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Sm–Nd isotopic data are presented for 23 drill-core samples from five aeromagnetically and geochronologically (U–Pb zircon) distinct domains of the Precambrian basement of northern Alberta. The domains in question are the Taltson (1.96–1.94 Ga), Buffalo Head (2.32–1.99 Ga), Chinchaga (2.19–2.09 Ga), Ksituan (1.99–1.90 Ga), and Nova (2.81 Ga). These domains are truncated to the north and south by the Great Slave Lake shear zone and the Snowbird tectonic zone, respectively.Initial εNd values are −5.0 to −9.7 for the Taltson, +0.2 to −6.3 for the Buffalo Head, +0.6 to −1.8 for the Chinchaga, −1.8 to −2.1 for the Ksituan and +5.6 for the Nova. Crustal residence model ages fall in the 2.5–2.8 Ga range. The Nd isotopic signatures may be viewed in terms of mixing a minimum of 10% Archean continental crust with a depleted-mantle component. Speculations on the tectonic history of the basement domains in question involve the assembly of Archean crustal nuclei to form the Buffalo Head – Chinchaga composite domain. Arc magmatism resulting from plate subduction to the east and west of the Buffalo Head – Chinchaga composite domain would have generated the Taltson and Ksituan domains. The Nd isotopic data suggest that the basement of northern Alberta consists of crust of late Archean crustal residence age which has been extensively remobilized in the Early Proterozoic.

s, 15: A4. ARMSTRONG, R. L., TAUBENECK, W. H., and HALES, P. 0.1977. Rb-Sr and K-Ar geochronometry of Mesozoic granitic rocks and their Sr isotopic composition, Oregon, Washington and Idaho. Geological Society of America Bulletin, 88: 39741 1. BALLY, A. W., GORDY, P. L., and STEWART, G. A. 1966. Structure, seismic data and orogenic evolution of southern Canadian Rockies. Bulletin of Canadian Petroleum Geology, 14: 337-381. BENNETT, V. C., and DEPAOLO, D. J. 1987. Proterozoic crustal history of the western United States as determined by neodymium isotopic mapping. Geological Society of America Bulletin, 99: 674-685. BERRY, M. J., JACOBY, W. R., NIBLEIT, E. R., and STACEY, R. A. 1971. A review of geophysical studies in the Canadian Cordillera. Canadian Journal of Earth Sciences, 8: 788-801. BOWRING, S. A., and PODOSEK, F. P. 1989. Nd isotopic evidence from Wopmay Orogen for 2.0-2.4 Ga crust in western North America. Earth and Planetary Science Letters, 94: 217-230. BURWELL, A. D. M. 1975. Rb-Sr isotope geochemistry of lherzolites and their constituent minerals from Victoria, Australia. Earth and Planetary Science Letters, 28: 69-78. CAMPBELL, R. B. 1968. Canoe River, British Columbia. Geological Survey of Canada, Map 15-1967. CARR, S. D., and BROWN, R. L. 1990. Southern Cordilleran Lithoprobe transect lines 6 to 10: crustal structure and tectonic chronology. Southern Canadian Cordillera Transect Workshop, March 3 4 , University of Calgary, Calgary, Alta., pp. 10-18. COLLERSON, K. D., VAN SCHMUS, W. R., LEWRY, J. F., and BICKFORD, M. E. 1988. Buried Precambrian basement in south-central Saskatchewan: provisional results from Sm-Nd model ages and U-Pb zircon geochronology. In Summary of investigations 1988. Saskatchewan Geological Survey, Miscellaneous Report 88-4, pp. 142-150. COOK, F. A., SIMONY, P. S., COFLIN, K. C., GREEN, A. G., MILKEREIT, B., PRICE, R. A., PARRISH, R., PATENAUDE, C., GORDY, P. L., and BROWN, R. L. 1987. Lithoprobe southern Canadian Cordilleran transect: Rocky Mountain thrust belt to Valhalla gneiss complex. Geophysical Journal of the Royal Astronomical Society, 89: 91

Two undeformed biotite granites recovered from exploratory hydrocarbon drill holes that penetrated basement in the Fort Simpson magnetic high were analyzed for U–Pb zircon geochronology and Sm–Nd isotopic composition. Both samples give crystallization ages of 1845 Ma, with errors of less than 5 Ma. This age overlaps with the waning stages of magmatism in the Great Bear magmatic zone of Wopmay Orogen, 200 km to the east. One sample has an initial εNd of +1.3 and a TDM of 2.14 Ga, whereas the other yielded an initial εNd of −2.1 and a TDM of 2.45 Ga. The latter sample indicates that Early Proterozoic light rare-earth element enriched lithosphere with a crustal history dating back to at least 2.45 Ga is present in the subsurface west of Wopmay Orogen.

It has recently been shown that transition metal cations Zn2+ and Cu2+ bind to histidine residues of nerve growth factor (NGF) and other neurotrophins (a family of proteins important for neuronal survival) leading to their inactivation. Experimental data and theoretical considerations indicate that transition metal cations may destabilize the ionic form of histidine residues within proteins, thereby decreasing their pK(a) values. Because the release of transition metal cations and acidification of the local environment represent important events associated with brain injury, the ability of Zn2+ and Cu2+ to bind to neurotrophins in acidic conditions may alter neuronal death following stroke or as a result of traumatic injury. To test the hypothesis that metal ion binding to neurotrophins is influenced by pH, the effects of Zn2+ and Cu2+ on NGF conformation, receptor binding and NGF tyrosine kinase (trkA) receptor signal transduction were examined under conditions mimicking cerebral acidosis (pH range 5.5-7.4). The inhibitory effect of Zn2+ on biological activities of NGF is lost under acidic conditions. Conversely, the binding of Cu2+ to NGF is relatively independent of pH changes within the studied range. These data demonstrate that Cu2+ has greater binding affinity to NGF than Zn2+ at reduced pH, consistent with the higher affinity of Cu2+ for histidine residues. These findings suggest that cerebral acidosis associated with stroke or traumatic brain injury could neutralize the Zn2+-mediated inactivation of NGF, whereas corresponding pH changes would have little or no influence on the inhibitory effects of Cu2+. The importance of His84 of NGF for transition metal cation binding is demonstrated, confirming the involvement of this residue in metal ion coordination.

Activation of the Ras pathway is central to mitogenesis by a variety of growth factors such as the epidermal growth factor, platelet-derived growth factor, or hepatocyte growth factor. Ras activation requires the function of adaptors such as growth factor receptor-binding protein 2, which can bind either directly or indirectly through Src homology 2 domains to the activated receptor. To examine the role of the Src homology 2 domain of growth factor receptor-binding protein 2 in the mitogenic response triggered by these growth factors, we introduced a peptide (PVPE-phosphono-methylphenylalanine-INQS) that can selectively bind this domain into mouse, rat, or human cells growing on conductive indium-tin oxide-coated glass by in situ electroporation. Cells were subsequently stimulated with growth factors and assessed for activation of a downstream target, extracellular signal-regulated kinase (ERK) 1/2, by probing with antibodies specific for its activated form. Electrodes and slides were configured to provide nonelectroporated control cells side by side with the electroporated ones, both growing on the same type of indium-tin oxide-coated glass surface. The data demonstrate that the peptide can cause a dramatic inhibition of epidermal growth factor or platelet-derived growth factor-mediated ERK1/2 activation and DNA synthesis in vivo, compared with its control phenylalanine-containing counterpart. In contrast, the peptide had a very limited effect on hepatocyte growth factor-triggered ERK1/2 activation and DNA synthesis. These results demonstrate the potential of the in situ electroporation approach described here in the study of the coupling of activated receptor tyrosine kinases to the ERK1/2 cascade.

Ionising radiation remains one of the most effective tools in the therapy of cancer. It combines the properties of an extremely efficient DNA-damaging agent with a high degree of spatial specificity. Nonetheless, there remain considerable differences in the outcome for treatment of tumours of differing histological type treated by radiotherapy. Tumours arising from lymphoid or germ cells are significantly more radiocurable than most solid tumours of epithelial origin. The molecular mechanisms underlying such differences in cellular radiosensitivity are the subject of current research. When normal mammalian cells are subjected to stress signals--e.g. radiation, chemotherapeutic drugs, oxygen deficiency--a range of gene products involved in the sensing and signalling of such stresses are activated. The response of eukaryotic cells to ionising radiation includes activation of DNA repair pathways and cell cycle checkpoints, with subsequent full 'biological' recovery or cell death. Radiation induces two different modes of cell death termed mitotic or clonogenic cell death, and apoptosis. Until recent years, there was surprisingly little mechanistic understanding of the events following induction of physical damage by radiation and biological outcome for the cell. There have been recent major advances in our understanding of the signal transduction pathways involved in determining the fate of cells after irradiation.

Ascorbate is a well-known reducing agent, but it can generate oxidative potential under appropriate condition. In rat cerebral cortex homogenate, 1 mM ascorbate decreased thiobarbituric acid-reactive substances (TBARS) content to 86% +/- 4% of control values, confirming that ascorbate is a reducing agent. However, ascorbate increased TBARS, in a dose-related manner, in slices prepared from cerebral cortex. Ferrous ion (Fe2+) had little effect on ascorbate-induced lipid oxidation in cortical slices, and EDTA did not have an influence on the ascorbate-induced oxidative action. Conversely, ascorbate plus Fe2+ elevated TBARS content to more than threefold over ascorbate alone in tissue homogenates. In summary, ascorbate is a reducing agent in the brain tissue homogenate but has an oxidizing effect in brain slices. A hypothesis is proposed to explain the oxidative effects of ascorbate in cortical slices, wherein extracellular ascorbate is oxidized to dehydroascorbate, which is rapidly carried into the cells via a glucose transporter (GLUT). The dehydroascorbate in cytosol is then reduced back to ascorbate, and, during the reduction process, cellular components are oxidized.

There is growing evidence that nerve growth factor (NGF) may function as a mediator of persistent pain states. We have identified a novel nonpeptidic molecule, ALE-0540, that inhibits the binding of NGF to tyrosine kinase (Trk) A or both p75 and TrkA (IC50 5.88 +/- 1. 87 microM, 3.72 +/- 1.3 microM, respectively), as well as signal transduction and biological responses mediated by TrkA receptors. ALE-0540 was tested in models of neuropathic pain and thermally-induced inflammatory pain, using two routes of administration, a systemic i.p. and a spinal intrathecal (i.th.) route. Morphine was also tested for comparison in the antiallodynia model using mechanical stimuli. We show that either i.p. or i.th. administration of ALE-0540 in rats produced antiallodynia in the L5/L6 ligation model of neuropathic pain. The calculated A50 values (and 95% confidence intervals) for ALE-0540 administered i.p. and i. th. were 38 (17.5-83) mg/kg and 34.6 (17.3-69.4) microgram, respectively. ALE-0540 given i.th., at doses of 30 and 60 microgram, also blocked tactile allodynia in the thermal sensitization model. Although morphine displayed greater potency [A50 value of 7.1 (5.6-8. 8) mg/kg] than ALE-0540 in anti-allodynic effect when given i.p. to L5/L6-ligated rats, it was not active when administered i.th. These data suggest that a blockade of NGF bioactivity using a NGF receptor antagonist is capable of blocking neuropathic and inflammatory pain and further support the hypothesis that NGF is involved in signaling pathways associated with these pain states. ALE-0540 represents a nonpeptidic small molecule which can be used to examine mechanisms leading to the development of agents for the treatment of pain.

Equilibrium binding of 125I-nerve growth factor (125I-NGF) to cells coexpressing the tyrosine kinase receptor A (TrkA) and common neurotrophin receptor (p75NTR), cells coexpressing both receptors where p75NTR is occupied, and cells expressing only p75NTR, revealed reciprocal modulation of receptor affinity states. Analysis of receptor affinity states in PC12 cells, PC12 cells in the presence of brain-derived neurotrophic factor (BDNF), and PC12nnr5 cells suggested that liganded and unliganded p75NTR induce a higher affinity state within TrkA, while TrkA induces a lower affinity state within p75NTR. These data are consistent with receptor allosterism, and prompted a search for TrkA/p75NTR complexes in the absence of NGF. Chemical crosslinking studies revealed high molecular weight receptor complexes that specifically bound 125I-NGF, and were immunoprecipitated by antibodies to both receptors. The heteroreceptor complex of TrkA and p75NTR alters conformation and/or dissociates in the presence of NGF, as indicated by the ability of low concentrations of NGF to prevent heteroreceptor crosslinking. These data suggest a new model of receptor interaction, whereby structural changes within a heteroreceptor complex are induced by ligand binding.

Cytotoxicities induced by 1,1-dichloroethylene (DCE) are ascribed to cytochrome P450-dependent metabolism to an epoxide. Conjugation of the DCE-epoxide with glutathione (GSH) results in the formation of the conjugates 2-S-glutathionyl acetate (GTA) and 2-(S-glutathionyl) acetyl glutathione (GAG); GAG undergoes hydrolysis to form GTA, and thus GTA is a major metabolite of DCE metabolism. Our objective is to develop an antiserum against the chemically synthesized GTA, and for immunization, we have used a hapten that consists of GTA conjugated to bovine serum albumin (BSA) as the carrier protein and glutaraldehyde (GLUT) as a chemical cross-linker. The antisera were raised in rabbits and were characterized by using the following synthesized structural analogs: GTA, glycine-GLUT-BSA (GLY-GLUT-BSA), GTA-GLUT-ovalbumin (GTA-GLUT-OVB), GTA-1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-BSA (GTA-EDC-BSA), TRIS-GLUT-BSA, glutathione-GLUT-BSA (GSH-GLUT-BSA). The enzyme-linked immunosorbent assay (ELISA) and slot immunoblotting were used to characterize the specificity of the antisera. Noncompetitive ELISA experiments showed that the reaction of the antiserum with the antigen was concentration-dependent. In the competitive ELISA, GTA-GLUT-BSA inhibited binding efficiently; in contrast, the unconjugated GTA did not inhibit binding to the antigen. Competitive studies with the other analogs indicated low or minimal reactivities with the antibodies, which were blocked by incubation with GLY-GLUT-BSA. However, there was residual reactivity with the antigen that was not competitively inhibited by either the GTA-EDC-BSA or the GSH-GLUT-BSA conjugates. Slot-blotting experiments confirmed the findings of the ELISA studies and revealed high specificity of the antiserum to detect the hapten. These results demonstrated the successful development of polyclonal antibodies to detect GTA and hence DCE-epoxide.

The radiosensitive mutant xrs-6, derived from Chinese hamster ovary cell line CHO-K1, has been demonstrated to be defective in DNA double-strand break repair and also in its proficiency to undergo V(D)J recombination. Recent work has provided both genetic and biochemical evidence that the M(r) 80,000 subunit of the Ku protein is able to complement the radiosensitivity and the V(D)J recombination defect in the xrs-6 mutant. We demonstrate here that complementation of the radiosensitive phenotype in xrs-6 cells by the introduction of Ku80 cDNA is accompanied by the concomitant restoration of DNA double-strand break rejoining proficiency to almost that of the parental CHO-K1 cells, as measured both by neutral single-cell microgel electrophoresis (Comet) technique and by pulsed-field gel electrophoresis. These results provide further biochemical evidence for the involvement of the Ku protein in the repair of DNA double-strand breaks.

Loss of p53 function has been shown to cause increased resistance to ionizing radiation in normal murine cells; however, the role of p53 in radioresistance of human tumor cells is less clear. Since wild-type p53 function is required for radiation-induced G1 arrest, we measured G1 arrest in 12 human tumor cell lines that have a wide range of radiosensitivities (surviving fraction at 2 Gy, 0.11-0.8). We observed a significant correlation between the level of ionizing radiation-induced G1 arrest and radiosensitivity. Cell lines having G1 arrest are more radiosensitive. There is no correlation between maximal G2 arrest and radiosensitivity. Expression of a dominant-negative mutant of p53 (codon 143, Val to Ala) in transfectants of the radiosensitive human ovarian cell line A2780 abrogates the radiation-induced G1 arrest. Such mutant p53 transfectants are more resistant to ionizing radiation than the parental line and vector-alone transfectants, as measured by clonogenic assays. These results support the concept that wild-type p53 function is required for sensitivity of tumor cells to DNA-damaging agents, such as ionizing radiation, and that the loss of p53 function in certain human tumor cells can lead to resistance to ionizing radiation.

Summary Grey-scale ultrasound is a useful investigation in selected patients with a painful swollen leg. It is of particular value in cases in which there is a clinical suspicion of deep vein thrombosis (DVT) but other features, such as an atypical history or equivocal radiology, suggest alternative pathology. Five such cases are presented in which ultrasound showed transonic lesions. The cause of the swelling of the leg was thus shown to be ‘cystic’ in nature and therefore not due to DVT. This enabled inappropriate and potentially harmful therapy to be avoided and the correct therapy, such as surgical drainage, to be undertaken.

Scintiscans using technetium 99m sulphur colloid, and ultrasonic scans were carried out on 99 patients. Twentythree had normal livers, 21 had cirrhosis, 15 had tumour in the liver, six had obstructive jaundice, seven had fatty livers, five had abnormal livers without histological confirmation, six had cysts or abscesses of the liver, ten had miscellaneous conditions and in six one or other scan was unsatisfactory. In the normal group only two patients had abnormal scans by both methods, although ten had an abnormal isotope scan. In patients with cirrhosis both scans were usually abnormal. When tumour was present in the liver it was usually detected by the scintiscan, but in only half the ultrasonic scans could this abnormality be distinguished from that produced by obstructive jaundice or cirrhosis of the liver. The ultrasonic scan could distinguish cystic from solid lesions in the liver whereas the scintiscan could not.

The individual accuracies of A-scan and compound B-scan ultrasonography in the diagnosis of liver disease are similar. The development of neither technique is fully advanced, and it is to be expected that improvements in instrumentation and analysis will lead to better diagnostic accuracy. It is emphasised that the two methods are complementary, and a higher degree of accuracy is obtained when both methods are used together.

The use of combined isotope and ultrasonic scanning in the diagnosis of amoebic liver abscess is described, together with details of three cases of this condition seen in the Bristol area in a period of two years. The addition of ultrasonic scanning greatly increases the accuracy of diagnosis by demonstrating a fluid-filled, space-occupying lesion and should ideally be employed whenever liver abscess is suspected.

The incidence of ectopic pregnancy is higher in women who have an intrauterine contraceptive device (IUCD) (Vessy et al., 1974; Lehfeld et al., 1970). There has been little published on the greyscale appearances of ectopic pregnancy and we can find no published case illustrating the grey-scale ultrasound appearances of an ectopic pregnancy with a co-existing correctly placed IUCD. Such a case is now reported. A 36-year-old multiparous woman had been fitted with a Lippe's loop four years previously. Her last menstrual period had been heavy and the loss had persisted intermittently for five weeks with two weeks of low left iliac fossa pain. A pregnancy test was positive and she was referred by her general practitioner for an ultrasound scan of her pelvis at 35 days following her last menstrual period.

Churchill’s second visit to Moscow took place in very different circumstances from his first meeting with Stalin in August 1942. Then the tide of war had not yet turned in favour of the Allies; the United States had still to become involved in European military operations; planning for the peace settlement was still in an embryonic stage. Moreover in 1942 Churchill had the single if not easy aim of persuading Stalin to accept the postponement of the invasion of France in favour of Operation Torch. By the autumn of 1944, however, the defeat of Germany seemed to be only a matter of time. American and British forces were established on the Continent; the Red Army was advancing through Poland and into the Balkans. But military success brought political problems. The post-war structure of Eastern and South-eastern Europe had to be an object of Allied intentions, whatever the variations in their motives. By now the United States was exerting a growing influence over post-war and strategic planning. 1944 was after all the year of Bretton Woods and Dumbarton Oaks. In 1942 Averell Harriman had accompanied Churchill to Moscow as a demonstration of American support; in 1944 as Ambassador in Moscow his task was to act only as an observer. He was to be a physical reminder that Roosevelt would not let his associates commit him in advance, as indeed he reminded Churchill in his message of 4 October.1

The use of ultrasonic A- and B-scans has been evaluated in the diagnosis of fluid-filled lesions in the liver and abdomen, and in the detection of intraperitoneal fluid. Six patients with polycystic livers or suspected polycystic livers, three with solitary cysts, four with liver abscesses, and three with miscellaneous intraabdominal cystic lesions were scanned. The lesions could be clearly distinguished from solid masses by either technique. The presence of as little as 300 to 800 ml of intraperitoneal fluid could be detected by either the A- or B-scan.