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This paper, based on two main papers Fang and Giles (Adaptive Euler–Maruyama method for SDEs with non-globally Lipschitz drift: Part I, finite time interval, 2016, [2]), Fang and Giles (Adaptive Euler–Maruyama method for SDEs with non-globally Lipschitz drift: Part II, infinite time interval, 2017, [3]) which contains the full details of the literature review, numerical analysis and numerical experiments, aims to give an overview of the adaptive Euler–Maruyama method for SDEs with non-globally Lipschitz drift in a concise structure without any proof. It shows that if the timestep is bounded appropriately, then over a finite time interval the numerical approximation is stable, and the expected number of timesteps is finite. Furthermore, the order of strong convergence is the same as usual, i.e. order \(\frac{1}{2}\) for SDEs with a non-uniform globally Lipschitz volatility, and order 1 for Langevin SDEs with unit volatility and a drift with sufficient smoothness. For a class of ergodic SDEs, we also show that the bound for the moments and the strong error of the numerical solution are uniform in T, which allow us to introduce the adaptive multilevel Monte Carlo method to compute the expectations with respect to the invariant measure. The analysis is supported by numerical experiments.

Making the profound societal transitions and transformations called for in the UN Sustainable Development Goals for 2030 (UN, 2019) and beyond is a critical and urgent challenge for humanity. We propose the collection and analysis of digital narratives (DNs) to observe and assess significant concerns about sustainability and resilience (e.g., as reflected by social movements and interests). Observing temporal changes, globally, in the frequency, sources, and content of DNs can illuminate emerging trends in perceptions, attitudes, norms, hopes or fears of individuals and groups. Of particular interest are movements towards acceptance of, or resistance to, locally adaptive pathways to sustainable futures. We propose forming a Digital Observatory of Narratives of Sustainability (DONS) as a collaborative platform with associated open-source tools for analyzing and representing the societal landscape and its dynamics, thereby providing data to help model future societal trajectories and develop approaches to cope with systemic risks. The DONS opens a rich field for inter- and trans-disciplinary research on sustainability through narratives and their dynamics in different contexts and cultures.

© 2017 by the Ecological Society of America. Including stakeholders in environmental model building and analysis is an increasingly popular approach to understanding ecological change. This is because stakeholders often hold valuable knowledge about socio-environmental dynamics and collaborative forms of modeling produce important boundary objects used to collectively reason about environmental problems. Although the number of participatory modeling (PM) case studies and the number of researchers adopting these approaches has grown in recent years, the lack of standardized reporting and limited reproducibility have prevented PM's establishment and advancement as a cohesive field of study. We suggest a four-dimensional framework (4P) that includes reporting on dimensions of (1) the Purpose for selecting a PM approach (the why); (2) the Process by which the public was involved in model building or evaluation (the how); (3) the Partnerships formed (the who); and (4) the Products that resulted from these efforts (the what). We highlight four case studies that use common PM software-based approaches (fuzzy cognitive mapping, agent-based modeling, system dynamics, and participatory geospatial modeling) to understand human-environment interactions and the consequences of ecological changes, including bushmeat hunting in Tanzania and Cameroon, agricultural production and deforestation in Zambia, and groundwater management in India. We demonstrate how standardizing communication about PM case studies can lead to innovation and new insights about model-based reasoning in support of ecological policy development. We suggest that our 4P framework and reporting approach provides a way for new hypotheses to be identified and tested in the growing field of PM.

The gerotor is a planar mechanism consisting of two surfaces whose relative motion can be described by the kinematics of orbiting pitch circles. Typically, gerotor surfaces are prismatic with the axes of rotation parallel to the ruled surfaces. For a given position, the generated cross section of the mechanism in the plane of motion is independent of the location of the section along the axis of rotation. In this work, a mathematical derivation for producing gerotors with non-prismatic surfaces is presented. The implementation results in two types of gerotors, mechanisms with conical surfaces relative to the rotor axis, and mechanisms with helical surfaces. These are relatively new inventions and this is the first publication of the mathematical model describing these mechanisms. The derivations of the mathematics associated with each mechanism are presented. Comparisons of the mechanisms are presented based on the displacement, compression ratio and surface area to volume ratio.

The capacity to retrieve images containing objects with shapes similar to a query shape is desirable in medical image databases. We propose a similarity measure and an indexing mechanism for non-rigid comparison of shape which adds this capability to image databases. The (dis)-similarity measure is based on the observations that: (1) the geometry of the same organ in different subjects is not related by a strictly rigid transformation; and (2) the orientation of the organ plays a key role in comparing shape. We propose a similarity measure that computes a non-rigid mapping between curves and uses this mapping to compare oriented shape. We also show how KD-trees can index curves so that retrieval with our similarity measure is efficient. Experiments with real-world data from a database of magnetic resonance images are provided.

We present both a high-level symbolic model of the human brain, and a method of using this model to aid in the recognition of objects from medical images. The model is stored as a frame-based semantic network consisting of three coexisting graphs (a spatial adjacency graph, a part hierarchy and an inheritance graph). We propose a method similar to assumption-based truth maintenance systems for the collating and reasoning processes required in the labelling of input images.

We present a technique for the construction of multi-scale representations of grey-level images. Unlike conventional representations the scales are discrete as opposed to continuous and their level is solely determined by the data. The technique is based upon connecting singular points in the image with maximum gradient paths. We also describe two segmentation methods which use the maximum gradient paths generated during the construction of the multi-scale representation. In both segmentation techniques the paths are used to determine significant ridges and troughs. The first technique operates directly on the image, while the second technique uses the magnitude of the image derivative.

We present both a high-level symbolic model of the human brain, and a method of using this model to aid in the recognition of objects from medical images. The model is stored as a frame based semantic network consisting of three coexisting graphs (a spatial adjacency graph; a part hierarchy; and an inheritance graph). We propose a method similar to assumption-based truth maintenance systems for the collating and reasoning processes required in the labelling of input images.

Describes further efforts aimed at more accurately and objectively determining and quantifying the local, regional and global function of the left ventricle (LV) of the heart from four-dimensional (4D) image data. By studying the endocardial-epicardial surface properties of LV wall over many temporal frames within a cardiac cycle and over a range of conditions of LV wall abnormalities, one will be able to better understand the physiological processes associated with ischemic heart disease. Here, the authors first briefly describe the setup for an in vivo experimental model and the imaging techniques, including the use of implanted imaging opaque markers that will permit the authors to establish the gold standard against which the validity of their noninvasive image analysis algorithms can be evaluated, as well as permit them to study the efficacy of using in vivo, image-derived measures of function for predicting regional myocardial viability. Then, the shape-based image analysis methods, particularly the authors' new developments in surface triangulation from segmented contour stacks of LV wall, surface curvature estimation, pointwise non-rigid motion tracking, quantitative measures of LV motion and thickening, and 3D visualization techniques, are discussed. Finally, initial experimental results using image sequences from two different modalities are presented. >

Accurate estimation of heart wall dense field motion and deformation could help to better understand the physiological processes associated with ischemic heart diseases, and to provide significant improvement in patient treatment. We present a new method of estimating left ventricular deformation which integrates instantaneous velocity information obtained within the mid-wall region with shape information found on the boundaries of the left ventricle. Velocity information is obtained from phase contrast magnetic resonance images, and boundary information is obtained from shape-based motion tracking of the endo- and cardial boundaries. The integration takes place within a continuum biomechanical heart model which is embedded in a finite element framework. We also employ a feedback mechanism to improve tracking accuracy. The integration of the two disparate but complementary sources overcomes some of the limitations of previous work in the field which concentrates on motion estimation from a single image-derived source. >

Howard Earle Skipper died at his residence in Mountain Brook, Alabama on January 2, 2006 at age 90. He was born on November 21, 1915 at Avon Park, Florida to Chesley Allen Skipper and Estelle Wiggins Skipper. He grew up in Sebring, Florida, and in his youth he worked on his father's cattle ranch and

In most current investigations on bearing forces in screw compressors, the supports at the bearings are basically treated as ideal, simply supported boundary conditions [Adams and Soedel, 1995; Qin and Adams, 1996; You et al, 1994]. By using static mechanics, the loads on the rotors are resolved to equivalent loads at the bearings at suction and discharge ends. Studies on rotor dynamics have shown that the characteristics of a rotor bearing system are strongly dependent on thebearings that support the rotor. Therefore, it is important to study the rotor dynamic performance of screw compressors so that the bearing faces can be more accurately described. In this paper, a dynamic model of a rigid compressor rotor supported by two cylindrical roller bearingsand a four point contact ball bearing is developed from basic principles. This model is used to simulate the dynamic response of a typical screw compressor configuration. Under compression loads, the resulting bearing forces in the screw compressor are compared with those obtained by assuming ideal simply supported boundary conditions at the bearings. A more accurate model of the compressor response is believed to be obtained by coupling the global rotor motion with the local dynamics of nonlinear bearings.

The size and number of follicles present within an ovary may be used as an indicator of fertility in women.Ultrasound is the imaging modality of choice for obtaining information on the follicles as it is inexpensive and readily available. A method of segmenting the follicles and ovary and producing accurate 2D and 3D representa- tions would be of great benefit to a large segment of the population. However, the nature of ultrasound imagesmeans that standard approaches to segmentation based on image gradients or detecting regions of homogeneous grey-level alone are inadequate. A semi-automatic method of segmentation which combines a texture based classification for initial segmen-tation with deformable models to provide descriptions of individual objects is extended by imposing geometricconstraints on the relationships between the individual objects present within an image. Since we are interested in segmenting the individual objects over a 3D spatial stack we use the results from one

This paper describes efforts aimed at developing a unified framework to more accurately quantify the local, regional and global function of the left ventricle (LV) of the heart, under both normal and ischemic conditions, using four—dimensional (4D) imaging data over the entire cardiac cycle. The approach incorporates motion information derived from the shape properties of the endocardial and epicardial surfaces of the LV, as well as mid—wall 3D instantaneous velocity information from phase contrast MR images, and/or mid—wall displacement information from tagged MR images. The integration of the disparate but complementary sources of information overcomes the limitations of previous work which concentrates on motion estimation from a single image—derived source. 1

This study investigates the displacement, compression ratio and surface area to volume ratio of epitrochoidal gerotor mechanisms created with non-uniform cross sectional areas perpendicular to the rotor axis of rotation, skew gerotors. An algorithm is presented for modelling the gerotor mechanisms using a quadratic surface as the generating pin. The method used to model the skew gerotors consists of rotating the axis of the generating pin such that it is skewed relative to the rotor axis of rotation. The resulting effects on the displacement, compression ratio and surface area to volume ratio are presented for various configurations.

This paper describes efforts aimed at more objectively and accurately quantifying the local, regional and global function of the left ventricle (LV) of the heart from 4D image data. Using our shape-based image analysis methods, point-wise myocardial motion vector fields between successive image frames through the entire cardiac cycle will be computed. Quantitative LV motion, thickening, and strain measurements will then be established from the point correspondence maps. In the paper, we will also briefly describe an in vivo experimental model which uses implanted imaging-opaque markers to validate the results of our image analysis methods. Finally, initial experimental results using image sequences from two different modalities will be presented.

This paper describes efforts aimed at more accurately and objectively determining and quantifying the local, regional, and global function of the left ventricle (LV) of the heart under both normal and ischemic conditions. These measurements and evaluations are made using non-invasive, 3-D, cardiac diagnostic imaging sequences (i.e., 4-D data) and rely on an approach that follows the shape properties of the endocardial and epicardial surfaces of the LV over the entire cardiac cycle. Our efforts involve the development of an acute infarct animal model that permits us to establish the validity of our noninvasive image analysis algorithms, as well as permits us to study the efficacy of using in vivo, image-derived measures of function for predicting regional myocardial viability (immediately post mortem). We first describe the experimental setup for the animal model, including the use of implanted imaging-opaque markers that assist in setting up a gold standard against which image-derived measurements can be evaluated. Next, the imaging techniques are described, and finally the image analysis methods and their comparison to the validation technique are discussed.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

A method is presented for the accurate combination of magnetic resonance (MR) and computed tomographic (CT) images of the head. Our technique is based on user identified 3D landmarks followed by data combination and display as adjacent slices, a single fused slice representation, colour overlay and three-dimensional (3D) rendered scenes. Validation with a point phantom and computer simulation has established the relationship of registration accuracy with point location accuracy, the number of points used and their spatial distribution. The technique is in clinical use in the planning of skull base surgery, transferring MR images acquired without a stereotaxic frame to stereotaxic space, and staging and planning therapy of nasopharyngeal tumours.

In this paper we present an application in which multimodal images are used to generate pseudo-3D scenes to assist in the planning and execution of skull base surgery. Image data from CT, MRI and MR Angiography are registered such that the relationship between their image coordinates is known. The images are then transformed into occupancy maps for the structures of interest. Commercially available rendering algorithms then require that either the data from the multiple imaging modalities be combined into a single volumetric dataset prior to rendering, or that the data from each modality is rendered separately and subsequently overlaid. We present an algorithm that allows us to bypass this last stage and leave the objects in their original datasets. The 3D scenes are rendered by casting a ray simultaneously through the multi-dimensional space represented by the individual datasets.

In the absence of a priori information on scales of interest vision systems should initially process in a scale invariant manner. The fact that any signal can only be sampled discretely further constrains the initial processing. The paper argues that a representation satisfying these requirements is an hierarchical segmentation of scalespace. An algorithm is presented to compute such representations. The algorithm has been designed so that its operation is scale invariant in the following sense: the addition of finer scale information only ever adds to the computed representation and never changes what was discoverable from coarser scales. It is noted that such a scheme has benefits even when the scales of interest are known.

This paper describes our methodology for combining and visualizing registered MR, CT, and angiographic images of the head. We register the individual datasets using the location of a number of user identified anatomical point landmarks to derive the rigid body transformation between datasets. The combined images are displayed either as 2-D slices or as 3-D rendered scenes. Three independent observers performed a detailed assessment of the usefulness of the combined images in the planning of resection of skull base lesions in seven patients. We have shown that in all patients studied at least one of our observers obtained significant extra clinical information from the combined images, while all observers showed significantly increased confidence in the pre-operative surgical plan in all but one patient. Initial evaluation of the 3-D rendered displays showed that the size, shape, and extent of the tumors were better visualized, 3-D spatial relationships between structures were clarified, viewing the resection site in 3-D was very useful, and movie loops provided a very strong 3-D cue. An improved method of registering information from multiple imaging modalities is described and future directions for image combination and visualization are suggested.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

We present a graph-based approach to the production of hierarchical segmentations of grey- level images. The technique is designed to be as responsive as possible to the structure of the image but general in the sense that it is independent of the exact edge measure used. We present results using a novel edge measure which combines the first and second derivatives of the image to calculate the phase of the image with respect to scale. We combine this with the gradient to produce a value which reflects both the strength and the stability of candidate edges.

An efficient scheme for representation of the shape of anatomical and pathological structures is required for intelligent computer interpretation of medical images. We present an approach to the extraction and representation of shape which, unlike previous shape representations, does not require complete boundary descriptions. It is based on the `Delaunay triangulation' and its dual the `Voronoi diagram.' Our method of using this dual leads to both a skeleton description and a boundary description. The basic step in the algorithm is that of deciding whether to treat any pair of neighboring points as adjacent (lying next to each other on the same boundary) or opposite (lying on opposing sides of a skeleton separating two boundaries). The duality of the skeleton and boundary descriptions produced means that the splitting of one object into two separate objects, or the merging of two objects into one, can be easily accomplished.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

In this paper we present the Delaunay/Voronoi selection graph (DVSG), an approach to the representation of the shape of 2-D objects which does not require a complete segmentation, merely a pattern of dots which are believed to lie on the edges of objects. The technique produces both a skeleton and boundary representation and, with subsequent processing, generates a hierarchical description of the topology of individual objects. We compare the DVSG to other methods used for obtaining information from dot-patterns, and show how this technique can be extended to 3-D.

We propose a method of extracting and describing the shape of features from medical images which provides both a skeleton and boundary representation. This method does not require complete closed boundaries nor regularly sampled edge points. Lines between edge points are connected into boundary sections using a measure of proximity. Alternatively, or in addition, known connectivity between points (such as that available from traditional edge detectors) can be incorporated if known. The resultant descriptions are objectcentred and hierarchical in nature with an unambiguous mapping between skeleton and boundary sections.

Nuclear medicine images have comparatively poor spatial resolution, making it difficult to relate the functional information which they contain to precise anatomical structures. A 3D neuro-anatomical atlas has been generated from the MRI data set of a normal, healthy volunteer to assist in the interpretation of nuclear medicine scans of the brain. Region growing and edge-detection techniques were used to semi-automatically segment the data set into the major tissue types within the brain. The atlas was then labelled interactively by marking points on each 2D slice. Anatomical structures useful in the interpretation of SPECT images were labelled. Additional, more detailed information corresponding to these structures is provided via an interactive index which allows access to images, diagrams and explanations. Registration of patient SPECT studies with the atlas is accomplished by using the position of the skull vertex and four external fiducial markers attached to the skin surface. The 3D coordinates determined from these points are used to calculate the transformation required to rotate, scale and translate the SPECT data, in 3D, to match the atlas. Corresponding 2D slices from the two 3D data sets are then displayed side-by-side on a computer screen. A cursor linking the two images allows the delineation of regions of interest (ROIs) in the SPECT scan based on anatomical structures identified from the atlas. Conversely regions of abnormal isotope distribution in the SPECT image can be localized by reference to corresponding structures in the atlas.

This paper describes two methods to aid interpretation and quantification of SPECT or PET images. In the first method 3D SPECT or PET data sets are aligned and scaled to a 3D MRI data set of the same patient using 4 skin markers visible on each modality. Three display schemes have been implemented for viewing the aligned slices. Examples of these displays are provided. The second method uses a labelled 3D MRI reference data set from a volunteer to identify major anatomical structures. The MR reference data set is aligned with the isotope image using the same 4 markers plus a marker on the vertex of the skull. The reference data set is segmented approximately into the major tissue types - cerebrospinal fluid (CSF) and grey and white matter. Major structures are identified via labels in the 3D data set. A linked cursor aids delineation of anatomical regions on the isotope image using the outline of structures on the reference data set as a template. Directions for future research in the generation of complete digital anatomical atlases, which include inter-individual variations, are outlined.

A hierarchical model of the brain has been developed, based on the ARTTM system, in which nodes represent the structures of interest, and arcs represent 3-D topographical relationships between organs and part-of relationships. The nodes contain attributes of the organs which encode their expected shape and identifying features; they also attach to the recognition rules, which use the measured attributes and relationships to identify the structures. In this paper the image data is pre-processed to create a Laplacian Pyramid by using multiple Difference of Gaussian (DoG) filters (see Figure 2). Most of the reasoning used in the recognition rules is based on zero crossing features of the DoG images, which may be tracked between scales, or between images of adjacent slices.

Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with alpha-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated hydrochloric acid regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and disulfide linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with alpha-halo ketones either in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3-, and 2,2,3-substituted ethyl (5-amino-2H-pyridol[4,3-b][1,4]thiazin-7-yl)carbamates 9. The effects of these pyridooxazines and pyridothiazines upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 leukemia were determined.

Reaction of alpha-aminoacetophenone oximes (2) with ethyl 6-amino-4-chloro-5-nitropyridine-2-carbamate (1) gave ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridine-2-carbamate oximes (3), which were hydrolyzed under acidic conditions to give the corresponding ketones (4). Related pyridines substituted with a keto side chain were prepared from 1 and 1,3-diaminopropanone oximes and by oxidation of the side-chain hydroxy group of ethyl 6-amino-4- [[3-(N-methyl-N-phenylamino)-2-hydroxypropyl]amino]-5-nitropyridine-7- carbamates (6). Catalytic hydrogenation of the nitro group of 4 over Raney nickel in a large volume of ethanol gave the 1-deaza-7,8-dihydropteridines (7). Several of the oximes 3 were successfully hydrogenated to give 7 directly. The resulting 1-deaza-7,8-dihydropteridines showed potent cytotoxicity against cultured L1210 cells and significant anticancer activity against lymphocytic leukemia P-388 in mice. These biological activities are attributed to the accumulation of cells at mitosis.

Certain derivatives containing the 1,2-dihydropyrido[3,4-b]pyrazine (1-deaza-7,8-dihydropteridine) ring system are active against experimental neoplasms in mice. The mechanism of action of these agents has been attributed to the accumulation of cells at mitosis. Identification of the structural features that are necessary for activity was accomplished by evaluation of modified 1-deazapteridines and ring and ring-opened analogues. Relative to ethyl 4-amino-1-deaza-7,8-dihydro-6-[(N-methylanilino)methyl]pteridine-2-carbamate (11) and the corresponding 6-phenyl compound (12), no antitumor activity was observed with 7,8-dihydropteridines, 3-deaza-7,8-dihydropteridines, and the corresponding heteroaromatic compounds. Also, activity was diminished or destroyed when 1-deaza-7,8-dihydropteridines were oxidized to 1-deazapteridines or reduced to 1-deaza-5,6,7,8-tetrahydropteridines. In addition, replacement of the 4-amino group with other substituents destroyed activity. The presence of a 6-substituent containing an aryl group appeared to be necessary for activity, which was increased when a methyl group was substituted at the 7-position.

SummaryThe cell cycles of Leukemia L1210 cells proliferating in mice after serial transplantation, proliferating in mice following inoculation of cultured cells, and proliferating in vitro in spinner cultures have been examined by the method of waves of labeled mitoses following pulse exposure to thymidine-(methyl-3H). The cycles for the 3 groups of cells were essentially the same. The following mean values were obtained: TC, 15.7 hr; TG2, 1.5 hr; TM, 0.5 hr; Ts, 11.7 hr; TG1, 2.0 hr.

Purines, pyrimidines, ribonucleosides, ribonucleotides, carboxylic acids, and amino acids were tested for activity in preventing the growth-inhibition of Escherichia coli by urethan, formamide and N-methylformamide. 2: 6-Diaminopurine and phenylalanine were the only compounds tested that caused true reversal of the inhibition of growth of E. coli 9637 by these agents, but neither of these compounds rereversed the inhibition of a purine-requiring mutant or, in experiments with urethan, the inhibition of a pyrimidine-requiring mutant. On the other hand, glutamic acid caused true reversal of the inhibition of the purine-requiring mutant and, in experiments with urethan, of the inhibition of the pyrimidine-requiring mutant, but the apparent reversal of the inhibition of E. coli 9637 by glutamic acid was found to be due to stimulation of the overgrowth of drug-resistant mutants. A number of other compounds also stimulated the overgrowth of drug-resistant mutants in overnight growth experiments. Urethan, formamide and N-methylformamide, individually, inhibited the formation of diazotizable amine by resting E. coli B96 cells. The inhibition by urethan was partially prevented by phenylalanine; the inhibition by formamide was partially prevented by glutamic acid and by 2: 6-diaminopurine; and the inhibition by N-methylformamide was partially prevented by 2: 6-diaminopurine. The data indicate that there are probably multiple sites of action for each of these inhibitors.

Experimental evidence indicates that an analogue of nicotinamide adenine dinucleotide in which the adenine moiety is replaced by 2,6-diaminopurine is formed when cultured mammalian cells are grown in the presence of 2,6-diaminopurine. It is also likely that the corresponding analogue containing nicotinic acid is formed when both 2,6-diaminopurine and nicotinic acid are added to the culture medium.

Experimental evidence is presented which strongly suggests that C 14 from injected nitrogen mustard-C 14 H 3 is fixed in the nucleic acid fractions of animal tissues chiefly as a result of the combination of the nitrogen mustard with nucleic acid moieties. The specific activity of the RNA purine fraction was consistently higher than that of any other nucleic acid fraction examined.

4-Hydroxypyrazolo(3,4-d)pyrimidine (HPP) injected i.p. caused an inhibition of xanthine oxidase activity in the livers and kidneys (but not the spleens) of rats, as measured by catabolism of hypoxanthine-8- 14 C ( in vivo and in vitro ), inosine (8- 14 C)-5'monophosphate ( in vitro ), and xanthine-8- 14 C ( in vitro ). This action of HPP was transient, and there was no evidence of cumulative effects. Administration of HPP in the diet proved as effective as i.p. injection, but again there was no cumulative effect. It caused a decrease in xanthine oxidase activity and an inhibition of purine biosynthesis in host liver and Morris 5123-C hepatoma. No difference in growth rate of the hepatomas or in body weights of rats maintained on control and HPP-containing diets was observed.

Incubation at physiological conditions of erythrocytes from a person bearing the sickle-cell trait with 1-methyl-1-nitrosourea, 1,3-bis-(2-chloroethyl)-1-nitrosourea, or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea prevented sickling of the cells upon subsequent treatment of the cells with sodium metabisulfite. In these experiments these compounds were more effective than potassium cyanate as inhibitors of sickling. It is assumed that the inhibition results from the carbamoylation of the hemoglobin S by the isocyanic acid or the isocyanates derived from the nitrosoureas.

Treatment of either deoxyribonuclease or deoxyribonucleic acid with nitrogen mustard caused a decrease in the rate of enzymic degradation of deoxyribonucleic acid, and the treatment of the nucleic acid caused a greater decrease than treatment of the enzyme. The significance of this finding is discussed.

A cell culture system has been used for screening iron chelating compounds for therapeutic use in patients with iron overload. Two conjugates of 2, 3 - dihydroxybenzoic acid (2, 3 - DHB) with spermidine are more effective than desferrioxamine in removing iron from cells and, in addition, are capable of removing iron from transferrin.

The material that is presented in this chapter is limited to that which relates directly or indirectly to the mechanism of action of the nitrosoureas. For a review of the results of experimental and clinical therapeutic trials with these agents, the reader is referred to other sections of this volume and to the review by Carter et al. (1972).