Biomedical subjects

D J Hart

Publications and source records attributed to D J Hart.

At least 19 recordsLinked to original sources

PubMed2006

Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population-based study.

BACKGROUND: Although age is the strongest predictor of osteoarthritis, the exact mechanism underlying this disorder remains elusive. OBJECTIVE: To examine the association between leucocyte telomere length (LTL), a bio-indicator of ageing, and radiographic hand osteoarthritis. METHODS: An unselected, predominantly female sample from the TwinsUK Adult Twin Registry (Twin Research and Genetic Epidemiology Unit, St Thomas Hospital, London, UK) was studied. Radiographs of both hands were obtained with a standard posteroanterior view and assessed for radiographic osteoarthritis according to the Kellgren/Lawrence (K/L) score. Individual radiographic features including osteophytes and joint space narrowing (JSN) were also assessed on a four-point scale using a standard atlas. Hand osteoarthritis was defined radiographically as having >or=3 osteoarthritis-affected joints of both hands (K/L score>or=2). Severity of hand osteoarthritis was indicated semiquantitatively by total K/L scores, osteophytes, JSN scores and proportion of joints affected. Mean LTL was measured by the terminal restriction fragment length using the Southern blot. RESULTS: A total of 1086 Caucasian subjects (mean (SD) age 55 (8.0) years) were studied. LTL was 6.95 (0.64) kb and was inversely correlated with age. After adjustment for age, sex, body mass index and smoking, LTL was significantly shorter by 178 bp in subjects with hand osteoarthritis (n = 160) than in those without (n = 926; p = 0.04). LTL was also significantly associated with semicontinuous measures of osteoarthritis (eg, total K/L score, JSN score, osteophyte score and proportion of joints affected) after adjustment (all p<or=0.02) in a dose-response fashion. CONCLUSION: Shorter LTL equivalent to around 11 years of annual loss in normal people is associated with radiographic hand osteoarthritis and disease severity, suggesting potential shared mechanisms between osteoarthritis and ageing, and implicating oxidative stress and low-level chronic inflammation in both conditions.

Adult↗

PubMed2006

Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study.

OBJECTIVE: Genetic influences on rates of osteoarthritis (OA) progression are unknown. Our aim was to estimate the heritability of progression of radiographic knee OA using a longitudinal twin study. METHODS: Unselected monozygotic (MZ) and dizygotic (DZ) twin pairs from the TwinsUK registry were utilized. Anteroposterior radiographs were performed on both knees at baseline and follow-up using the same protocol. Radiographic features of knee OA including osteophyte and joint space narrowing (JSN) were assessed on a four-point scale using a standard atlas. Progression of knee osteophyte and JSN was defined as the difference in the corresponding score between follow-up and baseline > or =1. Liability threshold modelling using logistic regression was utilized for heritability estimation. RESULTS: A total of 114 MZ pairs and 195 DZ pairs were studied. The average follow-up time was 7.2 years. Medial progression of osteophyte and JSN was more common than lateral progression. Prevalence of progression was generally higher in the MZs than the DZs. Similarly, concordances and tetrachoric correlations for both osteophyte and JSN were higher in the MZs than the DZs although only significant for overall and medial JSN and osteophyte. The heritability estimates were 69% [95% confidence interval (CI) 42-97%] and 80% (95% CI 50-100%) for medial osteophyte and JSN, respectively. The estimates were reduced by 7-15% after adjustment for age, body mass index (BMI), and the severity of osteophyte/JSN at baseline. CONCLUSION: Our data documented a substantial genetic influence on the progression of knee OA--as seen in the medial compartment, providing a solid basis to search for genes involved in this highly relevant clinical trait.

Aged↗

PubMed2005

The relation between progressive osteoarthritis of the knee and long term progression of osteoarthritis of the hand, hip, and lumbar spine.

BACKGROUND: The association between progression of knee osteoarthritis and progression of osteoarthritis at sites distant from the knee is unclear because of a lack of multisite longitudinal progression data. OBJECTIVE: To examine the association between radiological progression of knee osteoarthritis and osteoarthritis of the hands, hips, and lumbar spine in a population based cohort. METHODS: 914 women had knee x rays taken 10 years apart, which were read for the presence of osteophytes and joint space narrowing (JSN). Progression status was available for hand, hip, and lumbar spine x rays over the same 8 to 10 year period. The association between progression of knee osteoarthritis and osteoarthritis at other sites was analysed using odds ratios (OR) and 95% confidence intervals (CI) in logistic regression models. RESULTS: 89 of 133 women had progression of knee osteoarthritis based on osteophytes, and 51 of 148 based on JSN definition. Progression of JSN in the knee was predicted by progression in lumbar spine disc space narrowing (OR = 2.9 (95% CI 1.2 to 7.5)) and hip JSN (OR = 2.0 (1.0 to 4.2)). No consistent effects were seen for hand osteoarthritis. The associations remained after adjustment for age and body mass index. CONCLUSIONS: Progression of knee osteoarthritis is associated with progression of lumbar spine and hip osteoarthritis. This may have implications for trial methodology, the selection of patients for osteoarthritis research, and advice for patients on prognosis of osteoarthritis.

Adult↗

PubMed2005

A microcontroller system for investigating the catch effect: functional electrical stimulation of the common peroneal nerve.

Correction of drop foot in hemiplegic gait is achieved by electrical stimulation of the common peroneal nerve with a series of pulses at a fixed frequency. However, during normal gait, the electromyographic signals from the tibialis anterior muscle indicate that muscle force is not constant but varies during the swing phase. The application of double pulses for the correction of drop foot may enhance the gait by generating greater torque at the ankle and thereby increase the efficiency of the stimulation with reduced fatigue. A flexible controller has been designed around the Odstock Drop Foot Stimulator to deliver different profiles of pulses implementing doublets and optimum series. A peripheral interface controller (PIC) microcontroller with some external circuits has been designed and tested to accommodate six profiles. Preliminary results of the measurements from a normal subject seated in a multi-moment chair (an isometric torque measurement device) indicate that profiles containing doublets and optimum spaced pulses look favourable for clinical use.

Ankle Joint↗

PubMed2005

Controlling release from the lipidic cubic phase by selective alkylation.

The lipidic cubic phase can be viewed as a molecular sponge consisting of interpenetrating nanochannels filled with water and coated by lipid bilayers. It has been used as a delivery matrix for low-molecular-weight drugs. For those that are water-soluble, release is fast and unregulated. This study seeks to exploit the lipid bilayer compartment as a location within the cubic phase in which to 'hydrophobically' anchor the water-soluble drug. This was accomplished by controlling partitioning into, and thus release from, the aqueous compartment of the cubic phase. Tryptophan was used as a surrogate water-soluble drug and alkylation was implemented to regulate release. By adjusting alkyl chain length, exquisite control was realized. Without alkylation, 20% of the tryptophan was released under standard conditions (infinite sink with a 30-mg cubic phase source at pH 7 and 20 degrees C) over a period of 30 min (t(20)). In the case of derivatives with alkyl chains two and eight carbon atoms long, t(20) values of 3 and 13 days, respectively, were observed. Eliminating the charge on tryptophan completely by alkylation produced a derivative that became irreversibly lodged in the lipid bilayer. The release behavior of the short-chain derivatives was mathematically modeled and parameters describing transport have been obtained. Cubic phase partition coefficients for tryptophan and its derivatives were measured to facilitate modeling. The implications of these findings with regard to the cubic phase and related delivery systems, and to vaccine efficacy are discussed.

Alkylation↗

PubMed2004

Behavioural and psychological syndromes in Alzheimer's disease.

OBJECTIVES: The origins of behavioural and psychological symptoms of dementia are still poorly understood. By focusing on piecemeal behaviours as opposed to more robust syndrome change valid biological correlates may be overlooked. Our understanding of BPSD via the identification of neuropsychiatric syndromes. METHODS: We recruited 435 subjects from old age psychiatry and elderly care memory outpatient clinics fulfilling the criteria for diagnosis of probable Alzheimer's disease. Behavioural and psychological symptoms were assessed using the Neuropsychiatric Inventory. Principal components factor analysis was carried out on the composite scores of the 12 symptom domains to identify behavioural syndromes (factors). Results were confirmed by performing three different rotations: Varimax, Equamax and Quartimax. RESULTS: Four factors were identified (which accounted for 57% of the variance): 'affect' factor-depression/dysphoria, anxiety, irritability/lability and agitation/aggression; 'physical behaviour' factor-apathy, aberrant motor behaviour, sleep disturbance and appetite/eating disturbance; 'psychosis' factor-delusions and hallucinations; 'hypomania' factor-disinhibition and elation/euphoria. These groups were unchanged when different methods of rotation were used. CONCLUSIONS: We report novel observations that agitation/aggression/irritability cluster within a depressive symptom factor and apathy is found within a physical behaviour factor.

Aged↗

PubMed2004

Iron contents of Malawian foods when prepared in iron cooking pots.

The aim of this study was to determine the iron content of Malawian foods prepared in iron pots and to examine the effects of continuous cooking time and added oil on the iron content of the food prepared. Foods prepared, which included a staple (Nsima), relish vegetables, and beans, had an increased iron content when prepared in an iron compared to a glass pot. For these three foods, iron content per gram increased by 3.15 micrograms, 35.8 micrograms, and 147.32 micrograms, respectively. Continuous use of the iron pot for cooking could have a positive effect on the amount of iron added to the food, as the three foods' iron content increased by a further 2.9 micrograms iron/g, 7.6 micrograms iron/g and 20.1 micrograms iron/g, respectively. This effect needs more study. Food pH was significantly negatively correlated with food iron content. The use of oil reduced the amount of iron added to stir-fried vegetables by 52.37 micrograms/g and increased iron added to Nsima (1.2 micrograms/g). Malawian foods increased their iron content when cooked in iron pots. This method of food preparation potentially provides a low-cost sustainable means of improving the iron intakes of families and communities where this traditional method of food preparation is acceptable.

Cooking↗

PubMed2004

Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer's disease.

The rising number of people with cognitive impairment is placing health care budgets under significant strain. Dementia related behavioural change is a major independent risk factor for admission to expensive institutional care, and aggressive symptoms in particular are poorly tolerated by carers and frequently precipitate the collapse of home coping strategies. Aggressive change may result from known genetic risk factors for Alzheimer's disease (AD) and therefore accompany conventional markers such as apolipoprotein E (ApoE). We tested this hypothesis in 400 moderately to severely affected AD patients who were phenotyped for the presence of aggressive or agitated behaviour during the month prior to interview using the Neuropsychiatric Inventory with Caregiver Distress. The proportion of subjects with aggression/agitation in the month prior to interview was 51.8%. A significantly higher frequency of the e4 allele was found in individuals recording aggression/agitation in the month prior to interview (chi2 = 6.69, df = 2, p = 0.03). The additional risk for aggression/agitation conferred by e4 was also noted when e4 genotypes were compared against non-e4 genotypes (chi2 = 5.45, df = 1, p = 0.02, OR = 1.60, confidence interval (CI) 1.06 to 2.43). These results indicate that advanced Alzheimer's disease patients are at greater risk of aggressive symptoms because of a genetic weakness in apolipoprotein E.

Aged↗

PubMed2003

Risk factors for progression of lumbar spine disc degeneration: the Chingford Study.

OBJECTIVE: Few data exist concerning the natural history of lumbar spine disc degeneration and associated risk factors. We therefore undertook this study to examine the radiographic progression of lumbar spine disc degeneration over the course of 9 years in a population-based inception cohort of women from the Chingford Study. METHODS: Seven hundred ninety-six paired lumbar spine radiographs were read by a single reader for anterior osteophytes (AO) and disc space narrowing (DSN) using the Lane atlas at each lumbar disc space (L1-5). Disc degeneration was defined using thresholds of AO and DSN grade 1+ in one or more vertebrae (L1-5) within a subject. Progression was defined as an increase in grade in an affected year-1 vertebra. Potential risk factors were assessed using odds ratios and 95% confidence intervals adjusted for age, body mass index (BMI), and other potential confounders in logistic regression models using the STATA statistical package. RESULTS: The mean +/- SD age at baseline was 53.8 +/- 6.0 years, and mean +/- SD BMI was 25.4 +/- 4.1 kg/m(2). Progression rates for AO and DSN were 4% per annum and 3% per annum, respectively. Progression of DSN was predicted by age, back pain, and radiographic hip and knee osteoarthritis (OA). Progression of AO was predicted by age and radiographic hip OA, with borderline significance for BMI >30 kg/m(2). No significant effects were seen for smoking, physical activity, hormone replacement therapy use, multiparity, or hand OA. CONCLUSION: This is the first population-based longitudinal study to assess progression of the individual radiographic features of AO and DSN in lumbar spine disc degeneration. We demonstrated progression rates of 3-4% per annum, with important risk factors for progression, including age, back pain, and radiographic OA at the hip and knee.

Disease Progression↗

PubMed2003

A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer's disease.

AIM: To document the behavioural and psychological symptoms in patients with a diagnosis of established Alzheimer's disease (AD) for at least 3 years. METHODS: Patients with a > or =3 year history of AD (NINCDS/ADRDA) were recruited from old age psychiatrist and elderly care memory clinics. Information regarding duration of symptoms and non-cognitive symptomatology was obtained during interview with a carer or next-of-kin who had contact with the patient at least 3 times a week and for at least 3 years. MMSE, FAST and NPI including caregiver distress, were used to assess cognition, function and behavioural/psychological disturbance respectively. With each non-cognitive symptom the carer was asked to estimate its onset. RESULTS: The mean age of patients was 77 years and duration of illness 87 months. Mean MMSE was 8/30 and FAST score 6d. Of the psychological symptoms occurring at any stage, depression (56%), delusions (55%) and anxiety (52%) were most common, with hallucinations, elation and disinhibition occurring less frequently. In general, behavioural changes were more common with apathy occurring in 88% of patients, motor behaviour in 70%, aggression in 66%, irritability and appetite changes in 60% and sleep disturbance in 54%. All symptoms except apathy became less common when the carer was asked if they were still present in the last month. Mean onset of psychological symptoms was 47 months. Mean onset of behavioural symptoms was 48 months. Behavioural disturbance seemed to cause more care-giver distress than psychological change. CONCLUSION: The results show behavioural and psychological symptoms in AD are common and distressing for carers. They appear to require a consistent period of neurodegeneration in order to emerge.

Aged↗

PubMed2003

Kellgren & Lawrence grade 1 osteophytes in the knee--doubtful or definite?

The most universally accepted methods of classification of radiographic osteoarthritis (OA) is the Kellgren & Lawrence (K&L) grading system. However, there have been many criticisms of this including the grading of a doubtful osteophyte as a grade 1. We report the natural history of a given prevalent grade 1 osteophyte in a 10-year follow-up knee study. 62% of women graded at baseline with a doubtful osteophyte went on to develop true osteophytic knee OA compared with only 22% of controls with no sign of disease. So called 'doubtful' osteophytes appear to be 'real' and significantly related to OA knee and therefore cannot be ignored or classified as normal.

Chondrocytes↗

PubMed2003

Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of folate bioavailability studies.

Single (13)C6-labelled doses of pteroylmonoglutamic acid (PteGlu; 634 nmol) or 5-formyltetrahydrofolic acid (431-569 nmol) were given to fasted adult volunteers, and the rise in total and (13)C-labelled plasma 5-methyltetrahydrofolic acid metabolite monitored over 8 h by HPLC and liquid chromatography-MS. The dose-adjusted area under the curve (AUC) for total (labelled plus unlabelled) plasma 5-methyltetrahydrofolic acid following a 5-formyltetrahydrofolic acid test dose was 155 % that obtained following a PteGlu test dose. Surprisingly, an average 60 and 40 % of the total plasma 5-methyltetrahydrofolic acid response to [(13)C6]PteGlu and [(13)C6]5-formyltetrahydrofolic acid, respectively, was unlabelled; an observation never before reported. Short-term kinetics of plasma [(13)C6]5-methyltetrahydrofolic acid showed a slower initial rate of increase in plasma concentration and longer time to peak following an oral dose of [(13)C6]PteGlu compared with that for an oral dose of [(13)C6]5-formyltetrahydrofolic acid, while the [(13)C6]5-methyltetrahydrofolic acid AUC for [(13)C6]5-formyltetrahydrofolic acid was 221 % that for [(13)C6]PteGlu. These data indicate that PteGlu and 5-formyltetrahydrofolic acid, which are thought to be well absorbed (about 90 %) at physiological doses, exhibit dramatically different rates and patterns of plasma response. A limitation in the rate of reduction of PteGlu before methylation could result in slower mucosal transfer of [(13)C6]5-methyltetrahydrofolic acid derived from [(13)C6]PteGlu into the plasma. This, when coupled with an observed similar plasma clearance rate for [(13)C6]5-methyltetrahydrofolic acid metabolite derived from either folate test dose, would yield a comparatively smaller AUC. These findings suggest potential problems in interpretation of absorption studies using unlabelled or labelled folates where the rate of increase, the maximum increase, or the AUC, of plasma folate is employed for test foods (mainly reduced folates) v. a 'reference dose' of PteGlu.

Absorption↗

PubMed2002

Evaluation of an automated latex D-dimer immunoassay in the clinical assessment of suspected venous thromboembolism.

Because the reliability of clinical signs in venous thromboembolism (VTE) is poor, a highly sensitive, non-invasive test may improve the selection of patients requiring further investigation. We assessed the sensitivity and negative predictive value of an automated D-dimer latex immunoassay (IL-Test ) in 68 patients presenting with suspected VTE. The plasma D-dimer concentration was estimated and an appropriate diagnostic radiological investigation performed. Control values were obtained from healthy young and elderly volunteers. Using a cut-off value of 330 ng/ml, the assay had a sensitivity of 100% and negative predictive value of 100% for VTE. We conclude that the IL-Test. automated D-dimer assay has a suitably high sensitivity and adequate negative predictive value to be included in a pre-test clinical probability protocol for the evaluation of patients with suspected VTE.

Adult↗

PubMed2001

Analysis of the NF-kappaB p50 dimer interface by diversity screening.

An in vivo screen has been devised for NF-kappaB p50 activity in Escherichia coli exploiting the ability of the mammalian transcription factor to emulate a prokaryotic repressor. Active intracellular p50 was shown to repress the expression of a green fluorescent protein reporter gene allowing for visual screening of colonies expressing active p50 on agar plates. A library of mutants was constructed in which the residues Y267, L269, A308 and V310 of the dimer interface were simultaneously randomised and twenty-five novel functional interfaces were selected which repressed the reporter gene to similar levels as the wild-type protein. The leucine-269 alanine-308 core was repeatedly, but not exclusively, selected from the library whilst a diversity of predominantly non-polar residues were selected at positions 267 and 310. These results indicate that L269 and A308 may form a hot spot of interaction and allow an insight into the processes of dimer selectivity and evolution within this family of transcription factors.

Amino Acid Sequence↗

PubMed2001

Synthesis of ent-alantrypinone.

This paper presents a synthesis of ent-alantrypinone (ent-6), the enantiomer of a natural product produced by the fungus Penicillium thymicola. The synthesis revolves around the Li[Me(3)AlSPh]-promoted isomerization of iminobenzoxazine 33 to quinazolinone 34, an N-acyliminium ion cyclization that converts enamide 9 to bridged indole 35, and rearrangement of 35 to oxindole ent-6. Ancillary chemistry that involves thermal fragmentation of an iminobenzoxazine to a nitrile ylide and Me(2)AlSPh-mediated cyclization of oxime ether-ester 22 to pyrrolidinone 23 is also described.

Alkaloids↗

PubMed2001

Trapping of the putative cationic intermediate in the Morin rearrangement with carbon nucleophiles.

This paper presents reactions in which the putative cationic intermediate in the Morin rearrangement is trapped by aromatic carbon nucleophiles (indoles and furans). For example, reaction of sulfoxide 27 with trifluoroacetic acid in chloroform provides, among other products, indole 29 and indoline 30. The indoline was shown to be in equilibrium with the nine-membered ring bridged indole 31. Other examples of Morin rearrangement-trapping reactions are presented, and mechanisms for these transformations are proposed.

Carbon↗

PubMed2001

A new plasmid display technology for the in vitro selection of functional phenotype-genotype linked proteins.

BACKGROUND: Display technologies which allow peptides or proteins to be physically associated with the encoding DNA are central to procedures which involve screening of protein libraries in vitro for new or altered function. Here we describe a new system designed specifically for the display of libraries of diverse, functional proteins which utilises the DNA binding protein nuclear factor kappa B (NF-kappa B) p50 to establish a phenotype-genotype link between the displayed protein and the encoding gene. RESULTS: A range of model fusion proteins to either the amino- or carboxy-terminus of NF-kappa B p50 have been constructed and shown to retain the picomolar affinity and DNA specificity of wild-type NF-kappa B p50. Through use of an optimal combination of binding buffer and DNA target sequence, the half-life of p50-DNA complexes could be increased to over 47 h, enabling the competitive selection of a variety of protein-plasmid complexes with enrichment factors of up to 6000-fold per round. The p50-based plasmid display system was used to enrich a maltose binding protein complex to homogeneity in only three rounds from a binary mixture with a starting ratio of 1:10(8) and to enrich to near homogeneity a single functional protein from a phenotype-genotype linked Escherichia coli genomic library using in vitro functional selections. CONCLUSIONS: A new display technology is described which addresses the challenge of functional protein display. The results demonstrate that plasmid display is sufficiently sensitive to select a functional protein from large libraries and that it therefore represents a useful addition to the repertoire of display technologies.

Blotting, Western↗

PubMed2001

Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women.

The classic twin study is sometimes described as "the perfect natural experiment" for the investigation of the aetiology of complex disease, but assumptions of the twin design need to be empirically tested if their results are to be considered unbiased and representative of singleton populations. In this study comparisons of disease and prevalence of lifestyle characteristics have been made between twin participants in the St Thomas' Hospital UK adult twin registry, the largest twin volunteer register in the UK for the study of diseases of ageing, and a parallel population-based study of singleton women. The only differences found were for weight, where monozygotic (MZ) twins were lighter and had a smaller variance than dizygotic (DZ) twins and singletons. For the other variables studied, volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of: bone mineral density, osteoarthritis, blood pressure, hypertensive drug use, height, history of hysterectomy and ovariectomy, menopausal status and current alcohol and overall tobacco consumption. We conclude that the results of twin studies can be generalised to singleton populations for these measures and disease outcomes.

Alcohol Drinking↗