The Importance of Dosimetry and Radiobiology in Nuclear Medicine : Quantitative methods and modelling

Nuclear medicine uses radioactive pharmaceuticals for diagnostic or therapeutic purposes. The ionizing radiation emitted from the radiopharmaceutical is partially absorbed within the patient's body and internal dosimetry is the method to estimate the absorbed dose to a tumour or risk organ. This is of special importance in radiopharmaceutical therapy (RPT), where particle-emitting radionuclides are utilized for their therapeutic effect. A better understanding of where and to what extent the radiation energy is deposited, i.e. dosimetry, in combination with a better understanding of the irradiation-induced biological processes in tissues and tumours, i.e., radiobiology, is the foundation to establish an absorbed dose-effect relationship. This thesis comprises quantitative methods and modelling within dosimetry and radiobiology, with a special focus on quantitative methods for activity concentration, absorbed dose calculation and quantification of biological effects after nuclear medicine exposures. Nonuniformity of activity distribution and the biological effect of internal irradiation is considered in Paper I and Paper II. When a radiopharmaceutical primarily localizes within specific tissue substructures of an organ, the average absorbed dose to the whole organ may become insufficient for dosimetric analysis. Hence, the nonuniformities of the distribution of activity need to be considered and absorbed dose calculations to part of an organ, cellular, or a sub-cellular structure may be a better predictor of the therapy outcome or normal tissue toxicity. In Paper I, a small-scale anatomical dosimetry model of the liver tissue structure addressed the issue of activity nonuniformity. Monte Carlo simulations were performed to simulate the particle transport from various substructure sources within the organ model for some clinically available radionuclides. The model enabled comparison between the average absorbed dose to the entire organ and the local absorbed dose close to the source region, which for particle emitting radionuclides differed significantly. To address the resulting biological effect after internal irradiation, an ex vivo method using the γH2AX surrogate marker to visualize and quantify DNA double-strand breaks in in vivo-irradiated tissues was developed. The method was demonstrated to be useful for γH2AX-foci quantification in both the fast proliferating, radiosensitive testis tissue and the slow proliferating and more radioresistant liver tissue. Image-based activity quantification and absorbed dose estimation are considered in Paper III and Paper IV, using somatostatin receptor targeting agents for both diagnostic and therapeutic applications for neuroendocrine tumours. In Paper III, the quantitative accuracy of pre-therapeutic 111In-Octreoscan® SPECT/CT and [68Ga]Ga-DOTA-TATE PET/CT images was investigated due to the change in clinical method to use PET- instead of SPECT-imaging. Further, the quantitative relationship between the theragnostic pair of DOTA-TATE was investigated in Paper IV. The relationship between activity uptakes observed at [68Ga]Ga-DOTA-TATE PET imaging and absorbed doses at subsequent [177Lu]Lu-DOTA-TATE therapy was studied. The study demonstrated that on a group level, a higher tumour uptake measured from pretherapeutic PET images is associated with higher absorbed doses in subsequent therapy with [177Lu]Lu-DOTA-TATE. However, on the individual level, there are limitations of using the 68Ga PET as a predictor for therapy absorbed dose

Computational approaches to discovering differentiation genes in the peripheral nervous system of drosophila melanogaster

In the common fruit fly, Drosophila melanogaster, neural cell fate specification is triggered by a group of conserved transcriptional regulators known as proneural factors. Proneural factors induce neural fate in uncommitted neuroectodermal progenitor cells, in a process that culminates in sensory neuron differentiation. While the role of proneural factors in early fate specification has been described, less is known about the transition between neural specification and neural differentiation. The aim of this thesis is to use computational methods to improve the understanding of terminal neural differentiation in the Peripheral Nervous System (PNS) of Drosophila. To provide an insight into how proneural factors coordinate the developmental programme leading to neural differentiation, expression profiling covering the first 3 hours of PNS development in Drosophila embryos had been previously carried out by Cachero et al. [2011]. The study revealed a time-course of gene expression changes from specification to differentiation and suggested a cascade model, whereby proneural factors regulate a group of intermediate transcriptional regulators which are in turn responsible for the activation of specific differentiation target genes. In this thesis, I propose to select potentially important differentiation genes from the transcriptional data in Cachero et al. [2011] using a novel approach centred on protein interaction network-driven prioritisation. This is based on the insight that biological hypotheses supported by diverse data sources can represent stronger candidates for follow-up studies. Specifically, I propose the usage of protein interaction network data because of documented transcriptome-interactome correlations, which suggest that differentially expressed genes encode products that tend to belong to functionally related protein interaction clusters. Experimental protein interaction data is, however, remarkably sparse. To increase the informative power of protein-level analyses, I develop a novel approach to augment publicly available protein interaction datasets using functional conservation between orthologous proteins across different genomes, to predict interologs (interacting orthologs). I implement this interolog retrieval methodology in a collection of open-source software modules called Bio:: Homology::InterologWalk, the first generalised framework using web-services for “on-the- fly” interolog projection. Bio::Homology::InterologWalk works with homology data for any of the hundreds of genomes in Ensembl and Ensembgenomes Metazoa, and with experimental protein interaction data curated by EBI Intact. It generates putative protein interactions and optionally collates meta-data into a prioritisation index that can be used to help select interologs with high experimental support. The methodology proposed represents a significant advance over existing interolog data sources, which are restricted to specific biological domains with fixed underlying data sources often only accessible through basic web-interfaces. Using Bio::Homology::InterologWalk, I build interolog models in Drosophila sensory neurons and, guided by the transcriptome data, find evidence implicating a small set of genes in a conserved sensory neuronal specialisation dynamic, the assembly of the ciliary dendrite in mechanosensory neurons. Using network community-finding algorithms I obtain functionally enriched communities, which I analyse using an array of novel computational techniques. The ensuing datasets lead to the elucidation of a cluster of interacting proteins encoded by the target genes of one of the intermediate transcriptional regulators of neurogenesis and ciliogenesis, fd3F. These targets are validated in vivo and result in improved knowledge of the important target genes activated by the transcriptional cascade, suggesting a scenario for the mechanisms orchestrating the ordered assembly of the cilium during differentiation

Tubule detection in testis images using boundary weighting and circular shortest path

In studies of germ cell transplantation, measureing tubule diameters and counting cells from different populations using antibodies as markers are very important. Manual measurement of tubule sizes and cell counts is a tedious and sanity grinding work. In this paper, we propose a new boundary weighting based tubule detection method. We first enhance the linear features of the input image and detect the approximate centers of tubules. Next, a boundary weighting transform is applied to the polar transformed image of each tubule region and a circular shortest path is used for the boundary detection. Then, ellipse fitting is carried out for tubule selection and measurement. The algorithm has been tested on a dataset consisting of 20 images, each having about 20 tubules. Experiments show that the detection results of our algorithm are very close to the results obtained manually. © 2013 IEEE

Evolutionary trends in Heteroptera

1. This work, the first volume of a series dealing with evolutionary trends in Heteroptera, is concerned with the egg system of about 400 species. The data are presented systematically in chapters 1 and 2 with a critical review of the literature after each family.2. Chapter 3 evaluates facts about each egg character. I have attempted to distinguish between anagenetic and cladogenetic processes of evolution.3. The actual chorion reveals a wide range of types of architecture and of aeropylar systems (fig. 264-267). The aerostatic inner layer of the shell of most Geocorisae and of Hydrometra is not homologous with the porous inner layer of Saldidae, many Amphibicorisae and Hydrocorisae. A thin, entirely solid chorion is considered as a plesiomorphous condition (Hebrus, Mesovelia, Idiostolus, Embiophila, Oncylocotis). Some of the specific features of shells are: air clefts; respiratory horns on the rim or on the operculum; porous structures in different stages of evolution, ultimately acting as a plastron; regulation of respiration by movable slips of the rim.4. The general trend of evolution of the micropylar system (fig. 268-270) represents multiplication and displacement of the micropyles, starting from a single micropyle in the centre of the cephalic pole; in some groups reduction and complete loss of the micropyles is associated with traumatic insemination. The structure and orientation of the micropyle(s) and their changes during evolution have been discussed. Monalocoris, Bryocoris and Oncylocotis are divergent from the general pattern.5. The primitive longitudinal dehiscence of the shell has evolved independently and along different pathways into a cap in most major groups (schemes in fig. 270-272), sometimes intermediately on one of the lateral sides. The lygaeid-coreid types of eclosion are derived from a transitional, radial structure which has consolidated in Piesmatidae, and also in Malcidae after loss of a central polygon. The terms operculum and pseudoperculum are redefined on a more functional basis. The cap of the serosal cuticle has evolved more slowly than the cap of the chorion.6. The progressive evolution in size is usually accompanied by some regularities as shown graphically in fig. 273, 274: small eggs have a spacious hexagonal pattern from the follicle; plesiomorphous species are usually small, have a long period of oviposition and few ovarioles in which a few, relatively large, eggs ripen simultaneously; apomorphous species have a larger body, smaller egg and follicle cells, more ovarioles, and synchronous egg maturation and deposition.7. A survey is given of incubation periods, diapause phenomena and reproductive cycles; the phylogenetic consequences are limited. With one exception, diapause of the egg intervenes in embryonic development between the stages of the early germ band and revolution (fig. 275), but does not affect the formation of the serosal cuticle.8. Family groups are distinguished by different types of embryogenesis. A wide range of progressive evolution of the embryonic development is apparent within most of the major phyletic lines. Altogether, the diversity of embryonic features and processes in Heteroptera is not equalled in any other Order of insects as far as is known.9. The variable characteristics utilized in reconstructing the genealogy of embryogenic patterns (fig. 276) are: degree of visible development of the 'pregerm'; location of blastopore; growth, orientation, transformation in shape and displacement (mostly clockwise rotations) of the germ band, embryo and prolarva.10. Since relations between the various ontogenies of the embryo appear to be independent of evolutionary adaptations, the phylogeny of the embryogenetic patterns gives a most reliable picture to contrast with quite different characters used for major classification.11. The archetype of embryogenesis is distinguished by invagination of the embryo (morphologically at the caudo-ventral edge of the egg) along the longitudinal median axis of the yolk column without loss of contact between head lobes and serosa and by a 1800 rotation of the embryo before revolution. Hebrus most closely conforms to this type, followed by most Amphibicorisae and by cimicoid groups which tend to invaginate at the left side of the egg. Temporary complete invagination occurs in Saldidae, Gerris and Hesperoctenes, and in diapausing mirid eggs.12. The variability in the type of egg rotation and embryo rotation in Gerridae, Hydrometridae, Cydnidae and Acanthosomatidae suggests that the egg system is not yet in equilibrium.13. Pentatomomorpha reveal gradual loss of embryo rotation, while Hydrocorisae retain such rotation, sometimes with germ-band and prolarval rotations. Both groups show a transition (anagenetic intra se, cladogenetic inter se ) from the immersed towards the superficial type of embryogenesis.14. The superficial condition of the hydrocorisous type prevails in Reduviidae after complete loss of rotations. The progression in embryonic evolution reached a high level in Harpactorinae; many perform semi-invagination, and species of Coranus entirely omit the invagination stage, and have no blastokinesis in the broadest sense. This deficiency is associated with early differentiation of the prospective germ band in the blastoderm stage. Similar early development occurs in some Hydrocorisae and, through cladistic divergence, also in evolved taxa of the Pentatomomorpha.15. The standard of embryogenesis is not influenced by egg shape. The dimensions of the embryo do not foreshadow those of the future larva but allometry of the limbs appears already during bud formation.16. In contrast to other Heteroptera, saldid embryos have the eyes differentiated before revolution. They possess a peculiar cephalic organ, possibly hydropic, extending through the serosal cuticle and underlying a great part of the chorion.17. A survey is given of the various positions and fates of the serosal hydropyle. The revolution of the embryo is predominantly brought about by local contractions of the fused amnion and serosa, and not by intrinsic action of the embryo itself.18. The remains of the contracted serosa, the serosal plug, is rapidly engorged in course of time into the future pronotal region to form the secondary dorsal organ. The involution is the result of a spectacular peristalsis, in the first instance caused by sudden contraction of cells close to the line of fusion between amnion and serosa.19. In many Miridae, the serosal plug, with or without yolk content, persists till eclosion of the egg, apparently absorbing water from the outside in order to stretch the serosal cuticle. The subsequent lengthening of the egg enables the prolarva to escape out of the sunken oviposition slit.20. The blackening of the egg is reducible to different principles, depending on whether suprachorionic, chorionic or subchorionic layers are involved. The blackish exudate of the serosal cuticle, restricted to some families of Heteroptera, may play a role in water regulation. Extra-embryonic envelopes of uncertain origin have been noticed in a few species.21. The embryological data are compared with the literature dealing with other insect Orders. Because the evolution of embryonic development of insects seems to be largely governed by parallelism, a clearer distinction between cladogenetic and anagenetic phenomena in other Orders must be made first before relationships between Orders can be settled. The differences between the holometabolic and the hemimetabolic type of development may not be as fundamental as has been suggested.22. The evolution of structures involved in four different methods of eclosion is outlined in fig. 278. A transverse, paired ruptor ovi forming part of the embryonic cuticle and delimiting the anteclypeus from the postclypeus is considered as the archetypical condition (as in Hebrus).23. Cladogenesis of the eclosion process evolved within the Amphibicorisae. In Mesovelia, eclosion is caused by fluid pressure within the embryonic cuticle. The situation in the Nabidae represents a link between this procedure and that in the Cimicoidea sensu lato, but the function of pressure transfer is gradually taken over by the fluid-filled serosal cuticle.24. The main device in eclosion of Reduviidae and Hydrocorisae is part of the serosal cuticle. Sudden forcing of extra-embryonic fluid anteriad explosively breaks the chorion in Hydrocorisae. Prolarval rotations may accelerate solution of the inner layer of the serosal cuticle, and the function of the pleuropodia is discussed in relation to this behaviour.25. In Amphibicorisae other than Mesoveliidae, and in the Leptopodoidea the transverse clypeal ruptor developed into a longitudinal frontal ruptor; Saldidae have both a frontal and a clypeal ruptor.26. Pentatomomorpha reveal anagenesis of the ruptor system resulting in displacement of the cephalic armature up to the pronotum through loss of the vertex.27. An account is given of the many sorts of bilateral, mostly monostrophous asymmetries found in the heteropterous egg system. The typical flexing pattern of limbs and antennae of the prolarva (a characteristic of the hemipteroid Orders) is racemic. In Hydrocorisae this asymmetry is constant and either amphidromous or monostrophous (the reverse asymmetry occurs in Plea ). 28. The different orientations of the laid egg are reduced to three main types (Table 2, p. 332) the evolution of which is outlined in fig. 281. Some speculations are made on the selection factors involved in switching from one type to the other.29. The archetypal Heteroptera did not possess a well developed ovipositor, and they were able both to deposit the eggs 'backwards' or 'forwards'. The theoretical possibilities of oviposition in ancestors are shown within the central circle of fig. 281.30. Saldidae and Mesoveliidae have a firm 'concave' ovipositor; oviposition is such that 180° rotation of the longitudinal axis of the egg within the genital tract must be supposed. Gerris regulates delivery of rotated or non-rotated eggs according to the oviposition site selected. Pentatomids of the genera Aeliomorpha and Macrina exhibit 90° rotation of the eggs and the alteration in egg shape conforms with this mode of laying.31. Comparison of embryogenic types (fig. 276), the egg types drawn in a standardized way (fig. 282-285), and the stance of the depositing female demonstrated that 180° rotation of the eggs is more common in Heteroptera and most probably also in other insects.32. The side of the egg where the embryonic anlage develops into the blastoderm is taken as the ventral side. The following rules have been drafted for the dorsoventral polarity of the egg-system: 1. All eggs laid exposed, whether rotated or not, and whose embryo rotates through 180°, are attached with the ventral side against the substrate; the venter of the fully grown embryo lies below the dorsal side of the egg. 2. Eggs without embryo rotation are likewise ventrally attached to the substrate, except when the egg is rotated before laying; the morphological sides of the fully grown embryo correspond with those of the egg.The same rules hold for erect or embedded eggs, when these are figured as being laid horizontally.33. The data obtained from the study of heteropterous eggs have been compared with relevant data from other Orders of insects. The 'HALLEZ law' is redefined on pages 347- 348.34. A preliminary discussion of the phylogeny of the Heteroptera is given. The group characters derived from the egg system are discussed on p. 350-363.35. The Leptopodoidea forms a natural group sharply defined from others. It seems improbable that Amphibicorisae arose from a proto-saldid stock; the opposite direction of evolution, Saldidae from proto-amphibicorisae is more in accordance with our findings.36. The Amphibicorisae appear more diverse than was assumed on the basis of other character complements, and comprise more than one superfamily. Mesoveliidae and Hydrometridae deviate considerably from the group type. Gerridae and Veliidae could be delimited more clearly from each other. Macrovelia and other aberrant genera show close affinity with Veliidae, not with Mesoveliidae.37. Pentatomomorpha constitute a natural group of families but the Idiostolidae are remote. The families are distinguished by the height reached on the anagenetic scale. The origin of the Pentatomoidea dated further back and the anagenesis advanced further than in the other superfamilies. Stenocephalidae appear more lygaeid-like and Colobathristidae more coreid-like. Malcidae are cladogenetically derivable from Piesmatidae. Eggs of Pseudophloeinae and Hydara resemble those of Alydidae.38. Reduvioidea, Thaumastocoroidea and Dipsocoroidea ought to be excluded from the Cimicomorpha which should contain only the families of the Cimicoidea sensu lato. On the basis of the eggs, Bryocorinae, excluding the Helopeltis group, merit family status. Several mirid genera seem to be classed under wrong subfamilies. The eggs of Velocipedidae and Pachynomidae are essentially nabid-like.39. Thaumastocoridae, Dipsocoroidea and Enicocephalidae are all isolated groups. There seems to be no justification for combining the two latter in one group.40. Hydrocorisae, inclusive of Corixidae and Ochteridae, share similar types of embryogenesis and eclosion dynamics but are heterogeneous in chorionic architecture. The common predecessors of Hydrocorisae probably must be found in the naucorid, not in the ochterid branch. Several taxa, considered as subfamilies, perhaps merit family rank (Potamocorinae, Aphelocheirinae, Diaprepocorinae, Micronectinae).41. The unintentional nomenclatoral consequences of the new major classification of terrestrial Heteroptera (LESTON et al. 1954) are discussed. Terrestrial Heteroptera are widely polyphyletic. Hence, the taxonomic use of the name Geocorisae should be avoided.42. The results of our study lead to the recognition of the following, more or less equivalent, major groups; Amphibicorisae, Leptopodoidea, Cimicomorpha sensu stricto, Dipsocoroidea, Enicocephaloidea, Reduvioidea, Thaumastocoroidea, Pentatomomorpha and Hydrocorisae (eggs of Joppeicidae were not available).43. Fig. 306 presents a provisional scheme of the phylogeny of the Suborder. The terrestrial groups and the Hydrocorisae are presented as radiations from an extinct amphibicorisous stock.44. The book concludes with a concise account of some new aspects of evolutionary morphology, which will be elaborated later. The subjects refer, among others, to: eye of egg larva, trichobothria, pretarsus, scent glands, internal and external genitalia, caryotypes, salivary glands, alimentary system, stigmata. These and other characters will be evaluated and compared in Parts 2 and 3 of the series in search of a basis for phylogenetic weighting

Complementary Pediatrics

Complementary Pediatrics covers complementary issues of pediatric subspecialties consisting of ophthalmologic, surgical, psychosocial and administrative issues of frequently used medications. This book volume with its 16 chapters will help get us and patients enlightened with the new developments on these subspecialties' area

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes

The Practice of Sheep Veterinary Medicine

This book is intended to be a reference text for veterinarians who provide clinical services to sheep producers. It is directed first and foremost at Australian sheep-raising systems, but the approaches described herein will have wide application in all countries where sheep are raised under extensive grazing conditions. Most of the important conditions of sheep in Australia are relatively straightforward to diagnose, but the establishment of effective and economically sound control strategies is often the most difficult part of health management, particularly for those who are less familiar with sheep production systems. With six initial chapters focusing on providing readers with a basic understanding of the business and science underpinning sheep production, this book focuses its remaining chapters on reproduction and disease conditions, ordered largely on a systems basis. The book provides details about the way disease processes develop and manifest in sheep flocks, with numerous references for those who wish to read further. Australian sheep production is a profitable and fulfilling agricultural pursuit for a large number of farm owners, and this book is intended to assist those who work in the industry to add to the profitability and efficiency of sheep production systems, the quality of sheep products and the welfare of the sheep in those systems