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Biomedical subjects

S Booth

Publications and source records attributed to S Booth.

At least 19 recordsLinked to original sources
PubMed2006

Measurement of breathlessness in advanced disease: a systematic review.

BACKGROUND: There is a plethora of assessment tools available to measure breathlessness, the most common and disabling symptom of advanced cardio-respiratory disease. The aim of this systematic review was to identify all measures available via standard search techniques and review their usefulness for patients with advanced disease. METHODS: A systematic literature search was performed in Medline. All studies focusing on the development or evaluation of tools for measuring breathlessness in chronic respiratory disease, cardiac disease, cancer, or MND were identified. Their characteristics with regard to validity, reliability, appropriateness and responsiveness to change were described. The tools were then examined for their usefulness in measuring significant aspects of breathlessness in advanced disease. RESULTS: Thirty-five tools were initially identified, two were excluded. Twenty-nine were multidimensional of which 11 were breathlessness-specific and 18 disease-specific. Four tools were unidimensional, measuring the severity of breathlessness. The majority of disease-specific scales were validated for chronic obstructive pulmonary disease (COPD), few were applicable in other conditions. No one tool assessed all the dimensions of this complex symptom, which affects the psychology and social functioning of the affected individual and their family--most focused on physical activity. CONCLUSION: As yet there is no one scale that can accurately reflect the far-reaching effects of breathlessness on the patient with advanced disease and their family. Therefore, at present, we would recommend combining a unidimensional scale (e.g. VAS) with a disease-specific scale (where available) or a multidimensional scale in conjunction with other methods (such as qualitative techniques) to gauge psychosocial and carer distress for the assessment of breathlessness in advanced disease.

Dyspnea↗
PubMed2005

The rheological properties of self-emulsifying systems, water and microcrystalline cellulose.

The rheological properties of mixtures of equal parts of a range of ratios of a self-emulsifying system (MP) and water (W) added to microcrystalline cellulose (MCC), have been measured by an extrusion capillary rheometer. These measurements allow assessment of both the shear and tension components of flow plus the elastic behaviour of the wet powder masses, although the results for the estimation of shear stress require careful interpretation due to the limitation of the measuring system and the assumptions made in their derivation. The results indicate that there are three regions of behaviour of the systems, which are all significantly different from the mixtures containing only W and MCC. At low MP contents (1.5--23%), the masses increase in their resistance to shear and elongational flow and have lower elasticity. These similarities in behaviour occur in spite of considerable increase in the viscosity of the MPW mixtures and a change to non-Newtonian flow of the fluid. The behaviour of the 46% MP system is intermediate between these systems and the high MP concentrations (69, 80 and 92%). These latter systems show less resistance to shear and elongational flow than the first group of concentrations, but show considerably higher levels of elasticity. As the resistance to shear decreases, so does the impairment of the surface of the extrudate. There is clear evidence of a systematic change in behaviour of the wet powder masses as the values for the angle of entry of the wet mass into the die when plotted against the ratio of the resistance to die entry (upstream pressure loss) to the shear stress within the die, is linear on a log/log scale. Also, the values of compliance of the systems as a function of shear stress fall on a common curve. Changes in the ratio of the MPW to MCC for a system for a single level of MP (46%) resulted in a change in the values of the rheological parameters but not the type of behaviour. As all these wet powder masses had been shown previously to form pellets by the process of extrusion/spheronization, it is clear that systems with a wide range of rheological characteristics can be processed and no single rheological parameter can be used to provide complete characterisation of the processability of such systems.

Cellulose↗
PubMed2004

A model for the conservative management of mallet finger.

This prospective study assessed the results of a custom-made thermoplastic splint for treatment of mallet finger deformity. From April 1999 to April 2000, 42 patients with mallet finger deformity were recruited. All patients were seen within 1 week and treated with a thermoplastic splint custom-made by the hand therapy department. The splint was simple to make, easy to fit and suitable for all finger shapes and sizes. It improved the deformity in 30 out of 34 cases, and caused no skin irritation.

Female↗
PubMed2001

Parallel solid-phase synthesis of zatebradine analogues as potential I(f) channel blockers.

The first solid-phase synthesis of zatebradine 1 and its analogues is reported. This has resulted in the preparation of compounds with increased ability to reduce the spontaneous beating of isolated guinea-pig atria in a concentration-dependent manner. One example, 8g, showed a maximum reduction of beating of 80% at 3 microM compared to a reduction of 40% at 3 microM with zatebradine 1.

Animals↗
PubMed2001

Rab27a is required for regulated secretion in cytotoxic T lymphocytes.

Rab27a activity is affected in several mouse models of human disease including Griscelli (ashen mice) and Hermansky-Pudlak (gunmetal mice) syndromes. A loss of function mutation occurs in the Rab27a gene in ashen (ash), whereas in gunmetal (gm) Rab27a dysfunction is secondary to a mutation in the alpha subunit of Rab geranylgeranyl transferase, an enzyme required for prenylation and activation of Rabs. We show here that Rab27a is normally expressed in cytotoxic T lymphocytes (CTLs), but absent in ashen homozygotes (ash/ash). Cytotoxicity and secretion assays show that ash/ash CTLs are unable to kill target cells or to secrete granzyme A and hexosaminidase. By immunofluorescence and electron microscopy, we show polarization but no membrane docking of ash/ash lytic granules at the immunological synapse. In gunmetal CTLs, we show underprenylation and redistribution of Rab27a to the cytosol, implying reduced activity. Gunmetal CTLs show a reduced ability to kill target cells but retain the ability to secrete hexosaminidase and granzyme A. However, only some of the granules polarize to the immunological synapse, and many remain dispersed around the periphery of the CTLs. These results demonstrate that Rab27a is required in a final secretory step and that other Rab proteins also affected in gunmetal are likely to be involved in polarization of the granules to the immunological synapse.

Actin-Related Protein 2↗
PubMed2001

The influence of formulation variables on the properties of pellets containing a self-emulsifying mixture.

A method of converting self-emulsifying drug delivery systems to a pellet form has been studied. Formulations with varied relative quantities of an oil/surfactant mixture, water, microcrystalline cellulose (MCC), and lactose were chosen in a statistical design after preliminary ranging experiments. Pellets were produced by extrusion/spheronization. The characteristics of the pellets were studied by sieving, disintegration testing, diametral compression, image analysis, non-contact laser profilometry, and scanning electron microscopy. The effects of the formulation variables on pellet properties were evaluated by analysis of variance. It was possible to relate the formulation variables to all the quantified pellet properties except the shape. The relative quantities of oil/surfactant and water had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, extrusion force, median diameter, size spread, disintegration time, tensile strength, and surface roughness. The relative quantities of lactose and MCC had an effect on the amount of liquid and oil/surfactant that could be incorporated into the powder, tensile strength, and roughness only. Water was an essential element of the formulations. The maximum quantity of the specific oil/surfactant combination studied that can be incorporated was 42% of the dry pellet weight.

Drug Delivery Systems↗
PubMed2001

Cue dependency of nicotine self-administration and smoking.

A paradox exists regarding the reinforcing properties of nicotine. The abuse liability associated with smoking equals or exceeds that of other addictive drugs, yet the euphoric, reinforcing and other psychological effects of nicotine, compared to these other drugs, are more subtle, are manifest under more restricted conditions, and do not readily predict the difficulty most smokers experience in achieving abstinence. One possible resolution to this apparent inconsistency is that environmental cues associated with drug delivery become conditioned reinforcers and take on powerful incentive properties that are critically important for sustaining smoking in humans and nicotine self-administration in animals. We tested this hypothesis by using a widely employed self-administration paradigm in which rats press a lever at high rates for 1 h/day to obtain intravenous infusions of nicotine that are paired with two types of visual stimuli: a chamber light that when turned on signals drug availability and a 1-s cue light that signals drug delivery. We show that these visual cues are at least as important as nicotine in sustaining a high rate of responding once self-administration has been established, in the degree to which withdrawing nicotine extinguishes the behavior, and in the reinstatement of lever pressing after extinction. Additional studies demonstrated that the importance of these cues was manifest under both fixed ratio and progressive ratio (PR) schedules of reinforcement. The possibility that nicotine-paired cues are as important as nicotine in smoking behavior should refocus our attention on the psychology and neurobiology of conditioned reinforcers in order to stimulate the development of more effective treatment programs for smoking cessation.

Animals↗
PubMed2001

The immunological synapse of CTL contains a secretory domain and membrane bridges.

Cytotoxic T lymphocytes (CTL) rapidly destroy their targets. Here we show that although target cell death occurs within 5 min of CTL-target cell contact, an immunological synapse similar to that seen in CD4 cells rapidly forms in CTL, with a ring of adhesion proteins surrounding an inner signaling molecule domain. Lytic granule secretion occurs in a separate domain within the adhesion ring, maintaining signaling protein organization during exocytosis. Live and fixed cell studies show target cell plasma membrane markers are transferred to the CTL as the cells separate. Electron microscopy reveals continuities forming membrane bridges between the CTL and target cell membranes, suggesting a possible mechanism for this transfer.

Animals↗
PubMed2001

The shuttle walking test: a reproducible method for evaluating the impact of shortness of breath on functional capacity in patients with advanced cancer.

BACKGROUND: Breathlessness leading to exercise limitation is common in patients with advanced cancer and is ineffectively treated. There are few research data to guide clinicians on best practice. The shuttle walking test has been validated for some conditions such as chronic obstructive pulmonary disease but not for advanced cancer. One of the well documented difficulties of doing clinical research in palliative care is the acceptability of assessment tests. This study examined the reproducibility of the shuttle walking test in patients with advanced cancer to help facilitate the systematic evaluation of interventions designed to improve breathlessness. METHODS: Patients performed three shuttle walks on separate days with continuous monitoring of arterial oxygen saturation and heart rate; simple pulmonary function (FEV(1)) was also recorded. Data on quality of life, anxiety, and depression were collected throughout the study period using appropriate questionnaires. Breathlessness was measured before and after exercise using a visual analogue scale. RESULTS: Data from 22 patients were compared between visits 2 and 3. There were no significant differences between the FEV(1) (1.89 v 1.90, p=0.73), distance walked on each test (245 m v 256 m, p=0.14), end-exercise levels of heart rate (107/min v 108/min, p=0.11), oxygen saturation (93.4% v 93.2%, p=0.38), or breathlessness scores (p=0.62) on the two occasions. Indices of quality of life, anxiety, and depression were also not different between the two tests. The investigation was very acceptable to patients, families, and staff. CONCLUSIONS: The shuttle walking test is a reproducible test of functional capacity in ambulant patients with advanced cancer, WHO performance status 1 or 2. The data indicate that a practice session is needed. It is easy to carry out and acceptable for patients with advanced cancer.

Adult↗
PubMed2000

Molecular mechanisms affecting HTLV type 1-dependent fusion at the cell membrane: implications for inhibiting viral transmission.

Infection with human T cell leukemia virus type 1 is detected by screening programs and contact follow-up procedures. Where chronic infection results in overt pathology, this is treated largely symptomatically and control of transmission relies on physical and educational constraints. The poor infectious transmission rate of HTLV-1 has long been described but to date has not been exploited in preventative measures to combat the spread of the virus. We undertook to investigate some of the molecular steps involved in HTLV-1 cell-cell fusion, the main mechanism of transmission. We showed that poor transmission may relate in part to an inefficiency in adopting and maintaining a fusion competent conformation of the HTLV-1 envelope TM protein. In cell-cell fusion, this deficiency can be complemented by accessory molecules on both infected and target cells that stabilize the envelope/receptor interaction. In virion-cell fusion, this is less likely, leading to an inefficient interaction and poor infectious transmission by cell-free virus. A discussion of the accessory molecules involved in HTLV-1 fusion is presented. This weak envelope-dependent interaction with target cells in the host can be potently disrupted by peptides that destabilize the TM protein structure and significantly inhibit HTLV-1 fusion. These observations may be useful in the design of therapeutic agents to prevent HTLV-1 transmission.

Amino Acid Sequence↗
PubMed2000

Expression of two novel proteins in Chlamydia trachomatis during natural infection.

Genes for a putative membrane associated protein (mvi -homologue) and a 48 kDa protein (ctr48) in Chlamydia trachomatis were characterized. The mvi -homologue has 12 transmembrane domains and shows considerable homology to the members of this gene family in various organisms. The ctr48 has a leader sequence and the C-proximal half is tryptophan-rich. The latter region shares 65% identity with the N-proxima third of C. pneumoniae 76 kDa protein over an overlap of 231 amino acid residues. The genes for the mvi -homologue and the ctr48 are present in the B, Ba, D, E, J and L2 serotypes of C. trachomatis. Immediately downstream from the ctr48 gene are multiple stop codons which are followed by a functional rho-independent terminator. The mvi -homologue and ctr48 genes are independently transcribed, albeit poorly in serotype B. However, protein products corresponding to these genes could not be detected by western blotting in HEp2 cells infected with C. trachomatis. Nevertheless, antibodies to peptides corresponding to these proteins were detected in sera with high micro-immunofluorescence titre against C. trachoImatic, collected from a Chlamydia -endemic population. These results suggest that the mvi -homologue and ctr48 are expressed by C. trachomatis during natural infection.

Adult↗
PubMed2000

Mecamylamine prevents tolerance but enhances whole brain [3H]epibatidine binding in response to repeated nicotine administration in rats.

RATIONALE: Chronic administration of nicotine in rats results in upregulation of neuronal nicotinic receptors. Upregulation has been proposed to reflect receptor desensitization, which may underlie functional tolerance to nicotine's effects. However, evidence indicates that tolerance and upregulation do not always parallel each other, suggesting that either upregulation does not always reflect desensitization, or mechanisms other than receptor desensitization account for tolerance to nicotine. OBJECTIVES: The present studies examined tolerance to nicotine-induced antinociception and changes in receptor binding after two regimens of intermittent nicotine injections in rats. The role of receptor activation in upregulation and tolerance was also examined by co-administering nicotine with the non-competitive antagonist, mecamylamine. METHODS: Sprague-Dawley rats were administered a short (once-daily, s.c. for 6 days (0.35 mg/kg)) or long (twice-daily for 11 days (0.66 mg/kg)) series of injections and tolerance to nicotine-induced antinociception and [3H]epibatidine binding in whole brain were measured. RESULTS: The short series of injections resulted in tolerance to nicotine-induced antinociception, but failed to increase [3H]epibatidine binding. In contrast, the long series of injections resulted in both tolerance and increased receptor binding. Once-daily pairings of mecamylamine (1 mg/kg, s.c.) with nicotine (0.35 mg/kg) for 6 days blocked the development of tolerance, indicating receptor activation is necessary for tolerance to occur. Pairing mecamylamine with nicotine (0.66 mg/kg) twice daily for 11 days blocked tolerance but produced a greater increase in [3H]epibatidine binding than nicotine alone. CONCLUSIONS: A dissociation of tolerance from receptor upregulation was observed in the present study. The finding that receptor activation may be necessary for tolerance but not upregulation is discussed within the context of possible mechanisms controlling tolerance to nicotine.

Animals↗
PubMed2000

Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding.

RATIONALE: Research on smoking behavior and responsiveness to nicotine suggests that nicotine's effects may depend on the sex of the organism. OBJECTIVE: The present study addressed four questions: 1) Will female rats self-administer nicotine? 2) Does self-administration by females vary as a function of estrous cycle? 3) Does self-administration by females differ from that of males? 4) Does self-administration of nicotine result in up-regulation of nicotinic receptor binding and are these changes similar in males and females? METHODS: Male and female Sprague-Dawley rats were allowed to self-administer nicotine at one of four doses (0.02-0.09 mg/kg, free base) on both fixed and progressive ratio schedules of reinforcement. RESULTS: Females acquired nicotine self-administration across the entire range of doses. Acquisition of self-administration at the lowest dose was faster in females than males. However, few sex differences were found in the number of active responses, number of infusions, or total intake of nicotine during stable fixed ratio self-administration. In contrast, females reached higher break points on a progressive ratio. For both schedules, females had shorter latencies to earn their first infusion of each session and demonstrated higher rates of both inactive and timeout responding. There was no effect of estrous cycle on self-administration during either fixed or progressive ratio sessions. Self-administered nicotine resulted in average arterial plasma nicotine levels between 53 and 193 ng/ml and left hemi-brain levels between 174 and 655 ng/g, depending on dose. Nicotine self-administration produced similar up-regulation of nicotinic receptor binding sites in males and females, as reflected by increased right hemi-brain binding of [3H]-epibatidine, when compared to the brains of untreated control rats. CONCLUSIONS: These results suggest that while males and females may regulate their intake of nicotine similarly under limited access conditions, the motivation to obtain nicotine is higher in females.

Animals↗
PubMed2000

HTLV-1-induced cell fusion is limited at two distinct steps in the fusion pathway after receptor binding.

Human T-cell leukemia virus type 1 (HTLV-1) is notable among retroviruses for its poor ability to infect permissive cells, particularly as cell free virus. The virus is most efficiently transmitted between individuals by infected cells, where it is presumed that intracellular particles and viral RNA are transferred to target cells following fusion. Although the mandatory first step for HTLV-1 fusion is the binding of envelope SU (gp46) to the receptor, the events which follow this interaction and lead to fusion and infection have not been well characterized. To investigate these events, we studied two HTLV-1 chronically infected cell lines with different abilities to fuse with K562 target cells. Although not inherently fusion incompetent, the HTLV-1 envelope protein on MT2 cells was poorly able to undergo a change in membrane hydrophobicity required for fusion with the target cell membrane after binding to the receptor. High level expression of a fusion-competent HTLV-1 envelope protein on MT2 cells had little effect on improving this suggesting that the defect was encoded by the parent cell. Visible syncytia were seen after incubation of these cells with K562 target cells but complete fusion as measured by transfer of cellular contents into the recipient cell was not observed. In C91-PL cells, binding of SU to the receptor resulted in a sustained hydrophobic change of envelope accompanied by a cytopathic effect in mixed cell cultures and complete fusion. However, in C91-PL cells, overexpression of envelope protein blocked the transfer of cell contents after receptor engagement and initiation of cytopathic membrane changes, indicating that post binding fusion events were blocked. These data suggest that HTLV-1 fusion is a multistep process which is susceptible to inhibition at two seperate stages of the fusion pathway post receptor binding. This, and the inefficient infection by cell-free virions, may explain the poor infectivity of HTLV-1 in vivo and suggests strategies for preventative therapy.

Animals↗
PubMed1999

Nicotine self-administration in rats on a progressive ratio schedule of reinforcement.

RATIONALE: Robust intravenous (i.v.) nicotine self-administration (SA) in rats has been reported by several laboratories, including our own, using fixed ratio (FR) schedules of reinforcement. Studies on other drugs of abuse, however, suggest that progressive ratio (PR) schedules may provide additional information not gained using FR schedules. OBJECTIVE: Here, we attempt to establish and characterize nicotine SA on a PR. METHODS: One study allowed animals to acquire SA on a FR at four doses of nicotine (0.02, 0.03, 0.06, 0. 09 mg/kg) before being switched to a PR. A second study examined extinction by saline substitution or pretreatment with the nicotinic antagonist, mecamylamine, including a preliminary analysis into the role of secondary reinforcers in the extinction process. RESULTS: SA of nicotine on a PR was stable across repeated sessions. The number of infusions earned on a PR correlated with infusion rate on a FR; however, a large portion of the variance in SA on a PR could not be accounted for by infusion rate on a FR. Infusions on a PR increased across the same range of doses that produced a decrease in the infusion rate on a FR. Extinction of responding occurred after saline substitution or pretreatment with mecamylamine, and animals re-acquired when nicotine was again available without pretreatment. The presence of drug-paired stimuli appeared to lengthen the extinction process. CONCLUSIONS: Nicotine supports stable SA on a PR. Since PR and FR schedules may measure different aspects of nicotine reinforcement, PR schedules may be valuable in further characterizing group and individual differences in nicotine reinforcement.

Animals↗
PubMed1999

Human T-cell leukaemia/lymphoma virus type 1 syncytium formation is regulated in a cell-specific manner by ICAM-1, ICAM-3 and VCAM-1 and can be inhibited by antibodies to integrin beta2 or beta7.

Human T-cell leukaemia/lymphoma virus type 1 (HTLV-1) is a pathogenic retrovirus responsible for a number of inflammatory pathologies and adult T-cell leukaemia. Although T-cell tropic in vivo, HTLV-1 can infect a wide variety of cell types in vitro. Cell-to-cell spread of HTLV-1 may require specific binding of envelope to its cellular receptor, with other cell-surface molecules facilitating fusion. Here it is shown that intercellular adhesion molecule-1 or -3 (ICAM-1, ICAM-3) or vascular cell adhesion molecule-1 (VCAM-1) are required for syncytium formation of K562 with HTLV-1-infected MT2 cells but not C91-PL cells. The effect of ICAMs and VCAM-1 on MT2-induced fusion can be blocked by antibodies that bind beta-integrins. These fusion co-factor molecules are effective only when present in combination with HTLV-1 receptor-bearing cells and are not sufficient to mediate syncytium formation alone. The results suggest that engagement of HTLV-1-infected cells with susceptible target cells requires the simultaneous binding of viral envelope glycoprotein to the cellular receptor and co-factor molecules to beta-integrins. The tissue-specific expression of adhesion molecules might therefore influence HTLV-1 virus tropism and pathogenic changes associated with syncytium formation.

Animals↗