Biomedical subjects
M Cole
Publications and source records attributed to M Cole.
Intraventricular cerebral neuroblastoma. Analysis of subtypes and comparison with hemispheric neuroblastoma.
Two cases of intraventricular neuroblastomas were compared with cases of intraventricular and hemispheric neuroblastomas that have been reported in the published literature. The following order of tumor subtypes was found in patients with increasing age: hemispheric neuroblastoma, intraventricular undifferentiated neuroblastoma, intraventricular differentiated neuroblastoma, and intraventricular neurocytoma; for patients with intraventricular neuroblastomas, this was also the order of increasing cellular maturation and survival. Neuronal morphologic or epitope differentiation was associated with a longer survival time than lack of differentiation by Kaplan-Meier product-limit estimates and with a better survival rate (chi 2) for intraventricular tumors but not for hemispheric tumors. Pathologic distinction of a neurocytoma was confirmed with immunostaining or ultrastructural studies that suggested that a neurocytoma is a matured neuroblastoma of a granule-cell (interneuron) phenotype. Differences among neuroblastoma groups bolster previous suggestions that intraventricular tumors arise differently than do cases of hemispheric tumors and follow a more benign course when neuronal differentiation is present.
The mdm-2 oncogene is translocated and overexpressed in a murine plasmacytoma cell line expressing wild-type p53.
The cellular p53 protein has been demonstrated to possess growth-inhibitory activity. Recent work suggests that the murine double minute gene (mdm-2) encodes a protein that may function as a cellular regulator or mediator of p53 function. We were interested in determining if the mdm-2 gene was overexpressed in mouse tumor cells, in particular mouse plasmacytomas that harbor wild type-p53 protein. A novel chromosomal translocation of the mdm-2 gene was detected in the SP2 cell line, that is derived from plasmacytoma MOPC21. The translocation results in a head-to-head arrangement of the mdm-2 gene (chromosome 10) with the immunoglobulin C kappa gene (chromosome 6), analogous to the translocations that activate the c-myc gene in murine plasmacytomas. Based on Northern blot analysis, the translocation induces a 10-fold elevation of mdm-2 RNA. Primer extension assays demonstrate that the 5' end of the mdm-2 RNA from the translocated gene is colinear with the 5' mdm-2 mRNA from an unrearranged gene, suggesting that the mRNA and encoded protein are unaltered. This chromosomal translocation represents the first example in which mdm-2 overexpression is activated by a genetic alteration other than gene amplification.
Excitonic recombination of degenerate two-dimensional electrons with localized photoexcited holes in a single heterojunction quantum well.
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Etoposide pharmacokinetics in children: the development and prospective validation of a dosing equation.
Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.
The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival.
Observations have been made on a patient with Friedreich's ataxia who died 52 years after the onset of symptoms. The pathology of the brain and spinal cord was typical of this disorder. Apart from loss of dorsal root ganglion cells, severe loss of secondary sensory neurons was observed, including the nucleus dorsalis in the spinal cord, the spinal and principal trigeminal nuclei and, in particular, the mesencephalic trigeminal nucleus in the brain stem. Morphometric studies on the first sacral nerve root and on the sural nerve at levels from midthigh to ankle revealed a distally accentuated axonal loss that predominantly affected larger myelinated nerve fibres. Regenerative activity was seen, mainly in the spinal root and proximally in the sural nerve. Relative myelin thickness, assessed by a g ratios, tended to be reduced. As teased fibre studies showed only limited evidence of demyelination/remyelination and of axonal regeneration, this therefore suggests the presence of a hypomyelination. The results confirm the presence of a distal axonopathy and provide no evidence that this is preceded by axonal atrophy.
Creatinine related reference ranges for urinary homovanillic acid and vanillylmandelic acid at 6 months of age.
The relationship between homovanillic acid (HVA), vanillylmandelic acid (VMA), and creatinine in the urine of 6 month old babies has been studied and reference ranges in the form of centiles constructed for HVA and VMA against creatinine. Over 10,000 urine samples were collected from babies in four health districts in the north of England. HVA and VMA concentration, either independently or when divided by creatinine concentration, were dependent upon the absolute concentration of creatinine in the sample. After adjustment for creatinine significant differences in the mean concentration of HVA were found between sexes. No such differences were found for VMA. HVA and VMA were also found to be age dependent. Centiles were constructed using a procedure which makes no distributional assumptions about the data. The net effect of utilising these centiles was to increase the predictive value of a positive screening test from 20% to 40% without any increase in the false negative rate.
Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization.
Homozygous plasminogen activator inhibitor-1 (PAI-1)-deficient (PAI-1-/-) mice were generated by homologous recombination in D3 embryonic stem cells. Deletion of the genomic sequences encompassing the transcription initiation site and the entire coding regions of murine PAI-1 was demonstrated by Southern blot analysis. A 3.0-kb PAI-1-specific mRNA was identified by Northern blot analysis in liver from PAI-1 wild type (PAI-1+/+) but not from PAI-1-/- mice. Plasma PAI-1 levels, measured 2-4 h after endotoxin (2.0 mg/kg) injection were 63 +/- 2 ng/ml, 30 +/- 10 ng/ml, and undetectable (< 2 ng/ml) in PAI-1+/+, heterozygous (PAI-1+/-) and PAI-1-/- mice, respectively (mean +/- SEM, n = 4-11). PAI-1-specific immunoreactivity was demonstrable in kidneys of PAI-1+/+ but not of PAI-1-/- mice. SDS-gel electrophoresis of plasma incubated with 125I-labeled recombinant human tissue-type plasminogen activator revealed an approximately 115,000-M(r) component with plasma from endotoxin-stimulated (0.5 mg/kg) PAI-1+/+ but not from PAI-1-/- mice, which could be precipitated with a polyclonal anti-PAI-1 antiserum. PAI-1-/- mice were viable, produced similar sizes of litters as PAI-1+/+ mice, and showed no apparent macroscopic or microscopic histological abnormalities.
Measurement of dopamine, HVA and HMMA in untimed urine samples.
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Screening for neuroblastoma in the north of England.
OBJECTIVE: To determine the feasibility of establishing a system of screening for neuroblastoma. DESIGN: Prospective study of mass screening in four clearly defined geographical areas. SETTING: Four health districts of the Northern region of England. SUBJECTS: 20,829 babies aged 6 months, 92% of target population. INTERVENTIONS: Collection of urine on filter paper for analysis of content of homovanillic and vanillylmandelic acid in relation to urinary creatinine concentrations. MAIN OUTCOME MEASURES: Derivation of reference range. Identification of babies with homovanillic or vanillylmandelic acid > 3 SD above the mean (positive cases). Investigation of positive cases for evidence of neuroblastoma. RESULTS: The upper limit of normal (3 SD above the mean) for vanillylmandelic acid was 15 mumol/mmol creatinine and for homovanillic acid 24 mumol/mmol creatinine. Of the 20,829 babies screened, 2537 (12.2%) required a second sample to be taken because the first sample was inadequate. Of these, 527 (2.5%) provided a liquid urine specimen and 10 (0.04%) had positive results for neuroblastoma. Two of them had neuroblastoma (true positives) and eight did not (false positives). A further three children from the cohort were subsequently found to have neuroblastoma; they had raised homovanillic acid or vanillylmandelic acid values, or both, but screened negative at 6 months. CONCLUSIONS: Screening for neuroblastoma is possible in the health care system of the United Kingdom. Evaluation of the efficacy of screening in reducing the mortality from neuroblastoma requires a controlled trial.
"Decrease in childhood neuroblastoma death in Japan," Hanawa et al. (1990)
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Thalamic amnesia: Korsakoff syndrome due to left thalamic infarction.
In order to support the concept that a lesion of the thalamus is sufficient to cause a Korsakoff syndrome, we are presenting 5 patients, all of whom developed the syndrome after sustaining a left (dominant) thalamic infarction. Two patients had pure thalamic strokes followed by a permanent Korsakoff syndrome. One of these patients was studied with neuropsychometric testing, as well as with a modern MRI scan. In 2 other patients, clinical and imaging data indicate that infarction was not limited to the thalamus. Another patient had bilateral thalamic infarcts but only a temporary Korsakoff syndrome. Neuropathological data are needed to elucidate the exact anatomical substrate of dominant thalamic Korsakoff syndrome.
A trial of the prostaglandin E1 analogue, enisoprost, to reverse chronic cyclosporine-associated renal dysfunction.
Cyclosporine (CYA) reduces the renal synthesis of prostaglandins of the E series (PGE). Analogue of PGE1 have been shown to mitigate the vasoconstriction and abnormal renal function of experimental acute CYA nephrotoxicity. We examined the hypothesis that the orally bioavailable PGE analogue enisoprost (EP) would improve renal function in renal transplant recipients chronically exposed to CYA. In a randomized double-blind study, 40 patients at two centers who were being monitored for 3 to 30 months after renal transplantation, were allocated to receive either EP 100 micrograms orally four times daily or placebo (P) for 2 weeks. CYA dosing was fixed at existing levels. There could be no evidence of concurrent acute renal injury, including that of acute rejection. Glomerular filtration rate (GFR) was measured by the clearance of radiolabeled DTPA, while effective renal plasma flow (ERPF) was measured as the clearance of p-aminohippuric acid (PAH). The acute effects of EP were examined twice, by comparing immediate postdose to predose values for GFR and ERPF on day 1 and again on day 14. Chronic effects were examined by comparing baseline (predose) values only for GFR and ERPF between days 1 and 14 and by an examination of creatinine clearances (CCR) on days 0, 14, and 21. At enrollment, patients were well matched for renal function (CCR:EP 47 +/- 5 v P 49 +/- 4 mL/min/1.73 m2; P = NS). Baseline demographics were similar, although patients treated with EP were older (46 +/- 2 v 36 +/- 3 years, mean +/- SEM, P = 0.003). CYA doses and blood levels did not change significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Intraoperative identification of a radiofrequency lesion allowing validation of catheter mapping of ventricular tachycardia with a computerized balloon mapping system.
Radiofrequency current was utilized to mark the anatomic location of earliest endocardial activation during catheter mapping of ventricular tachycardia. Intraoperative identification of the radiofrequency lesion allowed validation that the site of earliest endocardial activation determined by a catheter mapping study was the same as assessed by a computerized balloon mapping system. Radiofrequency current may be a useful method of marking areas of endocardium thought to be potential sites for ablative surgery as well as allowing correlation between different mapping techniques.
Screening for neuroblastoma in the northern region of England. Laboratory aspects.
Our pilot study for neuroblastoma screening started in 1986. The study has progressed through several phases, with use of several analytical methods to a procedure based primarily on the use of automated gas chromatography mass spectrometry. The northern region of England has a relatively static population of approximately 3.5 million, with an annual birth rate of 41,000. The region consists of 16 administrative health districts. In 4 years, we have screened 20,829 infants from four health districts. In this program, we screen all children at 6 months of age. A urine sample is collected on filter paper by a health visitor, either at the time of the infant's routine clinic visit or during the health visitor's follow-up visit at home. In the laboratory, the sample is dried and processed for analysis of homovanillic acid (HVA) and vanillylmandelic acid (VMA), using a benchtop Hewlett Packard gas chromatograph mass spectrometer. The results are related to the creatinine content of the urine. Using cut-off limits of 39 micrograms/mg of creatinine for HVA and 25 micrograms/mg of creatinine for VMA, 2,537 infants (12.2%) required a second paper sample and 527 infants (2.5%) were observed with a liquid urine collection. Of these, the conditions of nine infants with elevated levels of HVA or VMA were investigated clinically for the possible presence of neuroblastoma. Two infants were found to have neuroblastoma; the other seven showed no evidence of tumor. In addition, there were three children who, when screened at 6 months of age, had normal levels of HVA and VMA but in whom neuroblastoma subsequently developed.
A pilot study of screening for neuroblastoma in the north of England.
A pilot study has been carried out to assess the feasibility of screening for neuroblastoma in 6-month-old infants in the north of England. A total of 20,829 infants were screened. Two true-positive cases were found, along with eight false-positive and three false-negative cases. It was shown that the concentrations of catecholamine metabolites in the urine are dependent on the creatinine content; centiles have been established to allow this relationship to be taken into account. Five of the eight false-positive cases would have been correctly assessed as normal if the new centiles had been used. Preliminary results lend support to the need for a well-designed study of neuroblastoma screening to be carried out, with death from this disease as the only end point.
max encodes a sequence-specific DNA-binding protein and is not regulated by serum growth factors.
Max and c-Myc proteins, produced in bacteria, were studied for DNA-binding activity using the electrophoretic band-shift assay (EMSA). Both Max homodimers and c-Myc-Max heterodimers selected the same sequence CA(C/T)GTG from an initial pool of 10(6) DNA molecules. From the pool of sequence-specific binding sites, the palindromic site (CACGTG) was preferentially selected over the CATGTG site using two different degenerate oligonucleotide probes. max expression is identical in myc-induced tumor cell lines relative to other cells. Furthermore, max expression is constant in both confluent and serum-stimulated A31 fibroblasts, in contrast to c-myc expression, which is barely detectable in confluent fibroblasts and induced 20-fold by serum growth factors. Based on recognition of the same DNA sequence by Max and c-Myc-Max complexes and differential expression of the two genes, we propose that Max homodimers and c-Myc-Max heterodimers may bind to a common set of cellular target genes.
Locked-in syndrome: a team approach.
A person who suffers brainstem infarction resulting in quadriplegia, lower cranial nerve paralysis and mutism with intact cortical function may survive in a condition aptly termed "locked-in syndrome" (LIS). Literally a mind locked inside the body, the person remains fully aware without the ability to move or communicate. Because of the awesome nature of the condition and its likely permanent basis, family and staff may feel hopeless and incapacitated when planning care. Anatomical findings, etiologies, manifestations and outcomes are discussed in the literature but offer few suggestions for case management. Our clinical team has worked intensively with several LIS patients and has found that an interdisciplinary team approach is essential for providing creative patient care.