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Biomedical subjects

A M Hughes

Publications and source records attributed to A M Hughes.

At least 19 recordsLinked to original sources
PubMed2006

Occupational exposure to power frequency magnetic fields and risk of non-Hodgkin lymphoma.

OBJECTIVES: To investigate the risk of non-Hodgkin lymphoma (NHL) using a job-exposure matrix (JEM) to assess exposure to occupational magnetic fields at the power frequencies of 50/60 Hz. METHODS: The study population consisted of 694 cases of NHL, first diagnosed between 1 January 2000 and 31 August 2001, and 694 controls from two regions in Australia, matched by age, sex and region of residence. A detailed occupational history was given by each subject. Exposure to power frequency magnetic fields was estimated using a population-based JEM which was specifically developed in the United States to assess occupational magnetic field exposure. The cumulative exposure distribution was divided into quartiles and adjusted odds ratios were calculated using the lowest quartile as the referent group. RESULTS: For the total work history, the odds ratio (OR) for workers in the upper quartile of exposure was 1.48 (95% CI 1.02 to 2.16) compared to the referent (p value for trend was 0.006). When the exposure was lagged by 5 years the OR was 1.59 (95% CI 1.07 to 2.36) (p value for trend was 0.003). Adjusting for other occupational exposures did not significantly alter the results. CONCLUSIONS: These findings provide weak support for the hypothesis that occupational exposure to 50/60 Hz magnetic fields increases the risk of NHL.

Adult↗
PubMed2005

Factors determining the optimal body site and method for obtaining punch biopsies of human skin as a tissue in which to assess pharmacodynamic and pharmacokinetic endpoints in drug development studies.

There are potential advantages to detecting pharmacodynamic (PD) and pharmacokinetic (PK) endpoints in a tissue-based compartment such as the skin during the development of molecularly targeted drugs. We explored regional differences between inner arm, inner thigh, lower back and buttocks in 12 healthy male Caucasian volunteers in the tolerability of skin biopsy procedures; the Ki67 proliferation index; the frequency of detecting hair follicles and sweat glands; and the percentage of melanocytes. We also explored the amounts of tissue and protein obtained, and two separate methods of splitting biopsies for processing in mutually exclusive media. Biopsies from all body sites were well tolerated. The subjective ranking order was inner arm > buttocks = back > thigh. There were no statistically significant differences in the Ki67 labelling index (P > 0.05). The frequency of detecting sweat glands was the same in all body sites, but the frequency of detecting hair follicles was higher in back and buttock, compared to arm and thigh. The percentage of melanocytes was significantly lower in the buttocks compared to the back and thigh (P < 0.05), but not compared to the arm (P = 0.07). A 4-mm punch biopsy yielded a mean of 16.8 mg of tissue (range: 9-28 mg) and 160 microg of protein (range: 80-270 microg). In vivo sample splitting, by following a 2-mm punch with a 4-mm overpunch, had a shorter time from devascularisation to immersion into processing medium than ex vivo dissection of a 4-mm sample, which may be of importance to the assessment of labile endpoints. We conclude that multiple punch biopsies of the skin are feasible, with the buttocks representing the studied body site with the optimal balance between tolerability, hair follicle density and melanocyte density for obtaining tissue in which to assess PD and PK endpoints during drug development studies.

Adolescent↗
PubMed2005

Occupational exposure to pesticides and risk of non-Hodgkin's lymphoma.

Pesticide exposure may be a risk factor for non-Hodgkin's lymphoma, but it is not certain which types of pesticides are involved. A population-based case-control study was undertaken in 2000-2001 using detailed methods of assessing occupational pesticide exposure. Cases with incident non-Hodgkin's lymphoma in two Australian states (n = 694) and controls (n = 694) were chosen from Australian electoral rolls. Logistic regression was used to estimate the risks of non-Hodgkin's lymphoma associated with exposure to subgroups of pesticides after adjustment for age, sex, ethnic origin, and residence. Approximately 10% of cases and controls had incurred pesticide exposure. Substantial exposure to any pesticide was associated with a trebling of the risk of non-Hodgkin's lymphoma (odds ratio = 3.09, 95% confidence interval: 1.42, 6.70). Subjects with substantial exposure to organochlorines, organophosphates, and "other pesticides" (all other pesticides excluding herbicides) and herbicides other than phenoxy herbicides had similarly increased risks, although the increase was statistically significant only for "other pesticides." None of the exposure metrics (probability, level, frequency, duration, or years of exposure) were associated with non-Hodgkin's lymphoma. Analyses of the major World Health Organization subtypes of non-Hodgkin's lymphoma suggested a stronger effect for follicular lymphoma. These increases in risk of non-Hodgkin's lymphoma with substantial occupational pesticide exposure are consistent with previous work.

Adult↗
PubMed2005

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development.

Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n = 10) and multiple (n = 12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter- and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways.

Adult↗
PubMed2005

Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence.

Activation of the endothelin A receptor (ET(A)) by endothelin-1 (ET-1) mediates events that regulate mitogenesis, apoptosis, angiogenesis and metastasis in tumours. Specific blockade of ET(A) may have anticancer effects, while retaining beneficial endothelin B receptor (ET(B))-mediated effects such as apoptosis and clearance of ET-1. ZD4054 is an orally active, specific ET(A) antagonist in clinical development. In receptor-binding studies, ZD4054 specifically bound to ET(A) with high affinity; no binding was detected at ET(B). In a randomised placebo-controlled trial in eight healthy volunteers, a single oral dose of ZD4054 reduced forearm vasoconstriction in response to brachial artery infusion of ET-1, thus providing clinical evidence of ET(A) blockade. ET(B) blockade was assessed in an ascending, single-dose, placebo-controlled trial in 28 volunteers. For all doses of ZD4054, mean plasma ET-1 concentrations measured at 4 and 24 h were within the placebo reference range (a rise in ET-1 would indicate ET(B) blockade) and there was no evidence of dose-related changes. These data confirm the specificity of ZD4054 for ET(A), with no activity at ET(B) in a clinical or preclinical setting. As a result of this specificity, ZD4054 has the potential to block multiple ET(A)-induced pathological processes, while allowing beneficial ET(B)-mediated processes to continue, which may, in turn, lead to an effective cancer therapy.

Animals↗
PubMed2005

Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies.

We have demonstrated the feasibility of detecting and quantifying six cell-cycle-related nuclear markers (Ki67, pRb, p27, phospho-p27 (phosphorylated p27), phospho-pRb (phosphorylated pRb), phospho-HH3 (phosphorylated histone H3)) in plucked human scalp and eyebrow hair. Estimates of the proportion of plucked hairs that are lost or damaged during processing plus the intra- and intersubject variability of each nuclear marker with these techniques are provided to inform sizing decisions for intervention studies with drugs potentially impacting on these markers in the future.

Adolescent↗
PubMed2005

Recurrent miscarriage and long-term thrombosis risk: a case-control study.

BACKGROUND: Recurrent miscarriage has been associated with antiphospholipid syndrome (APS) and other prothombotic conditions. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic recurrent miscarriage. METHODS: A retrospective case-control study was performed using validated questionnaires. A total of 141 women with recurrent miscarriage and APS alone were matched with 141 women with idiopathic recurrent miscarriage for age, number and type of pregnancy loss and number of years of follow-up. A subgroup of eight women included those who initially presented with recurrent miscarriage, thrombosis and APS. RESULTS: The mean length of follow-up was 7.3 years and response rate 74%. The incidence of thrombosis was similar in the recurrent miscarriage and APS women (6/1000 women-years) and in the idiopathic recurrent miscarriage women (2/1000 women-years) (P = 0.18). All eight women who presented with recurrent miscarriage, APS and thrombosis reported further thrombotic events. CONCLUSIONS: Both idiopathic and APS-associated recurrent miscarriage were associated with a similar long-term risk of thrombosis.

Abortion, Habitual↗
PubMed2004

Use of the WHO lymphoma classification in a population-based epidemiological study.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is pathologically diverse. Epidemiological investigations into its increasing incidence and aetiology require accurate subtype classification. PATIENTS AND METHODS: Available pathology reports of 717 cases aged from 20 to 74 years in an Australian, population-based epidemiological study of NHL were reviewed by one anatomical pathologist to assign a World Health Organization (WHO) classification category. High or low confidence was assigned to the diagnosis of NHL, cell phenotype and WHO category and reasons given for low confidence. RESULTS: The most informative biopsy reports were from open tissue biopsy (79% of cases), tissue core biopsy (8%), cytology (4%) and bone marrow (9%); 8% of cases had inadequate biopsies for diagnostic purposes. Immunohistochemistry or flow cytometry reports were available for 96% of cases, gene rearrangement studies for 6% and cytogenetics for 3%. The reviewer assigned high confidence to the diagnosis of NHL in 93% of cases and also the phenotype in 88%. While a WHO classification could be assigned in 91% of cases, confidence was high in only 57.5%; insufficient immunophenotyping was the commonest reason for low confidence. CONCLUSIONS: Expert pathology review of a population-based sample of NHL can provide a WHO classification category for most cases. A high level of confidence in the classification, however, would require review of diagnostic material and additional phenotyping.

Adult↗
PubMed2004

An investigation of components of variance and tachyphylaxis in a placebo-controlled intravenous tyramine study.

AIMS: To explore inter- and intra-volunteer variability for the dose of intravenous tyramine eliciting a 20 mmHg increase in systolic blood pressure from baseline (TYR20) and to evaluate potential tachyphylaxis. METHODS: Twelve healthy volunteers received blinded placebo-controlled ascending and descending sequences of intravenous tyramine injections on two separate occasions. The TYR20 was derived by linear interpolation, using three interventions to deal with missing data. RESULTS: Analysis of covariance (ancova) demonstrated no significant difference in TYR20 between sequences, regardless of the missing data methodology applied. Inter-volunteer variability was 2.4-3.4 times larger than within-volunteer variability. No evidence of tachyphylaxis was seen using either the sign test or generalized additive models. CONCLUSIONS: Since inter-volunteer variability was greater than intra-volunteer variability, a crossover study design would be a more efficient study design, and the descending sequence of injections could be omitted since tachyphylaxis was not demonstrated.

Adult↗
PubMed2002

Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers.

AIMS: The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. METHODS: The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. RESULTS: Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. CONCLUSIONS: Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.

Acute Disease↗
PubMed2001

Associations of CCR5, CCR2, and stromal cell-derived factor 1 genotypes with human immunodeficiency virus disease progression in patients receiving nucleoside therapy.

Genotype data for CCR5, CCR2, and stromal cell-derived factor 1 (SDF-1) were obtained from 354 human immunodeficiency virus type 1 (HIV-1)-positive subjects who were being treated with nucleosides. Associations with HIV-1 load, HIV syncytium-inducing (SI) phenotype, CD4 cell count, and disease progression were analyzed. No differences in HIV-1 load or CD4 cell count were observed between wild type (+) and variant genotypes. Changes from non-SI to SI viral phenotype were more frequent in heterozygotes with a 32-bp deletion (Delta32) in the CCR5 gene than in + homozygotes (40% vs. 7%; P=.01). In a multivariate analysis, heterozygous CCR5 Delta32 was associated with reduced hazard of progression (hazard ratio, 0.32; P=.02). Subjects homozygous for the SDF-1 3'A variant had more-rapid disease progression (P=.008). The SDF-1 homozygous 3'A variant was related to more-rapid disease progression, and CCR5 Delta32 was associated with reduced rates of hazard for disease progression in nucleoside-treated subjects.

Adult↗
PubMed2000

Diurnal variation in the quantitative EEG in healthy adult volunteers.

AIMS: To define the change in power in standard waveband frequencies of quantitative cortical electroencephalogram (EEG) data over a 24 h period, in a drug free representative healthy volunteer population. METHODS: This was an open, non randomised study in which 18 volunteers (9 male and 9 female) were studied on 1 study day, over a 24 h period. Volunteers had a cortical EEG recording taken at 0, 2, 4, 6, 8, 10, 12, 16 and 24 h. Each recording lasted for 6 min (3 min eyes open, 3 min eyes closed). All EEG recordings were taken in a quietened ward environment with the curtains drawn round the bed and the volunteer supine. During the 3 min eyes open, volunteers were asked to look at a red circle on a screen at the foot of the bed, and refrain from talking. RESULTS: Plots produced of geometric mean power by time of the standard wave band frequencies gave some indication of a circadian rhythm over the 24 h period for theta (4. 75-6.75 Hz), alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.50 Hz) wavebands. Mixed models were fitted to both the eyes open and eyes closed data which confirmed a change in mean waveband power with time with statistical significance at the conventional 5% level (P < 0.05). CONCLUSIONS: These data indicate the presence of a diurnal variation in the cortical quantitative EEG. They support the use of a placebo control group when designing clinical trials which utilize quantitative EEG to screen for central nervous system (CNS) activity of pharmaceutical agents, to control for the confounding variable of time of day at which the EEG recordings were made.

Adult↗
PubMed2000

A community study of lower urinary tract symptoms in older men in Sydney, Australia.

BACKGROUND: The aim of the present paper was to determine the prevalence, bother attributable to and self-reported management of uncomplicated lower urinary tract symptoms (LUTS) in men aged 40-80 years in Sydney, Australia. METHODS: A total of 340 randomly selected men aged 40-80 years (65% response rate) participated in a community-based study (computer-assisted telephone survey). RESULTS: Lower urinary tract symptoms are common: 54% of men needed to wake up at least once at night to urinate; 47% indicated they had terminal dribbling 'sometimes' or 'frequently'; 30% experienced urgency although few (4%) had urge incontinence; 21% experienced hesitancy; and 19% could retain urine in their bladder during the day for no more than 2 hours. Urinary symptoms correlated poorly with self-rated bother and there was no increase in age-specific prevalence of bothersome symptoms with increasing age. Only 37 (26%) men inconvenienced by urinary symptoms had seen a general practitioner (GP) about these symptoms in the last 5 years: of these, two-thirds had been referred to a urologist and half of these received surgical treatment. Independent predictors of attending a GP were increasing age (adjusted odds ratio (AOR) = 12.3; P = 0.0015); place of birth outside Australia (AOR = 3.8; P = 0.0036) and anxiety about prostate cancer (AOR = 2.6; P = 0.0318), but not the degree of worry due to urinary symptoms. CONCLUSION: Lower urinary tract symptoms are common in men, but their experiences of bother correlate weakly with symptoms and do not appear to influence referral and treatment. Public and professional campaigns might increase wider understanding of the benefits of surgery for bothersome symptoms, not symptoms per se.

Adult↗
PubMed2000

Evaluation of a (pilot) stage-tailored brief smoking cessation intervention among hospital patients presenting to a hospital pre-admission clinic.

Despite the significant benefits of advising all smokers to quit, hospital patients who smoke do not systematically receive this advice. This study sought to determine the prevalence of smoking, attitudes of patients towards not smoking while in hospital, and the feasibility and effectiveness of a brief smoking cessation intervention in a pre-admission clinic context. Over 230 smokers received a brief smoking cessation intervention, while a control group (n = 114) received only a free Quit Kit. The age-standardised smoking prevalence was 19%; a further 3% of patients were recent quitters. Most smokers do not expect or experience problems with not smoking while in hospital. Brief smoking cessation advice tailored to stage-of-change by a health worker in a hospital pre-admission clinic significantly increased the quit rates for females.

Adolescent↗
PubMed2000

Community study of uncomplicated lower urinary tract symptoms among male Italien immigrants in Sydney, Australia.

OBJECTIVE: To determine the prevalence, levels of bother and self-reported management of lower urinary tract symptoms (LUTS) in Italian-born men aged 40-80 years. METHOD: 305 randomly selected men aged 40-80 years (72% response rate) participated in a community-based study (computer-assisted telephone survey) in early 1997 in Sydney, Australia. RESULTS: LUTS are common: 41% of men needed to wake up at least once at night to urinate; 35% indicated they had terminal dribbling 'sometimes' or 'frequently'; 31% experienced urgency although few (3%) had urge incontinence; 19% could retain urine in their bladder during the day for no more than 2 h, and 19% experienced hesitancy. Urinary symptoms correlated moderately/poorly with self-rated bother. The prevalence of bothersome frequency and urgency was significantly age-related. Only half (n = 49, 52%) of the men bothered by urinary symptoms had seen a general practitioner (GP) about these symptoms in the last 5 years: of these three quarters had been referred to a urologist and half of these had received surgical treatment. Anxiety about prostate cancer, but not the degree of bother from urinary symptoms, independently predicted attendance at a GP (adjusted odds ratio 6.4, p = 0.006). CONCLUSIONS: Although LUTS are common in Italian-born men, their experiences of bother do not correlate well with symptoms and do not appear to influence referral and treatment. Education is needed to improve men's understanding of the importance of 'bother' as an indicator for urological surgery.

Adult↗
PubMed1999

Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers.

AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone.

Adolescent↗
PubMed1999

Smoking: rates and attitudes among nursing staff in central Sydney.

The objectives of this study were to determine the prevalence and predictors of smoking and attitudes to smoking-related issues among nurses employed by the Central Sydney Area Health Service in Sydney, Australia. A self-administered questionnaire, was distributed via the internal mail system of the Central Sydney Area Health Service in November 1997 to 610 randomly selected nursing staff. Twenty-one per cent (n = 127) of respondents smoked. Smokers were significantly younger than non-smokers and were more likely to speak mainly English at home. There were clear differences between smokers and non-smokers in response to all attitude statements. Interventions specifically directed at nurses who smoke to assist them to stop and maintain cessation are indicated. Future health service workplace tobacco control programmes should address deficits in knowledge about the health effects of passive smoking, should raise awareness among nurses who smoke about their potential to affect the behaviours of others through modelling, and should provide all nurses with the skills required to be smoking educators and advocates for tobacco control.

Adult↗