The rediscovery of methadone for cancer pain management.
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Humans↗
Biomedical subjects
K Turner
Publications and source records attributed to K Turner.
Vascular endothelial growth factor-B and vascular endothelial growth factor-C expression in renal cell carcinomas: regulation by the von Hippel-Lindau gene and hypoxia.
Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently VEGF-B and VEGF-C, two new VEGF family members, have been identified that bind to the tyrosine kinase receptors flt-1 (VEGFR1), KDR (VEGFR2), and flt-4 (VEGFR3). Although the importance of VEGF-A has been shown in renal carcinomas, the contribution of these new ligands in kidney tumors is not clear. We have, therefore, measured the mRNA level of VEGF-B and VEGF-C together with their receptors by RNase protection assay (RPA) in 26 normal kidney samples and 45 renal cell cancers. We observed a significant up-regulation of VEGF-B (P = 0.002) but not VEGF-C (P = 0.3) in neoplastic kidney compared with normal tissues. In addition, although VEGF receptors were higher in tumors than normal kidney, there was a significant up-regulation of only flt-1 (P = 0.003) but not KDR (P = 0.12) or flt-4 (P = 0.09). There was also a significant correlation between VEGF-C and both of its receptors flt-4 (P = 0.006) and KDR (P = 0.03) but no association between VEGF-B and its receptor flt-1 (P = 0.23). A significant increase was observed in flt-1 (P < 0.001), KDR (P = 0.02), and flt-4 (P = 0.01) but not VEGF-B (P = 0.82) or VEGF-C (P = 0.52) expression in clear cell compared with chromophil (papillary) carcinomas. No significant association was demonstrated between VEGF-B, VEGF-C, flt-1, KDR, and flt-4 with patient sex, patient age, or tumor size (P > 0.05). The effect of von Hippel-Lindau (VHL) gene and hypoxia on VEGF-B and VEGF-C expression in the renal carcinoma cell line 786-0 transfected with wild-type and mutant VHL was determined by growing cells under 21% O2- and 0.1% O2. In wild-type VHL cells, whereas VEGF-A was significantly up-regulated under hypoxic compared with normoxic conditions (P < 0.001), expression of VEGF-C was reduced (P < 0.002). Nevertheless, the repression of VEGF-C was lost in mutant VHL cell lines under hypoxia. In contrast VEGF-B was not regulated by VHL despite clear up-regulation in vivo. These findings strongly support an enhanced role for this pathway in clear cell carcinomas by regulating angiogenesis and/or lymphangiogenesis. The study shows that clear cell tumors are able to up-regulate angiogenic growth factor receptors more efficiently than chromophil (papillary), that clear cell tumors can use pathways independent of VHL to regulate angiogenesis, and that this combined regulation may account for their more aggressive phenotype, which suggests that targeting VEGFR1 (flt-l) may be particularly effective in these tumor types.
Adenocarcinoma, Clear Cell↗
Biosensor based on enzyme-catalysed degradation of thin polymer films.
A biosensor based on the enzyme-catalysed dissolution of biodegradable polymer films has been developed. Three polymer-enzyme systems were investigated for use in the sensor: a poly(ester amide), which is degraded by the proteolytic enzyme alpha-chymotrypsin; a dextran hydrogel, which is degraded by dextranase; and poly(trimethylene) succinate, which is degraded by a lipase. Dissolution of the polymer films was monitored by Surface Plasmon Resonance (SPR). The rate of degradation was directly related to enzyme concentration for each polymer/enzyme couple. The poly(ester amide)/alpha-chymotrypsin couple proved to be the most sensitive over a concentration range from 4 x 10(-11) to 4 x 10(-7) mol l(-1) of enzyme. The rate of degradation was shown to be independent of the thickness of the poly(ester amide) films. The dextran hydrogel/dextranase couple was less sensitive than the poly(ester amide)/alpha-chymotrypsin couple but showed greater degradation rates at low enzyme concentrations. Enzyme concentrations as low as 2 x 10(-11) mol l(-1) were detected in less than 20 min. Potential fields of application of such a sensor system are the detection of enzyme concentrations and the construction of disposable enzyme based immunosensors, which employ the polymer-degrading enzyme as an enzyme label.
Biodegradation, Environmental↗
Late-onset depression: genetic, vascular and clinical contributions.
BACKGROUND: Neuropsychiatric research needs to examine the relationships between aetiological, genotypic and clinical risk factors and behavioural phenotypes. These relationships can now be examined in older patients with depressive disorders. METHODS: Key behavioural features, clinical and vascular risk factors and putative genotypes for late-onset neurodegenerative disorders and/or vascular disease were recorded in 78 older patients with depression (mean age = 549 years, S.D. = 14.1) and 22 healthy control subjects (mean age = 55.5 years, S.D. = 9.6). RESULTS: Two or more vascular risks were more common in older patients (65% v. 26% of control subjects, P < 0.01), and in patients with late-onset disorders (82% v. 57% in patients with early-onset disorders, P < 0.05). Patients with late-onset depression had a higher prevalence of the homozygous or heterozygous forms of the C677T mutation of the methylenetetrahydrofolate reductase enzyme (MTHFR)(74% v. 48% in patients with early-onset disorders, P < 0.05). In a multivariate model, only presence of the MTHFR gene mutation predicted late-onset depression (odds ratio = 3.8, 95% CI = 1.1-12.9). Neither apolipoprotein E epsilon 4 or epsilon 2 was associated with depression, late-onset depression, cognitive impairment, or psychomotor change. Patients with apolipoprotein E epsilon 4 were less likely to have psychotic forms of depression. CONCLUSIONS: Patients with late-onset depression had an increased rate of the C677T MTHFR gene mutation and other vascular risk factors. This suggests that a proportion of these patients may have genetically-determined and/or other vascular aetiologies. Patients at risk of these disorders may be assisted by currently-available preventative strategies.
Adult↗
Dynamic biosynthesis of heparan sulphate sequences in developing mouse brain: a potential regulatory mechanism during development.
Over recent years our understanding of the functions of the heparan sulphate (HS) family of complex polysaccharides has shifted dramatically. Once seen as simply structural scaffolding in the extracellular matrix, they are now viewed as critical players in the regulatory network of cells. They are strategically located at the cell surface and in the extracellular matrix, and there has been an increasing realization that specific sequences in the HS chains are designed for selective interactions with many proteins. Functionally, these interactions result in regulation of the protein activities. It is becoming clear that HS functions as a new class of multifunctional cell regulator. There is also growing evidence that cells can dynamically alter the structure of HS sequences that they express. Here we review recent developments and describe evidence for regulated changes in the synthesis and structure of HS chains expressed during early mouse brain development. The data suggest a new concept in which dynamic changes in biosynthesis of different HS sequences create distinct cellular HS repertoires, the heparanome. Their expression, in specific spatio-temporal patterns, is likely to endow organisms with novel regulatory mechanisms for controlling the activity of specific HS-binding proteins.
Animals↗
Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations.
Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.
Aged↗
Drooling in Parkinson's disease: a novel speech and language therapy intervention.
Drooling and difficulty swallowing saliva are commonly reported in people with Parkinson's disease (PD). Drooling in PD is the result of swallowing difficulties rather than excessive saliva production. Currently, there is little research into the effectiveness of treatments to reduce drooling. The aims of the study were to develop objective measures of saliva volume and drooling for PD and to assess the efficacy of two therapeutic strategies to control drooling, i.e. specific speech and language therapy (SLT) including a portable metronome brooch to cue swallowing and injections of botulinum toxin into both parotid glands to reduce the amount of saliva produced. This paper will describe the assessments used, including the measurement of saliva, swallowing and drooling. The main focus will be the strategies used in the SLT intervention. The preliminary results are presented.
Aged↗
A transducer based on enzyme-induced degradation of thin polymer films monitored by surface plasmon resonance.
A novel transducer based on the dissolution of biodegradable polymer films as a direct result of enzymatic reaction has been developed. Three polymers were investigated for use in the transducer: a poly(ester amide), which is degraded by the proteolytic enzyme alpha-chymotrypsin; a dextran hydrogel, which is degraded by dextranase; and poly(trimethylene) succinate, which is degraded by a lipase. Degradation of the polymer films was monitored by surface plasmon resonance (SPR) and impedance measurements. SPR was shown to be suitable for a greater variety of materials, since it does not require the polymer film to be electrically insulating. Rate of degradation was shown to be directly related to enzyme concentration for each polymer/enzyme couple. The poly(ester amide)/alpha-chymotrypsin couple proved to be the most sensitive. Degradation of the films was complete in less than 20 min for enzyme concentrations greater than 9 x 10(-9) mol dm-3. Enzyme concentrations as low as 4 x 10(-11) mol dm-3 were detected in less than 30 min. The transducer has great potential for the detection of enzyme concentrations as well as for use in immunosensing where the enzyme degrading the polymer would be the enzyme label.
Chymotrypsin↗
Mental health needs and services for severely troubled and troubling young people including young offenders in an N.H.S. region.
Penal, social services, special education and health agencies in one National Health Service Region were screened for severely troubled and troublesome young people in need of mental health services. One hundred and sixteen detailed assessments were undertaken on young people: 57 in "penal" and 59 in "welfare" establishments. Little difference was found between those in these two types of setting except that the "penal group" were much more likely to have high levels of violent behaviour and to have had more changes of placement. The needs for mental health care greatly outstripped supply. As part of this overall neglect, 11 of 15 young people with serious mental illnesses and all 13 who had suffered sexual abuse in the sample were not receiving appropriate treatment. A tentative estimate of the size of the problem in the region yielded a rate of around 11.4 per million with very severe disorder but this is probably an under estimate. The effectiveness of treatment for the problems of these young people is discussed and a possible structure for a service is explored.
Adolescent↗
Vascular endothelial growth factor in prostate cancer.
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Endothelial Growth Factors↗
Changes in viability and macromolecular content of long-term batch cultures of Salmonella typhimurium measured by flow cytometry.
Exposure of many Gram-negative bacteria to prolonged starvation induces alternative programmes of gene expression, along with a transition into a dormant condition sometimes referred to as a viable non-culturable (VBNC) state. Knowledge of how pathogenic species respond to nutrient limitation is therefore important for their detection and dissemination. This study used flow cytometry, coupled with fluorescent dyes for viability and macromolecular content, to study the responses of the pathogen Salmonella typhimurium to prolonged batch culture. Statistical analysis of the flow cytometric data, together with total and culturable cell counts, failed to demonstrate a VBNC state in this pathogen, contrary to reports from other workers. Analysis of rRNA and protein content identified a small proportion of cells in 110 day-old cultures that represented an active sub-population. This observation may provide an explanation for the long-term survival properties of this organism during prolonged exposure to nutrient limitation, as well as the high degree of heterogeneity observed in labelled cells.
Bacterial Proteins↗
A double-blind randomized controlled trial and economic evaluation of transurethral resection vs contact laser vaporization for benign prostatic enlargement: a 3-year follow-up.
OBJECTIVE: To evaluate the effect of contact laser prostate surgery in the treatment of benign prostatic hyperplasia. PATIENTS AND METHODS: A prospective double-blind randomized controlled trial of transurethral resection of the prostate (TURP) and contact laser prostatectomy was conducted, with an economic evaluation of both procedures. The primary outcome measure was the change in the American Urologic Association symptom score, with secondary outcome measures being the peak urinary flow rate, treatment-related complications, re-operation rate and health service costs. RESULTS: The perioperative blood loss and transfusion requirements were statistically significantly lower for laser prostatectomy than for TURP. There was no clinically significant difference between TURP and contact laser prostatectomy in the mean change in symptom scores and flow rates. There were distinct perioperative advantages in favour of the contact laser treatment, but some disadvantages in terms of re-catheterization and re-operation rates. CONCLUSIONS: Contact laser prostatectomy is a valid treatment for benign prostatic hypertrophy. The performance of contact laser prostatectomy as day-case surgery would have cost advantages to the National Health Service.
Aged↗
Elevated serum vascular endothelial growth factor in patients with hormone-escaped prostate cancer.
OBJECTIVE: To investigate the role of serum vascular endothelial growth factor (VEGF) in the assessment of patients with prostate cancer. Patients, subjects and methods Serum from 78 men was assayed for VEGF using a commercially available enzyme-linked immunosorbent assay kit. Forty-eight patients had a histopathological diagnosis of prostate cancer (16 local disease, 32 metastatic), nine had benign prostatic hyperplasia (BPH) and 21 were healthy controls. RESULTS: The mean serum VEGF level was significantly higher in patients with hormone-escaped prostate cancer than in all other groups (P </= 0. 02). There were no significant differences in serum VEGF levels among the other groups. In 18 patients with serial measurements there was no significant difference in serum VEGF level during either response to or escape from hormonal therapy. CONCLUSIONS: The significantly higher serum VEGF level in patients with hormone-escaped prostate cancer suggests a role in the pathogenesis of advanced disease. However, the lack of significant differences among the other groups and the failure to indicate either response to or escape from hormonal therapy suggests that serum VEGF in this setting is of limited use.
Aged↗
Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis.
OBJECTIVE: To determine whether angiogenesis can be used as an additional prognostic indicator in patients with stage 1 germ cell tumours of the testis. PATIENTS AND METHODS: Paraffin sections were assessed immunohistochemically from 51 patients with clinical stage 1 germ cell tumours of the testis (28 seminoma, 23 teratoma) treated by orchidectomy and surveillance only. Sections were analysed for microvascular density (MVD), and expression of the angiogenic factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). In addition, in the seminoma cases the presence of mRNA for the lymphangiogenic factor VEGF-C was examined by in situ hybridization, and its corresponding receptor VEGFR-3 by immunohistochemistry. RESULTS: Teratoma specimens had a significantly higher mean (range) MVD (85, 26-163; P < 0.01) than both seminoma (37, 16-91) and four normal specimens (26, 18-30). Teratoma specimens also had significantly higher VEGF expression than both seminoma and normal specimens (P < 0.01). Despite these differences between groups, and indeed individual tumours, there was no significant correlation between MVD and VEGF, or between either MVD or VEGF and relapse-free survival. TP expression was significantly greater in tumours than in normal specimens (P < 0.02) but with very little inter-tumour variation. VEGF-C mRNA and VEGFR-3 protein were detected in a third to a half of cases, with expression mostly around endothelial vessels. CONCLUSIONS: The marked differences between normal testis and tumours implicate angiogenesis in the biology of germ cell tumours of the testis. In addition, the detection of factors involved in lymphangiogenesis in some seminomas, tumours which initially metastasize primarily to lymph nodes, indicate that although not prognostic in this study, further studies are warranted in both these areas in the search for further prognostic indicators and therapeutic targets.
Adult↗
Suppressive effects of TNF-alpha, TGF-beta1, and chemokines on megakaryocytic colony formation in CD34+ cells derived from umbilical cord blood compared with mobilized peripheral blood and bone marrow.
CD34+ cells from human umbilical cord blood (CB) were isolated and investigated for megakaryocytic (MK) colony formation in response to recombinant human (rh) stimulatory and suppressive cytokines and compared with their counterparts in normal BM and G-CSF-mobilized peripheral blood (mPBL). First, we observed that IL-11 by itself at any dosage had no stimulator activity on MK colony formation derived from CD34+ cells in CB, mPBL, and BM. IL-3, steel factor (SLF), or thrombopoietin (Tpo) alone stimulated numbers of colony-forming unit-megakaryocyte (CFU-MK) in a dose-dependent fashion. Maximum growth of MK progenitor cells was noted in the presence of a combination of cytokines: IL-11, IL-3, SLF, and Tpo. The frequency of CFU-MK in CB and mPBL was significantly greater than that in BM, and the size of colonies in CB and mPBL was significantly greater than that in BM, and the size of colonies was larger as well. In addition, an increased number of big mixed colonies containing MK were observed in CB and mPBL. In the presence of IL-11, IL-3, SLF, and Tpo, CFU-MK derived from CB, mPBL, and BM was suppressed by tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1). CFU-MK derived from normal BM was inhibited by some chemokines evaluated, whereas CFU-MK derived from CB was suppressed only by platelet factor-4 (PF-4), IFN-inducible protein-10 (IP-10), Exodus-1, Exodus-2, and Exodus-3, but to a lesser degree. In CB, unlike granulocyte-macrophage (CFU-GM), erythroid (BFU-E), high-proliferative potential (HPP-CFC), or multipotential (CFU-GEMM) progenitors, at least a subpopulation of MK progenitors are in S-phase. Therefore, CB MK progenitors respond to the suppressive effects of some members of the chemokine family. Similar results were noted for burst-forming unit-MK (BFU-MK). Our results indicate that CB and mPBL are rich sources of MK progenitors and that MK progenitors in CB are responsive to the suppressive effects of TNF-alpha and TGF-beta1 and some members of the chemokine family.
Antigens, CD34↗
Graduated elastic compression stockings on a stroke unit: a feasibility study.
BACKGROUND: thrombo-embolic complications are important causes of morbidity and mortality after acute stroke. Anticoagulant prophylaxis is contraindicated in intracerebral haemorrhage and not recommended in acute ischaemic stroke because of increased risk of cerebral haemorrhage. Graduated elastic compression stockings are a simple alternative but are not widely used in stroke patients, perhaps because of perceived contraindications and problems with tolerability. OBJECTIVES: to establish the feasibility and tolerability of graduated compression stockings on a stroke unit. DESIGN: we assessed 112 consecutive stroke patients for contraindications to and tolerability of graduated compression stockings. MEASUREMENTS: we used clinical indices and ankle-brachial Doppler pressure measures to assess suitability. We prospectively assessed tolerability of the stockings. RESULTS: Ninety-four (84%) of the 112 patients had no contraindications to the use of the stockings. The most common contraindication was an ankle-brachial index of <0.8. Other contraindications were marked dependent leg oedema (1/18) and severe venous ulceration. Eighty-nine (95%) of the 94 patients tolerated the stockings and wore them until discharge. Skin irritation was the most common reason for intolerance. CONCLUSIONS: contraindications to the use of graduated compression stockings can be defined using clinical criteria and a Doppler machine to calculate an ankle-brachial pressure index. If this is done, tolerability is excellent. This approach may be a useful alternative in preventing venous thrombo-embolism in stroke patients.
Adult↗
Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion.
PURPOSE: To evaluate interleukin-6 (IL-6) levels in the conjunctival epithelium of patients with moderate to severe dry eye disease before and after treatment with cyclosporin A ophthalmic emulsion (CsA) or its vehicle. METHODS: Conjunctival cytology specimens were obtained from a subset of patients enrolled in a 6-month randomized, double-masked clinical trial of the efficacy and safety of topical CsA at baseline and after 3 and 6 months of B.I.D. treatment with 0.05% cyclosporine emulsion (n = 13), 0.1% cyclosporine emulsion (n = 8), or vehicle (n = 10). RNA was extracted and a competitive reverse transcriptase polymerase chain reaction (RT-PCR) was used to evaluate the levels of mRNA encoding the inflammatory cytokine IL-6 and a housekeeping gene, G3PDH. Levels of IL-6 and G3PDH were measured and compared. RESULTS: There was no change from baseline in the level of G3PDH after 3 or 6 months in any group. IL-6 normalized for G3PDH (IL-6/G3PDH ratio) was not different from baseline at 3 months but showed a significant decrease from baseline in the group treated with 0.05% CsA (p = 0.048) at 6 months. No significant between-group differences were noted and no correlation was observed between the change in IL-6/G3PDH and corneal fluorescein staining. CONCLUSIONS: This preliminary, small-cohort study showed a decrease in IL-6 in the conjunctival epithelium of moderate to severe dry eye patients treated with 0.05% CsA for 6 months. The observed decrease suggests that dry eye disease involves immune-mediated inflammatory processes that may be decreased by treatment with topical ophthalmic cyclosporine.
Administration, Topical↗
Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies.
Hedonistic homeostatic dysregulation is a neuropsychological behavioural disorder associated with substance misuse and addiction. The disorder has been recognised as a consequence of dopamine replacement therapy (DRT) in 15 patients with Parkinson's disease. The syndrome typically develops in male patients with early onset Parkinson's disease, and can occur with orally and subcutaneously administered DRT. These patients take increasing quantities of their DRT, despite increasingly severe drug induced dyskinesias, and may develop a cyclical mood disorder with hypomania or manic psychosis. There is impairment of social and occupational functioning. Tolerance develops to mood elevating effects of DRT and a negative affective withdrawal state occurs if the drugs are withdrawn or doses decreased. The clinical features and guidelines for managing this syndrome are discussed. A set of diagnostic criteria for further investigating this condition is proposed.
Adult↗