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Biomedical subjects

T C Cox

Publications and source records attributed to T C Cox.

At least 73 records · Page 4Linked to original sources
PubMed1991

X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.

Molecular linkage analysis was performed on a kindred with X-linked sideroblastic anemia and ataxia. Two-point analysis with a DNA probe for phosphoglycerate kinase (PGK1), which maps to Xq13, suggested linkage to the disorder by a lod score of at least 2.60 at a recombination fraction of zero. The disease in this kindred appears to be clinically and genetically distinct from that in previously reported families with X-linked hereditary ataxia or spastic paraparesis. No mapping data are available for inherited X-linked sideroblastic anemia without neurologic abnormalities. However, structural alterations of band Xq13 may be involved in the development of idiopathic acquired sideroblastic anemia. No alterations in the restriction patterns of two X-linked genes involved in erythrocyte formation-i.e., a DNA-binding protein (GF-1) and 5-aminolevulinate synthase (ALAS)-were detected in DNA from affected males, arguing against a large deletion in either of these candidate genes.

Anemia, Sideroblastic↗
PubMed1990

Effects of isoproterenol on Na+ and K+ transport in frog skin epithelium.

The acute effects of isoproterenol on Na+ extrusion and K+ uptake across the basolateral membrane of the isolated epithelium of the frog skin were examined. A chloride-free sulfate Ringer was used in all experiments. Isoproterenol caused an approximate doubling of the short-circuit current (Isc) and the transepithelial Na+ flux (J13Na). Isc remained equal to J13Na. After isoproterenol treatment, ouabain inhibited Isc and J13Na in a manner similar to control tissues. Ouabain-sensitive K+ uptake was also measured under comparable conditions. In two sets of experiments, K+ uptake was increased on average by only 5 and 17 percent after isoproterenol treatment. Thus, isoproterenol caused Na+ flux to more than double while K+ uptake increased by only 5-17%. These data cannot be readily accounted for by a pump with a fixed Na+/K+ exchange ratio.

Animals↗
PubMed1990

Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation.

Serial cranial computed tomograms were carried out in 136 children with acute lymphoblastic leukaemia who were receiving 24 Gy or 18 Gy of cranial irradiation and continuing treatment with doses of methotrexate given weekly orally or intramuscularly. The findings were correlated with treatment variables, the development of fits, and the intelligence quotient (IQ). Reversible brain shrinkage, attributed to treatment with steroids, was found on 87 of 114 initial scans (76%); 14 showed changes in white matter during treatment (10%), and calcification was found in 13 either during or after treatment (10%). Eight children (6%) had fits, and in six of the eight there were changes in white matter or calcification on the scans. Comparison of the two radiotherapy dosages showed no difference in the incidence of abnormalities seen on computed tomography, fits, or serial IQ measurements, but children receiving intramuscular methotrexate had a higher incidence of calcification and a lower mean IQ at one year than those who received the drug orally, although this difference was not apparent later. Younger children were more likely to develop changes on computed tomograms and fits, and to have low IQs on completion of treatment, with changes most apparent in those less than 2 years of age. There were highly significant correlations between abnormalities on computed tomography, fits, and IQ. These findings confirm the neurological vulnerability of younger children with acute lymphoblastic leukaemia, show an association between abnormalities on computed tomography and intellectual deficit, and suggest that methotrexate is more toxic when given intramuscularly than orally. They provide no evidence that 18 Gy of cranial irradiation is less toxic than 24 Gy, and indicate the need for alternative treatment regimens.

Administration, Oral↗
PubMed1990

Net basolateral potassium flux and short-circuit current in ouabain-treated frog skin.

A new technique has been developed to correlate K loss from cells (JK) across the basolateral membrane into a K-free ouabain Ringer solution and short-circuit current (Isc) for a model Na-transporting epithelium, the frog skin. Distinct differences were observed when the tissue was bathed in sulfate or chloride Ringer. In sulfate Ringer, K-free ouabain treatment caused both JK and Isc to decline in a nearly parallel fashion with time. JK-Isc was approximately 1 microA/cm2. In sulfate Ringer, isoproterenol caused parallel increases, whereas amiloride (apical side) caused parallel decreases in JK and Isc. In chloride Ringer, K-free ouabain treatment caused Isc to decline at a slightly faster rate than JK.JK-Isc was approximately 8 microA/cm2. Bumetanide decreased JK with very little effect on Isc. Barium caused small parallel changes in both Isc and JK. Amiloride decreased Isc with very little effect on JK. These experiments show that after ouabain treatment changes in JK from the cells across the basolateral membrane can largely account for changes in Isc. However, JK also occurs via neutral mechanisms and perhaps from cells not related to the transport pathway, demonstrating that there is not always a tight coupling of K loss at the basolateral membrane with Na entry across the apical membrane.

Animals↗
PubMed1990

Molecular regulation of 5-aminolevulinate synthase. Diseases related to heme biosynthesis.

All nucleated animal cells synthesize heme to provide the prosthetic group of respiratory cytochromes. Large amounts of heme are synthesized by erythroid cells for hemoglobin production and by liver cells for drug-induced cytochromes P450. This review focuses on the first enzyme of the heme biosynthetic pathway, 5-aminolevulinate synthase (ALAS), which catalyzes the rate-controlling step in liver and possibly other tissues. We report that there are two distinct human genes for ALAS: one, a housekeeping gene, is probably ubiquitously expressed while the other is active only in erythroid tissue. By contrast it has been reported that, for porphobilinogen deaminase, the third enzyme of the heme pathway, there is a single human gene with two promoters; one functional in all tissues, the other erythroid specific. In liver, transcription of the housekeeping ALAS gene is induced by drugs and repressed by heme. Heme also acts in a novel way to prevent transport of ALAS into mitochondria, its site of function. Porphyrias result from inherited defects in enzymes of the heme pathway subsequent to ALAS and the molecular abnormality is now known for the most common subtype of acute intermittent porphyria. In developing red cells, levels of ALAS are regulated by increased gene transcription and by a post-transcriptional mechanism, in which iron most probably controls translation of erythroid ALAS mRNA through an iron-responsive element identified in the 5' untranslated region of the mRNA. The human erythroid ALAS gene is located on the X-chromosome, suggesting that a defect in this gene may be responsible for X-linked sideroblastic anemias.

5-Aminolevulinate Synthetase↗
PubMed1990

Erythroid 5-aminolevulinate synthase is located on the X chromosome.

The gene for erythroid 5-aminolevulinate synthase has been mapped to Xpter-Xq26 by Southern blot hybridization analysis of a mouse/human hybrid cell panel. In situ hybridization maps the gene to Xp21-Xq21, with the most likely location being on band Xp11.2. The mapping of the erythroid 5-amino-levulinate synthase gene to the X chromosome suggests that a defect in this gene may be the primary cause of X-linked sideroblastic anemia.

5-Aminolevulinate Synthetase↗
PubMed1989

Temporal bone venous anomaly of surgical significance.

Variability in the size of the dural sinuses and jugular bulb is not uncommon and usually manifests as a high jugular bulb encroaching upon the floor of the middle ear. A rarer entity is the superior and medial extension of the jugular bulb into the bone of the posterior wall of the internal auditory meatus. We report a case where this anomaly was encountered during acoustic neuroma surgery making exposure of the fundus of the internal auditory meatus technically impossible. The possibility of a communication with the superior petrosal sinus is discussed.

Female↗
PubMed1988

Potassium dependence of sodium transport in frog skin.

22Na+ and 42K+ fluxes across the basolateral membrane of the isolated epithelium of frog skin were investigated with regard to dependence on K+ in the basolateral solution. When K+ was removed from the basolateral solution (K+-free Ringer), there was a transient rise in short circuit current (Isc) that could be eliminated by pretreatment with ouabain. Concurrently, the apparent sodium efflux across the basolateral membrane (JNa*13) showed either no change or an immediate (1-2 min) small decrease (approximately equal to 10%) that was followed by a small transient increase. K+ fluxes showed either no change or a small decrease under these conditions. JNa*13 was partially ouabain sensitive during all of the above treatments. Furosemide partially inhibited both sodium and potassium flux after K+-free treatment. The pump, as defined by ouabain sensitivity of Na+ flux, continued to work even after 20 minutes of K+-free treatment. Pump activity may be maintained by potassium leaking from the cells that is recycled by the pump. However, the ouabain-sensitive transient rise in Isc after K+-free treatment cannot readily be explained by changes in either Na+ or K+ flux. A change in pump coupling ratio provides one explanation for these data.

Animals↗
PubMed1987

Effect of verapamil on in vitro cytotoxicity of adriamycin and vinblastine in human tumor cells.

Verapamil has been shown to reverse acquired drug resistance to Adriamycin (ADR) and vinblastine in the P388 leukemia and Ehrlich ascites carcinoma model systems. Because of its potential clinical application, we evaluated the ability of verapamil to modulate the effect of ADR and vinblastine on the in vitro cloning of fresh human tumor cells. Fifty-three tumors were cloned in a soft agar system. Continuous exposure to verapamil at concentrations of 1.0, 5.0, and 10.0 micrograms/ml, did not significantly modulate the overall inhibitory activity of ADR and vinblastine (P greater than 0.05). There was no evidence of an effect when results were analyzed by tumor type or previous treatment except in the subgroup of 13 tumors obtained from patients who previously had a clinical response to ADR but were relapsing at the time the tumor specimen was obtained. In this population, at three concentrations of ADR, there was a significant modulation of drug effect (P = 0.10, 0.03, 0.03, respectively). In each subgroup, some tumors showed marked modulation of drug effect by verapamil. These results suggest that the mechanisms of acquired in vivo resistance to ADR may be similar to those occurring in cell lines. However, the effect on human tumors was minor as compared to the results with cell lines. The in vivo significance of this finding remains to be determined.

Breast Neoplasms↗
PubMed1987

Dihydroouabain, a reversible inhibitor of the sodium pump in frog skin.

In many studies of the sodium pump in epithelia, a readily reversible analog of ouabain would be most useful. This would enable studies of pump activity to be made under control and experimental conditions on the same tissue. Of three compounds examined on the basolateral membrane of the isolated epithelia of frog skin, dihydroouabain (DHO) had characteristics very similar to ouabain except that it was apparently much more reversible. DHO (1 mmol/l) inhibited short circuit current (Isc) and transepithelial Na flux (JNa13) in a fashion similar to ouabain. Isc was inhibited from 17.0 +/- 2.5 to 10.2 +/- 1.0 microA/cm2 in 2-4 min while JNa13 was decreased from 16.8 +/- 1.9 to 4.7 +/- 0.8 microA/cm2 in the same time interval. After 60 min of washout, Isc and JNa13 recovered to about 70% of control values and were nearly equal. In another set of experiments, the washout of DHO and ouabain were compared directly on the same tissue. Sodium flux recovered four times faster after removal of DHO when compared to ouabain. Pretreatment of tissues with DHO prior to ouabain greatly increased the rate of Na flux recovery after washout of both drugs suggesting that DHO competes for ouabain sites. These data suggest that DHO can be used as a reversible analog for ouabain in studies of the Na pump in frog skin.

Animals↗
PubMed1986

Na+ and K+ transport at basolateral membranes of epithelial cells. I. Stoichiometry of the Na,K-ATPase.

The stoichiometry of pump-mediated Na/K exchange was studied in isolated epithelial sheets of frog skin. 42K influx across basolateral membranes was measured with tissues in a steady state and incubated in either beakers or in chambers. The short-circuit current provided estimates of Na+ influx at the apical membranes of the cells. 42K influx of tissues bathed in Cl- or SO4-Ringer solution averaged approximately 8 microA/cm2. Ouabain inhibited 94% of the 42K influx. Furosemide was without effect on pre-ouabain-treated tissues but inhibited a ouabain-induced and Cl--dependent component of 42K influx. After taking into account the contribution of the Na+ load to the pump by way of basolateral membrane recycling of Na+, the stoichiometry was found to increase from approximately 2 to 6 as the pump-mediated Na+ transport rate increased from 10 to 70 microA/cm2. Extrapolation of the data to low rates of Na+ transport (less than 10 microA/cm2) indicated that the stoichiometry would be in the vicinity of 3:2. As pump-mediated K+ influx saturates with increasing rates of Na+ transport, Na+ efflux cannot be obligatorily coupled to K+ influx at all rates of transepithelial Na+ transport. These results are similar to those of Mullins and Brinley (1969. Journal of General Physiology. 53:504-740) in studies of the squid axon.

Animals↗
PubMed1986

Na+ and K+ transport at basolateral membranes of epithelial cells. II. K+ efflux and stoichiometry of the Na,K-ATPase.

Changes of 42K efflux (J23K) caused by ouabain and/or furosemide were measured in isolated epithelia of frog skin. From the kinetics of 42K influx (J32K) studied first over 8-9 h, K+ appeared to be distributed into readily and poorly exchangeable cellular pools of K+. The readily exchangeable pool of K+ was increased by amiloride and decreased by ouabain and/or K+-free extracellular Ringer solution. 42K efflux studies were carried out with tissues shortcircuited in chambers. Ouabain caused an immediate (less than 1 min) increase of the 42K efflux to approximately 174% of control in tissues incubated either in SO4-Ringer solution or in Cl-Ringer solution containing furosemide. Whereas furosemide had no effect on J23K in control tissues bathed in Cl-rich or Cl-free solutions, ouabain induced a furosemide-inhibitable and time-dependent increase of a neutral Cl-dependent component of the J23K. Electroconductive K+ transport occurred via a single-filing K+ channel with an n' of 2.9 K+ efflux before ouabain, normalized to post-ouabain (+/- furosemide) values of short-circuit current, averaged 8-10 microA/cm2. In agreement with the conclusions of the preceding article, the macroscopic stoichiometry of ouabain-inhibitable Na+/K+ exchange by the pump was variable, ranging between 1.7 and 7.2. With increasing rates of transepithelial Na+ transport, pump-mediated K+ influx saturated, whereas Na+ efflux continued to increase with increases of pump current. In the usual range of transepithelial Na+ transport, regulation of Na+ transport occurs via changes of pump-mediated Na+ efflux, with no obligatory coupling to pump-mediated K+ influx.

Amiloride↗
PubMed1986

Na+ and K+ transport at basolateral membranes of epithelial cells. III. Voltage independence of basolateral membrane Na+ efflux.

Na+ efflux across basolateral membranes of isolated epithelia of frog skin was tested for voltage sensitivity. The intracellular Na+ transport pool was loaded with 24Na from the apical solution and the rate of isotope appearance in the basolateral solution (JNa23) was measured at timed intervals of 30 s. Basolateral membrane voltage was depolarized by either 50 mM K+, 5 mM Ba++, or 80 mM NH+4. Whereas within 30 s ouabain caused inhibition of JNa23, depolarization of Vb by 30-60 mV caused no significant change of JNa23. Thus, both pump-mediated and leak Na+ effluxes were voltage independent. Although the pumps are electrogenic, pump-mediated Na+ efflux is voltage independent, perhaps because of a nonlinear relationship between pump current and transmembrane voltage. Voltage independence of the leak Na+ efflux confirms a previous suggestion (Cox and Helman, 1983. American Journal of Physiology. 245:F312-F321) that basolateral membrane Na+ leak fluxes are electroneutral.

Ammonia↗
PubMed1986

Infarction of a growth hormone-secreting macroadenoma during a TRH test.

Pituitary infarction occurring immediately after TRH injection (200 micrograms) is reported in a patient with gigantism due to a growth hormone-secreting pituitary macroadenoma. Evidence of infarction was seen in CSF and in serial CT scans. Regression of symptoms and sign of acromegaly, abolition of abnormal growth hormone secretion, and virtually complete anterior and partial posterior pituitary failure rapidly followed. The infarction was probably initiated by a hypertensive response to TRH. TRH testing in acromegalic subjects may require smaller doses of TRH to avoid unwanted pressor responses.

Acromegaly↗
PubMed1985

Action of polyvalent cations on sodium transport across skin of larval and adult Rana catesbeiana.

The actions of alkaline earth (AE) and transition element (TE) cations on Na+ transport across skin of larval and adult Rana catesbeiana were compared. Bathed on the outside by Ca+2-free Ringer's, both larval and adult skins maintained a stable short-circuit current (3-4 mu Amps cm-2 for larval skin and 20-30 mu Amps cm-2 for adult skin). Addition of Ca+2 to the external bath reduced the SCC; maximal inhibition was about 36% for larval skin and 22% for adult skin. Other AE divalent cations were also inhibitory. The order of effectiveness was: Ba+2 = Ca+2 greater than Sr+2 greater than Mg+2 for larval skin and Ba+2 greater than Ca+2 = Mg+2 for adult skin. Sodium influx was markedly elevated when Ca+2 was removed from the external medium. Current-voltage analysis indicated that Ca+2 increases the resistance of the active pathway without affecting the shunt resistance or the electromotive force of Na+ transport (ENa) in larval and adult skins. The SCC across adult skin was stimulated by TE cations (Co+2, Cd+2, La+3). These ions were inhibitory on larval skin. The transition in the response occurred at stage XXI. The inhibitory effect of TE on larvel skin resembles that seen in response to AE cations and we postulate a common mechanism. Since larval skin lacks the selective Na+ channels found in apical membranes of adult skin, we infer that the mechanism of inhibition by AE cations is not on these channels. A more general phenomenon such as change in surface charge at the apical membrane seems more reasonable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Measurement of blood flow, oxygen utilisation, oxygen extraction ratio, and fractional blood volume in human brain tumours and surrounding oedematous tissue.

The blood flow, oxygen utilisation, oxygen extraction ratio, and fractional blood volume were measured in brain tumours and the surrounding cerebral tissues. A total of 21 patients were studied. These included 10 primary tumours, eight secondary and three with unknown histology. Measurements were performed using the oxygen-15 steady state inhalation technique and positron emission tomography. Within the tumours no relation between blood flow, oxygen utilisation and blood volume was found. In all tumours oxygen supply was in excess of the oxygen demand of the tissues as reflected in oxygen extraction ratios that were lower than those of normal brain tissue. No indication of local ischaemia in peritumour oedema was found.

Blood Volume↗
PubMed1984

Evidence of vascular disease from CT scanning in late onset epilepsy.

The CT scans of 74 patients presenting with late-onset epilepsy not due to cerebral tumour were compared with those of an age and sex-matched control group for evidence of cerebral vascular disease. Changes in the scan indicative of cerebral atrophy (enlarged ventricles and cortical sulci) were seen in similar numbers in both patients and controls. However, the scans revealed a highly significant excess of ischaemic lesions in the epileptic patients, in the form of discrete areas of infarction and low attenuation of the periventricular white matter. These changes, which were only seen in two of the controls, were present in 13 of the epileptic patients. The median age at the onset of epilepsy in the 13 patients with ischaemic lesions was 62 years, and they showed an increased incidence of systemic vascular disease and of abnormal neurological signs. In six of the 13 cases, however, clinical examination was normal and CT scanning provided the only evidence of underlying vascular disease.

Adult↗