Search

Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2. Biochemical and co-crystallization analyses demonstrate that A-196 is a substrate-competitive inhibitor of both SUV4-20 enzymes. In cells, A-196 induced a global decrease in H4K20me2 and H4K20me3 and a concomitant increase in H4K20me1. A-196 inhibited 53BP1 foci formation upon ionizing radiation and reduced NHEJ-mediated DNA-break repair but did not affect homology-directed repair. These results demonstrate the role of SUV4-20 enzymatic activity in H4K20 methylation and DNA repair. A-196 represents a first-in-class chemical probe of SUV4-20 to investigate the role of histone methyltransferases in genomic integrity.

3D-2D registration is a fundamental task in image guided interventions. Due to the physics of the X-ray imaging, however, traditional point based methods meet new challenges, where the local point features are indistinguishable, creating difficulties in establishing correspondence between 2D image feature points and 3D model points. In this paper, we propose a novel method to accomplish 3D-2D registration without known correspondences. Given a set of 3D and 2D unmatched points, this is achieved by introducing correspondence probabilities that we model as a mixture model. By casting it into the expectation conditional maximization framework, without establishing one-to-one point correspondences, we can iteratively refine the registration parameters. The method has been tested on 100 real X-ray images. The experiments showed that the proposed method accurately estimated the rotations (< 1°) and in-plane (X-Y plane) translations (< 1 mm).

Through the Nuclear Liabilities Management Authority White Paper, the UK Government and the Regulators have signalled a commitment to further improving the operation of the regulatory regime and to its operating within the principles of proportionality, transparency, consistency and accountability which underpin the Government's approach to regulation in general. Particular emphasis is placed upon ensuring that there is greater consistency in the treatment of risk and hazard; proportionate and cost effective delivery of public, worker and environmental protection; and an open and transparently applied regulatory system. The paper uses the historical record of radioactive discharges from BNFL's Sellafield reprocessing site in the UK and seeks to identify what have been the key drivers for change, particularly over the past 20 years of significant discharge reductions. The paper examines the current context for ongoing and future discharges from the site, and the incorporation of the use of the concepts of best practicable environmental option and best practicable means. Intergovernmental commitments such as the OSPAR Sintra and Bremen statements and the developing UK policy framework are also considered, together with BNFL's work with a wide range of 'green' stakeholders. The paper outlines the principal components of BNFL's decision-making processes for discharge control and abatement; and how these interact with the relevant external pressures. It then analyses whether the overall drivers and outcomes align with the declared desire of the UK Government to ensure that the taxpayer receives value for money in the new national arrangements for managing historic nuclear liabilities.

Razoxane is one of the few agents which has shown activity in the treatment of advanced colorectal cancer. The drug has therefore been evaluated in a prospective randomized controlled trial as an adjuvant to surgery for resectable colorectal cancer. The results to median follow-up of 5 years are reported here. Accrual has ceased and a total of 272 patients entered the trial (133 control, 139 treatment). Treated patients received razoxane postoperatively on a continuous, long-term basis while control patients received identical clinical care but no adjuvant chemotherapy. Analysis of the results shows a significant prolongation of the time to recurrence for Dukes' C patients. All other groups including the overall analysis show no benefit although there is a consistent trend in favour of the treated patients except in Dukes' group ‘D’. Razoxane is tolerated well by patients and causes minimal side-effects. However acute leukaemia occurred in three patients (2·45 per cent) after prolonged exposure to the drug and further evaluation should be in patients who are at high risk of developing recurrent cancer, in whom such a risk may be acceptable. It is concluded that razoxane is suitable for further evaluation in colorectal cancer and for incorporation into combination chemotherapy regimens.

The use of resistive glazes on high tension insulators to control flashover caused by pollution has proved only partially successful as a result of deterioration of the glazes in service. The most promising and now most widely used glaze relies upon the semiconducting properties of SnO2 doped with Sb2O5, incorporated in an alumino-silicate base glaze. The structure of glazes containing various amounts of SnO2 has been studied by a variety of techniques and particularly by scanning microscopy and electron probe microanalysis. These techniques have revealed both the existence and composition of relatively conducting and relatively insulating areas in the glaze, and a detailed analysis of the distribution of all the elements across the glaze surface and through the glaze thickness has been carried out. The results of this structural survey suggest that activated conduction proceeds through overlapping solubility rims around SnO2 particles in the glaze.

The diffusion coefficients of Sn(IV) in an aluminosilicate glass and a commercial glaze have been measured from 809 to 1505° C. Two experimental techniques have been used. In one method, single crystals of SnO2 were embedded in either the powdered glass or sealed into a bar of the glass. After the diffusion anneal, the Sn(IV) concentration profile was determined by EPMA. In the other method, radioactive 113Sn was used as a tracer and the profile determined by measuring the X-ray emission. The results gave a good agreement between the two methods. The diffusion coefficients in the glaze ranged from 7×10-20 m2 sec-1 at 809° C to 1.9×10-14 m2 sec-1 at 1250° C and in the glass, from 5.6×10-15 m2 sec-1 at 1307° C to 1.6×10-11 m2 sec-1 at 1505° C.

The population size, distribution, breeding, and onshore habitats of New Zealand fur seals in the Nelson-northern Marlborough region, New Zealand, were investigated. Breeding occurs at four relatively new rookeries along the southern shores of Cook Strait: at Stephens Island in the outer Marlborough Sounds, at Archway Islands and Pillar Point near Cape Farewell, and at Tonga Island in Tasman Bay. These rookeries were established in about 1970, 1980, 1988, and 1988, respectively. In 1993-94 about 500 pups were born and the extant population breeding or born at the four rookeries was assessed as 2410. There were also 17 hauling grounds, each with 25 or more seals ashore in winter, and about 50 other sites where lesser numbers hauled out regularly. Comparison with earlier estimates indicates that the summer population increased from about 70 in 1973 to about 1000 in 1994—a sevenfold increase of yearling and older seals. The number of pups produced increased at a mean annual rate of 23% since 1970-71. The population in this region is expanding rapidly in both numbers and breeding range, and similar trends have been reported from elsewhere in New Zealand and Australia. These changes relate to a re-colonisation of traditional breeding grounds following cessation late last century of nearly 1000 years of human exploitation of New Zealand fur seals.

New Zealand fur seals, Arctocephalus forsteri (Lesson, 1828), at the Bounty Islands (47°45'S, 179°03'E) were virtually annihilated by commercial sealing in the period 1808-1890. Legal protection and the cessation of sealing in 1891 were followed by a slow increase in numbers. Aerial photography is a practical method for monitoring fur seal numbers at the Bounty Islands, where the animals show up clearly on the smooth granite substrate. Low-level oblique aerial photographs taken between May 1974 and December 1980 have been used to determine the present distribution of seal colonies and estimate the numbers ashore. The number of seals (excluding new-born pups) ashore on 29 December 1980 was estimated as 6700, and the number of pups as 3280, from sample counts of 3050 and 477 respectively. Calculations based on estimated pup production, and published figures on immature mortality, sex ratio, and pregnancy rate from other fur seal populations, suggest that the total population of the Bounty Islands is about 16 000, including pups.

Cooper, J., Brooke, R.K., Cyrus, D.P., Martin, A.P., Taylor, R.H. & Williams, A.J. 1992. Distribution, population size and conservation of the Caspian Tern Sterna caspia in southern Africa. Ostrich 63: 58-67.The Caspian Tern Sterna caspia occurs along the whole southern African coastline and on large river systems and water bodies away from the coast. A total of 28 definite breeding localities has been recorded in southern Africa. Breeding has occurred recently at at least 14 coastal localities between Swakopmund, Namibia, and Lake St Lucia, Natal, South Africa. Inland breeding has been recorded in recent years at Sua Pan, Botswana and Kalkfonteindam, Orange Free State, South Africa. Based on censuses conducted between 1980 and 1991, the southern African breeding population is estimated to be of the order of 500 pairs, 91% of which breed coastally and 89% breed on islands. Up to 290 pairs (58%) bred at Lake St Lucia. Seventyone per cent of the 1980-1991 breeding population falls within eight nature reserves. Conservation of the Caspian Tern in southern Africa requires protection at breeding localities, including commercial salt and soda ash extraction works, against the effects of changing water levels, human disturbance and predation. Pesticide levels of addled and abandoned eggs should be measured at selected breeding localities.

A number of SnO2-Sb2O5 semiconducting glaze samples have been examined by transmission electron microscopy. The distribution, morphology and size distribution of the SnO2 particles have been determined, both for glazes used to control pollution flashover on electrical insulators and for glazes used to produce electrical resistors. Careful analysis suggests that in the insulator samples, point contact between SnO2 particles is not achieved but each particle is surrounded by a rim of glass, typically a few tenths of a micron in thickness. It is shown that this model is in qualitative agreement with the results of measurements of glaze conductivity as a function of SnO2 concentration. An estimate is made of the size of these rims as a function of concentration, from the known SnO2 content of the glazes and from measured particle sizes. The distribution of shapes and sizes of the SnO2 particles in the glaze are related to the distribution in the SnO2 powder used to make the glaze. It is suggested that the smaller particles in the original powder are dissolved in the glaze during firing and recrystallize around the larger particles which are not fully dissolved. The influence of this process on the Sn distribution in the solution rims is discussed. In the resistor glazes, the wide range of SnO2 particle sizes makes it more difficult to determine whether point contacts occur between the particles. Indirect evidence seems to suggest that percolation paths through the material do exist. It is shown that in a number of the glazes, fine-scale phase separation in the base glass occurs. Two distinct types of devitrified region in the insulator glazes have been observed, one of these types appears to correspond to the devitrified areas in the glass observed by scanning microscopy and the other type is a-quartz probably undissolved in the firing process.

Singh P, Taylor RH, Colin-Jones DG. Prolonged remission of oesophagitis does not alter the magnitude of oesophageal acid exposure. Scand J Gastroentrol 1994;29:11-16.In a previous study we reported lack of improvement in oesophageal motor function after complete healing of oesophagitis achieved by treatment with omeprazole for a median duration of 12 weeks. This study investigates the effect on oesophageal acid exposure of a longer period of complete remission. It was decided to approach all patients who had 24-h pH monitoring as part of the earlier project and whose second endoscopy showing complete healing of oesophagitis as done at least 24 weeks previously. Of 38 such patients, 24 underwent endoscopy, which showed relapse of oesophagitis in 5 of them. In 18 patients who were eligible and agreed to take part, omeprazole/ranitidine was withdrawn for at least 7 days, after which pH monitoring was repeated. The median duration of remission was 39.5 weeks (range, 26-81 weeks). The median percentage of total time with pH below 4 was 11.5% before and 11.0% after (NS). The corresponding figures for the upright and supine reflux, the number of reflux episodes longer than 5 min, and the duration of the longest reflux episode were 10.7% versus 7.7%, 11.4% versus 12.1%, 7.5 versus 7.5, and 35.5 versus 30.5 min, respectively (NS for all variables). These results suggest that maintenance of remission of oesophagitis for prolonged periods does not alter the degree of acid reflux on discontinuation of medication. This has important implications for the understanding of the natural history of gastro-oesophageal reflux disease.

Au-Fe alloys have been studied by magnetic measurements of various types in the composition range where ferromagnetism evolves from spin-glass character. The percolation limit identified from the results and other data is 15.5 + 0.3 at.% Fe. Between this composition and ∼28% Fe, finite clusters co-exist in significant concentrations with the infinite cluster, and a fairly well-defined temperature observed in the magnetic properties is ascribed to a freezing of these clusters that parallels that of finite clusters in the pre-percolation alloys. Magnetic resonance is observed in alloys with more than about 13% Fe (i.e. in alloys containing large nearest-neighbour clusters) and the temperature dependence of the linewidth correlates with the interpretation given of the magnetization data.

1. To test whether impaired carbohydrate tolerance in cirrhosis could be modified by dietary means ten cirrhotic patients, five of them taking insulin, took as breakfast either lentils or whole-meal bread and cottage cheese containing the same amount of carbohydrate and protein. 2. Lentils resulted in significantly diminished blood glucose, insulin (in those not on insulin) and gastric inhibitory peptide responses. 3. Enteroglucagon and neutrotensin levels were high with lentils, suggesting that absorption of lentil carbohydrate continued into the ileum with perhaps some malabsorption, so confuming the results of earlier studies in vitro. 4. However, breath hydrogen studies on a separate group of eight healthy volunteers indicated that the difference in carbohydrate malabsorption between lentil, and wholemeal bread was insignificant. 5. It is suggested that slowly digested carbo-hydrate foods, such as leguminous seeds, may minimize carbohydrate intolerance in patients with cirrhosis.

The ribosomal RNA ("13S" RNA) of the small ribosomal subunit of hamster cell mitochondria has been found to have a distinctive pattern of methylated residues. Each molecule contained, on the average, approximately one residue of m4Cp, m5Cp and m5Up, and two residues of m62Ap. The natural occurrence of m4Cp has not previously been reported; we propose that this nucleotide is homologous to its ribose-methylated congener, m4Cmp, which is characteristic of bacterial 16S ribosomal RNA. We detected neither m4Cp nor m4Cmp in the hamster cell cytoplasmic ribosomal RNA. This is the first documentation of a modified residue present in mitochondrial RNA but absent from the cytoplasmic RNA of the same cells.

SYSTEM 37 VIGGEN: ARMS, TECHNOLOGY, AND THE DOMESTICATION OF GLORY. Ingemar Dörfer. Universitetsforlaget, Oslo, 1973. 258 pp. N.Kr.90 ($US18.00).SIR JOHN MONASH. A. J. Smithers. Angus and Robertson, Sydney, 1973. 0-207-12587-2. 303 pp. $7.95.RADICAL POLITICAL ECONOMY: COLLECTED ESSAYS. E. L. Wheelwright. ANZ Books, Sydney, 1974. 0-85552-018-3. 414 pp. $5.95 paper.JAPAN'S FOREIGN POLICY. F. C. Langdon, University of British Columbia Press, Vancouver, 1973. 321 pp. $US9.00 hardcover.THE PATHET LAO: LEADERSHIP AND ORGANISATION. Joseph J. Zasloff. Lexington Books, Lexington, Massachusetts, 1973. 174 pp. $US10.00.PERVASIVE POLITICS: A STUDY OF THE INDIAN DISTRICT. Donald F. Miller Melbourne Politics Monographs, Department of Political Science, University of Melbourne, 1972. 226 pp. $2.80, $1.80 (students), paper (postage: local 85c, overseas $1.05).CHINA IN BURMA'S FOREIGN POLICY. Ralph Pettman. Australian National University Press, Contemporary China Papers No. 7, Canberra, 1973. 56 pp. $2.50 paper.ZAMBIA. SECURITY AND CONFLICT. Jan Pettman. Julian Friedmann Publishers Ltd., Lewes, Sussex, 1974. 284 pp. £4.25.THE DIPLOMACY OF CONSTRAINT: CANADA, THE KOREAN WAR AND THE UNITED STATES. Denis Stairs. University of Toronto Press, Toronto, 1974. 371 pp. $C15.00 hard cover.ALL TOGETHER NOW: THE ORGANIZATION OF THE DEPARTMENT OF NATIONAL DEFENCE IN CANADA, 1964-1972. Vernon J. Kronenberg. Canadian Institute of International Affairs, Toronto, 1973. 124 pp. $C2.50 paper.WAR MACHINERY AND HIGH POLICY: DEFENCE ADMINISTRATION IN PEACETIME BRITAIN 1902-1914. Nicholas d'Ombrain. Oxford Historical Monographs, Oxford University Press, London, 1973. 302 pp. $13.15.BRITAIN'S LEGACY OVERSEAS. Geoffrey Bolton. Oxford University Press, 1973. 168 pp. $2.10, paper.GREAT POWER POLITICS AND NORWEGIAN FOREIGN POLICY: A STUDY OF NORWAY'S FOREIGN RELATIONS NOVEMBER 1940-FEBRUARY 1948. Nils Morten Udgaard. Universitetsforlaget, Oslo, 1973.EUROPE 1945 TO 1970. Charlotte Waterlow and Archibald Evans. Methuen, London, 1973. 423-87840-9. 316 pp. $11.60.

A prospective study of 111 patients thought to have sustained a recent scaphoid fracture on clinical grounds but who were radiologically negative was undertaken over a period of 7 months. All such patients were subjected to ultrasound scanning within a week of their injury under double blind conditions. All patients were re-X-rayed 2-3 weeks after their injury. The authors' results suggest that ultrasonic diagnosis of the possibly fractured scaphoid is unreliable. [ABSTRACT FROM PUBLISHER]

POPULATION studies of the wild rabbit (Oryctolagus cuniculus) in New Zealand and elsewhere have emphasized the need for reliable methods of age determination. Since weight is a satisfactory criterion of the age of young rabbits up to 3–4 months, when they become sexually mature1. the sequence of epiphyseal fusion of bones was examined in an attempt to determine the age of older animals. This work was initiated by Watson and Tyndale-Biscoe2, who found that the epiphysis at the head of the tibia fused at 41 weeks (range 33–44 weeks). Further work by Tyndale-Biscoe3(and unpublished work) showed that the epiphyses of all other long bones unite at about the same age or earlier than do those at the head of the tibia, but that the epiphyses of the vertebræ do not fuse to the centrum until later in life, and could therefore provide an age criterion for older animals.

Conventional surgical tracking configurations carry a variety of limitations in line-of-sight, geometric accuracy, and mismatch with the surgeon's perspective (for video augmentation). With increasing utilization of mobile C-arms, particularly those allowing cone-beam CT (CBCT), there is opportunity to better integrate surgical trackers at bedside to address such limitations. This paper describes a tracker configuration in which the tracker is mounted directly on the Carm. To maintain registration within a dynamic coordinate system, a reference marker visible across the full C-arm rotation is implemented, and the "Tracker-on-C" configuration is shown to provide improved target registration error (TRE) over a conventional in-room setup - (0.9±0.4) mm vs (1.9±0.7) mm, respectively. The system also can generate digitally reconstructed radiographs (DRRs) from the perspective of a tracked tool ("x-ray flashlight"), the tracker, or the C-arm ("virtual fluoroscopy"), with geometric accuracy in virtual fluoroscopy of (0.4±0.2) mm. Using a video-based tracker, planning data and DRRs can be superimposed on the video scene from a natural perspective over the surgical field, with geometric accuracy (0.8±0.3) pixels for planning data overlay and (0.6±0.4) pixels for DRR overlay across all C-arm angles. The field-of-view of fluoroscopy or CBCT can also be overlaid on real-time video ("Virtual Field Light") to assist C-arm positioning. The fixed transformation between the x-ray image and tracker facilitated quick, accurate intraoperative registration. The workflow and precision associated with a variety of realistic surgical tasks were significantly improved using the Tracker-on-C - for example, nearly a factor of 2 reduction in time required for C-arm positioning, reduction or elimination of dose in "hunting" for a specific fluoroscopic view, and confident placement of the x-ray FOV on the surgical target. The proposed configuration streamlines the integration of C-arm CBCT with realtime tracking and demonstrated utility in a spectrum of image-guided interventions (e.g., spine surgery) benefiting from improved accuracy, enhanced visualization, and reduced radiation exposure.

The routinely used procedure for evaluating tunnel positions following anterior cruciate ligament (ACL) reconstructions based on standard X-ray images is known to pose difficulties in terms of obtaining accurate measures, especially in providing three-dimensional tunnel positions. This is largely due to the variability in individual knee joint pose relative to X-ray plates. Accurate results were reported using postoperative CT. However, its extensive usage in clinical routine is hampered by its major requirement of having CT scans of individual patients, which is not available for most ACL reconstructions. These difficulties are addressed through the proposed method, which aligns a knee model to X-ray images using our novel single-image 3D-2D registration method and then estimates the 3D tunnel position. In the proposed method, the alignment is achieved by using a novel contour-based 3D-2D registration method wherein image contours are treated as a set of oriented points. However, instead of using some form of orientation weighting function and multiplying it with a distance function, we formulate the 3D-2D registration as a probability density estimation using a mixture of von Mises-Fisher-Gaussian (vMFG) distributions and solve it through an expectation maximization (EM) algorithm. Compared with the ground-truth established from postoperative CT, our registration method in an experiment using a plastic phantom showed accurate results with errors of (-0.43°±1.19°, 0.45°±2.17°, 0.23°±1.05°) and (0.03±0.55, -0.03±0.54, -2.73±1.64) mm. As for the entry point of the ACL tunnel, one of the key measurements, it was obtained with high accuracy of 0.53±0.30 mm distance errors.

Background. Levobupivacaine, the S(–)enantiomer of racemic bupivacaine is less cardiotoxic than racemic bupivacaine and the R(+)enantiomer dexbupivacaine, while retaining similar local anaesthetic properties and potency to racemic bupivacaine. The pharmacokinetic profiles of the two bupivacaine enantiomers differs and that of racemic bupivacaine may be age dependent. We examined the pharmacokinetics of levobupivacaine after its single shot caudal epidural administration in children. Methods. An open‐label phase 2 study was undertaken to examine the pharmacokinetics of levobupivacaine 0.25% 2 mg kg–1 in 49 children aged less than 2 yr, after single shot caudal epidural administration. Plasma concentrations were determined at intervals up to 60 min after caudal injection. Results. Time to peak plasma concentration (Tmax) ranged between 5 and 60 min (median 30 min) and was reached later in children aged less than 3 months (P<0.005). Peak plasma concentration (Cmax) ranged between 0.41 and 2.12 µg ml–1 (median 0.80, mean (sd) 0.91 (0.40) µg ml–1). Conclusion. After the caudal epidural administration of levobupivacaine 2 mg kg–1 in children less than 2 yr of age, Cmax was within the accepted safe range for racemic bupivacaine. Tmax varied and occurred later in some children, particularly those aged less than 3 months. Sampling in future pharmacokinetic studies in this age group should extend beyond 60 min. Br J Anaesth 2004; 92: 218–22