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Biomedical subjects

R Bell

Publications and source records attributed to R Bell.

At least 19 recordsLinked to original sources
PubMed2003

Ketamine as an adjuvant to opioids for cancer pain.

BACKGROUND: Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of cancer pain, particularly when opioids alone prove to be ineffective. Ketamine is known to have hallucinogenic side effects. To date no systematic review of the benefits and harms of adjuvant ketamine for cancer pain has been undertaken. OBJECTIVES: To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids in the treatment of cancer pain. SEARCH STRATEGY: Studies were identified from MEDLINE (1966-2001), EMBASE (1980-2001), CancerLit (1966-2001), the Cochrane Library (Issue 1, 2001); by handsearching reference lists from review articles, trials, and chapters from standard textbooks on pain and palliative care. The manufacturer of ketamine (Pfizer Parke-Davis) provided search results from their in-house database, PARDLARS. SELECTION CRITERIA: RCTs of adult patients with cancer and pain being treated with an opioid, and receiving either ketamine (any dose and any route of administration) or placebo or an active control. DATA COLLECTION AND ANALYSIS: Two independent reviewers identified four RCTs for possible inclusion in the review, and 32 case studies/case series reports. Quality and validity assessment was performed by three independent reviewers, and two RCTs were excluded because of inappropriate study design. Patient reported pain intensity and pain relief was assessed using visual analog scales, verbal rating scales or other validated scales, and adverse effects data were collated. MAIN RESULTS: Two trials were eligible for inclusion in the review and both concluded that ketamine improves the effectiveness of morphine in the treatment of cancer pain. However, pooling of the data was not appropriate because of the small total number of patients (30), and the presence of clinical heterogeneity. Some patients experienced hallucinations on both ketamine plus morphine and morphine alone and were treated successfully with diazepam. No other serious adverse effects were reported. REVIEWER'S CONCLUSIONS: Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More randomized controlled trials are needed.

Adult↗
PubMed2002

The effects of vigorous exercise during pregnancy on birth weight.

Whether or not vigorous exercise during pregnancy affects birth weight is an important issue because birth weight is the single most important determinant of neonatal mortality. A current meta-analysis of randomised trials of exercise during pregnancy did not find, although also did not exclude, a clinically important effect of exercise on birth weight. Randomised trials may miss the women exercising at the most elite levels during pregnancy. We should remain open-minded on this issue until sufficient evidence is available on which to base recommendations.

Birth Weight↗
PubMed2002

Characterization of film-coated aerosol canisters using electrochemical impedance spectroscopy.

Drug adhesion to the walls of an aerosol canister can be prevented/reduced by coating the canister with a hydrophobic polymer (e.g., a fluoropolymer). In this study, three batches of fluoropolymer-coated canisters were investigated by electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). The EIS technique showed that only one of the batches presented as a monolithic, non-porous film. The other two batches were either partially porous or highly porous. Scanning electron micrographs showed evidence of cracks, within the films, but could not alone establish the porous nature of these defects. For the non-porous and partly porous films it was possible to use the EIS data to determine the approximate film thickness. Estimates of 2-4 microm were obtained for the mean film thickness. These values compared favorably with micrometer estimates obtained following acid dissolution of the aluminum canister. It remains to be seen whether the properties of the films (i.e., the porosity and film thickness, determined by EIS) translate to differences in drug adhesion. Nevertheless, the EIS technique was shown to be a powerful, non-destructive method that lends itself to the rapid analysis of batch-to-batch variation in film-coated canisters.

Aerosols↗
PubMed2002

Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24.

INTRODUCTION: Lymphoedema-distichiasis syndrome (LD) (OMIM 153400) is a rare, primary lymphoedema of pubertal onset, associated with distichiasis. Causative mutations have now been described in FOXC2, a forkhead transcription factor gene. Numerous clinical associations have been reported with this condition, including congenital heart disease, ptosis, varicose veins, cleft palate, and spinal extradural cysts. SUBJECTS: We report clinical findings in 74 affected subjects from 18 families and six isolated cases. All of them were shown to have mutations in FOXC2 with the exception of one family who had two affected subjects with lymphoedema and distichiasis and linkage consistent with the 16q24 locus. RESULTS: The presence of lymphoedema was highly penetrant. Males had an earlier onset of lymphoedema and a significantly increased risk of complications. Lymphatic imaging confirmed the earlier suggestion that LD is associated with a normal or increased number of lymphatic vessels rather than the hypoplasia or aplasia seen in other forms of primary lymphoedema. Distichiasis was 94.2% penetrant, but not always symptomatic. Associated findings included ptosis (31%), congenital heart disease (6.8%), and cleft palate (4%). Other than distichiasis, the most commonly occurring anomaly was varicose veins of early onset (49%). This has not been previously reported and suggests a possible developmental role for FOXC2 in both venous and lymphatic systems. This is the first gene that has been implicated in the aetiology of varicose veins. CONCLUSION: Unlike previous publications, the thorough clinical characterisation of our patients permits more accurate prediction of various phenotypic abnormalities likely to manifest in subjects with FOXC2 mutations.

Abnormalities, Multiple↗
PubMed2002

Eosinophilic granuloma. A different behaviour in children than in adults.

Localised Langerhans-cell histiocytosis of bone (eosinophilic granuloma) is a benign tumour-like condition with a variable clinical course. Different forms of treatment have been reported to give satisfactory results. However, previous series all contain patients with a wide age range. Our aim was to investigate the effect of skeletal maturity on the rate of recurrence of isolated eosinophilic granuloma of bone excluding those arising in the spine. We followed up 32 patients with an isolated eosinophilic granuloma for a mean of five years; 17 were skeletally immature. No recurrences were noted in the skeletally immature group even after biopsy alone. By contrast, four of 13 skeletally mature patients had a recurrence and required further surgery. This suggests that eosinophilic granuloma has a low rate of recurrence in skeletally immature patients.

Adolescent↗
PubMed2002

Preliminary indication of a high prevalence of polycystic ovary syndrome in indigenous Australian women.

We aimed to estimate the likely prevalence of polycystic ovary syndrome (PCOS) in indigenous Australian women in a cross-sectional survey based on structured interviews. In the Kimberley region of Western Australia and south-western Victoria, between February and June 1999, women over the age of 18 available for interview and willing to participate were included. Menstrual status, anthropometric measures, fasting blood biochemistry and hirsutism were assessed. A total of 38 premenopausal women completed the survey. Of these, 50% had regular menstrual cycles of normal duration and no hirsutism; seven had oligomenorrhea and hirsutism/hyperandrogenemia; and of the nine women with hirsutism and regular menses, three had hyperandrogenemia. Thus, possibly ten women fulfilled the criteria of PCOS. This unique data set suggests a high prevalence of PCOS in indigenous Australian women. Further research to document this formally is warranted, in view of the potential adverse effects of PCOS on reproduction and metabolism.

Adult↗
PubMed2001

Rational design of diflunisal analogues with reduced affinity for human serum albumin.

Many lead compounds bind to serum albumin and exhibit markedly reduced efficacy in vivo as compared to their potency in vitro. To aid in the design of compounds with reduced albumin binding, we performed nuclear magnetic resonance (NMR) structural and binding studies on the complex between domain III of human serum albumin (HSA-III) and diflunisal, a cyclooxygenase inhibitor with antiinflammatory activity. The structural studies indicate that the aromatic rings of diflunisal are involved in extensive and specific interactions with hydrophobic residues that comprise the binding pocket in subdomain IIIA. The carboxylic acid of diflunisal forms electrostatic interactions with the protein similar to those observed in the X-ray structure of HSA complexed to myristic acid. In addition to the structural studies, NMR-derived binding constants were obtained for diflunisal and closely related analogues to develop a structure-affinity relationship for binding to subdomain IIIA. On the basis of the structural and binding data, compounds were synthesized that exhibit more than a 100-fold reduction in binding to domain III of HSA, and nearly a 10-fold reduction in affinity for full length albumin. Significantly, several of these compounds maintain activity against cyclooxygenase-2. These results suggest a rational strategy for designing out albumin binding in potential drug molecules by using structure-based design in conjunction with NMR-based screening.

Amino Acid Sequence↗
PubMed2001

Observation of compressional Alfvén modes during neutral-beam heating on the national spherical torus experiment.

Neutral-beam-driven compressional Alfvén eigenmodes at frequencies below the ion cyclotron frequency have been observed and identified for the first time in the National Spherical Torus Experiment. The modes are observed as a broad spectrum of nearly equally spaced peaks in the frequency range from approximately 0.2omega(ci) to approximately 1.2omega(ci). The frequency has a scaling with toroidal field and plasma density consistent with Alfvén waves. The modes have been observed with high bandwidth magnetic pickup coils and with a reflectometer.

Journal Article↗
PubMed2001

Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials.

PURPOSE: Two identical, concurrent, parallel, multicenter, randomized, double-blind, double-dummy trials were conducted to compare the efficacy and safety of zoledronic acid and pamidronate for treating hypercalcemia of malignancy (HCM). PATIENTS AND METHODS: Patients with moderate to severe HCM (corrected serum calcium [CSC] > or = 3.00 mmol/L [12.0 mg/dL]) were treated with a single dose of zoledronic acid (4 or 8 mg) via 5-minute infusion or pamidronate (90 mg) via 2-hour infusion. A protocol-specified pooled analysis of the two parallel trials was performed. Clinical end points included rate of complete response by day 10, response duration, and time to relapse. RESULTS: Two hundred eighty-seven patients were randomized and evaluated for safety; 275 were evaluated for efficacy. Both doses of zoledronic acid were superior to pamidronate in the treatment of HCM. The complete response rates by day 10 were 88.4% (P = .002), 86.7% (P = .015), and 69.7% for zoledronic acid 4 mg and 8 mg and pamidronate 90 mg, respectively. Normalization of CSC occurred by day 4 in approximately 50% of patients treated with zoledronic acid and in only 33.3% of the pamidronate-treated patients. The median duration of complete response favored zoledronic acid 4 and 8 mg over pamidronate 90 mg with response durations of 32, 43, and 18 days, respectively. CONCLUSION: Zoledronic acid is superior to pamidronate; 4 mg is the dose recommended for initial treatment of HCM and 8 mg for relapsed or refractory hypercalcemia.

Adult↗
PubMed2001

Analysis of lymphoedema-distichiasis families for FOXC2 mutations reveals small insertions and deletions throughout the gene.

Lymphoedema-distichiasis (LD) is a dominantly inherited form of primary lymphoedema with onset of lower limb swelling at puberty or later. There is variable penetrance of this disorder, but the most consistently inherited feature is distichiasis, viz. fine hairs arising inappropriately from the meibomian glands. We established linkage of this disorder to 16q24.3 and the gene has recently been identified as the forkhead transcription factor FOXC2. We report the mutational analysis of 14 families with LD. All but one of these pedigrees have small insertions or deletions in the gene, which seem likely to produce haploinsufficiency. The mutation sites are scattered throughout the gene. There is one family with a mis-sense mutation in the forkhead domain of the protein. This base alteration is not a common polymorphism, is co-inherited with the disease and produces a non-conservative amino acid change.

DNA↗
PubMed2001

Evaluation of community mental health services: comparison of a primary care mental health team and an extended day hospital service.

Alongside mental health policies emphasising the need to focus on people experiencing serious, long-term problems, recent general healthcare policy is leading to the development in the UK of a primary care-led National Health Service. While most primary care-led mental health initiatives have focused on supporting general practitioners (GPs) in managing milder depression and anxiety, this article describes an evaluation comparing primary care-based and secondary care-based services for people with serious long-term problems. A survey of service users was carried out at three points in time using three measures: the Camberwell Assessment of Need, the Verona Satisfaction with Services Scales and the Lancashire Quality of Life Profile. Staff views were sought at two time intervals and carers' views were obtained towards the end of the 2-year study period. The results indicate that both services reduced overall needs and the users' need for information. The primary care service also reduced the need for help with psychotic symptoms whereas the secondary care service reduced users' need for help with benefits and occupation. There were no major differences in terms of satisfaction or quality of life. Primary care-based services therefore appear to have the potential to be as effective as more traditional secondary care services. However, a more comprehensive range of services is required to address the whole spectrum of needs, a conclusion supported by the views of staff and carers.

Adolescent↗
PubMed2001

How reliable are reported plasma clozapine levels?

OBJECTIVE: Many practitioners use plasma levels to determine the optimum dosage of clozapine. The aim of this study was to determine the intra- and interlaboratory accuracy in assaying samples of clozapine dissolved in human plasma. METHOD: Three samples were sent to one laboratory to obtain an initial determination of accuracy (phase I). Then samples of clozapine dissolved in human plasma were prepared at concentrations of 140, 310 and 580 ng/mL and dispatched on dry ice to 10 assaying centres in Australia and New Zealand. The results of the survey were analysed and posted to each centre (phase II). The programme was repeated using concentrations of 160, 380 and 640 ng/mL (phase III). Samples prepared in purified water and freeze-dried samples were also dispatched. RESULTS: In phase II there were two centres with results significantly different from the mean. In phase III all the centres returned concordant results. There was a high level of consistency in the measurement of samples with a maximum coefficient of variation of 0.16. The concentrations determined by the centres, however, were significantly lower than the nominal concentrations of the prepared solutions. CONCLUSIONS: Clinicians in Australia and New Zealand who wish to know their patients' plasma-clozapine levels can be confident that the result of the assay is unlikely to vary with the choice of centre or the operator who performs the assay.

Analysis of Variance↗
PubMed2001

Two families with blepharophimosis/ptosis/epicanthus inversus syndrome have mutations in the putative forkhead transcription factor FOXL2.

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) is an autosomal dominant disorder that is characterized by distinctive eyelid abnormalities. Two clinical subtypes have been described in which type I, but not type II, is associated with premature ovarian failure. Both types of BPES are linked to 3q22-23, and the gene has recently been identified as the putative forkhead transcription factor FOXL2. We report mutation screening of FOXL2 in two families with this condition. The two mutations detected were frameshift mutations resulting from a small insertion or duplication within the gene. Both mutations would result in the production of novel carboxyl terminii, one terminating the predicted protein earlier than the wild type, and the other giving rise to a larger protein product, assuming these proteins or their mRNA were not degraded. Based on the present data, this would suggest that the first family should be type I and the second, type II. Although there is evidence of infertility in the first family, all 3 females in the youngest generation have normal pelvic ultrasound and hormone levels, suggesting that the divide between types I and II may not be as distinct as has been suggested.

Blepharophimosis↗
PubMed2001

Ongoing trials with trastuzumab in metastatic breast cancer.

Following the pivotal clinical trials of trastuzumab (Herceptin), further phase II and III studies have been initiated. Preliminary results from a phase II, dose-response study of single-agent trastuzumab in 113 HER2-positive metastatic breast cancer patients without prior chemotherapy for stage IV disease have shown that the overall response rate was 23% (six complete responses and 20 partial responses), with similar results using both standard- and high-dose regimens of trastuzumab. Another phase II study of trastuzumab plus paclitaxel, both given weekly, in 63 HER2-positive and -negative patients with metastatic breast cancer produced an overall response rate of 62% in HER2-positive and 44% in HER2-negative patients. A further phase II study is underway to investigate the combination of trastuzumab plus docetaxel in 30 HER2-positive patients with metastatic breast cancer. Finally, a number of European studies are at an advanced stage of planning or are about to start patient recruitment. These include docetaxel +/- trastuzumab, aromatase inhibitor +/- trastuzumab, CMF (cyclophosphamide, methotrexate, 5-fluorouracil) +/- trastuzumab, vinorelbine + trastuzumab, all in HER2-positive patients, and epirubicin-cyclophosphamide (EC) + trastuzumab in HER2-positive patients vs. EC alone in HER2-negative patients. The results from these trials should be available over the next one to two years.

Antibiotics, Antineoplastic↗
PubMed2001

Duration of therapy in metastatic breast cancer: management using Herceptin.

Despite progressive developments in therapeutic interventions, including surgery, radiotherapy and chemotherapy, there has been no major improvement in the survival of women with metastatic breast cancer (MBC). Based on knowledge of tumor growth patterns, approaches addressing this issue have included increasing chemotherapy dose or dose density and extending the duration of therapy. However, only the latter approach has resulted in improved clinical benefit, although not survival; and its use is restricted by the cumulative toxicity of chemotherapeutic agents. Therefore, the best hope for improved survival lies with new classes of anticancer drug and particularly biological agents. This review focuses on the first oncogene-targeted therapy for human epidermal growth factor receptor-2 (HER2)+ MBC patients. The humanized anti-HER2 monoclonal antibody Herceptin has proven clinical benefits in HER2+ MBC patients, most importantly improved survival, and is rapidly becoming a standard of care for these patients. In contrast to the fixed number of cycles used for chemotherapeutic agents, Herceptin is administered until disease progression, with some data suggesting that continuation beyond disease progression should be investigated. The preclinical and clinical findings on which the current recommended duration of Herceptin therapy are based are reviewed and alternative strategies are discussed.

Antibodies, Monoclonal↗