Biomedical subjects
Publications and source records attributed to N Clarke.
In a case-note review of 120 women and 227 men presenting with muscle-invasive bladder tumours in 1998, survival was worse for women in 3 years of follow-up, with the greatest difference, of 19.9%, at 6 months. For more deprived women, 6-month survival was 52.3%, and 32 (37.2%) presented with advanced disease, compared with 73.5%, and three (8.8%) for less deprived women.
Retinoic acid (RA) cures more than 75% of patients with acute promyelocytic leukemia (APL). Here, we review the various anti-cancer activities of retinoids and rexinoids, alone and in combination with other drugs, with emphasis on the RA-dependent induction of a cancer-cell-selective apoptosis signaling pathway to which multiple anti-cancer signals converge. These findings identify the TRAIL (tumor-necrosis-factor-related apoptosis-inducing ligand) pathway as a central cell-autonomous anti-cancer weapon that can act independently of the immune system.
Binary mixtures of ultra-thin films are subject to both height and concentration fluctuations, either of which, under the appropriate conditions, can become unstable. We investigate a simple general thermodynamic model which shows that, due to the constraint imposed upon coupling between these fluctuations, a thin-film binary mixture will be less stable than if either height or concentration fluctuations are considered in isolation. We investigate the height dependence of the stability condition, discuss equilibrium conditions when higher-order contributions to the free energy are negligible, and predict the scaling behaviour.
The interference in the metabolism of a drug by another drug, food or other foreign chemical is commonly observed and often leads to clinically significant adverse drug reactions. In Jamaica, there is an extensive use of natural products as medicines, although there is little information on whether natural medicines are used along with prescription medicines, which might increase the likelihood of drug adversities. This current pilot survey was initiated to gain information on the prevalence of such polypharmacy practices. Two concurrent surveys were carried out in Kingston (an urban parish) and Clarendon (a rural parish) in 743 patients above age 14 years with diabetes mellitus, hypertension and gastrointestinal disorders of persons who visited health centres and pharmacies. Patrons visiting these places at various times of the day were informed of the nature of the questionnaire and willing participants with the above disease conditions and who were on prescription medicines were included in the survey. The results indicated that 80% of the respondents reported combining natural products in their treatment along with prescription medicines, with only 13% of those patients informing their physicians of such practices. Such polypharmacy practices were independent of the type of disease among both males and females and was statistically most prevalent (p < 0.001) in the 47-57-year age group. There was a significant association (p < 0.001) between such treatment practices and place of residence with 92% of the rural community engaging in polypharmacy but 70% of the urban did likewise. Therefore, being aware of the prevalence of multiple therapy practices would be especially useful when designing a pharmaco-vigilance system.
Along with a steady reduction of acid inputs during 14 years of intensive forest monitoring in Norway, the influence of acid deposition upon soil water acidity is gradually reduced in favour of other and internal sources of H+ and sulphate, in particular from processes in the upper soil layer. We used statistical analyses in two steps for precipitation, throughfall and soil water at 5, 15 and 40 cm depths. Firstly, we employed time series analyses to model the temporal variation as a long-term linear trend and a monthly variation, and by this filtered out residual, weekly variation. Secondly, we used the parameter estimates and the residuals from this to show that the long term, the monthly and the weekly variation in one layer were correlated to similar temporal variation in the above, adjacent layer. This was strongly evident for throughfall correlated to precipitation, but much weaker for soil water. Continued acidification in soil water on many plots suggests that the combined effects of anthropogenic and natural acid inputs exceed in places the buffering capacity of the soil.
Poly n-butyl cyanoacrylate has been used in the synthesis of nanoparticles by dispersion polymerisation in aqueous media. Following establishment of a thermometric procedure for assessment of monomer reactivity, the relationships between monomer-polymer conversion reactions and particle development at various pH values was investigated. Particle size was measured during the synthesis process using a laser diffraction technique and final particle character was assessed by scanning electron microscopy. Optimum conditions for particle production were a dispersion medium of pH 2.5 at a temperature of 65 degrees C, with dextran 70 used as a steric stabiliser. In the presence of dextran, following a period of equilibration, colloidally stable particles form, but in the absence of dextran particles are colloidally unstable and rapidly coalesce. Measurement of molecular weight changes through the synthesis process show an upward shift consistent with the initial formation of oligomers, which then further polymerise through a re-initiation re-polymerisation process until an equilibrium molecular weight is reached.
Much confusion still surrounds the concept of empowerment and how it is to be translated into practice within the context of community care for service users and carers. A major limitation has been the tendency to treat empowerment as synonymous with participation in decision-making with little attention given to the 'ecological' model of empowerment where linkages have been found between community participation and measures of psychological empowerment. Training has been suggested as a means through which carers might become empowered, yet to date little empirical evidence has appeared within the literature to support this proposition. This study investigated whether attendance on a training programme to empower carers resulted in improvements in carers' levels of perceived control, self-efficacy and self-esteem as partial measures of psychological empowerment. The findings demonstrated that whereas carers' knowledge of services and participation increased as a result of the programme, no changes were found in measures of carer empowerment. The failure to consider how training needs to be designed in order to achieve changes in individual competence and self-agency are suggested as the most likely explanation for the lack of change observed in carers' psychological empowerment. It is suggested that community care agencies should focus greater energies in determining how the policy objectives of empowerment are to be achieved through training, and in so doing make far more explicit the supposed linkages between training content, design, and its posited impact on individual behaviour or self-agency.
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Five methods for aluminium fractionation used in different laboratories in Norway and Finland were compared using six control, 75 soil water and 10 lake water samples. Different fractionation principles [cation exchange, formation of the Pyrocatechol Violet (PCV) or quinolin-8-ol (oxine) complex], types of cation exchanger [Amberlite (Na/H) or Bond Elut (H)], reaction time (from 2.3 s), flow systems (flow injection analysis or segmented flow) and determination principles (molecular absorption spectrometry or ICP-AES) were tested. Determination of the 'labile' fraction was strongly dependent on the method used and the largest differences were observed between the ICP-AES method with cation exchange (Bond Elut H form) and the 'quickly reacting' method (oxine, 2.3 s). Different flow systems, both using cation exchange and determination of the PCV complex but with different reaction times and an extra acidification step, resulted in large differences in the 'reactive' and 'non-labile' fractions determined. However, the determination of the labile fraction gave similar results with both these methods. The two different types of cation exchanger used (with and without pH buffering and with different counter ions) in the ICP-AES methods resulted in differences, mainly because of a smaller 'non-labile' fraction in the non-buffered system. The two flow injection systems (oxine and PCV complexation) showed common trends, which may be connected with the short reaction times used. Comparison with theoretical equilibrium calculations using the model ALCHEMI suggested that the best correlation for the determination of the 'labile' fraction were obtained with the ICP-AES method with an Amberlite column.
Calcified microspheres, about 1 microm in diameter, appear at sites of bone formation where they invest the collagenous matrix, become confluent and disappear. Evidence that the particle boundaries are not lost with compaction but merely deformed is supported in section by the granular histochemical staining of the inorganic phase for bone salt, lipid, fibronectin and acid phosphatase in osteomalacic, acid-etched and normal human bone. Their persistence as discrete objects is confirmed by the application of methods for their isolation from the collagenous matrix of immature mouse calvarium and mature bovine femur. Five methods have been used to extract them and include (i) biochemical, (ii) chemical, (iii) mechanical, (iv) pyrogenous and (v) biological separation. Under the optical microscope, all isolates consisted of similar discrete objects and bridged assemblies, whose birefringence varied with treatment. After decalcification, their organic 'ghosts' remained. Each isolated microsphere had a complex substructure of clusters of non-collagenous calcified filaments surrounding a less dense centre. The filaments were 5 nm in diameter with a 5 nm periodicity and regular fine interfilamentous connections. It is concluded that the microspheres are independent, complex, pervasive and central to the containment (i.e. packaging) of calcium phosphate in bone. Their extraction will enable further analysis.
The use of biodegradable particles as oral delivery vehicles for macromolecular drugs was investigated. We evaluated the binding, uptake and absorption of poly-dl-lactide (PLA) micro- and nanoparticles in Caco-2 monolayers and in ileal tissue and gut associated lymphoid tissue (GALT) of anaesthetised rats and rabbits. Using a range of experimental techniques, we found that approximately 10% of administered micro- and nanoparticles were adsorbed to the apical membranes of each of the five intestinal models. Nanoparticles were found to be absorbed better than microparticles. Overall, little discrimination in uptake patterns was evident between Peyer's patch (PP) and non-PP tissue while rat ileum showed a greater uptake capacity than rabbit. Our results show that uptake of PLA particles was low capacity, size-dependent and predominantly transcellular in all systems. A low proportion of the apically-bound particles was absorbed, with uptake exclusion evident for particles >4microm. The affinity of PLA particles for intestinal epithelia and GALT needs to be greatly enhanced in order to achieve improved oral bioavailability of macromolecules.
The c-jun proto-oncogene encodes a transcription factor which is activated by mitogens both transcriptionally and by phosphorylation by Jun N-terminal kinase (JNK). We have investigated the cellular signalling pathways involved in epidermal growth factor (EGF) induction of the c-jun promoter. We find that two sequence elements, which bind ATF1 and MEF2D transcription factors, are required in HeLa cells, although they are not sufficient for maximal induction. Activated forms of Ras, RacI, Cdc42Hs, and MEKK increased expression of the c-jun promoter, while dominant negative forms of Ras, RacI, and MEK kinase (MEKK) inhibited EGF induction. These and previously published results suggest that EGF activates the c-jun promoter by a Ras-to-Rac-to-MEKK pathway. This pathway is similar to that used for posttranslational activation of c-jun by JNK.
A 51 year old male received an orthotopic transplant because of end stage ischaemic heart disease. The donor was a healthy male teenager with no history of arrhythmias or other cardiac conditions. The patient presented with haemodynamically stable tachycardia and dyspnoea five weeks post-transplant. The ECG showed a regular tachycardia of 140 beats/min with a right bundle branch block morphology, left axis deviation, and a QRS duration of 135 ms. There were independent P waves, capture, and fusion beats confirming the diagnosis of ventricular tachycardia. Endomyocardial biopsy showed moderate focal rejection that was thought to be responsible for the arrhythmia. During the following six months the patient had recurrent tachyarrhythmias; on each occasion the ECG morphology was the same and there was no cellular rejection. The patient continued to have frequent hospital admissions with ventricular tachycardia requiring DC cardioversion despite the empirical use of amiodarone, sotalol, disopyramide, and procainamide. Eighteen months after transplantation the diagnosis of fascicular tachycardia was suspected by ECG morphology and supported by successful termination with intravenous verapamil. The arrhythmia was successfully managed by radiofrequency ablation. This patient shows that arrhythmias following transplantation are not always related to rejection, and that other potentially reversible causes should be considered, particularly when the ECG during arrhythmia conforms to a classic configuration.
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Endothelin-1 (ET-1) is thought to play an important role in the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Because hypertension is associated with an increased incidence of coronary artery disease, this study was designed to determine if coronary vascular contraction to ET-1 is altered in DOCA-salt hypertensive rats and to determine the effect of chronic treatment of DOCA-salt rats with the selective ETA receptor antagonist A-127722. Male Sprague-Dawley rats were divided into four groups: DOCA, Placebo, DOCA + A-127722, and Placebo + A-127722. A-127722 was administered in drinking water at a concentration of 8 mg/100 ml. After 3 wk, mean arterial pressure (MAP) was significantly enhanced in DOCA-salt compared with Placebo rats. A-127722 significantly inhibited the increase in MAP. Contraction to ET-1 (10(-11) to 3 x 10(-8) M) was measured in isolated coronary and mesenteric small arteries (200-300 micron, intraluminal diameter) maintained at a constant intraluminal pressure of 40 mmHg and was significantly impaired in vessels from DOCA-salt compared with Placebo rats. Dose-dependent contractions to KCl were also inhibited in coronary, but only minimally impaired in mesenteric, arteries of DOCA-salt rats. Inhibition of nitric oxide synthase activity did not restore contraction to ET-1 in coronary small arteries. However contractions to ET-1 were enhanced in mesenteric small arteries. Chronic treatment with A-127722 significantly restored contraction to ET-1 in coronary, but not in mesenteric, arteries of DOCA-salt rats. Because ETA receptor blockade impairs the development of hypertension and improves coronary vascular reactivity, these data indicate that ET-1 plays an important role in coronary vascular dysfunction associated with DOCA-salt hypertension.
The preparation of microparticles of the biodegradable poly-DL-lactide (PLA) and polylactide-co-glycolide (PLGA) polymers using spray-drying technology was studied. Formulation parameters investigated include polymer type, polymer molecular weight, polymer concentration, and viscosity. Microparticles were characterized using electron microscopy, particle size analysis, and gel permeation chromatography. Kinematic viscosity was determined for each of the sprayed polymer solutions. Polymer molecular weight and polymer concentration were found to be important parameters when preparing PLA and PLGA microparticles using spray-drying technology.
Families of children with AIDS are often at risk for substance abuse, child neglect, and homelessness. Effective service delivery to the pediatric AIDS population requires a holistic, team-oriented approach for the whole family.