-administration of sildenafil 25 mg did not significantly alter the plasma indinavir levels. However, plasma sildenafil AUC was markedly increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in this clinical setting.

Adult↗
PubMed1998

The effectiveness of coping strategies used by HIV-seropositive women.

The effectiveness of active and passive coping strategies was examined in a sample of 264 women infected with HIV. Coping was measured concurrent with, and 3 months prior to, measurement of physical symptoms and emotional distress. Two causal models were tested: one for active coping and one for passive coping. Active coping strategies examined included seeking social support, managing the illness, and spiritual activities. Avoidance was used as an indicator of passive coping. In both models, physical symptoms and emotional distress were positively and significantly related. The findings indicated that, whereas current avoidance coping was not related to emotional distress, current active coping was positively related to physical symptoms and negatively related to emotional distress. The immediate effects of active coping appeared to serve a protective function in that emotional distress decreased with greater use of active coping, even as physical symptoms increased. Avoidance coping had no such protective effect for emotional distress. In addition, the use of avoidance coping decreased and active coping increased as physical symptoms increased, suggesting that active coping is more likely to be used with increasing levels of physical symptoms. The findings suggest that interventions that support attempts to use active coping strategies as physical symptoms increase may be effective in promoting positive adaptation to HIV disease.

Adaptation, Psychological↗
PubMed1998

Partner notification in the real world: a four site time-allocation study.

BACKGROUND AND OBJECTIVES: Although partner notification has been a long-standing intervention and prevention strategy for sexually transmitted diseases (STD), variations in partner notification practices across sites have never been documented. GOALS OF THE STUDY: To describe provider-assisted partner notification practices in four STD programs in the United States. STUDY DESIGN: Eleven disease intervention specialists (DIS) in each of three urban sites and seven DIS in one rural site documented their activities and clients for 14 working days using a personal digital assistant. RESULTS: Of 2,506 recorded activity hours across sites, 37.4% of the recorded time was spent on partner notification (PN) activities with 1148 clients. Field visits to locate contacts accounted for the largest proportion of time spent on PN. Overall, PN clients were cases of or were contacts to nonprimary and secondary (P&S) syphilis (39.6%), gonorrhea (25.5%), chlamydia (18.0%), HIV/AIDS (10.4%), and P&S syphilis (6.5%). CONCLUSION: The activities which constitute PN, the diseases for which PN is used, and the time spent on each PN client vary across sites. More research is needed on the determinants of these variations and their association with the ultimate goal of disease prevention.

Centers for Disease Control and Prevention, U.S.↗
PubMed1997

Identifying the social contexts of effective sex refusal.

A factorial survey was conducted to identify social situations that inhibit or promote college students' sex-refusal skills. Respondents evaluated five different situations in which sexual intercourse might occur and ranked each according to how certain the respondent would be to refuse to have sexual intercourse in that context. Regression analysis of the survey data showed that knowing the other person well, being with one's boyfriend or girlfriend, having condoms available, wanting to have sex, and both persons' wanting to have sex reduced the probability of refusal. On the other hand, having no condoms and the presence of drugs in the situation increased the probability the individual would refuse to have sex. In addition, men, individuals with previous sexual experience, and drinkers displayed diminished ability to refuse sex. However, the lack of condoms, when combined with these three respondent characteristics, acted to increase the ability to refuse sex.

Adult↗
PubMed1997

The impact of HIV on emotional distress of infected women: cognitive appraisal and coping as mediators.

This study examined the role of psychological factors as mediators of the impact of HIV-related stressors on emotional distress of a clinic-based sample of 264 HIV+ women. Based upon Lazarus and colleagues' cognitively oriented theory of stress and coping, causal modeling was used to test for mediating effects of cognitive appraisal (intrusive thoughts and perceived stigma) and coping variables (avoidance and fatalism) on emotional distress within the context of HIV-related stressors (functional impairment and work performance impairment). The findings supported the mediating effects of cognitive appraisal but not of the coping variables. Consistent with theory, the effect of HIV-related stressors on emotional distress was indirect through cognitive appraisal; however, there were no significant direct effects of HIV-related stressors, fatalism or avoidance on emotional distress. The causal model accounted for significant portions of variance in emotional distress (R2 = .49) and the model fit, as a whole, was more than adequate. The findings indicate that how HIV+ women think about HIV-related stressors is an important factor that may account for individual variability in the ability to maintain a sense of subjective well-being in the face of a devastating fatal disease.

Adaptation, Psychological↗
PubMed1996

A factorial survey study to assess the acceptability of HIV vaccine trial designs.

To aid in the design of human immunodeficiency virus (HIV) vaccine trials that maximize volunteer participation, factorial surveys were administered to 73 gay men who were participants in a larger study assessing HIV vaccine trial feasibility. Factorial surveys are "vignettes" that are randomly constructed through the combination of descriptive statements (dimensions) that reflect essential features. In this study, the dimensions define components of clinical trials to assess the efficacy of hypothetical HIV vaccines. Regression analysis shows that anticipated participation was decreased by a sustained vaccine-induced antibody response lasting 3 years, absence of gay men as research subjects in earlier phase trials for the products being tested, and rectal vaccine administration. Three years of scientific experience with the vaccine encouraged participation. We conclude that willingness to participate in vaccine trials varies systematically with some of their characteristics. Where there are design alternatives for identified negative components, these should be considered. If this is not possible, options for decreasing aversion to such features will need to be evaluated, including appropriate education regarding both the benefits and the risks associated with negatively evaluated features.

AIDS Vaccines↗