bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Dawn of the One Gene—One Enzyme Hypothesis During the Classical Period
Authors: Maas Werner 
Published: November 2023

Abstract
We have seen that during the Classical Period geneticists occupied themselves mainly with working out the mechanism of gene transmission from one generation to the next. Yet many of them could not resist speculating about the way in which genes produce specific effects on the appearance of organisms. Since enzymes were known to be specific catalysts in cellular metabolism, these speculations usually ended up with the involvement of enzymes. In surveying the literature I found the names of 17 geneticists who implicated enzymes in gene action. Some of them, such as Bateson, Muller, and Cuenot, are encountered in the Chapter 2.
Escherichia coli Enters the Field
Authors: Maas Werner 
Published: November 2023

Abstract
EScherichiA coli (E.coli) is a bacterium whose normal habitat is the intestine of man and animals. It is named after Theodor Escherich, a German pediatrician, who first isolated it in 1885 from feces of children whose intestinal function he was studying at the University of Munich. At first, E. coli was considered to be a harmless organism that formed part of the normal intestinal flora. In later years, it was found to be the causative agent of a number of infectious diseases, including diarrhea, urinary tract infection, and frequently fatal infections of the blood stream. This paradoxical situation was resolved when it was found that only certain strains of E. coli caused these diseases. In recent years the characteristics of these strains that are responsible for their virulence have been an important subject for investigation by medical microbiologists. Outbreaks of diarrheal infections caused by food contaminated with a virulent strain of E. coli have been reported frequently in the daily newspapers.
The Operon Model
Authors: Maas Werner 
Published: November 2023

Abstract
The culmination of the work on gene action and its regulation occurred in 1961 with the formulation of the Operon Model by Jacob and Monod. This combined all the steps of protein synthesis, so carefully assembled since 1953, with the regulatory mechanisms described in Chapters 12 and 13, in a complete picture. It was a peak in the history of gene action from which one could view the past and obtain a glimpse of the future.
Pharmacokinetics I: developmental principles
Authors: Vinks Alexander A , Walson Philip D 
Published: November 2023

Abstract
Rational pharmacotherapy is dependent upon a basic understanding of the way patients handle drugs (pharmacokinetics) and their response to specific drug effects (pharmacodynamics). Most drugs have been developed and tested in young to middle-aged adults. The evaluation of medications in children has always lagged behind that in adults. In 1964, Dr. Harry Shirkey first called attention to this major public health problem. He coined the term “therapeutic orphans” to describe children as a result of the lack of formal drug studies in children (Shirkey, 1968, 1999).
Pharmacogenetics
Authors: et.al. George M Anderson 
Published: November 2023

Abstract
Pharmacogenetics is usually defined as the study of genetic influences on drug response. Pharmacogenomics, a more recently coined and largely interchangeable term, refers to the area of research that employs genetic information in drug design and treatment. Initial pharamacogenetic research dealt with genetic variation in catabolizing enzymes, and examined how this variation influenced the pharmacokinetics of different drugs. More recently, pharmacogenetics has begun to consider pharmacodynamic aspects of drug response. These studies have investigated how genetic variation at the site of drug action can influence drug effects. It is an exciting time for pharmacogenetics/genomics, as recent applications across medical specialties suggest that the approach has great potential. This appears to hold true for neuropsychopharmacology, and for child and adolescent psychopharmacology in particular.
Neurobiology of early-onset mood disorders
Authors: Kaufman Joan , Blumberg Hilary 
Published: November 2023

Abstract
In this chapter we review extant data on the neurobiology of unipolar and bipolar depressive disorders in children and adolescents. A complement to two recent reviews (Kaufman and Ryan, 1999; Kaufman et al., 2001), this chapter places primary emphasis on those studies in which neuroimaging techniques have been used. Unfortunately, such studies are few and far between. Preclinical models that have guided research on the neurobiology of affective disorders in adults are discussed, and, given the limits in the application of these models to juvenile samples, especially in the case of unipolar disorder, the need for more developmentally focused preclinical work is emphasized.
Neurobiology of eating disorders
Authors: Strober Michael , Klump Kelly L 
Published: November 2023

Abstract
Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior and weight regulation, and disturbances in attitudes and perceptions toward body weight and shape. In AN, there is an inexplicable fear of weight gain and unrelenting obsession with fatness even in the face of increasing cachexia. Bulimia nervosa usually emerges after a period of dieting, which may or may not have been associated with weight loss. Binge eating is followed by either self-induced vomiting or some other means of compensation for the excess of food ingested. Most people with BN have irregular feeding patterns and satiety may be impaired. Although abnormally low body weight is an exclusion for the diagnosis of BN, some 25% to 30% of bulimics presenting to treatment centers have a prior history of AN; however, all bulimics have pathological concern with weight and shape. Common to individuals with AN or BN are low selfesteem, depression, and anxiety.
Antipsychotic agents: traditional and atypical
Authors: Findling Robert L , McNamara Nora K , Gracious Barbara L 
Published: November 2023

Abstract
Drugs that are marketed for the treatment of psychotic disorders in adults, the antipsychotics, are prescribed for a range of problems in children and adolescents. At present, 15 medications are marketed as antipsychotics in the United States. These agents come from several different classes of chemical compounds (Table 26.1). In addition, there are several drugs that are related to the antipsychotics that may also be prescribed to youths for other conditions. These include the antidepressant amoxapine and the preanesthetic droperidol. Metoclopramide and prochlorperazine are related agents that are marketed for their effects on the gastrointestinal system.
Anxiolytics: benzodiazepines, buspirone, and others
Authors: Barnett Shannon R , Riddle Mark A 
Published: November 2023

Abstract
In the treatment of children and adolescents with anxiety disorders clinicians have a wide variety of pharmacologic options beyond the antidepressants (Shader and Greenblatt, 1995; Lydiard et al., 1996; Riddle et al., 1999). The benzodiazepines (BZs), with their favorable safety profile and quick onset of action, are attractive alternatives for the treatment of acute anxiety. While the clinical effectiveness of buspirone has not been proven in children, buspirone is used alone or in combination with other drugs in the treatment of anxiety disorders. The antihistamines are often used to treat insomnia and may reduce acute mild agitation. Zolpidem (Ambien) is occasionally used for its sedative properties. This chapter reviews the structure, proposed mechanisms of action, pharmacodynamic principles, and pharmacokinetic principles of these drugs.
Attention-deficit hyperactivity disorder
Authors: Spencer Thomas , Biederman Joseph , Wilens Timothy , Greene Ross 
Published: November 2023

Abstract
Attention-deficit hyperactivity disorder (ADHD) is the most common juvenile psychiatric disorder presenting to mental health workers, child psychiatrists, and pediatricians. This disorder is one of the major clinical and public health problems because of its associated morbidity and disability in children, adolescents, and adults. Its relevance to society is significant in terms of financial cost, stress to families, and impact on academic and vocational activities, as well as the negative effects on self-esteem. The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) recognizes three subtypes of ADHD: a predominantly inattentive subtype, a predominantly hyperactive-impulsive subtype, and a combined subtype (American Psychiatric Association, 1994). These categories acknowledge clinical heterogeneity and reflect a change in emphasis from earlier definitions that stressed motoric symptoms to the current nosology, which emphasizes deficits in the regulation of cognitive function.
Depressive disorders
Authors: Birmaher Boris , Brent David 
Published: November 2023

Abstract
Major depressive disorder (MDD) is a familial recurrent illness associated with poor psychosocial and academic outcome; an increased risk for other psychiatric disorders, suicide, and suicide attempts; and a high rate of depression and psychological difficulties in adult life (Birmaher et al., 1996b; Goodyer et al., 1997; Lewinsohn et al., 1999; Pine et al., 1998; Rao et al., 1999; Weissman et al., 1999a,b). The prevalence of MDD in children and adolescents is approximately 2% and 6%, respectively (Birmaher et al., 1996b). Thus, early identification and prompt treatment of this disorder at its early stages is critical.
Clinical trials methodology and design issues
Authors: Vitiello Benedetto 
Published: November 2023

Abstract
There is an increasing interest in clinical trials of psychotropic medications in children and adolescents. Several factors contribute to this interest. It is now evident that mental illness often starts in the first two decades of life and both parents and clinicians are more attentive to the presence of psychopathology in youths. New classes of psychotropic medications with a more favorable safety profile than that of older drugs have become available, and are often prescribed to children off-label, that is without pediatric indications approved by the Food and Drug Administration (FDA). Efficacy and safety cannot be entirely extrapolated to children from data collected from adults, as development can affect pharmacokinetics, metabolism, therapeutic response, and drug toxicity. Thus, there are currently no reasonable alternatives to conducting well-designed clinical trials in youths with mental illness as a necessary step toward developing effective and safe treatments for this age group.
Regulatory issues
Authors: Laughren Thomas P 
Published: November 2023

Abstract
Psychiatric illness is recognized in the pediatric population, and there is evidence of substantial use of psychotropic medications in this age group, including in the preschool population (Zito et al., 2000). Unfortunately, the evidence base is inadequate to support the current level of prescribing in this area; neither the efficacy nor the safety of these medications in pediatric patients is well established for most indications. This lack of critical information to support prescribing is reflected in the approved labeling for most of the drug products that are prescribed for pediatric patients with psychiatric illness, which simply states that safety and effectiveness have not been established in pediatric patients. Thus, most prescribing of psychotropic drugs in the pediatric population is off-label, and each child treated is, in a sense, an experiment, but one that is not likely to generate much useful information. There is a critical need for more and better information on the efficacy, safety, dosing, and pharmacokinetics of the psychotropic drugs used to treat psychiatric illness in pediatric patients. There are a number of explanations for the lack of research in pediatric psychopharmacology (Jensen et al, 1994), but this is not the focus of this chapter. Rather, it will review Food and Drug Administration (FDA) initiatives in recent years to stimulate drug research in the pediatric population and the impact of these initiatives on drug development in pediatric psychopharmacology. The chapter will also consider the assessment of safety, the balancing of science and ethics, the preschool population, and other problems that must be addressed for drug development in this area to progress. The chapter will begin with a brief overview of drug development and the regulatory process. In some cases it will be necessary to limit details of the discussion to protect the proprietary rights of individual sponsors who have drug development programs underway in this area.
Ethics, Politics, and Priorities in the Italian Health-Care System
Authors: Ruberto Giovanna 
Published: November 2023

Abstract
A rational man acting in the real world may be defined as one who decides where he will strike a balance between what he desires and what can be done. It is only in imaginary world that we can do whatever we wish. Walter Lippermann, The Public Philosophy The constitutions of all Western countries revised after World War II incorporated a new focus on citizens’ rights: the right to personal liberty, to health, to well-being, and so forth. In fact, equal and free access to health care and to education are now seen as fundamental rights throughout Western Europe. They are considered to be as basic as the right to freedom of speech, and they are seen as necessary constituents of and means to freedom. In the Constitution of Italy, individuals’ right to health care is specifically decreed in Article 32 where the government pledges free health care to all, including the indigent. Legislation related to the health-care system was revised in 1978 by Law 883 and also by subsequent legislative decrees. As recently as 1998, Law 40 was passed, which clearly asserts that all foreign citizens, even illegal immigrants, have an equal right of access to health care. The sum total of this legislation makes health care a fundamental right for everyone in Italy. Access to the health-care system is free for every one living in or simply visiting the nation.
Age Rationing Under Conditions of Injustice
Authors: Francis Leslie Pickering 
Published: November 2023

Abstract
How can an egalitarian justifiably reject age rationing in health care, if rationing is necessary at all? The elderly have had more of the good of life, a “fair innings” in British parlance, so it would seem to follow that they should be of lower priority when it comes to fulfilling health care needs. Or so Daniel Callahan contends (1998). And so Norman Daniels (1985) also contends, but for different reasons. Daniels’s view is Rawlsian: If we do not know our circumstances with respect to health, we would choose health care for ourselves that attempts to further the normal opportunity range over a life span, rather than care extending life beyond that range. Perhaps Daniels is right, and we would so choose. In the real world, however, we do not have the luxury of choosing a health-care system for a complete life, at least for those who are already in the middle of life or nearing life’s end. Instead, we must think about how to apply whatever system turns out to be in place to a wide variety of individuals, some of whom will have enjoyed relative wealth and good health care over a life span but others of whom will not have been so fortunate. The suggestion on which this discussion is based is that Callahan and Daniels consider the problem of age rationing as a problem of “ideal theory.” Daniels, for example, argues that age rationing is justified as a choice made within individual lives, not among lives. Choosers behind the veil of ignorance can expect that earlier benefits will follow them across a lifetime.
Metaphor in Literature
Authors: Kövecses Zoltán 
Published: November 2023

Abstract
What is the relationship between the metaphors used in ordinary language and those used in literature, including poetry? Do literary metaphors constitute a distinct and independent category from ordinary metaphors? There is a widespread notion among lay people and scholars alike that the “real” source of metaphor is in literature and the arts. It is believed that it is the creative genius of the poet and the artist that creates the most authentic examples of metaphor. When we examine this notion from the point of view of cognitive linguistics, we will find that the idea is only partially true, and that everyday language and the everyday conceptual system contribute a great deal to the working of the artistic genius.
The Partial Nature of Metaphorical Mappings
Authors: Kövecses Zoltán 
Published: November 2023

Abstract
It has been emphasized throughout that conceptual metaphors can be characterized by the formula a is b, in which a target domain, a, is understood in terms of a source domain, b. But this formulation of what conceptual metaphors involve is not precise enough. In the case of structural metaphors this would mean that an entire target concept is understood in terms of an entire source concept. However, this cannot be the case because concept a cannot be the same as another concept b. In discussing this issue the idea of mappings is relevant. It’s been pointed out that a conceptual metaphor of the structural kind is constituted by a set of mappings between a source and a target. However, the mappings between a and b are, and can be, only partial. Only a part of concept b is mapped onto target a and only a part of target a is involved in the mappings from b. We need to ask which part(s) of the source are mapped onto which part(s) in the target.
Mammalian Hematopoietic Development and Function
Authors: Spangrude Gerald J 
Published: November 2023

Abstract
The origins of the mammalian immune response are found in hematopoiesis. Most of the diseases discussed in this book are mediated by mutations in genes that function during the course of hematopoietic development at the level of the progenitors for specific cell lineages (severe combined immunodeficiencies) or at the level of the expression of signaling molecules that promote differentiation (MHCII deficiency), or at the level of the functional potential of mature effector cells (leukocyte adhesion deficiency, chronic granulomatous disease). The common theme throughout the diseases discussed in this volume is the origin of the cellular components of specific and nonspecific immunity, the hematopoietic stem cell (HSC). While specific mutations in particular genes can result in defects in highly specialized mature cell populations, the resulting immunodeficiencies are distinguished by the biochemical result of the disrupting mutation and not by the developmental origin of the defective cellular response. This presents both an opportunity and a caution in the design of therapies for some of these diseases.
Lymphoid Organ Development, Cell Trafficking, and Lymphocyte Responses
Authors: Jalkanen Sirpa , Salmi Marko 
Published: November 2023

Abstract
A productive interaction between a lymphocyte and its cognate antigen is required to trigger an adequate immune response. Thus, it is not only the defects in the production and maturation of lymphocytes or in the activation machinery that can result in immunodeficiencies, but the same outcome can be seen if otherwise normal cells do not migrate properly within the body in search of foreign antigens. The best-known examples of this class of diseases are leukocyte adhesion deficiencies 1 and 2 (LAD1 and 2, see Chapter 38). The impact of proper lymphocyte recirculation between blood and different tissues and within the tissue stroma for eliciting an immune response already becomes evident by looking at the physical dimensions of our immune system.
Phagocytic System
Authors: Yang Kuender D , Quie, Paul G , Hill Harry R 
Published: November 2023

Abstract
Phagocytes were initially thought to be harmful to the host, contributing to the untoward consequences of infection and inflammation. In 1898, Metchnikoff first suggested that “the essential and primary element in typical inflammation consists in a reaction of the phagocyte against a harmful agent.”After establishing that phagocytes were helpful in defense against bacteria, Metchnikoff predicted that defects in phagocyte function might predispose the host to increased numbers and severity of infections due to microorganisms. Patients with decreased phagocyte counts or with phagocyte functional defects do, in fact, have recurrent or even fatal infections as well as impaired wound healing. Moreover, evidence has also accumulated demonstrating that aberrant phagocyte activation can contribute to untoward complications of inflammation. Functional defects in phagocytes can lead to recurrent cutaneous abscesses, periodontitis, paronychia, pneumonitis, osteomyelitis, and occasionally life-threatening sepsis.
Autosomal Recessive Severe Combined Immunodeficiency Due to Defects in Cytokine Signaling Pathways
Authors: Candotti Fabio , Notarangelo Luigi 
Published: November 2023

Abstract
The finding that cytokine receptors that use the δc always associate with the intracellular Janus-associated tyrosine kinase (JAK) designated JAK3 (Fig. 10.1) and the discovery that the major cytokine receptor transducing subunit binds to another JAK kinase, JAK1 (Miyazaki et al., 1994; Russell et al., 1994), provided clues to the molecular basis of AR B+ SCID. A mild form of X-linked SCID in humans was shown to result from a point mutation in the cytoplasmic tail of γc, diminishing but not completely abolishing its interaction with JAK3 (Russell et al., 1994). On the basis this information, it was hypothesized that AR B+ SCID in humans could be caused by defects in JAK3. This hypothesis was proved correct by two groups of investigators who reported markedly reduced expression of JAK3 protein due to mutations in the JAK3 gene in unrelated infants with B+ SCID (MIM *600173, #600802) (Macchi et al., 1995; Russell et al., 1995; Candotti et al., 1997; Online Mendelian Inheritance in Man, 2000).
Peptide Transporter Defects in Human Leukocyte Antigen Class I Deficiency
Authors: Salle Henri De La , Donato Lionel , Hanau Daniel 
Published: November 2023

Abstract
Human leukocyte antigen (HLA) class I molecules present peptides derived from proteins that are synthesized in the cell to cytotoxic α β CD8+ T lymphocytes. In this way, these molecules are involved in immune responses against intracellular pathogens and cancer cells. Although these molecules should a priori be essential to immune defense and thus to survival, a few cases have been described of children or adults who live with a defect in the expression of HLA class I molecules.
CD40, CD40 Ligand, and the Hyper-IgM Syndrome
Authors: Geha Raif S , Plebani Alessandro , Notarangelo Luigi D 
Published: November 2023

Abstract
Immunodeficiency with hyper-IgM (HIGM) is a rare congenital disorder, characterized by recurrent infections and very low levels of serum IgG, IgA, and IgE, with normal or elevated IgM (Notarangelo et al., 1992). Both primary and acquired forms of the disease have been reported. Among primary HIGM, X-linked (Krantman et al., 1980; Benkerrou et al., 1990), autosomal recessive (Pascual-Salcedo et al., 1983; Benkerrou et al., 1990; Revy et al., 2000; Ferrari et al., 2001, Imai et al., 2003b), and possibly autosomal dominant (Beall et al., 1980; Brahmi et al., 1983) variants are known, accounting for genetic heterogeneity. Acquired HIGM may be secondary to congenital rubella (Schimke et al., 1969; Espanol et al., 1986; Benkerrou et al., 1990), neoplasia (Raziuddin et al., 1989), or use of antiepileptic drugs (Mitsuya et al., 1979). The disease, originally named dysgammaglobulinemia, was first described in 1961 in a 15-year-old boy with recurrent pneumonia, meningitis, and lymphadenopathy (Burtin, 1961), and in two male brothers with a history of recurrent bacterial infections (Rosen et al., 1961).