Primary malignant rhabdoid tumour of the brain.
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Brain Neoplasms↗
Biomedical subjects
T C Cox
Publications and source records attributed to T C Cox.
Molecular defects of erythroid 5-aminolevulinate synthase in X-linked sideroblastic anemia.
The erythroid-specific isozyme of 5-aminolevulinate synthase (ALAS2), the first and rate-limiting enzyme of heme biosynthesis, is expressed concomitantly with the differentiation and maturation of the erythroid cell in order to accommodate generation of the large amounts of heme required for hemoglobin production. During the past few years the ALAS2 gene and its transcript have been characterized and the amino acid sequence of the enzyme deduced. The human genetic disorder X-linked sideroblastic anemia, previously postulated to be caused by defects of ALAS, has now been analyzed at the molecular and tissue-specific level. A heterogeneous group of point mutations in the catalytic domain of the ALAS2 enzyme has been found to cause the disorder. Impaired activity of recombinant mutant ALAS2 enzymes has also been demonstrated. Characterization of molecular defects in individuals with X-linked sideroblastic anemia has provided improved diagnosis for at-risk family members.
5-Aminolevulinate Synthetase↗
Molecular regulation of heme biosynthesis in higher vertebrates.
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5-Aminolevulinate Synthetase↗
Boar sperm plasma membrane Ca(2+)-selective channels in planar lipid bilayers.
Entry of Ca2+ through Ca2+ channels is thought to trigger the acrosome reaction of spermatozoa during fertilization. Antagonists of the L-type Ca2+ channel are known to prevent the intracellular Ca2+ (Ca2+) increase and inhibit acrosomal exocytosis in mammalian sperm. Planar bilayer recordings were used to study Ca2- channels incorporated from partially purified boar sperm plasma membranes. With symmetrical 50 mM NaCl and 100 mM BaCl2 on the cis side, single-channel events consistent with Ba2+ flux from cis to trans were observed. These channels were activated by the dihydropyridine agonist (+/-)BAY K 8644 and blocked by the antagonist nitrendipine. Sperm Ca2- channels did not require depolarization for activation and did not inactivate. The (+/-)BAY K 8644 and (S-)BAY K 8644 enantiomers increased apparent open time in a dose-dependent [half-maximal activity constant (K0.5) = 0.9 and 0.3 microM, respectively] manner. Dihydropyridine antagonists nitrendipine (K0.5 = 0.5 microM) and (R+)BAY K 8644 (K0.5 = 2.8 microM) decreased apparent open times. The channels described in this report share some properties with brain, cardiac, and skeletal muscle t tubule Ca2+ channels and may be involved in increasing Cai2+ before the acrosome reaction.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
X-linked pyridoxine-responsive sideroblastic anemia due to a Thr388-to-Ser substitution in erythroid 5-aminolevulinate synthase.
BACKGROUND: X-linked sideroblastic anemia is usually associated with reduced 5-aminolevulinate synthase activity in erythroid cells, and some cases are responsive to treatment with pyridoxine, the precursor to the cofactor of the enzyme. The recently identified gene for an erythroid-specific 5-aminolevulinate synthase isoenzyme and its localization to the X chromosome make it likely that one or more defects in this gene underlie the anemia. METHODS: Using a polymorphic dinucleotide-repeat sequence in the erythroid 5-aminolevulinate synthase gene, we confirmed the linkage of this gene to the disorder in a family with X-linked pyridoxine-responsive sideroblastic anemia. We therefore sought evidence of a nucleotide-sequence abnormality in the erythroid 5-aminolevulinate synthase gene by analyzing enzymatically amplified DNA. RESULTS: DNA-sequencing studies in two affected males and one carrier female in the kindred demonstrated a cytosine-to-guanine change at nucleotide 1215 (in exon 8). This change results in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wild type, and this reduction was comparable to that in erythroid cells of the proband during relapse of the anemia; the enzyme activity expressed in the presence of pyridoxine was comparable to that in the proband's marrow cells during remission. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appears to introduce a conformational change at the active site of the enzyme. CONCLUSIONS: We identified a point mutation resulting in an amino acid change near the pyridoxal phosphate-binding site of the erythroid 5-aminolevulinate synthase isoenzyme as the underlying defect in a kindred with X-linked pyridoxine-responsive sideroblastic anemia.
5-Aminolevulinate Synthetase↗
Accurate frameless registration of MR and CT images of the head: applications in planning surgery and radiation therapy.
PURPOSE: To evaluate the feasibility and efficacy of a three-dimensional image registration technique for planning skull base surgery, performing frameless image registration for stereotaxic neurosurgery, and staging nasopharyngeal carcinoma. MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) images from 35 patients were registered by identifying 12-16 homologous landmarks with each modality. Images were displayed as overlaid sections or rendered three-dimensional scenes. The clarity of the combined images from 15 patients undergoing skull base surgery was compared with that of the conventional displays. RESULTS: Images were combined for three applications, with an accuracy of 1-2 mm. For the 15 patients undergoing skull base surgery, the combined images were significantly better at depicting the relationship between bone and lesion than conventional display (P < .01). CONCLUSION: MR and CT images of the head can be accurately registered without using external markers or substantially altering image acquisition protocols. The resulting images can show the radiologic information more clearly than conventional viewing.
Adult↗
Combined and three-dimensional rendered multimodal data for planning cranial base surgery: a prospective evaluation.
Magnetic resonance (MR), X-ray computed tomography (CT), and angiographic images best depict soft tissue, bone, and blood vessels respectively. No one on its own is sufficient in the preoperative assessment of cranial base lesions. We have developed and evaluated a computational technique for the three-dimensional (3D) combination and display of multimodality images for planning cranial base surgery. This evaluation was prospective and performed in such a way that the results could be quantified. Eight patients (three acoustic neuromas, four subfrontal and suprasellar meningiomas, and one petrous apex meningioma) underwent MR, CT, and MR angiographic investigations. These images were registered with anatomical landmarks rather than an external frame. Two techniques were used to display the resulting combined images: multiple slices in which bone from CT was overlaid on soft tissue from registered MR and pseudo-3D-rendered movie sequences showing bone from CT, lesions and optic nerves from MR, and blood vessels from MR angiography. The advantages of the combined displays compared with those of conventional methods of viewing were assessed prospectively by the operating surgeon and by an independent surgeon, and the results were compared with operative findings. The preoperative assessment showed a significant improvement (P < 0.05, sign test) in the depiction of both individual structures (lesion and bone from overlaid slices and lesion and vasculature from 3D-rendered displays) and structural relationships (tumor-bone relationships from overlaid slices and of tumor-vasculature relationships from 3D-rendered displays). The operative findings indicated that a more accurate interpretation of this information was possible from the combined images.
Adult↗
Low-affinity mixed acetylcholine-responsive receptors at the apical membrane of frog tadpole skin.
The larval frog skin has a very high electrical resistance and a corresponding low rate of transepithelial ion transport. Amiloride, a blocker of sodium transport in adult skin, transiently stimulates rather than inhibits short-circuit current (Isc) across larval skin through nonselective cation channels. Acetylcholine (ACh) stimulates Isc like amiloride, although the response is more prolonged. Pretreatment with ACh markedly suppressed amiloride stimulation of Isc; amiloride pretreatment also suppressed ACh stimulation. Half-maximal stimulation of Isc by ACh occurred at 347 microM. Stimulation by ACh was inhibited by both d-tubocurarine [dissociation constant (Kd) = 57 microM] and atropine (Kd = 49 microM). The specific nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium and the specific muscarinic agonist oxotremorine-M both stimulated Isc and were blocked by either atropine or d-tubocurarine. Reciprocal desensitization and blocker cross-reactivity suggest that ACh activates the same population of receptors as amiloride. This ACh-responsive receptor has characteristics of both nicotinic and muscarinic receptors found in other tissues.
Acetylcholine↗
Human erythroid 5-aminolevulinate synthase. Gene structure and species-specific differences in alternative RNA splicing.
Erythroid 5-aminolevulinate synthase (ALAS) is expressed exclusively in differentiating erythroid cells as the principal isoform of the enzyme to catalyze the first step of the heme biosynthetic pathway. The human gene encoding this isozyme was isolated from a cosmid library, and its structure was characterized with restriction mapping followed by sequencing of fragments. The gene is 22 kilobases long and has 11 exons. Exon 2 encodes the N-terminal signal sequence required for mitochondrial import, exons 3 and 4 encode a variable portion of the N-terminal end, and exons 5-11 the highly conserved C-terminal portion of the mature protein, respectively. Enzymatic amplification of human reticulocyte RNA using PCR techniques revealed two erythroid ALAS mRNA transcripts predicted to encode both the prototypical 64-kDa isoform as well as a novel smaller isoform with a deletion of 37 amino acids near the N terminus. The two mRNA isoforms are generated by alternative splicing of exon 4 and are expressed in fetal erythroid cells as well as at all stages of erythroid development tested, so that there is no evidence of differentiation-specific regulation of exon 4 splicing. However, striking species-specific differences were observed in that alternative splicing of exon 4 was found in man but not dog or mouse; also, the previously described alternative splicing within exon 3 in mouse was not observed in man. This transcript heterogeneity suggests the existence of erythroid ALAS protein isoforms with potentially distinct functional or regulatory roles. The occurrence of species-specific splicing in the least conserved region of the enzyme may reflect another mechanism of gene evolution in eukaryotes.
5-Aminolevulinate Synthetase↗
MRI in diabetes insipidus due to metastatic breast carcinoma.
Magnetic resonance imaging (MRI) has been established as a valuable imaging modality in the evaluation of pituitary disorders. We describe three women with known carcinoma of the breast, who presented acutely with biochemically proven diabetes insipidus (DI), in whom MRI was used as the primary investigative tool. The patients were studied using a 1.5T superconducting system, with gadolinium enhancement in two cases. All three had thickened pituitary stalks and two had complete loss of the normal high signal from the posterior lobe of the pituitary gland. Two also had enlargement of the anterior pituitary gland. One subject was also noted to have other metastases to the brain. All three had multiple secondary deposits elsewhere in the body and one had metastases to the clivus but without evidence of extension to the pituitary fossa. DI is uncommon in systemic cancers and anterior pituitary dysfunction much more so, due to the separate blood supply of the two lobes. Thickening of the stalk has not been found frequently in large autopsy series. In the clinical context of DI in a patient with a known primary tumour the loss of high signal from the posterior lobe and stalk thickening are indicative of infiltration by metastases. A pituitary mass or metastases to adjacent bones are not necessary for diagnosis.
Acute Disease↗
Non-invasive assessment of the Circle of Willis using transcranial pulsed Doppler ultrasound with angiographic correlation.
The ability of transcranial pulsed Doppler ultrasound (TCD) to provide a dynamic assessment of the functional capability of the Circle of Willis was assessed using conventional cerebral angiography for anatomic correlation. Eleven patients had normal four-vessel cerebral angiography prior to being investigated with ultrasound. Angiography and ultrasound both demonstrated a functional anterior communicating artery in nine of the eleven patients, giving complete agreement between the two techniques. Posterior communicating arteries were visualized angiographically in all eleven patients. Ultrasound identified bilateral functional vessels in nine, the other two patients having non-functional vessels. In these latter two patients, angiography demonstrated three of the four posterior communicating arteries to be hypoplastic and it was uncertain whether these vessels carried significant blood flow. The fourth posterior communicating artery was shown to have an absent proximal segment of the ipsilateral posterior cerebral artery, with a persistent fetal posterior communicating artery. This anatomical variation is a potential limitation of ultrasound for assessing functional posterior communicating arteries. These preliminary results indicate that a combination of the anatomical (angiographic) and dynamic (ultrasonic) data may prove to be complementary for assessing the Circle of Willis.
Adult↗
Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia.
We have identified a compound dinucleotide repeat within intron 7 of the human erythroid 5-aminolevulinate synthase (ALAS2) gene with a minimum of 9 alleles and heterozygosity of 78%. ALAS2 was placed on the multipoint linkage map of the X chromosome in the pericentromeric region with the locus order: pter-(DXS255, TFE3, DXS146)-(DXS14, ALAS2, DXZ1)-AR-(DXS153, DXS159)-qter. No recombination was observed between ALAS2 and the centromere marker DXZ1. As ALAS2 has recently been shown to be the defective locus in X-linked pyridoxine-responsive sideroblastic anemia (PRSA), the ALAS2 marker has allowed placement of the gene for PRSA into the multipoint linkage map of the X chromosome. With the previous exclusion of close linkage between DXS14 and sideroblastic anemia with ataxia, our data show that there are at least two loci for X-linked sideroblastic anemia.
5-Aminolevulinate Synthetase↗
The spinal cord in neurologically stable spina bifida: a clinical and MRI study.
MRI scans of the brain and spinal cord, together with neurological and urological assessments, were carried out on 20 young people (aged between eight and 22 years) who had had surgical treatment of spina bifida in early life and in whom there had been no deterioration of spinal cord function. 19 were imaged successfully. The cord was tethered in all and it was low-lying in 18. Five had cavities within the cord; other abnormalities included cord thinning, lipomas and diastematomyelia. The relationship of these findings to subsequent deterioration and the use of MRI in these patients are discussed. These abnormalities, found in the absence of clinical deterioration, throw fresh light on the natural history of this condition.
Adolescent↗
Calcium channel blockers inhibit amiloride-stimulated short-circuit current in frog tadpole skin.
The larval frog skin has a very high electrical resistance and a corresponding low rate of transepithelial ion transport. Amiloride, a blocker of sodium transport in adult skin, transiently stimulates rather than inhibits short-circuit current (Isc) across larval skin. The time course and concentration response to amiloride and the effects of calcium channel blockers on Isc were studied with larval frog skin mounted in modified Ussing chambers. The amiloride (1 mM) transient was markedly blunted if the skin was previously exposed to low amiloride (0.01-0.1 mM) concentrations. The calcium channel blockers verapamil, nitrendipine, diltiazem, W-7, and lanthanum all blocked the amiloride transient. Diltiazem itself caused a rapid transient in Isc, indicating that it may be a partial agonist. These data suggest that the amiloride-stimulated cation channels rapidly desensitize in a manner similar to the acetylcholine receptor. The decline in Isc after amiloride stimulation could be caused by amiloride block of the open channel. Blockade of amiloride stimulation by well-known calcium channel blockers suggests that these larval cation channels may have some characteristics in common with calcium channels.
Amiloride↗
Human erythroid 5-aminolevulinate synthase: promoter analysis and identification of an iron-responsive element in the mRNA.
5-Aminolevulinate synthase (ALAS) catalyzes the first step of the heme biosynthetic pathway. cDNA clones for the human erythroid ALAS isozyme were isolated from a fetal liver library. It can be deduced that the erythroid ALAS precursor protein has a molecular weight of 64.6 kd, and is similar in size to the previously isolated human housekeeping ALAS precursor of molecular weight 70.6 kd. The mature mitochondrial forms of the erythroid and housekeeping ALAS isozymes are predicted to have molecular weights of 59.5 kd and 64.6 kd, respectively. The two isozymes show little amino acid identity in their N-terminal signal sequences but have considerable sequence identity in the C-terminal two-thirds of their proteins. An analysis of the immediate promoter of the human erythroid ALAS gene revealed several putative erythroid-specific cis-acting elements including both a GATA-1 and an NF-E2 binding site. An iron-responsive element (IRE) motif has been identified in the 5'-untranslated region of the human erythroid ALAS mRNA, but is not present in the housekeeping ALAS mRNA. Gel retardation experiments established that this IRE motif formed a protein - RNA complex with cytosolic extracts from human K562 cells and this binding was strongly competed with IRE transcripts from ferritin or transferrin receptor mRNAs. A transcript of the ALAS IRE, mutated in the conserved loop of the IRE, did not readily form this protein - RNA complex. These results suggest that the IRE motif in the ALAS mRNA is functional and imply that translation of the mRNA is controlled by cellular iron availability during erythropoiesis.
5-Aminolevulinate Synthetase↗
Dural sinus thrombosis. Diagnosis and follow-up by magnetic resonance angiography and imaging.
Magnetic resonance imaging has been reported to have advantages over conventional angiography in the diagnosis of dural sinus thrombosis. A case report is presented describing the application of MR techniques including MR angiography, to diagnose and monitor therapy for dural sinus thrombosis.
Adult↗
A comparison of CT and MRI in the assessment of the pituitary and parasellar region.
We have carried out a prospective study to compare high resolution thin slice, contrast-enhanced, axial computed tomography (CT) with unenhanced magnetic resonance imaging (MRI) at 1.5T in the assessment of the pituitary and parasellar region. Forty patients with suspected pituitary disease presenting to an endocrine unit were studied. MRI was superior to CT for the identification of the posterior pituitary and pituitary stalk and was better at showing the cystic nature of tumours. Visualization of the optic chiasm and assessment of displacement of the optic chiasm and the carotid arteries were also better with MRI. CT was equally good at showing cavernous sinus displacement or invasion, sphenoid sinus invasion and erosion of the floor of the sella turcica and was the only technique able to show calcification of the gland. More focal abnormalities were seen in the pituitary gland with CT than with unenhanced MRI, but there was a higher false positive rate for microadenoma detection with CT. All the scans were interpreted separately by three observers, two radiologists and one clinician. The percentage agreement between the observers for the identification of pituitary and parasellar structures was better for MRI than for CT and the clinician in particular found interpretation of the MR images easier. MRI thus not only gives more information overall than CT but it is a more reliable technique between different observers for the assessment of the pituitary and parasellar region.
Aged↗
Registration of MR and CT images for skull base surgery using point-like anatomical features.
We have developed a registration technique for combining magnetic resonance imaging (MRI) and computed tomography (CT) images of the skull base for use in surgical planning. The technique is based on user identification of point-like landmarks visible in both modalities. The combination of images involves a small amount of expert interaction, is relatively quick and preliminary evaluation indicates that it is accurate to within 1.5 mm. Registered or fused images can be viewed either on an image processing workstation, or fused images can be printed onto conventional film for convenience in clinical use. We present one patient in order to demonstrate the technique's indications and advantages.
Humans↗