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Biomedical subjects

G A Taylor

Publications and source records attributed to G A Taylor.

At least 19 recordsLinked to original sources
PubMed1992

Iron and aluminium in relation to brain ferritin in normal individuals and Alzheimer's-disease and chronic renal-dialysis patients.

Ferritin has been isolated and its subunit composition, iron and aluminium content determined in the cerebral cortex and cerebellum of normal individuals and in the cerebral cortex of Alzheimer's-disease and renal-dialysis patients. An e.l.i.s.a. for ferritin has been developed and the ferritin, non-haem iron and aluminium content of the parietal cortex were determined in normal individuals and Alzheimer's-disease patients. It was found that ferritin from the cerebral cortex and cerebellum of normal individuals had a high H-subunit content, similar to that of heart ferritin. The subunit composition of ferritin isolated from the cerebral cortex was not significantly altered in Alzheimer's-disease or renal-dialysis patients. Ferritin from the cerebral cortex of normal individuals had only approx. 1500 atoms of iron per molecule and the iron content of ferritin was not significantly changed in Alzheimer's-disease or renal-dialysis patients. Ferritin isolated from the cerebral cortex of normal, Alzheimer's-disease and renal-dialysis patients had less than 9 atoms of aluminium per molecule. The failure to find increased concentrations of aluminium associated with ferritin in dialysis patients, who had markedly increased concentrations of aluminium in the cerebral cortex, shows that aluminium does not accumulate in ferritin in vivo. This has important implications for the toxicity of aluminium, since it implies that cells are unable to detoxify aluminium by the same mechanism as that available for iron. Comparison of the concentrations of ferritin, aluminium and iron in the parietal cortex from normal and Alzheimer's-disease patients showed that, whereas the concentration of aluminium was not increased, both ferritin and iron were significantly increased in Alzheimer's disease.

Aged↗
PubMed1992

Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system.

Deposition of beta-amyloid and the formation of neurofibrillary tangles (NFTs) are central to the aetiopathogenesis of Alzheimer's disease (AD). The possible effects of aluminium on these processes have been investigated in patients with renal failure who are exposed chronically to high blood levels of aluminium. Focal accumulation of aluminium was observed in neurons with high densities of transferrin receptors, indicating transferrin-mediated uptake, in regions such as cortex and hippocampus which are selectively vulnerable in AD. Increased staining for the beta-amyloid precursor protein (APP) in cortical pyramidal neurons was evident in the majority of renal patients and immature senile plaques were present in 30% of cases, suggesting that aluminium may induce or accelerate beta-amyloid deposition. The absence of neurofibrillary changes in this group of renal patients indicates that aluminium does not directly cause the formation of NFTs. The brain aluminium content was not raised in neuropathologically assessed cases of AD and we have been unable to confirm claims of defective transferrin binding in this disorder. If aluminium contributes to the development of sporadic AD, it must do so indirectly, perhaps via effects on the synthesis or metabolism of APP, or by contributing generally to the age-related attrition of neurons and thus reducing the threshold for deficits produced by more specific disease-related processes.

Aluminum↗
PubMed1992

Germanium-68 as a possible marker for silicon transport in rat brain.

Silicon (Si) is an essential trace element normally present in brain and cerebrospinal fluid, although the mechanism by which it enters and distributes in brain is largely unknown. Due to the short radioactive half-life of 31Si (156 min) we have investigated the use of 68Germanium (68-Ge, half-life 282 days) as a possible marker for Si transport in rat brain over longer periods than are possible with 31Si. Adult male anaesthetised rats were given a bolus of 68Ge I.V. and arterial blood samples taken during experiments that lasted between 5 min and 3 days. At termination, the brain was removed and analysed for radioactivity as were the plasma samples. Data were analyzed by Graphical Analysis which showed that the blood-brain barrier permeability to 68Ge (Kin approximately 10(-4) ml/min/g) is similar to that for many non protein-bound electrolytes in plasma and that 68Ge fluxes across cerebral capillaries are bidirectional. The autoradiographic distribution of 68Ge in brain was homogenous. Our results are in agreement with those of previous studies using 31Si or 68Ge, which suggest 68Ge may be a useful marker for Si when investigating the role of this element in conditions such as neurodegenerative diseases.

Animals↗
PubMed1992

Aluminium accumulation in relation to senile plaque and neurofibrillary tangle formation in the brains of patients with renal failure.

The effects of long-term exposure to aluminium on the development of Alzheimer-type neuropathological changes have been studied post-mortem in patients with chronic renal failure who did not have dialysis encephalopathy. Administration of aluminium-containing phosphate binding compounds appears to be a major factor in the accumulation of aluminium in the brain of dialysis patients. The mean serum aluminium concentrations determined during life and brain aluminium concentrations determined post-mortem correlated with both the duration and total amount of aluminium hydroxide administered to these patients. No correlation was found between the presence of bone aluminium and either the mean serum or brain aluminium concentration. Longitudinal monitoring of serum aluminium concentrations may provide a more reliable index than bone biopsy of brain aluminium concentrations in dialysis patients. Dynamic secondary ion mass spectrometry revealed focal accumulations of aluminium associated with cortical pyramidal neurones. The majority of patients also showed immunostaining in pyramidal neurones with an antibody to the N-terminal region of the beta/A4 amyloid precursor protein, while staining was absent in age-matched control cases. One-third of the patients exhibited beta/A4-positive amorphous senile plaques in the cerebral cortex. However, there was no clear correlation between either the presence and intensity of beta/A4 amyloid precursor immunostaining or the presence of senile plaques and the concentration of aluminium in the cerebral cortex. Cortical neurofibrillary tangles were not observed in any of the dialysis patients. These data suggest that it is unlikely that aluminium plays any major role in neurofibrillary tangle formation and that its putative role in senile plaque formation is likely to be only part of a complex cascade of changes.

Aluminum↗
PubMed1992

The imaging and quantification of aluminium in the human brain using dynamic secondary ion mass spectrometry (SIMS).

Dynamic secondary ion mass spectrometry (SIMS) has been utilised to study the post-mortem distribution of aluminium in air-dried frozen sections from unfixed, unstained human brain in order to minimise contamination of the tissue and avoid redistribution and extraction of endogenous tissue aluminium. Substrates, sputter-coated with silver, were found to be free of focal aluminum surface contamination and thus minimised substrate induced artefacts in the tissue aluminium ion image. SIMS imaging of aluminium secondary ions at a mass resolution that eliminated the major molecular interferences, combined with a photomontage technique provided a unique strategy for studying aluminium distribution in tissue unrivalled by other spatially resolved microanalytical techniques such as laser microprobe mass spectrometry or X-ray microanalysis. Using this strategy, high densities of focal aluminium accumulations have been demonstrated in the cerebral cortex of the majority of chronic renal dialysis patients studied. In contrast, such aluminium accumulations were absent in control patients. SIMS imaging of aluminium appeared to provide much better discrimination between the dialysis patient group and the control group than one of the most widely used techniques for measuring aluminium in bulk samples, graphite furnace atomic absorption spectrometry. Preliminary studies have shown the feasibility of quantifying focal aluminium SIMS images obtained from brain tissue using aluminium-loaded brain homogenates as reference standards.

Adult↗
PubMed1992

Gastrointestinal absorption of aluminium in Alzheimer's disease: response to aluminium citrate.

Alzheimer's disease (AD) has been linked to genetic defects on chromosome 21 in some families, but most elderly cases appear to be sporadic and may, at least in part, involve environmental risk factors. Several lines of evidence suggest that aluminium may be involved in the aetiology of AD. However, despite universal exposure to aluminium in the diet, only some people develop the disease. We have developed a test of aluminium absorption using an aluminium citrate drink, to examine the hypothesis that sufferers from AD show increased aluminium absorption. In a younger group of AD patients aluminium absorption was significantly raised compared with age-matched controls. Aluminium absorption increased with age in the control group but was not significantly raised in older AD patients when compared with age-matched controls.

Adult↗
PubMed1992

Posttraumatic shock in children: CT findings associated with hemodynamic instability.

Twenty-seven of 1,018 children evaluated with contrast material-enhanced computed tomography (CT) after blunt trauma demonstrated a characteristic hypoperfusion complex. This complex was usually seen in young children (median age, 2 years). CT findings in all 27 patients included a dilated, fluid-filled bowel and abnormally intense enhancement of the bowel wall, mesentery, kidneys, aorta, and inferior vena cava. Twenty-four percent of all children with a Trauma Score of 10 or less and 20% with a Glasgow Coma Score of 6 or less had the hypoperfusion complex. All 27 patients had a normal blood pressure immediately before CT, but five (19%) became hypotensive within 10 minutes of intravenous contrast material administration. Twenty-three children (85%) died. Of 16 children who survived 24 hours, four (25%) developed renal insufficiency. The intense multiorgan enhancement pattern seen in the hypoperfusion complex indicates tenuous hemodynamic stability. Recognition that the constellation of CT findings is due to hypovolemic shock and not to injured viscera helps avoid unnecessary laparotomy.

Abdominal Injuries↗
PubMed1992

Intracranial venous system in the newborn: evaluation of normal anatomy and flow characteristics with color Doppler US.

To establish the effectiveness of color Doppler ultrasound (US) in identifying flow in the intracranial venous system in newborns, 20 healthy, full-term newborns were scanned. Visualization of the subependymal and internal cerebral veins, superior sagittal sinus, vein of Galen, straight sinus, and left transverse sinus was accomplished in almost every newborn (greater than or equal to 90%). Mean blood flow velocities were as follows: subependymal veins, 3.0 cm/sec; internal cerebral veins, 3.3 cm/sec; inferior sagittal sinus, 3.5 cm/sec; vein of Galen, 4.3 cm/sec; straight sinus, 5.9 cm/sec; and superior sagittal sinus, 9.2 cm/sec. Flow in the subependymal and internal cerebral veins was continuous in all but one newborn (5%), while low-amplitude pulsations were observed with increasing frequency in the more central venous structures such as the vein of Galen (15%), straight sinus (32%), and transverse sinuses (36%). It was concluded that visualization of the intracranial venous system with color Doppler US is possible in the majority of healthy neonates.

Cerebral Veins↗
PubMed1992

Intracranial venous system in newborns treated with extracorporeal membrane oxygenation: Doppler US evaluation after ligation of the right jugular vein.

There is little information regarding alterations in cerebral venous flow related to ligation of the right jugular vein in newborns treated with extracorporeal membrane oxygenation (ECMO). The authors performed duplex and color Doppler sonographic evaluations of the intracranial venous system in 23 consecutive newborns during ECMO. The superior sagittal sinus (SSS) was visualized in every newborn, and the left transverse sinus was seen in 14 newborns (61%). The relative contribution of a jugular bulb catheter was evaluated in 16 newborns by measuring average blood flow velocities in the SSS with the catheter open (baseline) and with the catheter temporarily occluded. Occlusion of the catheter resulted in significantly reduced SSS blood flow velocities (P = .01). Persistent reductions in SSS flow velocity were associated with a significantly higher risk of cerebrovascular injury (P = .002). These results show that alterations in cerebral venous drainage are not uncommon in newborns treated with venoarterial ECMO and suggest a possible association between abnormal venous drainage and cerebrovascular injury in these newborns.

Blood Flow Velocity↗
PubMed1992

Effect of scanning pressure on intracranial hemodynamics during transfontanellar duplex US.

The purpose of this study was to determine the effect of transducer scanning pressure during duplex ultrasonographic evaluation of intracranial hemodynamics in newborns. Doppler spectra were obtained from the anterior cerebral artery with use of light and firm scanning pressure over the anterior fontanelle in 23 healthy infants and 20 infants with reduced cranial compliance due to ventricular dilatation, intracranial hemorrhage, diffuse cerebral edema, and extraaxial fluid. In healthy infants, the mean resistive index (RI) increased from 69.9 +/- 3 to 74.8 +/- 3 (P < .005), and mean time average velocity (TAV) decreased from 11.1 cm/sec +/- 1.3 to 8.6 cm/sec +/- 1.3 (P < .0001) with firm scanning pressure. In infants with decreased cranial compliance, mean RI increased from 67.8 +/- 4 to 85 +/- 5, and mean TAV decreased from 16.3 cm/sec +/- 2 to 10.7 cm/sec +/- 2 (P < .0001 for both comparisons). A significant alteration in RI with firm technique (> or = 20% increase in RI, or reversal of diastolic flow) was observed in 12 of 28 examinations in infants with decreased cranial compliance and in only one of 23 healthy infants (P < .005). These data show that scanning pressures during duplex ultrasonography can significantly affect intracranial hemodynamics, especially in infants with altered cranial compliance.

Blood Flow Velocity↗
PubMed1992

Hepatic masses in infants and children: CT evaluation.

Hepatic masses are uncommon in children. Although some lesions may have overlapping appearances on CT, a careful analysis of the CT characteristics of the lesion, in combination with the age of the patient and the clinical and laboratory data, can lead to a specific diagnosis in many cases [1-5]. In this pictorial essay, the spectrum of hepatic masses in children is reviewed, with emphasis on the key CT findings that help in differentiating the various lesions.

Adolescent↗
PubMed1992

Blunt pancreatic trauma in children: CT diagnosis.

The purpose of this study is to determine the efficacy of CT in the diagnosis of pancreatic injury after blunt abdominal trauma in children. Pancreatic injury was diagnosed at surgery, at autopsy, or on the basis of the development of clinical pancreatitis or a pseudocyst on follow-up imaging evaluation in 18 of 1045 consecutive children examined with CT after blunt trauma. Types of pancreatic injury included laceration in 11 children, transection in two, contusion in one, and tumor with hemorrhage in one. Three children had clinical pancreatitis without a pancreatic abnormality noted on CT. The pancreatic injury was prospectively identified on CT in 12 children (67%). The presence of fluid in the lesser sac was a useful marker for injury to the pancreas. This was noted in 13 children with pancreatic injury, whereas it was observed in only six (1%) of 1028 children in the absence of pancreatic injury (sensitivity, 72%; specificity, 99%). Fluid in the anterior pararenal space was less helpful in establishing the diagnosis of pancreatic injury (sensitivity, 44%; specificity, 98%). A pancreatic pseudocyst developed in four of the 11 survivors. Our experience shows that direct signs of pancreatic trauma may be difficult to identify on CT. Recognition of the limitations of CT diagnosis of pancreatic injury is important in helping to reduce errors of interpretation.

Child↗
PubMed1992

Posttraumatic adrenal hemorrhage in children: CT findings in 34 patients.

The medical records and CT scans of 34 children with posttraumatic adrenal hemorrhage were reviewed. Adrenal hemorrhage was unilateral in 32 children; most injuries were on the right side. Bilateral hemorrhage was present in two children. The injured gland was oval in 27 cases and triangular in nine. Gland size ranged from 7 to 45 mm long and 4 to 30 mm wide. All adrenal hemorrhages had decreased attenuation relative to liver and spleen on contrast-enhanced CT. Ipsilateral diaphragmatic crural thickening was a frequent (61%) associated finding. Ipsilateral intraabdominal (61%) and intrathoracic (44%) injuries were often present. Clinical signs of adrenocortical insufficiency were not observed in any child. In summary, posttraumatic adrenal hemorrhage is uncommon in children. The hemorrhage is usually unilateral, right sided, and associated with ipsilateral visceral injury.

Abdominal Injuries↗
PubMed1992

Computed tomography imaging of abdominal trauma in children.

The authors discuss the role of computed tomography (CT) in the evaluation of children following blunt abdominal trauma. Appropriate techniques for scanning children are described, as well as clinical indications that place children at high risk and low risk for abdominal injury. Examples of both solid organ and bowel injuries are shown, with special emphasis on the correlation of CT appearance and clinical outcomes. The authors conclude that CT is an effective tool for the diagnosis of abdominal injury in the pediatric patient, and that the clinical impact of CT appears to be changing with the increasing use of nonoperative therapy for solid organ injury.

Abdominal Injuries↗
PubMed1991

The biochemical pharmacology of the thymidylate synthase inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583).

2-Desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583) is a more water-soluble analogue of the quinazoline-based thymidylate synthase (TS) inhibitor, N10-propargyl-5,8-dideazafolic acid (CB3717). A 3-fold loss in TS inhibitory activity (murine and human TS, Ki = 10 nM) was accompanied by a 40-fold increase in growth inhibitory potency against L1210 and W1L2 cells in vitro (IC50 = 0.085 and 0.05 microM, respectively) when compared with CB3717. In L1210 cells a concentrative uptake mechanism was demonstrated for [3H]ICI 198583 (Kt = 2.9 microM). The L1210:1565 cell line, with an impaired ability to transport reduced folates or methotrexate (MTX), was resistant (100-fold relative to the wild-type L1210 line) to ICI 198583 (but not CB3717) and did not take up [3H]ICI 198583 significantly. The measurement of folylpolyglutamate synthetase (FPGS) substrate activity demonstrated a Km of 40 microM for ICI 198583 and a Vmax/Km (relative to folic acid) of 3.5. The formation of intracellular polyglutamate derivatives was demonstrated in both L1210 (mouse) and WIL2 (human) cells grown in vitro after exposure to 1 microM [3H]ICI 198583. In L1210 cells, by 4 hr, approximately 50% of the intracellular 3H(approximately 1 microM) was found as polyglutamate forms of ICI 198583, principally as tri- and tetraglutamates. After 24 hr the ICI 198583 polyglutamate pool had expanded, the tetraglutamate metabolite predominated and there was significant formation of the pentaglutamate. Upon resuspension of L1210 cells in drug free medium, ICI 198583 was largely lost from the cells but the polyglutamates were preferentially retained, after 24 hr approximately 70% remained. Synthetic ICI 198583 polyglutamates were shown to be up to 100-fold more potent as inhibitors of isolated TS than the parent compound. Following in vivo administration (500 mg/kg i.v.) ICI 198583 was cleared rapidly from the plasma of mice (T1/2 beta = 16 min, clearance = 42 mL/min/kg). Despite this clearance there was prolonged, dose-dependent inhibition of TS in L1210:NCI cells in vivo. Thus, following 500 mg/kg i.v. the flux through TS was inhibited by greater than 80% for at least 24 hr. Administration of five doses at 5 mg/kg daily of ICI 198583 to L1210:ICR tumour-bearing mice resulted in greater than 60% of the mice being cured, a 10-fold improvement in potency over CB3717. The maximum tolerated dose (MTD) for ICI 198583 using this schedule was greater than 500 mg/kg/day compared with 200 mg/kg/day of CB3717.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study.

N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid. Inhibition of isolated L1210 TS by ICI D1694 is mixed noncompetitive (although tending toward competitive), with a Ki of 62 nM (Kies = 960 nM). The synthetic gamma-polyglutamates are up to 2 orders of magnitude more potent as inhibitors of TS; e.g., the tetraglutamate (glu4) has a Ki of 1.0 nM (Kies = 15 nM). Although inhibitory activity of ICI D1694 toward rat liver dihydrofolate reductase was similar to that of TS (Ki = 92 nM; competitive inhibition) the polyglutamate derivatives did not show enhanced activity. ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM). L1210 growth inhibition was not observed in the presence of thymidine, consistent with TS being the locus of action. Folinic acid antagonized L1210 growth inhibition in a competitive fashion such that the highest folinic acid concentration used (25 microM) increased the 50% inhibitory activity 6000-fold. When given as a 4-h delayed "rescue", folinic acid was much less effective in antagonizing growth inhibition. These observations are consistent with folinic acid competing with ICI D1694 for uptake into the cell and/or intracellular polyglutamation. The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells. L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4). Upon resuspension in drug-free medium for 24 h, approximately 75% of the cellular 3H was retained, this being the higher polyglutamate pool (glu4-6). In mice, after a single bolus injection of 10 mg/kg of ICI D1694, TS was inhibited greater than 80% for 24 h in ascitic L1210:NCI cells (as measured by the rate of 3H release from [5-3H]deoxyuridine). ICI D1694 cured the L1210:ICR ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, approximately 50 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗