Biomedical subjects

B A Bell

Publications and source records attributed to B A Bell.

At least 19 recordsLinked to original sources

PubMed2004

A comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children's Oncology Group).

INTRODUCTION: Mercaptopurine is an important antimetabolite for treatment of childhood acute lymphoblastic leukemia (ALL). It has been prescribed to be given daily without therapeutic monitoring of drug levels. After first-pass metabolism by hepatic xanthine oxidase (XO), mercaptopurine is converted into two major intracellular metabolites, thioguanine nucleotide (TGN) and methylated mercaptopurine metabolites (including methylated thioinosine nucleotides), which are cytotoxic in vitro. Its short plasma half-life and S-phase-dependent pharmacokinetics suggest that biologically active concentration and exposure duration may be critical to cell kill. METHODS: Pediatric Oncology Group (POG) 9605, a randomized, open label phase III study of standard-risk ALL, was designed to compare daily with twice-daily mercaptopurine during continuation therapy. Red blood cell (RBC) TGN and methylated mercaptopurine metabolite levels were measured as surrogates of leukemic cell levels in a randomly selected subset of patients. TGN and methylated mercaptopurine metabolites were analyzed quantitatively by high-performance liquid chromatography (HPLC) and reported in ng/8 x 10.8 RBC. Statistical inferences utilized multiple linear regression. RESULTS: One hundred eighteen patients received mercaptopurine 75 mg/m(2) daily and 108 received 37.5 mg/m(2)/dose twice daily. Descriptive statistics for the daily group showed the median TGN was 42 ng (mean and standard deviation [SD] = 48 +/- 35, quartiles 29-64). For the twice daily group, it was 40 ng (mean and SD = 40 +/- 27, quartiles 26-53). For methylated mercaptopurine metabolites, the daily group median was 2,020 ng (mean and SD = 2,278 +/- 1,559, quartiles 1,247-3,162); the twice daily group median was 1,275 ng (mean and SD = 1,580 +/- 1,240, quartiles 599-2,369). When adjusted for the covariables: actual dosage, days on study, age at diagnosis, white blood cell count, gender, Black race compared with not, and Hispanic compared with not, daily dosing resulted in significantly higher average methylated mercaptopurine metabolites by 668 (standard error [SE] = 179, P = 0.001) and a trend toward higher average TGNs by 6.2 (SE = 4.2, P = 0.14). CONCLUSIONS: Daily dosing of mercaptopurine resulted in higher mean red cell methylated mercaptopurine metabolites when compared to split (twice a day dosing). The data were inconclusive with respect to TGNs. The relationships of methylated mercaptopurine metabolites and TGNs to clinical outcomes will be elucidated as part of the maturing 9605 data.

Administration, Oral↗

PubMed2004

Deep brain stimulation of the subthalamic nucleus in Parkinson's disease 1993-2003: where are we 10 years on?

Since its advent in 1993, high frequency stimulation (HFS) of the subthalamic nucleus (STN) has rapidly developed into the most commonly practiced surgical procedure for the treatment of Parkinson's Disease (PD). Although its exact mechanism of action, be it through an inhibitory depolarization block, desynchronization of neuronal circuits or other means, is not clear, the efficacy and safety of the technique are now well established. HFS of the STN improves the motor function by at least 60%, drastically reduces the levodopa requirement and significantly improves the quality of life in PD. This review updates the recent concepts on the pathophysiology of PD and analyses the basic science principles underlying the clinical practice of the STN HFS. The evolution of the surgical technique and long-term patients' outcome are further discussed.

Antiparkinson Agents↗

PubMed2003

Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy.

Proton spectroscopy can noninvasively provide useful information on brain tumor type and grade. Short- (30 ms) and long- (136 ms) echo time (TE) (1)H spectra were acquired from normal white matter (NWM), meningiomas, grade II astrocytomas, anaplastic astrocytomas, glioblastomas, and metastases. Very low myo-Inositol ([mI]) and creatine ([Cr]) were characteristic of meningiomas, and high [mI] characteristic of grade II astrocytomas. Tumor choline ([Cho]) was greater than NWM and increased with grade for grade II and anaplastic astrocytomas, but was highly variable for glioblastomas. Higher [Cho] and [Cr] correlated with low lipid and lactate (P < 0.05), indicating a dilution of metabolite concentrations due to necrosis in high-grade tumors. Metabolite peak area ratios showed no correlation with lipids and mI/Cho (at TE = 30 ms), and Cr/Cho (at TE = 136 ms) best correlated with tumor grade. The quantified lipid, macromolecule, and lactate levels increased with grade of tumor, consistent with progression from hypoxia to necrosis. Quantification of lipids and macromolecules at short TE provided a good marker for tumor grade, and a scatter plot of the sum of alanine, lactate, and delta 1.3 lipid signals vs. mI/Cho provided a simple way to separate most tumors by type and grade.

Alanine↗

PubMed2003

Detection of elevated glutathione in meningiomas by quantitative in vivo 1H MRS.

Glutathione has major roles in removing free radicals and toxins from normal tissues, but its presence in tumor cells hinders the effectiveness of many anticancer therapies. Analysis of short echo time brain tumor (1)H spectra at 1.5 T using a linear combination of metabolite spectra (LCModel) suggested a significant contribution of glutathione to meningioma spectra. By in vivo MRS (TE = 30 ms, TR = 2020 ms), reduced glutathione was found to be significantly elevated in meningiomas (3.3 +/- 1.5 mM, Mann Whitney, P < 0.005) compared to normal white matter (1.2 +/- 0.15 mM) and low-grade gliomas (1.0 +/- 0.26 mM), in agreement with published histofluorescence studies of tumor biopsies. Glx concentrations were also found to be elevated in meningiomas compared to astrocytomas or normal white matter, indicative of metabolic differences. The ability to noninvasively quantify reduced glutathione in vivo may aid selection of treatment therapies and also provide an indication of tumor aggressiveness.

Astrocytoma↗

PubMed2003

Association between surgeon seniority and outcome in intracranial aneurysm surgery.

Specialist surgical registrars perform surgery as a requirement of their training, but the effect of the surgeon's level of training on outcome in intracranial aneurysm surgery is not known. This study addresses this question. A cohort of 278 consecutive patients who underwent a craniotomy to clip a recently ruptured intracranial aneurysm between January 1995 and December 1999 was assessed. Patients were divided into three groups according to whether the operating surgeon was a registrar, a senior registrar or a consultant. The frequency of a good outcome (defined as a Glasgow outcome score of 5) was compared in the three groups. Registrars operated on 91 patients (33%), senior registrars on 60 (21%) and consultants on 127 (46%). Between the three groups there was no statistically significant difference in patient age, male: female ratio, the timing of surgery after the haemorrhage, or the proportion of patients requiring preoperative ventriculostomy or with angiographic vasospasm, but more patients operated on by consultants had favourable admission World Federation of Neurological Surgeons grades. About two-thirds of patients achieved a Glasgow outcome score of 5 at 6 months, and there were no statistically significant differences in outcome between the three groups at discharge, at 6 months and at 1 year. Intracranial aneurysm surgery by trainees and consultants was not associated with differences in patient outcome in a cohort of patients treated at a University teaching hospital.

Clinical Competence↗

PubMed2002

Increased aquaporin 1 water channel expression in human brain tumours.

Aquaporin 1 is a water channel protein. There was little aquaporin 1 immunoreactivity in normal brain parenchyma. In astrocytomas, aquaporin 1 was expressed in microvessel endothelia and neoplastic astrocytes. In metastatic carcinomas, aquaporin 1 was present in microvessel endothelia and reactive astrocytes. Aquaporin 1 may participate in the formation of brain tumour oedema.

Adenocarcinoma↗

PubMed2002

The contribution of proton magnetic resonance spectroscopy (1HMRS) to clinical brain tumour diagnosis.

Proton magnetic resonance spectroscopy (1HMRS) provides biochemical information from tissue non-invasively, and has an evolving role in brain tumour diagnosis and management. We present 100 consecutive patients with brain tumours who had single voxel 1HMRS as part of their preoperative investigations. We report the histopathological findings and the diagnostic contribution of spectroscopy in an adjunctive role. On the basis of clinical and radiological information the preoperative diagnosis was unclear or inaccurate in 26 out of 100 cases. The discrepancy was of lesion grade in 17 cases and lesion type in 9 cases. In 6 of 100 patients with brain tumours 1HMRS could have made a significant contribution to the preoperative diagnosis if used as part of the routine assessment. There is therefore a useful role for 1HMRS in the evaluation of intracranial mass lesions.

Adolescent↗

PubMed2002

Neuropathological diagnostic accuracy.

This study investigated variations in neuropathological diagnosis when histopathological slides are evaluated with access to all information pertinent to a case, compared with evaluation of H & E stained slides with only limited clinical information. The aim of the study is to evaluate the role of 'local' factors in reaching a definitive, neuropathological diagnosis. Each of 227 cases was reviewed by the local neuropathologist at one of three European centres with access to all clinical, radiological and histopathological data. Each case was also reviewed by a second, independent neuropathologist at another European unit, who was blinded to the local pathologist's diagnosis, and only had access to the age and sex of the patient and the location of the lesion. For the histopathological evaluation, initially he had access to H & E and GFAP stains only. Diagnoses were made using the WHO 2000 classification system and the two evaluations were classified into one of the following four categories: complete agreement; minor disagreement (not affecting treatment); minor disagreement (affecting treatment); complete disagreement. In 175 (77.1%) cases there was complete agreement between the two neuropathologists and in 18 (7.9%) cases there were non-treatment altering discrepancies in the diagnoses. Overall, there was disagreement which might potentially affect treatment in 34 (15%) of the cases. Histopathological diagnosis of the majority (85%) of brain tumours is accurate and uniform. However, histopathology is subject to a degree of interpretation. The availability of full, 'local', clinical information may be of considerable importance to the diagnostic process.

Biopsy↗

PubMed2002

Aquaporin-4 expression is increased in oedematous human brain tumours.

Aquaporin-4 (AQP4) is a highly conserved water channel protein. In rats, AQP4 is expressed in astrocyte foot processes and is important in brain water homeostasis. AQP4 expression has not been investigated in non-neoplastic human brain or oedematous brain tumours, where water homeostasis is disrupted. Therefore, immunohistochemistry was used to study AQP4 expression in non-neoplastic and neoplastic human brain and blood-brain barrier permeability was assessed using contrast enhanced computed tomograms. AQP4 was present around microvessels in five specimens of non-neoplastic brain and five low grade (Daumas-Duport I or II) astrocytomas. AQP4 was massively upregulated in four and absent in one high grade (Daumas-Duport III or IV) astrocytoma. Massive upregulation of AQP4 was also found in reactive astrocytes in five metastatic adenocarcinomas. There was significant (p<0.0001) correlation between blood-brain barrier opening and upregulated AQP4 expression. Increased AQP4 expression in high grade astrocytomas and adenocarcinomas may facilitate the flow of oedema fluid.

Adenocarcinoma↗

PubMed2001

A phase II study of Homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study.

BACKGROUND: Homoharringtonine (HHT) is a plant alkaloid that is derived from a Chinese evergreen tree. Its mechanism of action is thought to be by inhibition of protein, DNA, and RNA synthesis by inhibition of chain initiation. The treatment of acute myelogenous leukemia (AML) in children, has been hampered by few new effective agents developed in the past 30 years. Significant numbers of children still die of this disease. The purpose of this study is to evaluate the efficacy and toxicity of HHT for the therapy of refractory AML in children. PROCEDURE: Patients entered the study and were treated with HHT 7mg/m(2)/day for 10 days. The cycles could be repeated every 21 days depending on recovery from myelosuppression. RESULTS: Thirty-seven patients entered the study, with twenty-eight evaluable for response. Complete response was obtained in four and a partial response in one (response rate 5/28 = 18%). Significant toxicities included prolonged severe myelosuppression in all responsive patients and neuropathogenic pain in two patients. The median duration of response was 62 days with a range of 28-126 days. CONCLUSIONS: HHT has activity against chemotherapy resistant AML in children, with tolerable toxicity. This agent warrants further clinical evaluation in combination with other agents or perhaps biologic response modifiers which will hopefully lead to useful therapeutic options. Med Pediatr Oncol 2001;37:103-107.

Adolescent↗

PubMed2001

Occludin expression in microvessels of neoplastic and non-neoplastic human brain.

The tight junction protein occludin 'glues' normal, adjacent brain microvessel endothelial cells together. Malignant brain tumours cause cerebral oedema because they have leaky endothelial tight junctions, which allow plasma fluid to enter the brain from the microvessel lumen. In order to identify molecular abnormalities in tumour endothelial tight junctions, we investigated occludin expression in microvessels from adult human non-neoplastic brain tissue using immunohistochemistry and immunoblotting. The proportions of microvessels immunolabelling for occludin were >2/3 in 5/5 non-neoplastic brain tissue samples, >1/3 in 5/5 low grade (Daumas-Duport I or II) astrocytomas and <1/3 in 5/5 high grade (III or IV) astrocytomas and 6/6 metastatic adenocarcinomas. Six non-neoplastic brain tissue immunoblots gave a 55-kDa occludin band, three low-grade astrocytomas gave 55-kDa and 60-kDa bands, 13 high-grade astrocytomas gave 60-kDa or no band and four adenocarcinomas did not give an occludin band. Expression of 55-kDa occludin inversely correlated with the presence of contrast enhancement on computed tomograms (P < 0.001). Electron microscopy showed open endothelial tight junctions in 0/2 non-neoplastic human brain specimens and 2/2 high-grade astrocytomas. We suggest that loss of 55-kDa occludin expression in human brain tumours may contribute to endothelial tight junction opening. Characterizing the molecular pathology of brain endothelial tight junctions may facilitate the design of novel drugs against cerebral oedema.

Adenocarcinoma↗

PubMed2001

Emerging molecular mechanisms of brain tumour oedema.

A common property of brain tumours is their ability to cause oedema in the surrounding brain. Oedema forms as a result of a leaky blood-tumour barrier and persists when the brain fails to clear the excess fluid. It is a significant source of morbidity and mortality. The principal anatomical component of the blood-brain barrier is the endothelial tight junction which opens in glioma microvessels. Multiple tight junction proteins have recently been identified, such as occludin, claudin, ZO-1, ZO-2 and ZO-3. We propose a model to explain tight junction opening in gliomas based on vascular endothelial growth factor secretion and loss of tight junction inducing factor production by tumour cells. The level of expression of the water channel aquaporin-4 in peritumoural astrocytes may determine the rate of oedema fluid clearance. The identification of the molecular mechanisms of brain tumour oedema may allow the design of novel anti-oedema medications.

Animals↗

PubMed2001

Crisis in resources: a neurosurgical prospective.

In the light of the recent recommendations of the Society of British Neurological Surgeons on safe neurosurgery, we prospectively audited the work load, availability and efficiency in the use of neurosurgical resources in our department over a 1-month period. There were a total of 130 admissions--70 emergency and 60 elective cases. Twenty-three patients referred as emergencies were denied admission, directly or indirectly, because of shortage of beds. Other emergency cases had to wait unacceptable long periods, up to 17 days, prior to admission for the same reason. For elective cases, there was a 33% cancellation rate due to lack of beds and competition with the emergency cases for the same resources. Overall bed occupancy rate exceeded 100%. We conclude that the current neurosurgical resources are inadequate and over-stretched leaving no safety margin. Neurosurgery as a core emergency service, therefore, should be given priority in NHS resource allocation.

Bed Occupancy↗

PubMed2001

Is the National Health Service at the edge of chaos?

We used chaos and complexity theory to analyse waiting-list data (1998-2001) pertaining to over 20 000 National Health Service (NHS) patients from general surgical, orthopaedic and neurosurgical units across England. Plots of frequency versus quarter-to-quarter change in waiting times revealed a power relation which seems independent of surgical specialty and hospital location. One interpretation of these findings is that, for the period in question, the NHS was a system at the edge of chaos. This hypothesis might explain why waiting times have resisted attempts at shortening.

Ambulatory Care↗

PubMed2000

Cerebral trypsinogen expression in human and rat cerebrospinal fluid.

Trypsinogen was identified in cerebrospinal fluid (CSF), where it has not previously been reported and its activation state in experimental subarachnoid haemorrhage (SAH) in rats and in neurosurgical patients was determined. Trypsinogen activation peptide (TAP) release provided an equimolar marker for trypsinogen. Total TAP was significantly reduced to 26% of the baseline level (P<0.02) following experimental SAH in 15 rats but not in ten sham operated controls (P=0.3). TAP was also measured in patients with ruptured (n=11) and unruptured (n=9) aneurysms who underwent craniotomy to clip an aneurysm. Postoperatively there was a significant fall in TAP concentration (P<0.005) in both groups. Trypsinogen, as identified by CSF levels of TAP, is activated by SAH in rats and by craniotomy for aneurysmal clipping in patients.

Animals↗

PubMed2000

An introduction to the changes in gene expression that occur after cerebral ischaemia.

Ischaemia is the final common pathway of brain cell death following a variety of insults. We consider the effect of cerebral ischaemia on gene expression, concentrating on immediate early genes, those encoding heat shock proteins, growth factors, cytokines, adhesion molecules, nitric oxide synthase and proteins involved in programmed cell death. We conclude that the changes in gene expression resulting from ischaemia are important determinants of neuronal and glial survival. In the future it may become possible to manipulate gene expression to limit the extent of damage arising from cerebral ischaemia.

Brain Ischemia↗

PubMed2000

Principles of gene therapy: potential applications in the treatment of cerebral ischaemia.

In this review we explore gene therapy as a possible treatment for conditions causing cerebral ischaemia and briefly consider other neurological pathologies such as brain tumours. DNA transfer may be achieved using retrovirus, herpes simplex virus, adenovirus, and adeno-associated virus vectors or liposomes. After cerebral ischaemia, these vectors are used to upregulate genes that increase survival and inhibit those that promote death in the injured cells. In contrast, in brain tumours gene therapy aims to kill the target cells. Examples from studies using cell culture, animal models and patients are presented. We conclude that manipulation of gene expression has potential for the treatment of cerebral ischaemia and brain tumours, although, at present, there are formidable technical obstacles to be overcome before clinical applications become a reality.

Adenoviridae↗

PubMed2000

Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group.

OBJECT: Delayed cerebral ischemia remains an important cause of death and disability in patients who have suffered subarachnoid hemorrhage (SAH). Endothelin (ET) has a potent contractile effect on cerebral arteries and arterioles and has been implicated in vasospasm. The authors administered ET(A/B) receptor antagonist (TAK-044) to patients suffering from aneurysmal SAH. They then assessed whether this agent reduced the occurrence of delayed cerebral ischemic events and examined its safety profile in this group of patients. METHODS: Four hundred twenty patients who had suffered an SAH were recruited into a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II trial. The primary end point was whether a delayed ischemic event occurred within 3 months after the first dose of the study drug and the secondary end points included determining whether a delayed ischemic event occurred by 10 days after the first dose of the study drug, whether a new cerebral infarct was demonstrated on a computerized tomography scan or at postmortem examination by 3 months after administration of the initial dose, the patient's Glasgow Outcome Scale scores at 3 months after the initial dose, and adverse events. There was a lower incidence of delayed ischemic events at 3 months in the TAK-044-treated group: 29.5% compared with 36.6% in a group of patients receiving placebo. The estimated relative risk was 0.8 with a 95% confidence interval of 0.61 to 1.06. There were no significant differences in the secondary end points, including clinical outcomes in the placebo-treated and TAK-044-treated groups. CONCLUSIONS: The TAK-044 was well tolerated by patients who had suffered an SAH, even though hypotension and headache--side effects compatible with the drug's vasodilatory properties--occurred. It would be valuable to proceed to a fully powered phase III trial of an ET receptor antagonist in treating aneurysmal SAH.

Adult↗