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Biomedical subjects

D A Hughes

Publications and source records attributed to D A Hughes.

At least 19 recordsLinked to original sources
PubMed2006

Extracellular matrix turnover and disease severity in Anderson-Fabry disease.

BACKGROUND: Anderson-Fabry Disease (AFD) is an inherited metabolic disease associated with premature death secondary to cardiovascular and renal disease. Patients with AFD develop progressive left ventricular (LV) remodelling and heart failure. We hypothesized that altered extracellular matrix (ECM) turnover contributes to the pathophysiology of cardiac disease in AFD. METHODS AND RESULTS: Twenty-nine consecutive patients (44.1 +/- 11.7 years, 15 male) with AFD and 21 normal controls (39.7 +/- 11.3 years, 10 male) had serum analysed for matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of matrix metalloproteinase-1 and -2 (TIMP-1, TIMP-2). All patients underwent clinical assessment, echocardiography and Mainz Severity Score Index (MSSI) measurement, a validated severity score in AFD. MMP-9 levels were significantly higher in patients than controls (1003.8 +/- 337.8 ng/ml vs 576.7 +/- 276.3 ng/ml respectively, p < 0.001). There were no differences in TIMP levels between patients and controls. There was a positive correlation between MMP-9 levels and MSSI (r = 0.5, p = 0.01). There was a negative correlation between MMP-9 and endocardial fractional shortening (FS) (r = -0.5, p = 0.01) and mid-wall FS (r = -0.6, p = 0.001). There was no correlation between other echocardiographic parameters and MMP-9 levels. These relations were independent of age and sex using stepwise linear regression analysis. CONCLUSIONS: Patients with AFD have abnormal ECM turnover compared to normal controls. The correlation between MMP-9 levels and systolic function suggests that altered ECM turnover is important in cardiac remodelling. The association between MMP-9 and overall disease severity suggests that circulating levels of MMP-9 may provide a useful marker for assessing the response of patients with AFD to enzyme replacement treatment.

Adult↗
PubMed2006

Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: a case report of 24 months' oral substrate reduction therapy with miglustat.

We report here the results of 24 months' treatment with oral miglustat of a patient with mild-to-moderate Gaucher's disease (GD) and Parkinsonism. The patient's progressive Parkinsonian tremor, in addition to restricted vascular access, necessitated switching treatment for GD from intravenously infused enzyme replacement therapy (ERT) that had been administered for the previous 7 years. With control of haematological parameters and markers of GD activity improved or maintained and no notable adverse effects, miglustat treatment proved an effective and well-tolerated therapeutic alternative to ERT. Oral miglustat should be considered for the treatment of patients with type I GD and concurrent movement disorders who are unsuitable for ERT.

1-Deoxynojirimycin↗
PubMed2006

Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes.

Telomeres are the repeat DNA sequences at the end of chromosomes necessary for successful DNA replication and chromosomal integrity. Telomeres shorten at cell division at a rate determined by oxidative DNA damage, and cells are triggered into replicative senescence once telomeres shorten to a critical length. Telomere-related chromosomal maintenance also has a role in carcinogenesis. Type 2 diabetes is characterised by increased oxidative stress, increased oxidative DNA damage, senescent retinal and renal phenotypes, and an increased risk of epithelial malignancy. We suggest that increased oxidative DNA damage and telomere attrition in type 2 diabetes leads to: (1) carcinogenic telomere-dependent chromosomal non-reciprocal translocations, genomic instability, and the development of epithelial cancers; (2) senescent retinal and renal phenotypes (expressed as diabetic retinopathy and nephropathy); and (3) senescent vascular endothelial, monocyte-macrophage and vascular smooth muscle cells (expressed as endothelial dysfunction and accelerated atherogenesis). An adverse intrauterine environment leads to increased feto-placental oxidative stress and feto-placental oxidative DNA damage. We also suggest that intrauterine oxidative DNA damage and telomere shortening is another point at which increased oxidative stress could contribute to a pre-programmed increased risk of senescent phenotypes in adult offspring, characterised by type 2 diabetes and epithelial malignancy. These suggestions can be used to understand early glucose intolerance in the young children of type 1 diabetes pregnancies, poor cancer outcomes in type 2 diabetes, beta cell fatigue in type 2 diabetes and the absence of increased epithelial cancer risk in type 1 diabetes.

Carcinoma↗
PubMed2005

Natural history of Fabry disease in females in the Fabry Outcome Survey.

BACKGROUND: Fabry disease is a rare X linked lysosomal storage disorder resulting from deficiency of alpha-galactosidase A activity. Although the severity of clinical features in male patients is well described, only recently have studies reported the high prevalence of disabling clinical features in heterozygous females. AIMS: This study sets out to examine the clinical features and natural history of Fabry disease in further detail in a large group of female patients. METHODS: Data were obtained from 303 females enrolled in the Fabry Outcome Survey. Pain was assessed using the Brief Pain Inventory, and health related quality of life (HRQoL) was assessed using the European Quality of Life Questionnaire. A modified version of the Mainz Severity Score Index was also applied. Data on left ventricular mass (LVM) index, mean ventricular wall thickness, and glomerular filtration rate (GFR) were used to assess cardiac and renal involvement. RESULTS: The most commonly reported clinical features in females were neurological (77%) and cardiac (59%). A history of renal involvement was recorded in 40% of cases. Neurological features were the earliest to develop (mean age: 16 years), whereas cardiac (mean age: 33.5 years) and renal (mean age: 37.3 years) features developed later. LVM index increased exponentially with age. In addition, age was negatively correlated with estimated GFR and HRQoL. CONCLUSIONS: Females with Fabry disease report important age related clinical features and clinical investigation demonstrates evidence of disease progression. This study highlights the importance of careful and longitudinal assessment of female heterozygote patients with Fabry disease.

Adolescent↗
PubMed2005

Drugs for exceptionally rare diseases: do they deserve special status for funding?

Ultra-orphan drugs are medicines used to treat exceptionally rare diseases that are chronically debilitating or life-threatening. Low patient numbers make it difficult for pharmaceutical companies to recoup research and development costs, and consequently these medicines are generally expensive on a per patient basis. European Union (EU) regulations promote the development of orphan drugs; but to contain costs, some EU healthcare systems assess the cost-effectiveness of therapies when deciding if they should be funded. As ultra-orphan drugs are invariably cost-ineffective, factors in addition to cost-effectiveness need to be considered if ultra-orphan drugs are to be provided by public health services. Health service funding of ultra-orphan drugs, which varies across the EU and within the UK, has led to geographical inequities in patients' access to treatment. In some instances, support for these drugs would appear to have been approved on the basis that diseases that are rare and severe are a special case. We explore whether ultra-orphan drugs merit special status by considering efficiency, effectiveness and equity criteria. Mechanisms are discussed for creating a policy that would reduce geographical inequalities in provision across Europe.

Budgets↗
PubMed2005

Vascular complications of Fabry disease: enzyme replacement and other therapies.

UNLABELLED: Fabry disease is an X-linked glycosphingolipid storage disorder resulting from deficiency of alpha-galactosidase A. Storage of globotriaosylceramide ultimately results in multiorgan pathology, including cerebrovascular, cardiovascular and renal disease. Vascular involvement is evident throughout the body but the mechanisms by which storage on a cellular level leads to end-organ pathology are unknown. Here the evidence for abnormal blood flow, vessel architecture and endothelial function will be reviewed and possible models of vascular pathology discussed. The effects of reversal of storage within vessels by enzyme replacement therapy (ERT) and the possibilities for intervention with additional agents will be considered. CONCLUSION: The pathology of Fabry disease has an important vascular component, although the underlying pathophysiology is unclear. Preliminary evidence suggests that ERT may have beneficial effects on the vascular component of this multisystem disease.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Are routine iron stains on bone marrow trephine biopsy specimens necessary?

AIMS: To determine the role of Perls' staining in bone marrow trephine biopsy sections. METHODS: The haemosiderin content of 155 Perls' stained, formic acid decalcified trephine biopsy sections was assessed and compared with Perls' stained aspirate samples in 105 cases and haematoxylin and eosin (H&E) stained biopsy sections in all cases. RESULTS: An evaluable aspirate film with positive iron or at least seven negative particles was available for 105 biopsies. Only 71 of 95 cases with detectable aspirate iron had haemosiderin detectable on a Perls' stained section. None of 10 samples with a negative aspirate had a positive trephine biopsy. Haemosiderin was positive in 101 of the 155 Perls' stained sections, and was detectable on the H&E stained section in 71 of these cases. In five of 54 cases with negative Perls' staining, a small amount of haemosiderin was thought to be present on H&E staining. CONCLUSIONS: Aspirate smears reflect bone marrow iron stores more reliably than formic acid decalcified trephine biopsy sections. The presence of iron in Perls' stained aspirates in 44% of cases with negative Perls' stained sections indicates that iron is often lost from sections during decalcification. However, 61% of cases with unassessable aspirate samples had a positive trephine biopsy Perls' stain, contributing useful clinical information about iron status. Preparation of Perls' stained sections only in cases in which aspirate samples are inadequate for iron assessment and no obvious haemosiderin is present in an H&E stained section could produce savings in staff time and reagent costs.

Algorithms↗
PubMed2004

How should stainable iron in bone marrow films be assessed?

AIMS: To identify how many particles should be examined to enable a confident assessment of the presence or absence of iron stores and the quantity of iron in a bone marrow aspirate to be made. METHODS: One hundred and ninety consecutive bone marrow aspirate samples were stained with Perls' stain and the iron content of 10 consecutive particles was recorded. The first particle found to be positive and the particle that was most positive were also noted. RESULTS: A minimum of seven particles must be examined to establish the absence of stainable iron. A minimum of nine particles must be reviewed to see the maximum iron stores in 100% of samples and therefore make a valid judgment of whether iron stores are reduced, normal, or increased. By these criteria, 46% of the samples tested here could not be optimally assessed for absence of iron or maximum iron stores. CONCLUSIONS: The sensitivity of examination of bone marrow aspirates for iron stores can be optimised by increasing the number of particles reviewed to seven or more. This may require the staining of additional slides.

Bone Marrow↗
PubMed2004

Role of intravenous urogram in investigation of urinary tract infection: an observational study.

OBJECTIVES: To examine the value of an intravenous urogram (i.v.U) in patients with abnormal differential (99m)Tc dimercaptosuccinic acid (DMSA) uptake without scarring or ultrasound abnormality. STUDY DESIGN: Forty patients (age 0-19 years) were identified over a two year period in whom the differential renal uptake was >10%, who had smooth renal outlines, and had no evidence of scarring. All patients had an ultrasound examination. Two had marked urological abnormalities on ultrasound and eight had a duplex system in the kidney with greater DMSA uptake. In 18 patients where no explanation was apparent for the discrepant DMSA uptake, an i.v.U was performed. RESULTS: Eight patients had a normal i.v.U. In the remaining 10 patients, six had duplex systems without scarring and four had appearances of scarring in the kidney with reduced DMSA uptake. CONCLUSIONS: In this small selected group an i.v.U will identify a significant number of patients with normal kidneys, unrecognised simple duplex systems, or scarring where the DMSA scan has been inconclusive. This will help in planning long term follow up.

Adolescent↗
PubMed2004

Rate and extent of compensatory changes in energy intake and expenditure in response to altered exercise and diet composition in humans.

We assessed the effect of no exercise (Nex; control) and high exercise level (Hex; approximately 4 MJ/day) and two dietary manipulations [a high-fat diet (HF; 50% of energy, 700 kJ/100 g) and low-fat diet (LF; 20% of energy, 300 kJ/100 g)] on compensatory changes in energy intake (EI) and energy expenditure (EE) over 7-day periods. Eight lean men were each studied four times in a 2 x 2 randomized design. EI was directly quantified by weight of food consumed. EE was assessed by heart rate (HR) monitoring. Body weight was measured daily. Mean daily EE was 17.6 and 11.5 MJ/day (P < 0.001) on the pooled Hex and Nex treatments, respectively. EI was higher on HF diets (13.4 MJ/day pooled) compared with the LF diets (9.0 MJ/day). Regression analysis showed that these energy imbalances induced significant compensatory changes in EB over time of approximately 0.3-0.4 MJ/day (P < 0.05). These were due to changes in both EI and EE in the opposite direction to the perturbation in energy balance. These changes were significant, small but persistent, amounting to approximately 0.2 and approximately 0.35 MJ/day for EI and EE, respectively.

Adaptation, Physiological↗
PubMed2003

Cross talk between physical activity and appetite control: does physical activity stimulate appetite?

Physical activity has the potential to modulate appetite control by improving the sensitivity of the physiological satiety signalling system, by adjusting macronutrient preferences or food choices and by altering the hedonic response to food. There is evidence for all these actions. Concerning the impact of physical activity on energy balance, there exists a belief that physical activity drives up hunger and increases food intake, thereby rendering it futile as a method of weight control. There is, however, no evidence for such an immediate or automatic effect. Short (1-2 d)-term and medium (7-16 d)-term studies demonstrate that men and women can tolerate substantial negative energy balances of < or = 4 MJ energy cost/d when performing physical activity programmes. Consequently, the immediate effect of taking up exercise is weight loss (although this outcome is sometimes difficult to assess due to changes in body composition or fluid compartmentalization). However, subsequently food intake begins to increase in order to provide compensation for about 30% of the energy expended in activity. This compensation (up to 16 d) is partial and incomplete. Moreover, subjects separate into compensators and non-compensators. The exact nature of these differences in compensation and whether it is actually reflective of non-compliance with protocols is yet to be determined. Some subjects (men and women) performing activity with a cost of < or = 4 MJ/d for 14 d, show no change in daily energy intake. Conversely, it can be demonstrated that when active individuals are forced into a sedentary routine food intake does not decrease to a lower level to match the reduced energy expenditure. Consequently, this situation creates a substantial positive energy balance accompanied by weight gain. The next stage is to further characterize the compensators and non-compensators, and to identify the mechanisms (physiological or behavioural) that are responsible for the rate of compensation and its limits.

Anorexia↗
PubMed2002

Monocyte and neutrophil adhesion molecule expression during acute hyperglycemia and after antioxidant treatment in type 2 diabetes and control patients.

OBJECTIVE: We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. METHODS AND RESULTS: Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P<0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P=0.03). CONCLUSIONS: Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.

Acute Disease↗
PubMed2002

The effect of graded levels of exercise on energy intake and balance in free-living men, consuming their normal diet.

OBJECTIVE: To assess the effect of graded increases in exercised-induced energy expenditure (EE) on appetite, energy intake (EI), total daily EE and body weight in men living in their normal environment and consuming their usual diets. DESIGN: Within-subject, repeated measures design. Six men (mean (s.d.) age 31.0 (5.0) y; weight 75.1 (15.96) kg; height 1.79 (0.10) m; body mass index (BMI) 23.3(2.4) kg/m(2)), were each studied three times during a 9 day protocol, corresponding to prescriptions of no exercise, (control) (Nex; 0 MJ/day), medium exercise level (Mex; approximately 1.6 MJ/day) and high exercise level (Hex; approximately 3.2 MJ/day). On days 1-2 subjects were given a medium fat (MF) maintenance diet (1.6 x resting metabolic rate (RMR)). MEASUREMENTS: On days 3-9 subjects self-recorded dietary intake using a food diary and self-weighed intake. EE was assessed by continual heart rate monitoring, using the modified FLEX method. Subjects' HR (heart rate) was individually calibrated against submaximal VO(2) during incremental exercise tests at the beginning and end of each 9 day study period. Respiratory exchange was measured by indirect calorimetry. Subjects completed hourly hunger ratings during waking hours to record subjective sensations of hunger and appetite. Body weight was measured daily. RESULTS: EE amounted to 11.7, 12.9 and 16.8 MJ/day (F(2,10)=48.26; P<0.001 (s.e.d=0.55)) on the Nex, Mex and Hex treatments, respectively. The corresponding values for EI were 11.6, 11.8 and 11.8 MJ/day (F(2,10)=0.10; P=0.910 (s.e.d.=0.10)), respectively. There were no treatment effects on hunger, appetite or body weight, but there was evidence of weight loss on the Hex treatment. CONCLUSION: Increasing EE did not lead to compensation of EI over 7 days. However, total daily EE tended to decrease over time on the two exercise treatments. Lean men appear able to tolerate a considerable negative energy balance, induced by exercise, over 7 days without invoking compensatory increases in EI.

Adult↗
PubMed2002

The effect of graded levels of exercise on energy intake and balance in free-living women.

AIM: We assessed the effect of graded increases in exercised-induced energy expenditure (EE) on appetite, daily energy intake (EI), total daily EE and body weight in six lean women using a within-subject, repeated measures design. METHOD: Subjects were each studied three times during 7 day treatments, corresponding to no-exercise (control; Nex; 0 MJ/day), medium exercise level (Mex; approximately 1.9 MJ/day) and high exercise level (Hex; approximately 3.4 MJ/day), with 2 day maintenance beforehand. Subjects self-weighed ad libitum food intake. EE was assessed by continual heart rate monitoring. During waking hours subjects recorded hourly sensations of hunger and appetite. RESULTS: EE amounted to 9.2, 11.0 and 12.1 MJ/day (F (2, 10)=5.67; P=0.023 (s.e.d.=0.87)) on the Nex, Mex and Hex treatments, respectively. The corresponding values for EI were 8.9, 9.2 and 10.0 MJ/day (F (2, 10)=4.80; P=0.035 (s.e.d.=0.36)). There were very weak treatment effects on hunger. Weight loss was significantly different from zero on the Mex and Hex treatments. CONCLUSION: Markedly increasing EE through exercise produced significant but partial compensations in EI ( approximately 33% of EE due to exercise). Accurate adjustments of El to acute increases in EE are likely to take weeks rather than days.

Adult↗
PubMed2001

Graded nanostructures produced by sliding and exhibiting universal behavior.

Nanostructured copper was produced by deformation under large sliding loads. In the near surface layers, 10 nm scale microstructures form and coarsen with increasing depth from the surface. The graded structure enables characterization of the structural scale over several orders of magnitude. Analysis reveals that universal scaling of the microstructure exists from 10,000 to 10 nm. The limit of scale is pushed to an order of magnitude of the ultimate scale at which the crystallinity is lost. This universality opens the door for easy manufacture of ever finer scale components by deformation.

Journal Article↗
PubMed2001

The impact of non-compliance on the cost-effectiveness of pharmaceuticals: a review of the literature.

Non-compliance with drug therapies not only limits their effectiveness, but in some instances, is associated with grave clinical sequelae and substantial economic burden. It is important, therefore, to consider non-compliance in economic evaluations. A review of pharmacoeconomic evaluations, which have applied sensitivity analysis to non-compliance rates, was undertaken to evaluate the impact of non-compliance on the cost-effectiveness of different drug therapies. Although 22 evaluations satisfied the inclusion criteria, additional information was obtained from the authors of most studies, as the published details were inadequate. The majority of evaluations assumed altered effectiveness owing to reduced compliance in the absence of supportive clinical evidence. Because of the disparity in the nature of the outcomes, the measures of non-compliance and the time horizon of the studies evaluated, it was not possible to compare the magnitude of the impact of non-compliance among different drug-disease combinations. However, it was evident that non-compliance always results in a reduction in efficacy, but its impact on costs varied substantially. The importance of incorporating measures of compliance is highlighted, as failing to account for 'real world' compliance rates in pharmacoeconomic evaluations may lead to selection of sub-optimal treatment strategies.

Cost-Benefit Analysis↗
PubMed2001

Description and evaluation of a Newton-based electronic appetite rating system for temporal tracking of appetite in human subjects.

This study assessed the reliability and validity of a palm-top-based electronic appetite rating system (EARS) in relation to the traditional paper and pen method. Twenty healthy subjects [10 male (M) and 10 female (F)] - mean age M=31 years (S.D.=8), F=27 years (S.D.=5); mean BMI M=24 (S.D.=2), F=21 (S.D.=5) - participated in a 4-day protocol. Measurements were made on days 1 and 4. Subjects were given paper and an EARS to log hourly subjective motivation to eat during waking hours. Food intake and meal times were fixed. Subjects were given a maintenance diet (comprising 40% fat, 47% carbohydrate and 13% protein by energy) calculated at 1.6xResting Metabolic Rate (RMR), as three isoenergetic meals. Bland and Altman's test for bias between two measurement techniques found significant differences between EARS and paper and pen for two of eight responses (hunger and fullness). Regression analysis confirmed that there were no day, sex or order effects between ratings obtained using either technique. For 15 subjects, there was no significant difference between results, with a linear relationship between the two methods that explained most of the variance (r(2) ranged from 62.6 to 98.6). The slope for all subjects was less than 1, which was partly explained by a tendency for bias at the extreme end of results on the EARS technique. These data suggest that the EARS is a useful and reliable technique for real-time data collection in appetite research but that it should not be used interchangeably with paper and pen techniques.

Adult↗