bluuebunny/crossref_metadata_2025 huggingface dataset:
Encoded combinatorial synthesis
Authors: Terrett Nicholas K
Published: November 2023

One perennial problem in the testing of combinatorial libraries is the process of identifying the structure of the most active library component. As previous chapters have described, the amount of each compound produced combinatorically is frequently insufficient to permit routine chemical or spectroscopic structural analysis. However, the identity of the active component in a library can often be determined by its spatial position within an array, such as the micro titre block or the VLSIPS chip, and a knowledge of the chemistry performed in that position. Alternatively, the most potent compounds in a library can be identified by the process of recursive deconvolution. But there are occasions when the library is too large to permit rapid compound identification by spatial position or by iterative resynthesize and screening.
Data representations for evolutionary computation
Authors: Parmee Ian C , Coello Coello Carlos A , Watson Andrew H
Published: November 2023

The data processing capabilities of genetic algorithms (GAs) have been recognized (within a wide variety of domains) in recent years, and have received much attention from researchers and practitioners working in many different disciplines (Goldberg 1989). As a stochastic, heuristic technique, the GA does not need specific information about the problem domain to guide search. Its structure is analogous to biological evolution theory using the principle of survival of the fittest (Holland 1975). Therefore, the GA resembles a ‘black box’ that can be attached to any particular application.
Covalent modification of PTPases
Authors: Goldstein Barry J
Published: November 2023

The large, transmembrane PTPases have been shown in several cases to undergo proteolytic processing of a proprotein that produces protein subunits, including LAR, RPTP-k and RPTP-σ. The site and determinants of LAR proprotein cleavage have recently been evaluated [105, 110, 116]. LAR is synthesized initially as a ∼200 kDa proprotein that is processed into a complex of two non-covalently associated subunits. The E-subunit (150 kDa) contains the cell adhesion molecule domains, the P-subunit (85 kDa) contains a short segment of extracellular region and the transmembrane and cytoplasmic domains. Cleavage occurs at a pentabasic (RRRRR) motif at residues 1148-1152, and is catalysed by a subtilisinlike endogenous enzyme. The unprocessed enzyme can also be detected at the cell surface. Studies in transfected HeLa cells have shown that the E-subunit is shed during cell growth; whether this is a mechanism for regulating PTPase function remains to be determined [110].
Modification of PTPase function by chemical agents and proteolysis
Authors: Goldstein Barry J
Published: November 2023

Work in this area has provided insight into structure function relationships in the PTPases as well as potential agents that might be used for pharmaceutical intervention in modulating PTPase function in clinical situations (Table 10). Proteolysis of PTPases in vitro has provided evidence for autoinhibitory domains in PTPIB, TCPTP and the SH2-domain-containing PTPases. It will be of interest to compare these findings to the results of the three-dimensional studies of PTPases to examine the changes in enzyme folding and substrate access to the catalytic centre which may occur with proteolytic cleavage on non-catalytic regions.
The physiology of PTPases
Authors: Goldstein Barry J
Published: November 2023

Many of the physiological effects of PTPases have either been discovered or substantiated in studies employing a variety of current molecular and cellular techniques in whole animal or cultured cell models. For the purposes of organizing the available data, I have separated these studies into two tables. Table 13 incorporates experiments using either transfection of recombinant PTPase cDNA constructs or microinjection of enzymes or antibodies that can perturb the activity of certain enzymes in situ. Table 14 compiles studies using those methodologies that eradicate the expression of specific PTPases either in transgenic animal models, known mutations in PTPases in animal strains, or expression of inactivated or mutated PTPases. Although there is some overlap in the published literature with some studies employing a combination of these techniques, this separation provides a useful way of presenting these data. This is one of the most active areas of current investigation, aimed at deciphering the role of specific PTPase homologues in growth, development and the function of various cells and organ systems. Insight into the available data for certain enzymes can be gleaned from the tabulated summaries.
Reflections on the archaeology of linguistic diversity
Authors: Renfrew Colin
Published: November 2023

We are, of course, as humans all members of one species, Homo sapiens sapiens,and the differences among us are really quite limited. Many of these are acquired cultural differences. These are the things which we learn and the various distinctions between us which develop after our birth. Language ability seems to be a general human attribute but the specific language which we learn in childhood is one of these acquired characteristics of the human individual. The specific culture in which we participate is another. Other differences are, of course, genetically determined.
Lower Bounds for Channel Assignment
Authors: Smith Derek , Allen Stuart , Hurley Stephen
Published: November 2023

The study of lower bounds for channel assignment (Raychaudhuri 1985; Gamst 1986; Lanfear 1989; Smith and Hurley 1997; Allen et al. 1999) is important for at least three reasons. First, lower bounds can be used to show how good a particular assignment is, and whether it is capable of improvement. Second, they can be used to assess the effectiveness of particular algorithms. This is a much more powerful technique than simply comparing the results of algorithms one with another. Indeed, it is unfortunate that many papers on channel assignment algorithms have simply given results for a particular algorithm on sets of test data which may not be accessible to the reader. This can make it impossible for the reader to assess the effectiveness of the algorithm. Third, it may be that identification of the particular structure in the problem that determines the best lower bound shows where the algorithm should concentrate its effort in order to find the best assignment.
Constraint Satisfaction
Authors: Cohen Dave , Jeavons Peter
Published: November 2023

In this chapter we will introduce the notion of a constraint satisfaction problem (CSP) (Montanari 1974; Dechter and Pearl 1988; Mackworth 1992; Ladkin and Maddux 1994). We will then investigate some of the properties of CSPs, and use the CSP abstraction to represent the frequency assignment problem (FAP) in several different ways.
Mathematical Model of a Geothermal Field Exchanger
Authors: Kujawa T , Nowak W , Szaflik W
Published: November 2023

An approximate model of a one-hole injection-production geothermal heat exchanger is presented and an analysis of the influencing parameters upon its operational characteristics is described. The discussion focusses on a field exchanger which passes through an impervious rock massif, the temperature of which is changing linearly, into a geothermal deposit to extract heat from the deposit at the steady-state temperature of the geothermal water.
Improved Methods for the Solution of Integral Equations
Authors: Willmott A J
Published: November 2023

Badie and Dragutinovic [1] rightly refer to “specialists and connoisseurs of the state of {the} open literature” in the solution of the integral equations in [2]. An interesting but not terribly useful competition has evolved as to how these might be solved with minimal computational effort, once the problems associated with the methods of Iliffe [3] and Nahavandi and Weinstein [4] have been overcome. For the engineer, wishing to exploit the mathematics for practical purposes, this competition leads nowhere. In this paper, the author wishes to suggest a possible way forward.
Sanfetrinems
Authors: Cabri Walter , Fabio Romano Di
Published: November 2023

Due to the rapid and growing emergence of infectious diseases caused by strains of bacteria highly resistant to antibiotics used in common practice, several pharmaceutical companies are still deeply involved in the search for new potent and biologically more stable antibacterial agents. In the last decades several classes of non-natural p-lactam derivatives have been specifically designed. In particular, after the discovery of imipenem, the modified 1-methyl carbapenems were identified.
Ldarubicin
Authors: Cabri Walter , Fabio Romano Di
Published: November 2023

This chapter deals with the industrial synthesis of the antitumour agent ida-rubicin 1 and covers 14 years of research mainly carried out in Farmitalia-Carlo Erba, now part of Pharmacia-Upjohn. The evolution of the synthesis of ida-rubicin 1 from the first route developed in medicinal chemistry to that used in the industrial process is interesting as it is related to the evolution of organometallic catalysis used in the synthesis of fine chemicals.
The estuarine benthos and its distribution
Authors: Little Colin
Published: November 2023

Because benthic habitats in estuaries vary from solid rock to sand and mud, and from bare regions to vegetated beds of salt marsh, seagrasses, or mangroves, they are homes to a wide variety of inhabitants, especially in parts of the tropics. But in comparison with the sea and fresh water, their species diversity is in fact surprisingly low, and there are some areas of estuaries that have very few species at all. One of the major preoccupations of estuarine biologists has been to explain the distribution of diversity in estuaries.
Reactions in crystals and time-resolved crystallography
Authors: Schlichting lime
Published: November 2023

In the general excitement of a time when new protein structures are published every week, it is often forgotten that a structure in itself does not tell one how an enzyme works. For that, one needs to know a great deal about mechanism, intermediates,1 and dynamics; a structure is only a beginning, although an important one.
Inelastic and quasielastic neutron scattering: complementarity with biomolecular simulation
Authors: Smith Jeremy C
Published: November 2023

Inelastic and quasielastic neutron scattering can be used to examine the dynamics of biological macromolecules. Our emphasis here is on the complementarity between these experiments and computer simulation, which can provide a stepping stone between experiment and simplified descriptions of the physical behaviour of complex systems.
Diffuse X-ray scattering from molecular crystals
Authors: Moss D S , Harris G W , Wbstrack A
Published: November 2023

In addition to Bragg reflections, real crystals give rise to diffuse scattering that occurs both at and between the Bragg positions. This diffuse scattering arises from the temporary or permanent breakdown of space group symmetry in the crystal and in crystals of macromolecules often accounts for most of the diffracted energy except at low Bragg angles. Unlike Bragg reflections, diffuse scattering contains information about the correlation of the atomic displacements in the crystal and is thus particularly relevant in the study of the conformational flexibility of molecules.
Small-angle neutron scattering
Authors: Zaccai Giuseppe
Published: November 2023

Small-angle scattering (SAS) of X-rays or neutrons arises from scattering density fluctuations of the order 10—100 A. In biological studies, samples are usually solutions of macromolecules in this size range. Depending on the experimental conditions such as macromolecular concentration, for example, SAS provides information on structural properties of individual particles as well as on interactions between them.
Biological spectroscopy using low energy (VUV/UV) synchrotron radiation
Authors: Jones G R , Munro I H
Published: November 2023

Synchrotron radiation (SR) storage rings provide the most highly collimated and intense continuous sources of X-rays, soft X-rays and extreme vacuum ultraviolet (UV) radiation. At longer wavelengths, in the UV, visible and infrared the photon flux of SR is often surpassed by alternative (usually less expensive) sources, such as lasers, arc lamps, blackbody sources, etc. However, there are inherent properties of synchrotron light that make it the preferred source for many experiments. Synchrotron light from bending magnets provides a wavelength continuum of highly collimated, linearly polarized radiation, emanating from a tiny source (of from 103 to ∼ 106 gm2 in cross-section) of electrons or positrons with a well-understood time structure and long term stability. This unique ensemble of properties is further augmented at third generation synchrotron radiation sources by the much higher flux and brightness available from insertion devices such as undulators or multipole wigglers.
Crystallography of viruses and very large macromolecules
Authors: Stuart David I , Crimes Jonathan M , Fry Elizabeth E
Published: November 2023

Crystallography, using synchrotron radiation, can reveal the internal structures of very large macromolecules and macromolecular complexes. The limitation is the requirement for well-ordered three-dimensional crystals. Thus it is very difficult to determine the structure of a macromolecular complex which does not have a single, well-defined structure or which is difficult to obtain in a pure and stable state. Since the late 1970s, when technical and methodological advances opened the way to the determination of the structures of complete virus particles, virus crystallography has led the way in the analysis of complex structures. Crystallography is an extraordinarily powerful tool in the pursuit of a fuller understanding of the biological functions of viruses [see Chiu et al. (1997) for a recent compendium]. However, an intact virus structure determination is not a trivial undertaking and entails a significant scaling up in most respects compared to a traditional crystallographic analysis of a protein. This is because the number of data required to perform an analysis of a crystal by X-ray diffraction (at a fixed resolution) is proportional to the volume of the asymmetric unit of the crystal. Thus for a virus of particle mass 70 MDa (the approximate size of the largest particle thus far solved at reasonable resolution) there are 5000 times as many data to be measured as for, say, lysozyme (the first enzyme structure determined). Not only are there 5000 times as many X-ray reflections to be measured, but these reflections will each be, on average, about 5000 times weaker than those for lysozyme. Virus crystallography makes considerable demands on the qualities of X-ray sources, the performance and sensitivity of X-ray detectors and the computer hardware and software necessary to deal with this enormous increase in data. Nevertheless, the field is now sufficiently mature that it has become quite routine to solve the structure of a relatively small icosahedral virus. Here we give a brief introduction to the methods and take an example from our current work. Before embarking on the crystallographic analysis of a virus, the reader is referred to, e.g. Arnold et al. (1987), Luo et al. (1989), Fry et al. (1993) and Rossmann (1989) for a detailed treatment of various methods.
Some Applications
Authors: Buttazzo Giuseppe , Giaquinta Mariano , Hildebrandt Stefan
Published: November 2023

In this section we shall discuss a few applications of direct methods to some significant examples with the aim of illustrating the existence and regularity results of the previous sections.
Principles of voltammetry, electrolysis, spectroelectrochemistry, and other techniques employed in studies involving solution phase and surface-based electrode processes
Authors: Bond A M
Published: November 2023

Since Faraday’s pioneering studies (Table 1.1), it has been known that the transfer of electrons between a redox active species, dissolved in a solution phase, and solid metal, or carbon, or liquid mercury electrodes, results in interesting reaction pathways. However, voltammetric techniques, which involve the measurement and interpretation of I–E–t curves have only become popular since the 1940s, when instrumentation required to conveniently conduct such experiments became readily available. The early studies invariably used a constant or linear sweep of the direct current (DC) potential and measurement of DC cur rent at the potential of interest. In the last 50 years a wide range of techniques have emerged (Table 1.1).
Electrode processes that illustrate the influence of irreversible homogeneous reactions and the competition between reactions that occur in the solution phase and on the electrode surface: fundamental studies, photovoltaic dye-sensitizers, stripping voltammetry and glucose biosensors
Authors: Bond A M
Published: November 2023

In Chapter 3, the solution-phase voltammetric theory presented in Chapter 2 was applied to the electrochemically and chemically reversible electrode processes associated with some polyoxometalate compounds. However, examples of this relatively straightforward reversible class of processes are not too common and the influence of complexities that may arise in a voltammetric study are now illustrated in the examples of voltammetric studies in this chapter.
Use of metalloprotein voltammetry to illustrate the nuances of electrochemistry related to blocked electrodes, chemically modified electrodes, electrode functionality, and microscopic aspects of electrode behaviour
Authors: Bond A M
Published: November 2023

As noted in Chapters 3 and 4, voltammetric studies on small redox active inorganic, organometallic, and organic molecules frequently provide an efficient method of obtaining important thermodynamic and kinetic information. Logically, therefore, it would be expected that extensive solution-phase voltammetric studies on important electron-transfer metalloproteins such as the cytochromes, ferredoxins, rubredoxins, plastocyanins, and azurins would have been undertaken almost as soon as these water-soluble biologically important molecules had been isolated and characterized.
Demography of the Tar chimpanzee community
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

Forest scene, Survival: 21 August 1996: Mognié, a six-year old female, was in the company of her mother Mystère with baby Mozart, Sirène and Brutus were also there. Suddenly, at 13.40, there was a violent outburst of screams, sign of a possible leopard attack. Grégoire Nohon heard Mystère bark very loudly and very aggressively. He hurried to the site to find all the chimpanzees in trees. Mognié was badly wounded. Claws had raked her chest and belly. Five holes were visible with a piece of intestine popping out of one. Her respiration could be heard through one of the holes in her chest. Forty minutes after the attack, all the chimpanzees moved westwards. Mystère licked some of the blood off Mognié’s chest. Four minutes later, Mognié again climbed a tree to rest in a nest. At 16.45, they all moved further west. At 16.50 Mognié climbed into a Uapaca tree and Grégoire saw that the piece of intestine that had been popping out must be back in place, but the respiration was still strongly audible through this hole. Mystère and her baby Mozart remained with Mognié for two days. She entered Mognié’s nest many times, but it was not possible to see what she did to her.
Female life histories
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

Forest scene: Salomé, a high-ranking female, was in full oestrus with an impressive pink swelling. All the adult and adolescent males of the community guarded her closely and followed her every move. She was leading this crowd for the whole day. Snoopy, her 16-year-old son, a strong young male normally very interested in oestrus females, followed her like the others, but did not try to mate. Her youngest son, Sartre, now 6 years old, seemed fascinated by the success of his mother and at the same time required her full attention and wanted to be carried for all longer distances. He was clearly one of the oldest infants to still enjoy such favour. There was also Ondine and her offspring in the cortège, the highest-ranking female and very close friend of Salomé. Ondine in contrast to Salomé had only daughters: Chloé, her oldest, was starting to produce some small swellings and tried to gain some attention from all these males (she will soon migrate). Her second daughter had died during the early days of the habituation before we could identify her. The third one, Orée, was now 4 years old and Ondine was again beginning to show some sexual swellings. She is to have another daughter within a year, whereas it will take two more years before Salomé will give birth to a female infant.
Social structure of the Taï chimpanzees
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

Forest scene: On 3 January 1986, we followed Falstaff, the oldest male of the community. He was on his own, eating the young leaves of saplings while he moved on slowly. It had not been clear what direction the chimpanzees would take. Now at 6.30, we heard pant-hoots from the west, while in the south we heard the young adult male Snoopy drum loudly. Falstaff sat and listened to his group mates. A third party was vocalizing farther away north. Loukoum, Gauloise, and Goma passed, heading northwards with their youngsters Lychee and Gallus wildly chasing one another. As they disappeared, Mystè re passed by, running after them. We heard Schubert, the beta male, drum loudly to the north and Macho bark in support. Snoopy replied by drumming three more times. To the west, someone was pant-grunting intensively at a dominant individual. Falstaff started slowly to move in this direction, 10 minutes later silently joining Ondine and Salomé, the two highest-ranking females, who were feeding on fruits of Dacryodes.
Hunting behaviour in wild chimpanzees
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

Forest scene: 4 January 1994: Attracted by the deep and loud calls of diana monkeys that are usually associated with other monkey species, Fitz, Kendo, Darwin, Macho, Ella, Bijou, and Gala move silently to the north. After three minutes, they stop and listen. Further on we hear the typical sound of branches bent by monkeys moving in the trees. With a glance towards Fitz and Darwin, Kendo leads them in this direction. After 150 metres, we locate the agitating foliage. Soundlessly, the chimpanzees place themselves underneath and sit and scrutinize the foliage. Directly above diana monkeys utter little contact calls, unaware of the chimpanzees. About 60 metres ahead, we see branches being moved, probably by heavier monkeys, possibly red colobus. Darwin and Macho rush there silently, climb immediately, and run after the fleeing monkeys. As so often happens, no monkey is caught during this first move. The diana monkeys immediately give alarm calls and most monkeys climb higher in the trees and flee in all directions.
Intelligence in wild chimpanzees
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

Once in the early days of the study, when habituation was close to zero, we had searched for chimpanzees all day long without success, when suddenly nearby we heard the typical sound of nuts being pounded with a heavy tool. Very carefully, we approached the chimpanzee, expecting it would disappear before we could get a glimpse of it. However, thanks only to a rustling sound, we saw the shadow of a chimpanzee that was obviously collecting nuts. Surprisingly, at the same time, we heard the pounding go on. Then the spell broke, and in a second the two animals had disappeared. As expected, we found nuts and shells of Panda oleosa but only one stone hammer. We were left with the intriguing question of what exactly these chimpanzees had been doing.
Chimpanzee and human evolution
Authors: Boesch Christophe , Boesch-Achermann Hedwige
Published: November 2023

For centuries the quest for our identity has been a major incentive for philosophical and scientific work. Understanding the uniqueness of human beings with regard to other living beings has often been biased by the difficulty of reasoning impartially about ourselves. The literature is full of statements praising human uniqueness and claiming that we occupy the highest position in evolution. It has been claimed that humans are the only species with a reflective intelligence, the only species that cares for wounded conspecifics, or that depends on cultural products for survival. Similarly, some sets of human behaviour are claimed to be especially demanding, solely because they are performed by humans, such as tool-use, tool-making, coalition building, or language. Such circular arguments that declare a behaviour as unique to humans and therefore representing a proof of the highest evolutionary achievement, do not add much to the understanding of what distinguishes humans from other animals. Although historically such an attitude may have been justified by lack of information, it is not justified today.
Divergent natural selection between environments
Authors: Schluter Dolph
Published: November 2023

Divergent natural selection is the ultimate cause of phenotypic differentiation in adaptive radiation, according to the ecological theory. The two proposed sources of divergent selection are differences between populations and species in external environments and interspecific resource competition. In the present chapter, I investigate the first of these claims. I begin below by clarifying the concept of an adaptive landscape for phenotypic traits. I then address the evidence for divergent natural selection between environments.
Ecological opportunity
Authors: Schluter Dolph
Published: November 2023

In the most remarkable living examples of adaptive radiation, the span of resources utilized by the taxon surpasses typical bounds to include items normally taken by unrelated taxa missing or poorly represented in the region. For example, in addition to ordinary seeds finches on remote archipelagoes take foods otherwise exploited by warblers, woodpeckers, and honeyeaters in more diverse mainland faunas. The marsupial mammals attain their highest diversity in Australia where placental mammals are underrepresented, and the vast array of phenotypes to have evolved there include likenesses of wolves, shrews, moles, and other types of placental mammals that roam the other continents.
Collagen VII and the formation of anchoring fibrils
Authors: Ricard-Blum Sylvie , Dublet * Bernard , der Rest Michel van
Published: November 2023

Collagen VII was first isolated from chorioamniotic membranes by limited pepsin digestion and was termed long-chain collagen (LC) before being referred to as collagen VII [911, see 7, 8, 9 for reviews]. Collagen VII is the major structural component of anchoring fibrils [691, 724], the specialized fibrous structures located immediately beneath the lamina densa of many epithelia and which are critical for epidermal-dermal adhesion. Table 12 gives the Swiss Prot database entries for collagen VII.
The balance between order and disorder
Authors: Williams R J P , Silva J J R Fraústo Da
Published: November 2023

In Chapter 1 we took, as an historical starting point for the discussion of all observations concerning the material objects we sense around us, the four ‘elements’ of certain Greek philosophers and scientists such as Aristotle (see Fig. 1.1). We also noted the relationship to similar thinking in Chinese philosophy (Fig. 1.4).
Evaluating the effects of chemistry
Authors: Anastas Paul T , Warner John C
Published: November 2023

How does a chemist evaluate a chemical product or process for its effect on human health and the environment?

It is easiest to assess a chemical product or process in stages rather than trying to evaluate the whole system in its entirety. Certainly, with the number of parameters that it would be necessary to evaluate at each step of the process, it would be virtually impossible to conduct a systematic assessment on a product or process as a whole. Therefore, a simple approach is to identify the various parts of the process and to ask the necessary evaluative questions at each of those stages. As was mentioned earlier, the five aspects can be thought of as follows.

For each of these aspects, the same questions need to be addressed. Whether dealing with a solvent, reagent, product, etc., there are essential characteristics that need to be known in order to conduct a green chemistry evaluation.
Evaluating feedstocks and starting materials
Authors: Anastas Paul T , Warner John C
Published: November 2023

One of the greatest effects that the manufacture, processing, and use of a chemical substance has can be determined from its starting material. If the starting material, or feedstock from which the chemical product is made, has a negative environmental effect, it is very likely that the overall effect of the chemical substance itself will have a net negative effect. It is for this reason that evaluation of the feedstock or starting material is fundamental when conducting a green chemistry assessment of a chemical product or process.

The magnitude of the effect of the feedstock on the overall profile of the chemical product is dependent on a number of parameters, including the complexity and the length of the process that makes the chemical. If the preparation of the chemical is a one-step catalytic conversion to a petrochemical building block, then the environmental profile of the starting material is of paramount importance. If the end-product is a pharmaceutical that is manufactured via a 12-step synthetic pathway with complex processing and purification, the importance of the starting material may be somewhat diminished. In either of these cases, the profile of the starting material is the first step in evaluating the green chemistry of the chemical product or process.
Clinical trials
Authors: Lindsey J K
Published: November 2023

One of the main driving forces behind the development of new statistical methods in recent years has been the importance of clinical trials both in public health initiatives and in industry. Public control of the release of new medications by national agencies has led to their more rigorous testing, with the accompanying need for reliable statistical procedures. A long-term goal must be the understanding of why a drug works and not just an empirical demonstration that it produces a better result than a placebo or the standard treatment. This will require mechanistic models at all stages of the development process. In this and the following chapters, I shall explore some of the tools that are available.

In medical research, clinical trials are the main method used to evaluate the effectiveness of some treatment(s), such as drugs, surgery, physiotherapy, diet, health education, and so on, in curing some illness or improving health. Here, I shall consider the more advanced, and more publicized, stages of this process, before going on, in the following chapters, to look at some of the more fundamental phases of drug discovery and development.
Quality of life
Authors: Lindsey J K
Published: November 2023

As we have seen, a major goal of clinical trials is to evaluate the effectiveness of some treatment for illness or health problems. Although good health is important, if only defined in a narrow sense of curing a disease or longer life, it may not necessarily lead to increased well-being of a population in all its aspects.

Many modem medical treatments have important side effects that can make life difficult while, at the same time, perhaps alleviating or curing the condition being treated. Weighing the relative importance of the many dimensions of improved health is an extremely difficult problem, especially because each can have a different meaning and importance for different people.s
Assays and formulations
Authors: Lindsey J K
Published: November 2023

Medical statistics does not only involve directly medical (human) problems. More chemical aspects are also important and raise interesting nonlinear modelling issues. In this chapter, I shall look at two of these that occur at opposite ends of the development process: the analysis of assays, needed at the beginning, and the development of formulations for the administration of a medication, required once its value has been established.

In drug development, one must be able to measure the concentration of a new molecule in samples taken from the human body. Thus, one important step is the derivation of suitable assays for measuring the level of the drug in serum, plasma, or other supports. Thus, all of the measurements used in pharmacokinetics(Chapter 7) depend on the availability of such procedures.
Activation of receptors by oligomerization
Authors: Helmreich Ernst J M
Published: November 2023

Binding of the ligand leads to the activation of a membrane-bound receptor and initiates the cellular response to hormones, growth factors, and cytokines. The structural basis of ligand binding and receptor activation is therefore a central problem of cellular signalling. The question is how a single polypeptide chain which passes through the membrane only once, is activated on binding the ligand. The answer is by dimerization.
Regulation of gene transcription by growth factors and cytokines
Authors: Helmreich Ernst J M
Published: November 2023

General transcription factors have been discussed above, and now we turn to specific, signal-responsive transcriptional regulators. Specific transcription factors link extracellular signals, received by receptors and transmitted through cellular signalling pathways to the gene. Considering the central role of transcriptional activation for growth and differentiation of all cells and tissues, it is hardly surprising that thousands of factors control the expression of about 30 000 human genes. Therefore, the discussion in this chapter is, by necessity, simplistic and selective. Moreover, bear in mind that new factors are discovered all the time and that there is still a way to go until all facets of gene regulation are understood.
Regulation of the immune response
Authors: Helmreich Ernst J M
Published: November 2023

The immune response is complex and has many facets. It is an essential cell-specific function, guaranteeing our survival. This chapter concentrates on a few topics centred around signalling in the immune system. The processing of the ligands, the antigens, and their presentation to antigen receptors will be discussed, focusing on cell (T-cell) mediated immune responses. Outstanding textbooks on immunology and cell biology are available, which the reader could consult.
Epithelial tumors of the kidney
Authors: Stoerkel Stephen , Hinkel Andreas
Published: November 2023

The purpose of tumor pathology is to understand etiology and pathogenesis and to classify tumor diseases, to determine patients’ prognosis, and thus to guide clinicians to plan and justify their therapeutic regimens.
Molecular cytogenetics of renal cell tumors
Authors: Kovacs Gyula
Published: November 2023

Diagnostic and classification systems at any time reflect our technical abilities in the analysis of tumors and our actual theories on tumor development. For many years, renal cell tumors (RCT) were divided into clear and granular cell types on the basis of their cytoplasmic staining characteristics. Bannasch et al. (1974) worked out a cytomorphologically oriented classification of experimental kidney tumors of the rat, which later was ‘ translated’ for human kidney cancers (Thoenes et al. 1989). RCT were then divided into clear, chromophilic, chromophobe, and oncocytic as well as spindle cell type. Rarely occurring tumors such as collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), and metanephric adenoma (MA) have been recognized in recent years (Jones et al. 1995; Fleming and Lewi 1986; Jones et al. 1995).
Angiogenesis in renal cell carcinomas
Authors: Wieder Jeff A , Belldegrun Arie
Published: November 2023

Angiogenesis is the formation of new capillaries by outgrowth of endothelial cells from pre-existing blood vessels. The role of angiogenesis in tumor growth and metastasis was first described by Folkman and co-workers (Folkman 1971, 1972; Folkman et al. 1971). They demonstrated that a tumor can grow up to 1.75 mm when it obtains nutrients only by diffusion. Growth beyond this size requires angiogenesis (Folkman 1972). They concluded that tumors need new blood vessels to supply nutrients for growth and spread. Folkman suggested that cancer could be treated by inhibiting angiogenesis (Folkman 1971, 1972; Folkman et al. 1971). Tumors that are highly vascular, such as renal cell carcinoma (RCC), appear to be fertile targets for this type of therapy. Modern research seeks to elucidate the role of angiogenesis in the biology and treatment of kidney cancer.
Spontaneous regression and the natural history of renal cell cancer
Authors: Oliver R T D
Published: November 2023

It is now more than 30 years since Everson and Cole (1966) reviewed the occurrence of spontaneous regression of cancer in the world literature. They were the first to draw attention to the fact that renal cell cancer had nearly the highest frequency among such events. It is now 22 years since I first became interested in this phenomenon. This interest developed because of the untoward experience I had with the first renal cancer patient I treated using chemotherapy. He had had a single lung metastasis for nearly 10 years, which had been slowly growing and was beginning to become symptomatic. Three weeks after a single dose of cyclophosphamide he had widespread multiple lung metastases and was dead within 6 weeks.
Interferon for ronclavllcarcinoma
Authors: Godley Lucy A , Vogelzang Nicholas J
Published: November 2023

The treatment of metastatic renal cell cancer has remained a challenge for clinicians despite the many chemotherapy agents that are now available. Renal cell cancer is highly resistant to traditional cytotoxic chemotherapeutic drugs, and few are useful in the management of metastatic disease. An approach utilizing immunological agents, especially interleukin-2 and interferon alpha, along with selected chemotherapeutic agents has proven to be the most effective, with response rates averaging about 20 per cent. This chapter will review the use of chemotherapy, hormonal agents, and combination regimens that include immunotherapy to treat advanced renal cell cancer.

merely long- term stabilization of disease (Stadler et al. 1999).
Imaging of adrenal masses
Authors: Teeger Susan , Papanicolaou Nicholas , Vaughan E Darracott
Published: November 2023

Adrenal masses are relatively common, and have been reported to occur in about 9 per cent of post mortem examinations (Hedeland et al. 1968). Detection of adrenal masses has increased substantially since the advent of cross-sectional imaging techniques and especially computerized tomography (CT). One of the most common problems that one faces in daily practice is the discovery of an incidental adrenal mass. Most incidentally detected adrenal masses are nonfunctioning adenomas; however, they need to be distinguished from primary or secondary malignant lesions (Reed Dunnick et al. 1996). Even in patients with a documented malignancy elsewhere, only approximately 50 per cent (Katz and Shirkhoda 1985) or fewer (Oliver et al. 1984) of adrenal lesions are proved to represent metastases at pathology.
Laparoscopic versus open adrenalectomy
Authors: Meraney Anoop M , Gill Inderbir S
Published: November 2023

Rapid advances in adrenal surgery have occurred during the last decade. Increased utilization of minimally invasive surgical techniques has led to several centers worldwide adopting laparoscopic adrenalectomy as the standard of care. Since its initial description by Gagner and colleagues (1992), laparoscopic adrenalectomy has evolved rapidly and can now be performed employing varied approaches, each with their own technical nuances.
Cognitive behaviour therapy of acute stress disorder
Authors: Bryant Richard A
Published: November 2023

An important development in the early intervention of post-traumatic stress disorder (PTSD) occurred when the diagnosis of acute stress disorder (ASD) was introduced in 1994 in the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders [DSM-IV; American Psychiatric Association (APA), 1994]. This new diagnosis was important, because its aim was to identify people in the initial month after a trauma that would subsequently develop long-term PTSD. Implicit in this goal was the expectation that successful identification of people at risk of PTSD would receive early intervention to prevent chronic PTSD. This chapter reviews the evidence for the utility of ASD diagnosis as a predictor of subsequent PTSD, critiques the evidence for cognitive behaviour therapy of ASD, and highlights the advantages and disadvantages of early intervention with cognitive behaviour therapy.
The Lincolnshire Joint Emergency Services Initiative: an early intervention protocol for emergency services staff
Authors: Avery Anna , King Stephen
Published: November 2023

The First European Conference on Traumatic Stress held in Lincoln, England in 1988 highlighted the impact disasters can have on rescue personnel, as well as primary victims. A major achieve ment of this scientific meeting was to foster an appreciation that both these groups, as well as those described by Figley (1995) as being at risk for secondary ‘vicarious reasons’, should be studied and understood as part of the endeavours of modem psychotraumatology.
Training programmes for building competence in early intervention skills
Authors: Ruzek Josef I , Cordova Matthew J
Published: November 2023

Each disaster requires emergency response specifically for its survivors. Early interventions that seek to prevent or minimize psychosocial and mental health consequences of exposure to potentially traumatic events do so by promoting resilience and coping. This chapter offers a plan for training groups of helpers to integrate this perspective into early interventions following trauma. Three vignettes are used to exemplify the training processes and interventions that may follow from this new competency.
Neoplasms
Authors: Peterson Kendra
Published: November 2023

Although most malignant tumors that affect the nervous system are currently not curable, aggressive multimodality therapies are employed in many instances in an effort to prolong life, and to maintain function and quality of life for as long as possible. Skillful management of a patient with nervous system malignancy includes careful diagnosis and rendering of appropriate treatments; careful attention to symptom management must also be the goal throughout the course of the illness and at the end of life. In addition, the patient must be supported through the transition from hope for cure or prolonged survival, to the acceptance of the terminal illness. Inherent in malignancies that affect the nervous system are changes in cognitive ability, personality, physical function, autonomy, and family and community roles. Family members and other caregivers are profoundly affected by the illness and themselves need support, education, and care. Although the focus of this discussion is the care of patients with incurable, progressive, and malignant nervous system tumors, the remarks are largely applicable to the care of many patients with less malignant tumors and at earlier stages of illness as well.
Diseases of Motor Nerves
Authors: Meadway Jeanette
Published: November 2023

Motor neuron disease (MND)/amyotrophic lateral sclerosis (ALS) is a progressive disease with no curative treatment and a prognosis of three or four years for most people. Thus, the care of patients with MND/ALS requires a palliative care approach from the time of diagnosis, with the involvement of the wider multidisciplinary team. It is essential to consider all the aspects of the patient and family’s care, including the physical, psychological, social, and spiritual. As the disease progresses, the management of the various symptoms, including dysphagia, dyspnea, dysarthria, pain, and drooling, becomes increasingly important, to maintain the person’s quality of life. The support of the person with MND/ ALS and their family and carers is essential, as fears and concerns may develop as the disease progresses. There are often fears of a distressing death but, with this approach to care, actively managing and anticipating the potential problems, the majority of patients are able to die peacefully, with their symptoms controlled.
Persistent Vegetative State
Authors: Rudolf Topper , Wilhelm Nacimientq
Published: November 2023

The term ‘persistent vegetative state’ was coined in 1972 and has since been used to describe patients who respond to stimulation only in a reflex way but show no signs of awareness. Diagnosis is made by repeated clinical examination. The two most common causes of the vegetative state (VS) are trauma and cerebral hypoxia following cardiopulmonary arrest. The prognosis for patients in the VS depends on the time a patient has remained unresponsive. Overall, only 15 % of patients regain consciousness. Although neurophysiological and neuroimaging studies have some prognostic value, there are no reliable prognostic markers which are able to predict the clinical outcome of patients in the VS. At present there is no medical treatment of proven efficacy in promoting clinical recovery in these patients. Good palliative care is the mainstay of therapy in VS patients. Additionally, the therapeutic concept of sensory stimulation has gained some popularity in the treatment of VS patients and is widely used in neurorehabilitation units.
Neurological Emergencies
Authors: Hardy Janet , Martin Donal
Published: November 2023

Spinal cord compression (SCC) has the potential to impair, suddenly and drastically, the quality of life, not only of a patient but also their relatives and/or carers. The devastating effects of SCC and the speed at which irreversible neurological damage occurs defines this condition as a true oncological emergency. The outcome of treatment, as measured by the degree of residual neurological impairment, is dependent on the time from first development of symptoms to the start of treatment. In many instances, patients are left with marked impairment in performance status and neurological function. This has profound implications for palliative care services that are often called upon to provide the ongoing care for these patients. Raised intracranial pressure (ICP) is a common complication of both metastatic and primary brain disease. It is characterized by specific clinical features and can present as an oncological emergency because of the risk of seizures and loss of consciousness. The symptoms are often difficult to manage in the absence of any specific treatment of the underlying condition and can present a major challenge to those providing the palliative care of these patients.
Food and Hydration
Authors: Defanti Carlo A
Published: November 2023

While most patients with neurological disease will have functional gastrointestinal tracts, they will often have difficulty in taking food and fluids by mouth. This may be because of an impaired ability to swallow or because of a lack of desire to eat. The provision of food and fluids may be essential to maintain life in some patients. In the other extreme, the continued delivery of food and fluids may be inappropriate or even deleterious in those patients with very advanced stage disease. The issue of nutrition in patients with neurological disease is fraught with moral and ethical dilemmas. The involvement of a multiprofessional team is crucial to ensure best practice and optimum patient care. Every case must be treated on an individual basis and the patient and his/her family must be involved in all decision-making processes.