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Biomedical subjects

D J Hart

Publications and source records attributed to D J Hart.

At least 37 records · Page 2Linked to original sources
PubMed2000

Vinyl and alkynyl pyrimidines as michael acceptors: an approach to a cylindrospermopsin substructure.

Vinyl pyrimidine 9 and alkynyl pyrimidine 24 undergo base-mediated intramolecular conjugate addition reactions in which a carbamate and a urea, respectively, behave as nitrogen nucleophiles. The cyclic carbamate derived from 9 was converted to 11 via a metalation-oxidation reaction in which 2-phenylsulfonyl-3-phenyloxaziridine behaves as a hydroxylation reagent. The cyclic urea derived from 24 was converted to cylindrospermopsin substructure 30 using dimethyldioxirane to introduce the C(7) hydroxyl group.

Alkaloids↗
PubMed2000

Definition and epidemiology of osteoarthritis of the hand: a review.

The hand is a common site of peripheral joint involvement in osteoarthritis (OA) and although often underestimated as a cause of disability, the effect on quality of life from limitations in performing activities of daily living such as dressing and feeding may be considerable. Hand OA may also be an important indicator of a systemic tendency to OA which may involve weight bearing joints, notably the hips and knees. (1) The definition of hand OA, particularly for epidemiological studies, has undergone reassessment and revision over the last few years. In this paper we examine the issues relating to this and consider the epidemiology of hand OA.

Adult↗
PubMed1999

Antiretroviral antibodies: implications for schizophrenia, schizophrenia spectrum disorders, and bipolar disorder.

BACKGROUND: Some retroviral antigens share structural homology within a group of related retroviruses. It is possible that antibodies directed against one virus may cross-react with antigens from a different virus in the group. METHODS: Using this principle, the human immunodeficiency virus 1 (HIV-1) Western blot assay was used as an available source of human retroviral antigens to screen serum samples from an archived collection to ascertain whether there was an association between serum antiretroviral antibodies and mental illnesses. RESULTS: A statistically significant proportion (28/54, 52%) of patients suffering from psychiatric disorders had serum antibodies that recognized at least one antigen present on the blot, culminating in indeterminate HIV-1 tests. The majority of the reactive samples were directed against the HIV-1 group antigens p24 and p17. These findings contrast with those of nonpsychiatric patients, who had 4/16 (25%) indeterminate blots. CONCLUSIONS: The results suggest exposure to retroviral antigens related to those of HIV-1 in subpopulations of schizophrenic, schizophrenic spectrum disorder, and bipolar disorder patients.

Antibodies, Viral↗
PubMed1999

The salt dependence of DNA recognition by NF-kappaB p50: a detailed kinetic analysis of the effects on affinityand specificity.

The binding kinetics of NF-kappaB p50 to the Ig-kappaB site and to a DNA duplex with no specific binding site were determined under varying conditions of potassium chloride concentration using a surface plasmonresonance biosensor. Association and dissociation rate constants were measured enabling calculation of the dissociation constants. Under previously established high affinity buffer conditions, the k a for both sequences was in the order of 10(7) M-1s-1whilst the k d values varied 600-fold in a sequence-dependent manner between 10(-1) and 10(-4 )s-1, suggesting that the selectivity of p50 for different sequences is mediated primarily through sequence-dependent dissociation rates. The calculated K D value for the Ig-kappaB sequence was 16 pM, whilst the K D for the non-specific sequence was 9.9 nM. As the ionic strength increased to levels which are closer to that of the cellular environment, the binding of p50 to the non-specific sequence was abolished whilst the specific affinity dropped to nanomolar levels. From these results, a mechanism is proposed in which p50 binds specific sequences with high affinity whilst binding non-specific sequences weakly enough to allow efficient searching of the DNA.

DNA↗
PubMed1999

Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: the Chingford Study.

OBJECTIVE: To examine the natural history, role of risk factors, and incidence of knee osteoarthritis (OA) in a prospective study of women from a population cohort. METHODS: Women from the Chingford Study who had been recruited in 1989 were followed up with knee radiographs 4 years later. A total of 715 paired radiographs (71% of the original sample) were graded for osteophytes and 644 for joint space narrowing (JSN). Women whose radiographs had been graded as 0 in 1989 and as > or =14 years later were classified as having incident disease. Incident cases were compared with controls for associations with a number of risk factors. RESULTS: Eighty-one women (12.6%) developed JSN of the knee, equating to an incidence of 3.1% per year. No clear risk factors for JSN were identified. Reproducibility of measures of joint space is poor, however, leading to inaccuracy of definition. Incident knee osteophytes developed in 95 women (133%), equating to an incidence of 3.3% per year. Compared with controls, women with incident knee osteophytes were older, heavier, and had more hand OA and knee symptoms. Women in the top tertile of obesity (body mass index >26.4) had a significantly increased risk of incident knee osteophytes (odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.29-4.39). Incident knee osteophytes increased by 20% per 5-year age increase. A nonsignificant protective effect for incident knee osteophytes was seen with current estrogen replacement therapy (ERT) (OR 0.41, 95% CI 0.12-1.42). No effect was associated with smoking, physical activity, hysterectomy, or previous knee injury. CONCLUSION: Obesity and aging are associated with a high risk of new knee OA developing in women. Evidence of a protective effect of ERT was seen. No clear association was found for incident JSN, suggesting that different etiologic mechanisms are operating or that standard radiographs are an inaccurate measure of incident narrowing.

Female↗
PubMed1999

Family history of appendicular fracture and risk of osteoporosis: a population-based study.

Family and twin studies demonstrate a strong genetic component to osteoporosis, suggesting that a positive family history for this disease may be an important clinical risk factor. We have therefore explored the extent to which a history of wrist fracture in a female first-degree relative was associated with an increased risk of prevalent fracture at both appendicular and vertebral sites in a cross-sectional study design. One thousand and three Caucasian women (age range 45-64 years) were studied from a UK population cohort. Bone mineral density (BMD) was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Appendicular fractures (wrist and hip) were recorded by questionnaire and validated from radiographs and hospital records. Vertebral fractures were assessed using radiologic survey of the thoracolumbar spine and semi-automated morphometric analysis. A positive family history of osteoporotic fracture (hip and/or wrist) in either a mother and/or sister was reported in 138 of the 1003 women. When compared with those with a negative family history of fracture, BMD was significantly reduced in those with a positive history at both the spine (p = 0.02) and the hip (p = 0.02). In total, there were 63 validated fragility fractures found in the 1003 women (16 wrist, 6 hip and 41 vertebral). Family history of osteoporotic fracture was associated with an increased total risk for osteoporotic fracture, with an odds ratio (95% confidence interval) of 2.02 (1.02, 3.78). Site-specific analysis showed that a positive family history of wrist fracture was associated with a considerably elevated risk of wrist fracture, with an odds ratio of 4.24 (1.44, 12.67). These increases in risk remained after adjustment for BMD, suggesting that other genetic factors account for the familial risk of osteoporosis and fracture.

Case-Control Studies↗
PubMed1998

Changes in plasma carotenoid and vitamin E profile during supplementation with oil palm fruit carotenoids.

It has been hypothesized that supplementation with a single source of carotenoids causes perturbations in the plasma level of diet-derived carotenoids and that this may explain the lack of association between disease rates and the intake of carotenoid supplements. This article describes the effect of supplementation with an oil palm fruit extract, rich in beta-and alpha-carotene, on the plasma carotenoid profile of 15 healthy women volunteers. Volunteers were supplemented for 35 days with 15 mg/d of total carotenoids. Blood samples were taken at regular intervals during the supplementation period and analyzed for a range of carotenoids. Results indicate that the hydrocarbon carotenoid components of the supplement are absorbed and appear in the plasma disproportionately to the ratios in the supplement and that the plasma concentration of diet-derived lutein, a dihydroxy carotenoid ((3R,3S,6R)-beta,epsilon-carotene-3,3-diol), is depressed, whereas that of lycopene is unaffected. Plasma alpha-tocopherol concentrations were unaffected by supplementation. It is concluded that supplementation with carotenoids from a single source results in plasma carotenoid profile changes that are not predictable from a knowledge of supplement composition and that such changes should be monitored and considered when drawing conclusions as to the effect of carotenoid supplementation on health outcomes.

Adult↗
PubMed1998

Relation between Heberden's nodes and distal interphalangeal joint osteophytes and their role as markers of generalised disease.

OBJECTIVE: Heberden's nodes are often used as a marker for osteoarthritis (OA). This study examined how often Heberden's nodes and radiological distal interphalangeal (DIP) osteophytes coexist in the same digit and the sensitivity, specificity, and positive predicative value of each for OA at different sites or generalised disease. METHODS: This was a population-based study of 660 middle ages women taking part in a twin study of OA. Distal interphalangeal osteophytes were defined radiologically and graded on a four point scale (0-3) using a published atlas of individual features. Heberden's nodes were defined by standardised clinical examination. OA in other joint (knees, proximal interphalangeal (PIP) joints and carpometacarpal (CMC) joints) was defined radiologically using a published atlas. RESULTS: Poor agreement was observed between a Heberden's node (HN) and a radiological distal interphalangeal osteophyte in the same finger of the same hand (K statistic (95% CI) = 0.36 (0.33, 0.39)). Although HN and radiological DIP osteophytes had similar sensitivity, the specificity and positive predicative value of DIP osteophytes was considerably higher for detecting knee, CMC, PID OA, and OA in more than two groups of joint (knee, CMC, and DIP joints). CONCLUSION: HN are not synonymous with DIP osteophytes. Radiological DIP osteophytes are a better marker of knee and multiple joint OA than HN. HN may still be an imperfect surrogate for hand OA when radiology is impractical, but are not an accurate marker of generalised disease.

Female↗
PubMed1997

Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease.

OBJECTIVE: To examine the role of low-grade inflammation in the etiology and progression of early osteoarthritis (OA) of the knee. METHODS: We used a new, high-sensitivity, automated monoclonal antibody immunoassay for the classic acute-phase protein, C-reactive protein (CRP), in serum. Anteroposterior radiographs of the knee with weight bearing were obtained on 845 women (ages 44-67) on entry into a population-based study of OA in Chingford, North London. In those defined radiologically as "cases," the knee radiographs were repeated after 4 years. RESULTS: Levels of CRP were higher in 105 women with knee OA defined radiologically as Kellgren-Lawrence grade 2+ (median 2.4 mg/liter, interquartile range [IQR] 1.0-5.1), compared with 740 women without OA (median 0.7 mg/liter, IQR 0.3-1.8) (P < 0.001). Median levels of CRP were higher in the 31 women whose disease progressed at least 1 Kellgren-Lawrence grade (median 2.6 mg/liter, IQR 1.9-4.6), compared with the 39 whose disease did not (median 1.3 mg/liter, IQR 0.6-2.4) (P = 0.006) . The significance of these differences persisted after adjustment for age, weight, height, smoking, knee pain, or injury. Classifying disease by the presence of joint space narrowing or osteophytes alone produced similar results. CONCLUSION: CRP levels are modestly but significantly increased in women with early knee OA, and higher levels predict those whose disease will progress over 4 years, suggesting that low-grade inflammation may be a significant aspect of early OA and may be amenable to therapeutic intervention and secondary prevention.

Adult↗
PubMed1997

Association of early osteoarthritis of the knee with a Taq I polymorphism of the vitamin D receptor gene.

OBJECTIVE: To determine whether a polymorphism of the vitamin D receptor (VDR) gene, already associated with osteoporosis, might also relate to the risk of osteoarthritis (OA). METHODS: A population cohort of 351 postmenopausal women (ages 45-64 years) was studied using anteroposterior radiographs of the knee, which were graded for OA according to the Kellgren and Lawrence classification system. The VDR genotype was determined by using polymerase chain reaction and by digestion with the restriction enzyme Taq I. RESULTS: The VDR allele "T" was associated with an increased risk of knee OA compared with the "t" allele, with an odds ratio of 2.82 (95% confidence interval 1.16-6.85; P = 0.02). A dominant pattern of risk was suggested. The frequency of the VDR genotype differed significantly between OA cases and controls (P = 0.03 by Fisher's exact test). CONCLUSION: A Taq I polymorphism of the VDR gene appears to be associated with an increased risk of knee OA. This is the first genetic locus that has been shown to influence the risk of early knee OA within the general population.

Bone Density↗
PubMed1997

Absorption of all-trans and 9-cis beta-carotene in human ileostomy volunteers.

1. Mass balance studies were carried out in fasted ileostomy subjects (n = 5) given an oral physiological dose (10 mg) of beta-carotene [all-trans: 9-cis, 84:16 (w/w)] dispersed in vegetable oil. Blood and ileal effluent samples were collected and analysed for beta-carotene. 2. Results showed that 90% (range 97.0-74.3%) of the total beta-carotene was absorbed without measurable perturbation of plasma total beta-carotene concentration, or change in the all-trans: 9-cis beta-carotene ratio. Peak loss of beta-carotene in ileal effluent occurred at 4.9 h (range 2.9-8.4 h) postingestion, and no further loss was detected after 5.4-12.4 h, depending upon the individual. Comparison of the ratio of all trans-beta-carotene to 9 cis-beta-carotene in the test meal and effluent indicated that isomerization did not occur during passage through the gastrointestinal tract and that both isomers were similarly absorbed. However, the all-trans: 9-cis beta-carotene ratio of the plasma did not change. Reasoned assumptions allowed the construction of a mathematical model of plasma beta-carotene disposal. 3. It is concluded that physiological doses of isolated all-trans and 9-cis beta-carotene are well absorbed without necessarily causing detectable excursions in plasma beta-carotene concentrations, or altering the ratio of all-trans to 9-cis beta-carotene. Isomerization of beta-carotene does not occur during passage through the gastrointestinal tract. Absorbed beta-carotene is rapidly cleared from the plasma to an unobservable pool at a rate similar to that of chylomicron triacylglycerol.

Colitis, Ulcerative↗
PubMed1997

Is hormone replacement therapy protective for hand and knee osteoarthritis in women?: The Chingford Study.

OBJECTIVES: To explore whether hormone replacement therapy (HRT) has a protective role for osteoarthritis (OA) of the hand and knee in a cross sectional study of women in the general population. METHODS: 1003 women aged 45-64 (mean age 54.2) from the Chingford Study were asked details of HRT use. Standard anteroposterior radiographs of hands, knees were taken and scored according to the methods of Kellgren and Lawrence (grade 2+ positive for OA), and using individual features of osteophytes and joint space narrowing. Analysis compared ever use (> 12 months) versus never use, and current use (> 12 months) versus never use. Only 606 definitely postmenopausal women were included in the analysis. Odds ratios and 95% confidence intervals were calculated using logistic regression for risk of user versus non-user at each site, adjusted for age, height and weight, menopausal age and for bone mineral density of the femoral neck. RESULTS: For current users (n = 72) there was a significant protective effect of HRT for knee OA (defined by Kellgren and Lawrence grade or osteophytes 0.31 (95% CI 0.11, 0.93), and a similar but not significant effect for moderate joint space narrowing of the knee, 0.41 (95% CI 0.05, 3.15) and for distal interphalangeal OA 0.48 (95% CI 0.17, 1.42). No clear effect was seen for the carpometacarpal joint, CMC OA 0.94 (95% CI 0.44, 2.03). When analysing ever users (n = 129) the protective effect was reduced. For ex-users of > 12 months (mean duration 40.7 months), there was no overall protective effect of HRT for OA. Additional adjustment for hysterectomy, physical activity, social class, and smoking made little difference to the results. CONCLUSIONS: These data show an inverse association of current HRT use and radiological OA of the knee suggestive of a protective effect. The effect was weaker in the hand joints. The mechanism of the protection is unclear but has important implications for aetiopathogenesis.

Cross-Sectional Studies↗
PubMed1996

Biochemical characterization of the reverse transcriptase of a human intracisternal A-type particle (HIAP).

The discovery of novel human intracisternal A-type particle (HIAP) that may be associated with the autoimmune disease Sjŏgren's syndrome has been previously reported. Although the HIAP retrovirus has been shown to be antigenically related to HIV-1, the viruses were distinguishable by different hydrodynamic mobilities through a sucrose gradient by morphology and intracellular location, and by differing divalent cation requirements for their in vitro reverse transcriptase (RT) reactions. In this report, additional biochemical characteristics are provide that further differentiate the HIAP RT from HIV-1 RT. Data are also presented that distinguish the HIAP RT from the known cellular DNA polymerases.

Antiviral Agents↗
PubMed1996

Requirement for two conserved cysteine residues in the Ada protein of Escherichia coli for transactivation of the ada promoter.

Cysteine residue 69 of the Escherichia coli Ada transcription factor, which accepts a methyl group from methylphosphotriester in methylated DNA, was substituted by each of 19 other amino acids. Only the mutant Ada (C69H), carrying a histidine substitution of Cys69, exhibited a limited degree of transactivating potential for the ada promoter in E. coli cells although the mutant protein was completely devoid of methylphosphotriester-DNA methyltransferase activity. Using a multicopy plasmid system for the expression of Ada protein, we have shown that Ada C69H has a transactivating capacity equivalent to that of wild-type Ada protein in the absence of an alkylating agent. This indicates that the zinc-binding capacity of histidine at residue 69 is likely to be sufficient for Ada to recognize and bind to the ada promoter. Furthermore, transactivation of the ada promoter by Ada C69H was enhanced up to 6-fold by treatment with methylating agents. An additional substitution was made with alanine in Ada C69H, replacing Cys321, the site for acceptance of a methyl group from O6-methylguanine and O4-methylthymine residues in DNA, with alanine. This renders the protein completely inactive as a methyltransferase but this derivative is constitutively active as a transactivator for the ada promoter. Therefore, acquisition of a methyl group at Cys321 apparently enhances the transactivating capacity of Ada protein on the ada promoter. We propose that the transcription-regulating function of Ada protein is under dual control by methylation of cysteine residues at positions 69 and 321; the former enhances DNA binding, while the latter enhances the transactivating capacity of the protein.

Amino Acid Sequence↗
PubMed1996

Risk of osteoarthritis associated with long-term weight-bearing sports: a radiologic survey of the hips and knees in female ex-athletes and population controls.

OBJECTIVE: To estimate the risk of osteoarthritis (OA) of the hip and knee due to long-term weight-bearing sports activity in ex-elite athletes and the general population. METHODS: A retrospective cohort study was conducted of 81 female ex-elite athletes (67 middle- and long-distance runners, and 14 tennis players), currently ages 40-65, recruited from original playing records, and 977 age-matched female controls, taken from the age-sex register of the offices of a group general practice in Chingford, Northeast London, England. The definition of OA included radiologic changes (joint space narrowing and osteophytosis) in the hip joints, patellofemoral (PF) joints, and tibiofemoral (TF) joints. RESULTS: Compared with controls of similar age, the ex-athletes had greater rates of radiologic OA at all sites. This association increased further after adjustment for height and weight differences, and was strongest for the presence of osteophytes at the TF joints (odds ratio [OR] 3.57, 95% confidence interval [95% CI] 1.89-6.71), at the PF joints (OR 3.50, 95% CI 1.80-6.81), narrowing at the PF joints (OR 2.97, 95% CI 1.15-7.67), femoral osteophytes (OR 2.52, 95% CI 1.01-6.26), and hip joint narrowing (OR 1.60, 95% CI 0.73-3.48), and was weakest for narrowing at the TF joints (OR 1.17, 95% CI 0.71-1.94). No clear risk factors were seen within the ex-athlete groups, although the tennis players tended to have more osteophytes at the TF joints and hip, but the runners had more PF joint disease. Within the control group, a small subgroup of 22 women who reported long-term vigorous weight-bearing exercise had risks of OA similar to those of the ex-athletes. Ex-athletes had similar rates of symptom reporting but higher pain thresholds than controls, as measured by calibrated dolorimeter. CONCLUSION: Weight-bearing sports activity in women is associated with a 2-3-fold increased risk of radiologic OA (particularly the presence of osteophytes) of the knees and hips. The risk was similar in ex-elite athletes and in a subgroup from the general population who reported long-term sports activity, suggesting that duration rather than frequency of training is important.

Adult↗
PubMed1996

The effect of weight-bearing exercise on bone mineral density: a study of female ex-elite athletes and the general population.

The aim of this retrospective cohort study was to estimate the changes in bone mineral density (BMD) as a consequence of exercise in female ex-athletes and age-matched controls. Eighty-three ex-elite female athletes (67 middle and long distance runners, 16 tennis players, currently aged 40-65) were recruited from the original records of their sporting associations. Controls were 585 age-matched females. The main outcome measures were BMD of lumbar spine (LS), femoral neck (FN), and forearm, estimated by dual-energy X-ray absorptiometry (DXA) scan. Levels of physical activity were assessed using a modified Allied Dunbar Fitness Survey scale and classified as (a) ex-athletes, (b) active controls (> or = 1 h of vigorous physical activity currently and in the past), (c) low activity controls with inconsistent or intermediate levels of activity, and (d) inactive controls (< 15 minutes of exercise per week). After adjustment for differences in age, weight, height, and smoking, athletes had greater BMDs than controls: 8.7% at the LS (95% confidence interval [CI] 5.4-12.0; p < 0.001) and 12.1% at FN (CI 9.0-15.3; p < 0.001). The benefits of exercise appeared to persist after cessation of sporting activity. Active controls (n = 22) had greater BMDs than the inactive group (n = 347): 7.9% LS (CI 2.0-13.8; p = 0.009) and 8.3% FN (CI 2.7-13.8; p = 0.004). The low activity controls (n = 216) had an intermediate BMD. Tennis players had greater BMDs compared with runners: 12.0% LS (CI 5.7-18.2; p = 0.0004) and 6.5% FN (CI -0.2-13.2; p = 0.066). The BMD of tennis players' dominant forearms were greater than their nondominant forearms. In conclusion, regular vigorous weight-bearing exercise of 1 h or more per week is associated with an increase in BMD within a normal population. This study confirms long-term weight-bearing exercise as an important factor in the regulation of bone mass and fracture prevention.

Absorptiometry, Photon↗