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Biomedical subjects

S Watson

Publications and source records attributed to S Watson.

At least 55 records · Page 3Linked to original sources
PubMed2000

An audit of patient perception compared with medical and nursing staff estimation of pain during burn dressing changes.

In order to prescribe appropriate analgesia for burns dressing changes the pain experienced by 30 burned patients during this procedure was recorded. Patients received analgesia prior to their dressing changes according to the current protocol in the burns unit. During the same period the medical and nursing staff in the unit who were involved in prescribing and administering the analgesia for the dressing change, were asked to assess the severity of pain that they thought patients experienced during dressing changes. Patients recorded their worst pain as none or mild in 64% of procedures. In contrast, no surgeon and only one nurse, rated pain as none or mild. The discrepancy between severity of pain recorded by patients and the pain predicted by staff prescribing and administering analgesia has clinical implications.

Acetaminophen↗
PubMed2000

Children's nurses in the accident and emergency department: literature review.

It is estimated that over 30% of Accident and Emergency attendees are children; despite this, many hospitals still do not have arrangements for them. Children often receive care from health professionals who are unaware of their specialist requirements. If we are to meet the demands of the document A First Class Service (National Health Service Executive 1998), which states that all patients are entitled to high quality care, emergency services for children and young people must be planned specifically, as an adjunct to adult services.

Child↗
PubMed2000

Incidence of incomplete excision in surgically treated basal cell carcinoma: a retrospective clinical audit.

All the patients who had excision of basal cell carcinoma at the regional plastic surgery unit at Manchester over a period of 2 years from January 1995 to December 1996 were included in a retrospective audit. A total of 879 lesions were excised in 754 patients. In 41 lesions (4.7%) the tumour was incompletely excised, 16 of these lesions were further excised; the rest were managed by regular follow-up. The mean age of the incomplete excision group was slightly higher. The site where the incomplete excision rate was highest was the scalps followed by the ear, canthi,eyebrows and nose. There was a higher incidence of squamous differentiation and presence of foci of squamous cell carcinoma in the lesions excised incompletely. There was no statistically significant difference among the different groups of surgeons but in individual grades the rate was lower where more wounds were repaired by direct closure. The concept of a complexity ratio (number of wounds repaired by other methods/number of wounds repaired by direct closure) can be helpful in comparing the incomplete excision rates of different grades of surgeons or departments. The excision of basal cell carcinoma is one of the commonest procedures performed by all grades of surgeons in a plastic surgery department. Incomplete excision leads to further surgery or prolonged follow-up, thus significantly affecting the outcome. As the incidence of incomplete excision can be precisely monitored, it may be a useful tool for clinical governance.

Adolescent↗
PubMed2000

The support that mentors receive in the clinical setting.

This paper looks at the support systems that mentors in a trust both need and have. It was a study to examine the causes of stress within mentoring with a view to exploring this aspect of the role and to examine the clinical learning environment. The English National Board (ENB) has stated that mentoring is a requirement for all nurse training. The literature speaks of the importance of the role of the mentor to the student. There has also been research showing that this role is stressful and needs support if it is to be fully effective. However, there is little research into the nature and quality of the support received or required by mentors. This study addresses issues that had not been previously addressed in that it looks at the nature of the support required by the mentors to enable them to perform their duties both to the student and to the patients in their care. The study is largely ethnographic in nature. It consists of a short series of unstructured interviews of selected experienced mentors as a means of collecting data to enable the construction of a questionnaire that was submitted to all mentors within the trust. This is to allow the trust and educational institution to work on developing newer and better support systems both for the present placement and also for future placements.

Attitude of Health Personnel↗
PubMed2000

Update on collagen receptor interactions in platelets: is the two-state model still valid?

This review summarises some of the key developments that have taken place in our understanding of platelet-collagen interactions within the last 18 months. Within this time, the major activatory collagen receptor glycoprotein VI (GPVI) has been sequenced and shown to reconstitute collagen responses in a megakaryocytic cell line. It is a member of the Ig superfamily of proteins, with two extracellular Ig domains, and is constitutively associated with the Fc receptor gamma-chain (FcR gamma-chain). GPVI signals through a pathway that shares many features with those of immune receptors, with critical roles for Syk and the adapters LAT and SLP-76 in the activation of PLCgamma2. Significant developments have also taken place in regard to the role of the major adhesion receptor for collagen, the integrin alpha2beta1 (also known as GPIa-IIa). An alpha2beta1-selective collagen-based peptide has been developed and co-crystallised with the I-domain of the alpha2 subunit. Polymorphisms in alpha2 have been shown to cause wide variation in expression of alpha2beta1, with the alpha2 allele T807/A873 leading to a high level of the integrin and increased risk of stroke in young people. Activation of platelets by a wide range of agonists has been shown to increase the affinity of alpha2beta1 to intermediate or high affinity states. This has important implications for the two-site, two-state model of collagen-platelet interactions. A new model is proposed in which collagen binds initially to either alpha2beta1 or GPVI, leading to subsequent binding to the other receptor and conversion of the integrin to a high affinity state. In this model, both receptors generate intracellular signals which support platelet activation.

Animals↗
PubMed2000

The principles of management of congenital anomalies of the upper limb.

Management of congenital anomalies of the upper limb is reviewed with reference to classification and aetiology, incidence, diagnosis before birth, broad principles of treatment, timing of x rays and scans, functional aims, cosmetic appearance, counselling of parents, therapists, scars, skin grafts, growth, and timing of surgery. Notes on 11 congenital hand conditions are given.

Activities of Daily Living↗
PubMed2000

Antitumor imidazolyl disulfide IV-2 causes irreversible G(2)/M cell cycle arrest without hyperphosphorylation of cyclin-dependent kinase Cdk1.

Aberrant function of redox-regulated proteins is a possible cause for cellular transformation and loss of cell cycle control. The small protein thioredoxin has oncogenic properties and controls cell cycle movement through G(1), S, and G(2)/M phases. The redox-active, asymmetrical 1-methylpropyl-2-imidazolyl disulfide (IV-2) has previously been shown to react with and inhibit thioredoxin activity in vitro, the proliferation of human tumor cells in culture, and the growth of tumors in mice. We now examined the effects of IV-2 on cell cycle progression. In synchronized tsFT210 mouse mammary carcinoma cells, IV-2 halted cells in mitosis. In asynchronously growing MCF-7 human breast cancer cells, IV-2 exclusively and irreversibly blocked cells in G(2)/M at concentrations that correlated with its growth inhibitory activity. Neither the closely related, less redox active 2-hydroxy-1-methylpropyl-2-imidazolyl disulfide (AIV-2), which differs from IV-2 only by an additional hydroxyl group, nor the symmetrical diallyl disulfide caused a G(2)/M arrest under these conditions. Furthermore, MCF-7 cells treated with IV-2 showed increased Cdk1 kinase activity and a decrease in Cdk1 tyrosine phosphorylation, indicating that IV-2 did not directly inhibit Cdk1 or Cdc25 activities. IV-2 did, however, increase Bcl-2 phosphorylation. These data suggest that the thioredoxin inhibitor IV-2, despite its simple structure, is able to target redox-sensitive processes that are critical for cell cycle progression through mitosis. The results are also consistent with a role of thioredoxin regulating cell cycle progression through G(2)/M.

Allyl Compounds↗
PubMed1999

On the distribution patterns of D1, D2, tyrosine hydroxylase and dopamine transporter immunoreactivities in the ventral striatum of the rat.

The distribution of dopamine D1 and D2 receptor immunoreactivities in the nucleus accumbens and the olfactory tubercle of adult and postnatal male rats were compared with the distribution of tyrosine hydroxylase and dopamine transporter immunoreactivities. An overall co-distribution of D1 and D2 receptor immunoreactivities with tyrosine hydroxylase immunoreactivity was found in the nucleus accumbens and the olfactory tubercle. However, the major finding in this study was, following a more detailed analysis in coronal sections of the shell part of the nucleus accumbens, the existence of nerve cell patches of strong D1 receptor immunoreactivity associated with low D2 receptor, dopamine transporter and tyrosine hydroxylase immunoreactivities. These patches were mainly surrounded by areas of strong D2 receptor, tyrosine hydroxylase and dopamine transporter immunoreactivities and could be found also in the olfactory tubercle. Similar observations were made in postnatal rats. Serial reconstructions of the patches of strong D1 receptor immunoreactivity in the rostrocaudal direction were made. The patches formed a continuous tubular nerve cell system in the shell part of the nucleus accumbens. Since this nerve cell system was found to be surrounded by a high density of dopamine terminals, it may represent a compartment where dopamine transmission mainly acts on D1 receptors via local diffusion (i.e. via volume transmission). However, it must be noted that the D1 receptor rich patches constitute only a small fraction of the nucleus accumbens and the overall density of tyrosine hydroxylase immunoreactive terminals correlates with the density of both D1 and D2 receptors in the nucleus accumbens. In conclusion, the present paper gives new aspects on the chemical microarchitecture of the nucleus accumbens.

Aging↗
PubMed1999

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Pharmacokinetics of a once-daily oral dose of moxifloxacin (Bay 12-8039), a new enantiomerically pure 8-methoxy quinolone.

The pharmacokinetics, safety, and tolerability of oral moxifloxacin, a new 8-methoxy quinolone, were assessed in a randomized, double-blind, placebo-controlled study in which healthy male and female volunteers received either 400 mg of moxifloxacin once daily (n = 10) or a placebo once daily (n = 5) for 10 days. Plasma moxifloxacin concentrations on days 1 and 10 were measured by high-performance liquid chromatography and fluorometric detection. Standard pharmacokinetic parameters were estimated by noncompartmental methods. Natural logarithmic estimates for each pharmacokinetic variable of each subject were analyzed by a two-way analysis of variance. Hematology, blood chemistry, vital signs, and adverse events were monitored, and electrocardiograms (ECG) were performed. Plasma moxifloxacin concentrations of predicted therapeutic relevance were achieved in this study. For day 1, the mean maximum concentration of drug in serum (C(max)) and the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) were 3. 4 mg/liter and 30.2 mg. h/liter, respectively. Corresponding means on day 10 were 4.5 mg/liter and 48 mg. h/liter, respectively. On day 10, the mean elimination half-life was approximately 12 h. Plasma moxifloxacin concentrations exceeded the MIC for Streptococcus pneumoniae throughout the 24-h dosing period. The day 1 and day 10 mean AUC/MIC ratios were 121 and 192, respectively, and the mean C(max)/MIC ratios were 13 and 18, respectively. Moxifloxacin was well tolerated; no clinically relevant changes in the standard laboratory tests, vital signs, or ECG were observed. Pharmacokinetic parameters demonstrated linearity, and estimates of pharmacokinetic/pharmacodynamic ratios (AUC/MIC and C(max)/MIC) indicate that the regimen of 400-mg once daily should be effective for treating a variety of infections. Moxifloxacin was found to be safe and well tolerated in healthy volunteers when it was given as a single daily 400-mg dose for 10 days.

Adolescent↗
PubMed1999

Vinblastine pharmacokinetics in patients with non-small cell lung cancer given cisplatin.

The pharmacokinetics of vinblastine were studied in 16 patients with non-small cell lung cancer after a bolus intravenous dose of 3 mg/m2 given before or after cisplatin (100 mg/m2). Venous blood was collected at 0, 10, and 36 hr for analysis by radioimmunoassay. The mean plasma vinblastine concentration at 10 hr was similar when vinblastine was given before (4.8 ng/ml; 95% CI, 3.2-6.3) or after cisplatin (4.9 ng/ml; 95% CI, 2.7-7.1). Plasma vinblastine concentrations in patients given cisplatin were higher than previously reported in patients given vinblastine alone. Patients with plasma vinblastine concentrations less than 2.75 ng/ml at 10 hr experienced less severe neutropenia (37% fall in neutrophil count; 95% CI, 18-55) than those with levels greater than 2.75 ng/ml (69% fall in neutrophil count; 95% CI, 62-77). In conclusion, the pharmacokinetics of vinblastine predict the severity of neutropenia and may be altered when given in conjunction with cisplatin.

Aged↗
PubMed1999

Structure-based drug design: combinatorial chemistry and molecular modeling.

Drug discovery efforts are shifting to include the rapid synthetic procedures of combinatorial chemistry and the elegance of rational library design. The wealth of computational methods which explore both the receptor structure and the ultimate pharmacophore complementarity, provide novel avenues for chemists to discover new lead compounds or design virtual libraries for screening prior to the synthetic stage. This mini-review provides an overview of a few current methodologies of library generation, highlighting docking procedures which have utility in both the discovery and optimization stages of drug development. Three specific examples of different approaches to the use of docking are provided. These describe the development of inhibitors to the human A3 adenosine receptor and HIV-1 protease, and the evaluation of the activity of novel inhibitors of the redox regulator protein, human thioredoxin.

Chemistry, Organic↗
PubMed1999

Parallel syntheses of disulfide inhibitors of the thioredoxin redox system as potential antitumor agents.

We have reported previously that unsymmetrical disulfide inhibitors of the human thioredoxin/thioredoxin reductase redox system (hTrx/TR) possess antitumor activity. We have broadened the search for more potent inhibitors and evaluated a large range of mono- and bis-disulfide compounds, prepared using parallel syntheses. Reaction of isothioisourea-HCI salts (R') or bis-salts (R) with aromatic or aryl thiols (R") in wells of 96-well plates produced >450 derivatives with the structures R"SSR' and R"SSRSSR". The excellent yield and purity of the disulfides provided sufficient material for evaluations of enzyme inhibition and cytotoxicity. Selection criteria based on the IC50 values for hTrx/TR inhibition and for cytotoxicities of the disulfides identified agents for subsequent scale-up syntheses and in vivo evaluations of antitumor activity. These scale-up studies confirmed the original activities of agents synthesized in the plates and validated the parallel synthetic approach. Structure-activity information derived from the hTrx/TR IC50 data allow for a number of generalizations. The most potent inhibitors of the Trx system contained two heteroatoms ortho to the disulfide moiety in an aromatic functionality. The thioalkylating moieties had greatest activity with one branch point alpha to the disulfide. In the absence of branching, more potent inhibition was observed with the electron withdrawing functionalities. Bis-disulfides showed patterns of activity which depended on chain length, with optimum activity observed when the disulfide units were separated by 3.9 A, a similar distance to that separating the thioredoxin active site cysteine residues. From the agents selected for scale-up syntheses, three disulfide compounds were studied for their antitumor activity in vivo against human tumor xenografts in scid mice. One of the analogues discovered through the combinatorial syntheses/screening for Trx inhibition, 1-phenylethyl 2-imidazolyl disulfide, N1 (ProlX agent PX-C5), has demonstrated excellent in vivo activity against the MCF-7 human breast cancer and the HL-60 human leukemia, thus validating this approach for novel drug discovery.

Animals↗
PubMed1998

Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity.

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.

Angiotensin II↗