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Biomedical subjects

A Hill

Publications and source records attributed to A Hill.

At least 37 records · Page 2Linked to original sources
PubMed2003

Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection.

BACKGROUND: The rate of progression to cirrhosis varies among individuals chronically infected with the hepatitis C virus (HCV). Coagulation pathway activation in models of hepatic fibrosis suggests variation in coagulation pathway components may influence the rate of fibrosis. We hypothesised that polymorphisms of the coagulation factors II and V affect the rate of progression to cirrhosis in HCV infected subjects. METHODS: We studied the relationship between rate of fibrosis (calculated by dividing the fibrosis stage by duration of infection) and genotypes of specific coagulation pathway genes in 352 White European patients infected with HCV. Genotyping was performed using reverse line blot hybridisation. RESULTS: The rate of fibrosis was significantly higher in patients with the factor V Leiden genotype (Arg560Gln) (ANOVA, p=0.004). In disease association studies, a significant association was seen (Fisher's exact test, p=0.029; odds ratio 3.28 for fast progression to cirrhosis (expected to reach cirrhosis in less than 30 years) if heterozygous for factor V Leiden). No associations were seen between factor II genotype and fibrosis rate. CONCLUSIONS: Possession of the factor V Leiden polymorphism significantly increases the risk of rapid disease progression in HCV, suggesting a role for the coagulation system in the pathogenesis of fibrotic liver disease.

Adult↗
PubMed2003

Influence of the hormonal changes during the normal menstrual cycle in healthy young women on soluble adhesion molecules, plasma homocysteine, free radical markers and lipoprotein fractions.

AIM: Female sex hormones are known to exert a protective role on the vascular endothelial function, but the exact mechanisms of such protection is not known. We aimed to study the possible regulatory role of the female sex hormones changes during the normal menstrual cycle on soluble adhesion molecules E-selectin and ICAM-1, plasma homocyteine, free radical markers and lipoproteins in healthy young women. METHODS EXPERIMENTAL DESIGN: a cross sectional study of healthy female volunteers studied during a single normal menstrual cycle at 3 specific time points. SETTING: North Staffordshire Hospitals NHS Trust. SUBJECTS: 20 healthy young menstruating women, aged (mean +/- SEM) 34 +/- 1 years, with normal menstruation, defined as a menstrual cycle of 21-35 days were studied at 3 time points of the same menstrual cycle. First in the early follicular phase (M-phase), at mid-follicular phase (F-phase), and during the luteal phase (L-phase). INTERVENTION: none. MEASUREMENT: serum levels of soluble E-selectin, ICAM-1, plasma homocysteine, vitamin E and malondialdehyde (MDA), as well as lipoprotein fractions were measured at each time points. RESULTS: The mean percentage change for E-selectin between the M-phase and L-phase, F-phase and L-phase were 6% and 4%, respectively, p<0.005, p<0.066. Levels of ICAM-1, vitamin E and malondialdehyde did not vary through the cycle. Homocysteine was not different between M-phase and F-phase (10.39 +/- 0.68 micromol/l vs 10.33 +/- 0.65), nor between M-phase and L-phase (10.39+/-0.68 vs 9.77 +/- 0.75 micromol/l). Although the mean percentage decrease in homocysteine between F- and L-phases was significant (5.36 +/- 0.53%, p=0.029), the absolute decrease in concentrations was not (p=0.07). There were no cyclical changes in total, LDL, HDL cholesterol, triglycerides, apo A-I, apo B or Lp(a). Using a linear regression model, after correction for age, smoking, body mass index (BMI) and waist/hip ratio (WHR), oestrogen levels were the only predictor of E-selectin during the L-phase p<0.005. There were no significant correlations between oestrogen with lipids, apolipoproteins or homocysteine. There was an interesting significant univariate correlation between homocysteine with low-density-lipoprotein (LDL) cholesterol and apo B throughout all phases of the cycle, which persisted after correction for the effects of age, BMI, WHR and smoking history. Multiple regression analysis with all these factors showed homocysteine to be a significant predictor of apo B concentration during M (p=0.030) and L-phases (p=0.023) of the cycle and of LDL cholesterol in the M-phase (p=0.033). CONCLUSION: Female sex hormones may have small, though significant modulating role on E-selectin and homocysteine metabolism in healthy premenopausal women. Furthermore, the correlation between homocysteine, LDL and apo B levels suggests that induction of cholesterol synthesis by homocysteine, shown previously in vitro, may be of relevance in vivo.

Adult↗
PubMed2002

Investigation of environmental and host-related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design.

Host-related and environmental factors for tuberculosis have usually been investigated separately using different study designs. Joint investigation of the genetic, immunologic, and environmental factors at play in susceptibility to tuberculosis represents an innovative goal for obtaining a better understanding of the pathogenesis of the disease. In this paper, the authors describe methods being used to investigate these points in a West African study combining several designs. Patients with newly diagnosed smear-positive cases of tuberculosis are recruited. The effect of host-related factors is assessed by comparing each case with a healthy control from the case's household. The role of environmental factors is estimated by comparing cases with randomly selected community controls. The frequencies of candidate gene variants are compared between cases and community controls, and results are validated through family-based association studies. Members of the households of cases and community controls are being followed prospectively to determine the incidence of "secondary" tuberculosis and to evaluate the influence of geographic and genetic proximity to the index case. This type of design raises important methodological issues that may be useful to consider in studies investigating the natural history of infectious diseases and in attempts to disentangle the effects of environmental and genetic factors in response to infection.

Africa, Western↗
PubMed2002

Investigation of environmental and host-related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors.

In an accompanying paper (Am. J. Epidemiol. 2002;155:1066-73), the authors describe the design of a large multicenter study being carried out in three West African countries for investigation of the roles of environmental and host-related factors in the development of tuberculosis. In this paper, the authors review some evidence that host genetic factors play a role in susceptibility to tuberculosis. They describe the three components of the study that are designed to investigate the effect of host genetic factors on the development of tuberculosis: case-control and family-based association studies of candidate genes and analysis of affected relative pairs to screen the human genome for areas of linkage to the disease. The authors also address a number of methodological issues that arise, such as the effects of consanguinity, half-siblings, and nonpaternity. Lastly, they review opportunities to assess gene-environment interaction in the framework of the study, in light of current methodological knowledge. Consideration of these issues may be useful in the design of other studies of genetic susceptibility to infectious diseases, particularly those to be carried out in developing countries.

Africa, Western↗
PubMed2002

Prostate-Specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes.

Prostate Specific Ets factor is a recently identified transcriptional activator that is overexpressed in prostate cancer. To determine whether this gene is overexpressed in breast cancer, we performed a virtual Northern blot using data available online at the Cancer Genome Anatomy Project website. Ninety-five SAGE libraries were probed with a unique sequence tag to the Prostate Specific Ets gene. The results indicate that Prostate Specific Ets is expressed in 14 out of 15 breast cancer libraries (93%), nine out of 10 prostate cancer libraries (90%), three out of 40 libraries from other cancers (7.5%), and four out of 30 normal tissue libraries (13%). To determine the possibility that the Prostate Specific Ets gene is a novel marker for detection of metastatic breast cancer in axillary lymph nodes, quantitative real-time RT-PCR analyses were performed. The mean level of Prostate Specific Ets expression in lymph nodes containing metastatic breast cancer (n=22) was 410-fold higher than in normal lymph node (n=51). A receiver operator characteristic curve analysis indicated that Prostate Specific Ets was overexpressed in 18 out of 22 lymph nodes containing metastatic breast cancer (82%). The receiver operator characteristic curve analysis also indicated that the diagnostic accuracy of the Prostate Specific Ets gene for detection of metastatic breast cancer in axillary lymph nodes was 0.949. These results provide evidence that Prostate Specific Ets is a potentially informative novel marker for detection of metastatic breast cancer in axillary lymph nodes, and should be included in any study that involves molecular profiling of breast cancer.

Axilla↗
PubMed2002

The effect of ritonavir on saquinavir plasma concentration is independent of ritonavir dosage: combined analysis of pharmacokinetic data from 97 subjects.

OBJECTIVE: To determine the correlation between ritonavir (RTV) dose and the degree of enhancement of saquinavir (SQV) exposure. METHODS: Combined analysis of pharmacokinetic data at steady state obtained from two open-label, randomized, parallel-group, multiple-dose, single-centre studies involving healthy volunteers. Plasma samples for SQV assay were obtained from 97 healthy subjects following multiple dosing of a range of SQV (400-1800 mg) plus RTV (100-400 mg) dosages for 13-14 days. The pharmacokinetics of SQV were derived by model-independent, noncompartmental methods. Data were analysed by multivariate regression of log transformed Cmin and Cmax (geometric means) of SQV dosage as the dependent variable and independent variables of SQV and RTV dosage. Ritonavir was fitted as both a continuous and a categorical variable. RESULTS: There is a strong effect of any dose of RTV on Cmax and Cmin of SQV (P < 0.0001 for both parameters), but no greater effect of higher vs. lower RTV dosages on either parameter (Cmax: P=0.4373; Cmin: P=0.3393). Higher SQV dosage correlates linearly with higher Cmax (P=0.0093) and Cmin (P=0.0010), but the effects of increasing SQV dosages are less than with the addition of any RTV dose. CONCLUSIONS: RTV enhances SQV concentrations to increase Cmax and Cmin. This effect is similar for RTV dosages of 100-400 mg twice daily. Based on this concept of 'mini-dose' RTV, once-daily dosing of 1600 mg SQV/100 mg RTV and twice-daily 1000 mg SQV/100 mg RTV are currently being evaluated in clinical trials.

Drug Interactions↗
PubMed2002

A multicentre phase II trial of primary chemotherapy with cisplatin and protracted venous infusion 5-fluorouracil followed by chemoradiation in patients with carcinoma of the oesophagus.

BACKGROUND: We undertook a multicentre phase II trial to evaluate the safety and efficacy of primary chemotherapy followed by chemoradiation for localised adenocarcinoma or squamous carcinoma of the oesophagus. PATIENTS AND METHODS: Chemotherapy comprised five 3-weekly cycles of cisplatin and protracted continuous infusion 5-fluorouracil, with conformally planned radiotherapy commencing at the start of the fifth cycle. RESULTS: The planned treatment programme was completed by 39 of 72 patients (54%), and a further 13% completed chemotherapy and proceeded to surgical oesophagectomy. Response rates to chemotherapy and to the entire treatment programme were 47% [95% confidence interval (CI) 34% to 60%] and 56% (CI 43% to 68%). The dysphagia score improved in 54% of patients. The median survival duration was 14.6 months with 1- and 2-year survival rates of 58.7% and 44.1%, respectively. Grade III/IV chemotherapy-related toxicity occurred in 38% of patients, and there were no treatment-related deaths. CONCLUSIONS: This is a feasible and active treatment regimen providing palliative benefits for patients with poor-prognosis localised oesophageal cancer.

Adenocarcinoma↗
PubMed2001

Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial.

BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Adult↗
PubMed2001

Durability of HIV-1 viral suppression over 3.3 years with multi-drug antiretroviral therapy in previously drug-naive individuals.

BACKGROUND: Relatively little is known about the long-term durability of viral suppression in individuals initially achieving a viral load of less than 50 copies/ml within 24 weeks of starting antiretroviral therapy, nor the extent to which therapy interruption accounts for the loss of suppression. METHODS: We intensely followed all 336 antiretroviral-naive patients attending the Goethe Universitat Clinic who began multi-drug combination regimens and in whom a viral load of less than 50 copies/ml was achieved within 24 weeks, in order to assess the risk of viral load rebound. Inspection of case notes allowed the distinction of viral rebound according to whether there was an associated complete interruption of therapy. RESULTS: A total of 61 patients experienced viral rebound during 543.1 person-years of follow-up, giving a 25.3% risk of rebound by 3.3 years from first achieving viral suppression. However, for 47 of the patients with viral rebound there was an associated documented complete interruption of antiretroviral therapy, mostly as a result of co-morbidities, leaving 14 who appear to represent a failure of the virological efficacy of therapy (viral breakthrough; 5.2% risk by 3.3 years). The risk of viral breakthrough declined with the increased duration of suppression (P = 0.01). CONCLUSION: The intrinsic virological effectiveness of multi-drug antiretroviral therapy in previously drug-naive individuals appears to be such that viral suppression, once achieved, can be maintained for several years in patients not interrupting therapy. The major challenge is to develop regimens that can be taken consistently and safely for such long periods of time.

Adult↗
PubMed2001

The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages.

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.

Animals↗
PubMed2001

Treatment of suture line bleeding with a novel synthetic surgical sealant in a canine iliac PTFE graft model.

CoSeal mark surgical sealant (CoSeal) was evaluated for inhibiting suture line bleeding using a canine iliac PTFE graft model. Both iliac arteries of 12 heparinized canines were grafted with PTFE. CoSeal was applied to the suture lines of one graft in each animal. The contra-lateral graft served as a control and bleeding was controlled with gauze and pressure (tamponade). The cross-clamps were removed 30 s following application of CoSeal. Times to hemostasis and volume of blood loss at each graft site were determined. Compared to tamponade control, CoSeal significantly reduced the time to hemostasis (average of 5 min vs. greater than 15 min, p < 0.05) and blood loss (19 g vs. 284 g, p < 0.05). Small amounts of CoSeal were visible grossly or histologically at day 7. Histology showed moderate to marked inflammation in CoSeal sites and moderate inflammation in control sites at day 7. At 30 and 60 days, no CoSeal was visible grossly or histologically. Histology showed moderate inflammation in both CoSeal treated sites and in control sites at day 30 and mild to moderate inflammation in both CoSeal and control sites at day 60. CoSeal significantly reduced the time to hemostasis and blood loss in comparison to tamponade.

Animals↗
PubMed2001

Reducing sediment inputs to Scottish streams: a review of the efficacy of soil conservation practices in upland forestry.

The historical process by which a soil conservation strategy has evolved within the UK forestry industry is briefly reviewed. Particular attention is given to the development of practical and effective guidelines to prevent both soil damage and sediment entering water courses. It is concluded that the 'Forest and Water Guidelines', together with other forest industry manuals, largely provide adequate protection for aquatic habitats from pre-afforestation cultivation and from harvesting activities. The problem of soil erosion owing to ploughing of open furrows has largely been obviated by improved drainage network design coupled with the use of vegetated buffer strips and sediment catchpits. Alternative site preparation techniques, such as 'moling' or 'dolloping' of afforestation sites, are now preferred. However, the effects on slope hydrology and the improved soil conservation associated with these methods require quantifying. Additional understanding of effective buffer strip function, for example, on a variety of slope angles, soil types and vegetation associations would be beneficial. The design of forest roads and the associated network of drains, culverts and sediment catchpits is addressed in forestry guidelines. Future potential in this area may involve the use of Geographical Information Systems in the effective design of road networks which minimise adverse effects on slope hydrology. Similarly computer simulation of flow routing might aid in the design of road drain networks. At the more local scale there remains scope for further research aimed at minimising soil disturbance by machinery. Consideration should also be given to the long-term sustainability of the soil structure through second and subsequent crop rotations.

Conservation of Natural Resources↗
PubMed2001

An integrated physical map of 8q22-q24: use in positional cloning and deletion analysis of Langer-Giedion syndrome.

We have developed an integrated map for a 35-cM area of human chromosome 8 surrounding the Langer-Giedion syndrome deletion region. This map spans from approximately 8q22 to 8q24 and includes 10 hybrid cell intervals, 89 polymorphic STSs, 118 ESTs, and 37 known genes or inferred gene homologies. The map locations of 25 genes including osteoprotegerin, syndecan-2, and autotaxin have been refined from the general locations previously reported. In addition, the map has been used to indicate the location of nine deletions in patients with Langer-Giedion syndrome and trichorhinophalangeal syndrome type I to demonstrate the potential usefulness of the map in the analysis of these complex syndromes. The map will also be of interest to anyone trying to clone positionally disease genes in this region, such as Cohen syndrome (8q22-q23), Klip-Feil syndrome (8q22.2), hereditary spastic paraplegia (8q24), and benign adult familial myoclonic epilepsy (8q23.3-q24.1).

Child↗
PubMed2001

Internal and external antecedents of binge eating episodes in a group of women with bulimia nervosa.

OBJECTIVE: This research examined the internal and external factors that predict whether a food craving develops into a binge in bulimia nervosa. METHOD: Fifteen bulimic women kept diary records of food cravings over the course of a week, noting their internal state, environmental triggers, and whether the craving developed into a binge. Eighty cravings were examined, of which approximately one half developed into binges. RESULTS: At the bivariate level, binge eating resulted from cravings more often if the women were alone, in the morning, and following eating the craved food. These factors interacted, so that binges were more likely if the women avoided a craved food in the morning, but not later in the day. CONCLUSIONS: These findings support a model of binge eating for which both internal states (craving, eating the craved food) and external factors (time of day, social circumstances) need to be taken into account. Relevant models of craving are discussed, along with their implications for clinical practice.

Adult↗
PubMed2001

Prevalence of HBV core promoter/precore/core mutations in Gambian chronic carriers.

One hundred forty-two precore/core sequences were obtained from Gambian chronic hepatitis B virus (HBV) carriers and the predominant variants defined. The two point mutations, from A to T and G to A at nt positions 1762 and 1764 in the basic core promoter region, were found in only 7/99 (7%) of the samples where this region was sequenced. These mutations were found in both HBeAg-positive and -negative patients. The precore stop-codon mutation at nt position 1896 was found in 14/51 (27%) of HBeAg-negative samples, which is a lower prevalence rate in comparison with other parts of the world with high carrier rates. In HBeAg-positive patients the core amino acid sequences were conserved, but after seroconversion to anti-HBe significantly more changes were apparent. Several of the amino acid substitutions found have been described previously been in wild-type viruses of other genotypes.

Amino Acid Sequence↗