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J Kelly

Publications and source records attributed to J Kelly.

At least 55 records · Page 3Linked to original sources
PubMed2003

Geometrical optics approach in liquid crystal films with three-dimensional director variations.

A formal geometrical optics approach (GOA) to the optics of nematic liquid crystals whose optic axis (director) varies in more than one dimension is described. The GOA is applied to the propagation of light through liquid crystal films whose director varies in three spatial dimensions. As an example, the GOA is applied to the calculation of light transmittance for the case of a liquid crystal cell which exhibits the homeotropic to multidomainlike transition (HMD cell). Properties of the GOA solution are explored, and comparison with the Jones calculus solution is also made. For variations on a smaller scale, where the Jones calculus breaks down, the GOA provides a fast, accurate method for calculating light transmittance. The results of light transmittance calculations for the HMD cell based on the director patterns provided by two methods, direct computer calculation and a previously developed simplified model, are in good agreement.

Journal Article↗
PubMed2003

Evolution of a pigmentation gene, the melanocortin-1 receptor, in primates.

The melanocortin-1 receptor (MC1R) forms a critical switch in the production of orange/red pheomelanin and black/brown eumelanin pigments during hair development in mammals. The molecular evolution of the melanocortin-1 receptor gene was investigated in a broad range of primate species, including several groups with large differences in distribution of orange/red and black hairs. Primate MC1R has been subject to purifying selection throughout most of its evolution, with small changes in selective constraint being detected early in primate evolution. In contrast to the situation in humans and domestic mammals, many intraspecific and intrageneric differences in primate coat color cannot be attributed to changes in the MC1R coding sequence. Nevertheless, important changes in the biochemical function of MC1R are suggested by mutations in sites of known functional importance, particularly in New World monkeys and lemurs. The evolution of the MC1R in lion tamarins is anomalous, with a combination of a high nonsynonymous to synonymous substitution rate (dN/dS) ratio, deletions, and substitutions.

Adaptation, Physiological↗
PubMed2003

Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?

Maintenance treatment with PDE(4) inhibitor cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, cilomilast, or cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism.

The assessment of pretest probability (PTP), with stratification into low-, intermediate- and high-risk groups is an essential initial step in the current diagnostic management of patients with suspected venous thromboembolism (VTE). In combination with additional information, it reduces the need for initial and supplementary imaging, and allows considerable refinement of the posterior probability of VTE following non-invasive imaging. PTP may be assessed either empirically or by using various decision rules or scoring systems, the best known of which are the simplified Wells scores for suspected deep vein thrombosis (DVT) and pulmonary embolism (PE), and the Geneva score for suspected PE. Each of these approaches shows similar directional and categorical accuracy, and has been validated as facilitating clinically useful classification of the PTP, although an overview of data suggests that fewer patients tend to be classified as low PTP when assessed empirically. This group is the most important to identify, as several outcome studies have shown that imaging and treatment are safely obviated in outpatients with suspected DVT or PE who have a low PTP in combination with negative d-dimer testing, a subgroup accounting for up to half of all patients studied. Hence, while probably not of critical importance, the explicit approach offered by scoring systems might be preferred over empirical assessment, particularly when used by more junior staff.

Bayes Theorem↗
PubMed2003

Limited Pap screening associated with reduced risk of cervical cancer in South Africa.

BACKGROUND: We investigated the effect of Pap smear screening on the incidence of invasive cancer of the cervix in the Western Cape, South Africa where screening is limited. METHODS: Data were derived from a case-control study of the association of hormonal contraceptives and invasive cervical cancer. Incident cases (n = 524) of invasive cervical cancer who presented at two tertiary hospitals and controls (n = 1540) series matched for age, race, and place of residence were interviewed. Information on a wide range of variables was collected including whether the women had previously had a Pap smear taken and the number and timing of smears. Odds ratios (OR) and 95% CI were calculated using multiple logistic regression. RESULTS: The OR of cervical cancer was reduced among women who had ever had a smear (OR = 0.3, 95% CI: 0.3-0.4). The OR declined with increasing number of smears to 0.2 for >/=>3 smears (trend P = 0.0003). Among women who had a smear <5 years previously the OR was 0.3, but even if the smear was taken >/=15 years previously the women remained at reduced risk (OR = 0.5). CONCLUSION: The data suggest that even limited Pap smear screening reduces the risk of cervical cancer. Should a screening programme be successfully implemented, the incidence of cervical cancer might be reduced by as much as 70%.

Adult↗
PubMed2003

Do anticoagulants improve survival in patients presenting with venous thromboembolism?

Anticoagulants have been available since around 1940 and have become the standard of treatment for venous thromboembolism (VTE) for over four decades. However, as with other treatments which became established before the evidence-based era, there is a paucity of evidence from randomized controlled trials validating their effectiveness in preventing the most feared complication of VTE, recurrent fatal pulmonary embolism (PE). Only two such trials have been performed, the results of which conflict. The bulk of data supporting their use are derived from three sources. First, studies of thromboprophylaxis, and comparisons of shorter and longer courses of anticoagulants in high-risk patients with established VTE have clearly demonstrated their effectiveness in primary and late secondary prevention. Given that heparin has an immediate onset of action, anticoagulants should therefore also be effective in early secondary prevention, the proposed mechanism of action in the acute treatment of VTE. Secondly, studies of inadequately treated patients have consistently shown higher recurrence rates than in those adequately treated. Finally, comparisons of outcomes in untreated and treated historical series, and of untreated historical series to treated series in the modern era have shown substantially lower rates of fatal PE in anticoagulated patients. Because these differences are so marked, harmonize with our current understanding of the mechanism of action of anticoagulants and are supported by other evidence, it is much more likely that they at least partly reflect the effectiveness of anticoagulants as opposed to being explicable purely in terms of accumulated biases and a changing distribution of disease severity.

Anticoagulants↗
PubMed2002

Heterogeneity of O6-alkylguanine DNA-alkyltransferase expression in human breast tumours.

An important determinant of cellular resistance to chemotherapeutic O6-alkylating agents, which comprise methylating and chloroethylating agents, is the ability of cells to repair alkylation damage at the O6-position of guanine in DNA. This is achieved by a specific DNA repair enzyme O6-alkylguanine DNA-alkyltransferase. In this study O6-alkylguanine DNA-alkyltransferase expression was measured in human breast tumours using both biochemical and immunohistochemical techniques. O6-alkylguanine DNA-alkyltransferase activity was then compared with known clinical prognostic indices to assess the potential role of O6-alkylguanine DNA-alkyltransferase in predicting the behaviour of this common malignancy. The application of both biochemical and immunohistochemical techniques was feasible and practical. Most breast tumours expressed high levels of O6-alkylguanine DNA-alkyltransferase. Immunohistochemical analysis showed marked variation in expression not only between individuals but also within individual tumours, and in the same patient, between metastases and between primary tumour and metastatic site. O6-alkylguanine DNA-alkyltransferase activity in tissue extracts significantly correlated not only with immunohistochemical staining intensity determined by subjective quantitation, but also with measures of protein levels using a computerised image analysis system including mean grey (P<0.001), percentage of cells positive for O6-alkylguanine DNA-alkyltransferase (P<0.001), and integrated optical density (P<0.001). O6-alkylguanine DNA-alkyltransferase expression did not correlate with any of the established clinical prognostic indicators for current treatment regimens. However, immunohistochemical offers a rapid and convenient method for assessing potential utility of O6-alkylating agents or O6-alkylguanine DNA-alkyltransferase inactivating agents in future studies of breast cancer treatment.

Adenosine Triphosphatases↗
PubMed2002

Development of a nanofiltration process to improve the stability of a novel anti-MRSA carbapenem drug candidate.

The benzenesulfonate salt of an anti-methicillin-resistant Staphylococcus aureus carbapenem antibiotic studied is a crystalline, nonhygroscopic powder which is stable at room temperature, making it an ideal compound for long-term storage. However, the limited aqueous solubility of this salt prohibits parenteral administration. Conversely, the chloride salt of this carbapenem demonstrates opposing characteristics; it is quantitatively soluble in water, however is amorphous and subject to significant hydrolytic degradation in the solid state. Given two such extreme alternatives for pharmaceutical salt selection, a common approach taken is to develop the bioavailable salt and devise manufacturing and storage conditions that minimize degradation. This report describes a different approach to this manufacturing dilemma via the application of a simple and efficient nanofiltration process to convert the benzenesulfonate salt (storage entity) to the chloride salt (formulated drug product). Such an approach combines the positive attributes of these two salt forms into a single scalable process that reduces processing cycle times via elimination of redundant unit operations, increases the flexibility in manufacturing schedule, and improves overall product quality.

Benzenesulfonates↗
PubMed2002

Cilomilast (Ariflo) does not potentiate the cardiovascular effects of inhaled salbutamol.

We investigated the safety and potential pharmacodynamic interactions arising from the co-administration of inhaled beta(2)-agonist salbutamol and cilomilast (Ariflo), a new oral phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease and asthma. This was a randomised, double-blind, placebo-controlled, multiple-dose, three-period crossover study involving non-smoking volunteers between the ages of 18 and 50 years. Volunteers were randomly assigned to receive cilomilast plus nebulised salbutamol, cilomilast plus nebulised placebo or placebo plus nebulised salbutamol. Each volunteer received cilomilast (10 mg twice daily) or placebo for 5 days. On day 5, the morning dose of cilomilast or placebo was followed 1 h later with a single dose of nebulised salbutamol (2.5 mg) or placebo. Primary variables were average change from pre- to 1.5 h post-salbutamol or placebo inhalation in blood pressure, pulse rate, 12-lead ECG and total number of heartbeats measured by 4-h Holter ECG. Thirteen volunteers completed the study. There was no evidence of a clinically important pharmacodynamic interaction between cilomilast and salbutamol in healthy volunteers. Both agents were well tolerated. In conclusion, the pharmacodynamic effects associated with salbutamol inhalation were unaffected by co-administration of cilomilast.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Profound adrenal suppression secondary to treatment with low dose inhaled steroids and itraconazole in allergic bronchopulmonary aspergillosis in cystic fibrosis.

The case history is presented of a patient with cystic fibrosis in whom the treatment of allergic bronchopulmonary aspergillosis with itraconazole produced an initial response but was complicated by profound adrenal shutdown and impairment of inhaled steroid clearance resulting in paradoxical Cushing's syndrome. The authors conclude that, while it is laudable to attempt to reduce the steroid burden in any patient, it is imperative that due vigilance is exercised when using a combination of agents which interact. If such a combination therapy is embarked upon, regular assessment of the pituitary adrenal axis is advisable.

Adult↗
PubMed2002

Application of oligonucleotide probes for the detection of Thiothrix spp. in activated sludge plants treating paper and board mill wastes.

Filamentous bacteria belonging to the genus Thiothrix were detected in activated sludge samples using the fluorescent in situ hybridisation (FISH) technique. A 16S rRNA-targeted oligonucleotide probe was developed for the detection of members of the T. fructosivorans group, and the performance of probe TNI for the detection of Thiothrix nivea group was enhanced by using an unlabeled competitor. A set of 5 probes covering all phylogenetic groups of Thiothrix were used to examine samples taken from selected activated sludge plants treating paper and board mill wastes. Members of the T. eikelboomii group formed the predominant filamentous bacterial population in plants experiencing poor sludge settleability, whereas members of the T. nivea group were commonly found but not dominantly in the remaining plants. Members of the T. fructosivorans group were not detected at any significant level in any of the samples. The distribution of the main Thiothrix types remained unchanged throughout the investigation period. It was evident that mixed populations of Thiothrix spp. were present in all activated sludge samples investigated, the observed differences were in the relative abundance of the various groups. These findings were supported by the results obtained using conventional microscopy.

Bioreactors↗