bluuebunny/crossref_metadata_2025 huggingface dataset:
Siloxane dendrimers
Authors: Muzafarov Aziz M
Published: November 2023

Starch is the cheapest and most abundant food biopolymer worldwide. It is a complex carbohydrate which is insoluble in water; it is used by plants as a way to store excess glucose. Starch is often found in the fruit, seeds, rhizomes or tubers of plants. The four major resources for starch production and consumption in the USA are corn, potatoes, rice, and wheat. Pasta is an important dietary source of starch which is commonly prepared from wheat, rice or beans. Bread is another important source of starch and is commonly prepared from wheat.
Taking Sides, Making Sides
Authors: Batstone William W , Damon Cynthia
Published: November 2023

Characterization in a civil war narrative is more important, and more difficult, than it is in a colonial narrative, such as the Gallic War, of “us” against “them.” When the principal combatants are all Roman and all members of the governing elite, the difference between “us” and “them” needs careful delineation. But drawing the lines is complicated when the composition of the two parties shifts over time, as it did in dramatic fashion after the battle of Pharsalus in August of 48. Men who had joined Pompey at the outset of the conflict, in January of 49, or in the course of the ensuing months, faced a choice after his military defeat: to continue resisting Caesar, to withdraw from the contest, or to join Caesar. Those who chose the last moved from “them” to “us,” and the neutrals might still, it could be hoped, so realign themselves. Only the first group (and those who died at Pharsalus) remained in the category of “them.”
Mastering Victory
Authors: Batstone William W , Damon Cynthia
Published: November 2023

The three preceding chapters explored Caesar’;s literary achievement in the Civil War in terms of genre, structure, and characterization, and began to place the work in its contexts both literary and political. This chapter looks at how Caesar presents himself to his contemporaries through his text. The focus is not on what he says about himself and his virtues—his superiority to Pompey as general, for example, which was treated in chapter 3—but on the self he reveals to his readers by his authorial choices. At first glance, the Civil War seems to be structured around the contest for primacy between Pompey and Caesar. It begins with Pompey’;s assumption of leadership in the opposition to Caesar (1.1) and builds to their military confrontation in Greece (3.6–96). But neither Pompey’;s flight from Pharsalus (3.96.4) nor his death at Alexandria (3.104.3) is the end of the work.
From Genes to Genomes: A Historical Perspective
Authors: Dunham Ian , Powell Don
Published: November 2023

You may or may not have noticed, but during the past 10 or so years, you have just experienced the genomics revolution. A precise start point is difficult to define, but for argument’s sake we can identify the first publication of the genome sequence of a freeliving organism (Haemophilus influenzae) (Fleischmann et al., 1995) as the harbinger of the flood of genomic information that would appear over the next 10 years. Notably this flood included the first complete sequences of a human chromosome (Dunham et al., 1999), the completed sequence of the human genome (IHGSC, 2004), and draft sequences of the mouse (Waterston et al., 2002) and rat (Gibbs et al., 2004) genomes. After the wealth of whole-genome sequences have come the beginnings of genome re-sequencing as human genomes have been sampled to generate single nucleotide polymorphisms (SNPs) (Sachidanandam et al., 2001) and these SNPs have been used to build maps of the sequence content of different individual human genomes (Altshuler et al., 2005). All of this information is freely available through public domain Web servers such as Ensemble (Hubbard et al., 2005), so any researcher with access to the Internet can interrogate the human genome. It is now hard to imagine a time when genome sequence information was not central to human genetics. However, looking back to the time before genome sequencing was a reality there were genuine questions as to whether we could afford or indeed needed the human genome sequence (Lewin, 1986). Thus it is worth looking back to see how we got to the position we are now in and what were the motivating factors behind the drive toward genome sequencing (Table 1–1).
Pharmacogenomics: Drug Development, Drug Response, and Precision Medicines
Authors: Penny Michelle , McHale Duncan
Published: November 2023

In its broadest sense, pharmacogenomics can be defined as the investigation of variations of DNA and RNA characteristics as related to drug response. The last decade has seen a large increase in the amount of genomics data generated and, with it, increased the expectations of how improved understanding of disease will lead to the development of more effective therapies and personalized medicines. Despite the regular media reports of novel genes being identified in a range of disorders, by 2007 the much-heralded promise of the human genome project has yet to materialize. However, it is important to realize that this does not represent a failure of the science to deliver but is a reflection of the length of time it takes to develop new drugs. The 1980s and 1990s saw a boom time for the pharmaceuticals industry producing many highly effective new classes of drugs from statins to proton-pump inhibitors and quinolone antibiotics. All were novel therapeutic approaches offering significant benefit to individuals and society. The science that drove many of these advances was based on the greater understanding of biochemistry and pharmacology that emerged during the 1970s and early 1980s. This 10–15-year time-lag from gaining scientific knowledge to developing therapies is typical for the pharmaceutical industry, and reflects the complexity of drug discovery and the time required for preclinical and clinical testing to ensure safety and efficacy. This chapter will introduce the major concepts of drug discovery and development and give a broad overview of how genetics and genomics is used across the whole drug discovery and development pipeline, from pretarget identification to postmarketing surveillance to help discover and develop improved medicines.
Chronic Renal Disease
Authors: Ong Albert CM , Maxwell A Peter
Published: November 2023

The prevalence of end-stage renal disease (ESRD) is steadily increasing, contributing to growth in the provision of renal replacement therapy (RRT) (dialysis and transplantation) for over 1 million individuals worldwide (Collins et al., 2003). Living with ESRD is challenging for individuals and the economic costs of RRT for society are enormous (El Nahas and Bello, 2005). Figure 13–1 shows the relative prevalence of different primary renal diseases among the England and Wales population on RRT in 2003. Diabetic nephropathy is the most common cause of ESRD and is increasing in incidence worldwide. There is increasing evidence for genetic (polygenic) susceptibility for diabetic nephropathy. Autosomal dominant polycystic kidney disease (ADPKD) accounts for approximately 10% of treated ESRD and is the single most common monogenic cause of ESRD worldwide. In this chapter, we review the evidence of how genetic factors can modify the phenotypic expression of these two common diseases and illustrate the different experimental approaches that are being used to identify modifying genes, important in chronic renal failure.
Disorders of Platelets
Authors: Bahou Wadie F
Published: November 2023

Overview of Platelet Biology and Function

Blood coagulation is controlled by a tightly regulated cascade of proteases and their cofactors that sequentially lead to the generation of a gelatinous meshwork of protein called fibrin. This coagulation mechanism ensures the normal cessation of blood flow that occurs during physiological processes such as wounding or menstruation, and is termed hemostasis. Human blood platelets play a critical function in the maintenance of primary hemostasis, not only via adhesive interactions with the sub endothelial matrix but also by providing the negatively charged phospholipid required for coagulation factor assembly, amplification, and thrombin generation (Bahou, 2002). Platelets aresmall, discoid cells thatare 2–3 mindiameter with an approximate cell volume of 10 fl. Generated as cytoplasmic buds from precursor bone marrow-derived megakaryocytes, the normal human platelet count is 2,50,000 + 1,00,000/ml of whole blood. Although platelets are required for normal hemostasis, longstanding observations have established that their primary relevance to human diseases are their roles in situations of pathological thrombosis, that is, vascular disorders such as stroke or coronary occlusion with myocardial infarction (MI) (Wardle, 1973).
Neurodegenerative Disorders: Tauopathies and Synucleinopathies
Authors: Morris Huw R , Singleton Andrew
Published: November 2023

Neurodegenerative disorders are common and usually affect the elderly. This is set to become the most pressing health concern in the developed world, because of the projected rapid expansion in the aged population. The prevalence of Alzheimer disease (AD) is predicted to quadruple in the United States over the next 50 years (Kawas and Brookmeyer, 2001). Unlike cancer and vascular disease, there are no disease-modifying therapies for patients with neurodegenerative diseases. There is an immediate need to develop new treatments, based on an understanding of the underlying disease biology. The genomic analysis of neurodegenerative disease is progressing rapidly, and unlike other common sporadic conditions, this has largely been guided by the study of rare Mendelian families with inherited late onset neurodegenerative disease. Although, genomewide screens have been performed in series of affected sibling pairs (ASPs), small multiplex families and more recently in case–control series, more work has been done on systematic selective candidate gene analysis. Despite the inherent difficulties in studying Mendelian families with late onset disease, a series of genes have been identified which can be responsible, in mutated forms, for AD, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and other conditions (Hardy and Gwinn-Hardy, 1998). The identification of these genes has led to intensive work on basic protein biology, with the development of in vitro and transgenic in vivo disease models, and exploration of the role of these Mendelian disease proteins in sporadic human disease. Some investigators initially felt that Mendelian disease genes were unlikely to be relevant to sporadic disease. However, molecular neuropathology, and more recently, genomic association analysis have confirmed the validity of a Mendelian disease-driven approach.
Complex Skin Diseases II: Atopic Dermatitis
Authors: Morar Nilesh
Published: November 2023

Atopic dermatitis (AD) or atopic eczema is a chronic, itchy, inflammatory skin condition that predominantly affects the skin flexures. Approximately 70% of cases start in children younger than 5 years of age (Williams, 2000). The prevalence has increased three-fold over the past three decades in developed countries, with a higher prevalence in urban regions and in higher social classes (Taylor et al., 1984). The lifetime prevalence in children is 10%– 20% and in adults 1%–3% (Schultz-Larsen, 2002). Though 60% of children with AD are free of symptoms in adolescence (Rystedt, 1985), up to 50% may have recurrences in adulthood (Lammintausta, 1991). Asthma develops in 30% of children with AD and allergic rhinitis in 35% (Luoma et al., 1983). There has been substantial variation in disease definition and diagnosis due to the variable clinical appearance, distribution patterns, and the intermittent nature of the disease. On the basis of the original consensus criteria by Hanifin and Rajka (1980), a set of minimum and validated discriminators have been determined by the UK Working Party (Williams et al., 1994). The diagnosis requires evidence of itchy skin plus three or more of the following: history of involvement of the skin creases, history of asthma or hay fever, history of generally dry skin, onset in a child under 2 years of age, and visible flexural dermatitis. These robust criteria are crucial for effective and reproducible genetic studies.
Genomics and Global Health
Authors: Weatherall Sir David , Kumar Dhavendra
Published: November 2023

The provision of healthcare in the future offers completely different challenges to the developed, industrialized nations as compared to developing countries. For the former, the major problem is how to control the increasing costs of healthcare arising from the prevention and management of chronic disease in aged populations. The role of genetics and genomics in the prevention and management of these conditions is described in earlier chapters. Here, we focus on the quite different problems of the developing countries.
Genetic Testing and Genomic Screening
Authors: Clarke Angus
Published: November 2023

Twenty years ago, it became possible to isolate genes by first inferring their chromosomal location—the reverse approach to previous attempts at gene isolation. The recognition of widespread variation in the deoxyribonucleic acid (DNA) sequence of noncoding regions of the genome enabled the coinheritance of such variation with genetic diseases to be detected and measured, so that linkage could be established between the sites of variation and specific disease loci. This required (i) the preliminary work of gathering DNA samples and clinical information from many individuals in families segregating for Mendelian (monogenic) disorders, (ii) the ingenuity to manipulate the DNA with restriction enzymes and simple microbial vectors and then (iii) the ability to interpret the accumulated data in a statistically meaningful manner. Even when the protein encoded by a gene was completely unknown, it became possible to predict its amino acid sequence and then to recognize, isolate, and study the protein. This gave insight into completely novel cellular processes and greatly accelerated the pace of research in much of biology. Testing also become feasible for diagnostic and predictive purposes within many families affected by genetic diseases and some of the developmental disorders transmitted in the same fashion. These simply inherited conditions are, however, uncommon and together they account for only a small proportion of the overall burden of human disease.
The Regulation of Human Genomics Research
Authors: Kaye Jane
Published: November 2023

A key event in the regulation of medical research was the Nuremberg Trials that were held after World War II, which found Nazi physicians and researchers guilty of atrocities that were committed in the name of medical research. Since then, research ethics committees (RECs) and oversight mechanisms for medical research on human beings have become the accepted norm in most countries. The regulation of genomic research, like other subsets of medical research, is subject to the same regulatory controls that apply to medical research in general. Therefore, the focus of this chapter will be on the regulation of medical research on human beings, excluding the approval of medicine and medical devices, in order to discuss the ways in which these more general requirements apply to genomic research. This paper will also make reference to some of the specialist bodies that have been established as expert advisory agencies for genomics.
Neuroimaging in Addiction
Authors: Williams Tim M , Srivastava Shrikant , Lingford-Hughes Anne R , Nutt David J
Published: November 2023

Dependence on and harmful use of substances have wide reaching public health implications. In 2004, 19.1 million people in the United States (7.9% of the population aged 12 and over) were current illicit drug users, with marijuana being the most commonly used substance (SAMHSA, 2004). Recently there has been a significant increase in the nonmedical use of painkillers among young adults (aged 18–25 years). Alcohol is used regularly by the majority of the population in the United States; however, young adults report the highest prevalence of binge and heavy drinking (41.2 and 15.1%, respectively). Furthermore, 22.5 million people in the United States were classified with past-year substance dependence or abuse (9.4% of the population), 3.8 million of whom had received treatment in the 12 months prior to survey.
Adjuvants for Pain
Authors: Chang Craig K , Pappagallo Marco
Published: November 2023

An adjuvant for pain is a pharmacological agent that is added to a primary analgesic agent, for example, an opioid, to increase or aid its effect (see Table 25.1). Although adjuvants usually have treatment indications other than pain, advances in molecular biology and neuroscience have generated new strategies to treat pain with these medications.
Interventional Pain Medicine
Authors: Dubois Michel Y , Patel Roshni
Published: November 2023

Interventional pain medicine is an important part of pain management. Although there are many interventional approaches available for treating pain (Box 28.1), the expression ‘‘interventional pain medicine’’ is usually reserved for all procedures done with the use of a needle. Nerve blocks, a prime example, have been used for more than a century for both diagnostic and therapeutic purposes. Many minimally invasive interventions may be effective in diagnosing or managing chronic pain from a variety of sources. Performing these procedures requires an understanding of the relevant anatomy, physiology, and pharmacology, as well as the ability to interpret the results. Most of these techniques should be practiced only after special advanced training.
Behavioral Medicine Treatment in the Management of the Chemically Dependent Patient
Authors: Wootton Joshua
Published: November 2023

Where pharmacological approaches to chemical dependency are concerned, addiction is frequently considered essentially a brain disease, but no medication is likely ever to control addiction on its own, without treatment applied to the social and behavioral dimensions of chemical dependency (Leshner, 1997; NIDA, 1999). Even when immediate physiological dependency has been addressed and overcome, there will always remain those environmental and emotional cues that, when encountered, may tend to reawaken the craving and result in relapse (Beck et al., 2001). Visiting a certain neighborhood or location, pursuing activities with a particular group of people, or just being alone and experiencing feelings of boredom, emptiness, or anxiety can all trigger powerful and familiar cravings, even after prolonged periods of abstinence (Franken et al., 2001; Leshner, 1997).
Managing Pain and Substance Abuse in the Patient With HIV/AIDS
Authors: Breitbart William , Dhingra Lara K
Published: November 2023

In the past decade, adults in the United States diagnosed with human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) have benefited from profound advances in treatment and access to care. However, despite these improvements in survival and care, pain in HIV/AIDS patients continues to be a major problem affecting quality of life outcomes for the majority of patients diagnosed. Pain rates in HIV/AIDS patients are high (30% to 93%), with patients who have a history of substance abuse particularly underserved in pain management. HIV/ AIDS patients with a history of substance abuse are more likely to have their pain underassessed and undertreated than patients without a history of substance abuse. It is well-documented that current or past substance abuse is a formidable barrier to adequate pain management in HIV/AIDS care.
Abuse Liability Assessmentof Prescription Opioids in Chronic Nonmalignant Pain Patients
Authors: Zacny James P
Published: November 2023

The purpose of this chapter is to introduce the reader to the concept of abuse liability assessment (ALA) of opioids; how ALA of prescription opioids might be done in chronic nonmalignant pain (CNMP) patients; some of the problems that need to be addressed when designing ALA studies in this population and interpreting the results of the studies; and research questions that might be addressed in the conduct of such studies. Given the paucity of studies that have addressed issues of abuse liability of opioids in CNMP patients (Moulin et al. 1996; Tassain et al. 2003), this chapter is meant to serve as a catalyst to stimulate discussion between pain researchers, pain clinicians, addiction medicine specialists, and abuse liability researchers on this topic.
Beyond the Baton
Authors: Wittry Diane
Published: November 2023

Seasoned conductor Diane Wittry draws a comprehensive roadmap to a successful career in Beyond the Baton. With first-hand understanding of how the role of the conductor has changed across the years, she expertly examines the new set of duties--both on and off of the podium--that now fall upon the shoulders of the music director. From getting a job to fundraising and educational outreach, Wittry’s comprehensive tips and strategies guide students and professional conductors alike through the leadership and organizational skills necessary for success. Numerous real-life examples illustrate vital skills for artistic leadership such as programming subscription, pops, and educational concerts; understanding the budget and the music director’s role in funding the artistic vision; and presenting speeches, and radio and televised interviews. In informative conversations with the author, successful conductors Leonard Slatkin, Robert Spano, and JoAnn Falletta offer tips from personal experience on how music directors can work successfully with orchestras, and what their roles are with the board and the community. With up-to-date information and extensive listings, the resource section provides valuable information that conductors use every day in a convenient and practical format. Wittry gives conductors easy access to contact information for national musical organizations, guest artist managers, music publishers, internet sources, conducting competitions, summer festivals, grants, and scholarships. Programming lists and sample contracts and resumes can also be found within these pages. A comprehensive, step-by-step guide to success in the conducting world, Beyond the Baton is an indispensable companion, and its advice will help all aspiring and practicing conductors make the most of their talent and training.
Evaluation of Sleep, and Sleep Disorders
Authors: Lee-Chiong Teofilo
Published: November 2023

Inquiry should be made into the patient’s history of medical, surgical, or psychiatric disorders; family history of sleep conditions; medication and substance use; and nighttime activities.

The interview should include a thorough family history. Many disorders tend to be more prevalent among children, siblings, and other close relatives of patients. These include snoring, restless legs syndrome, narcolepsy, obstructive sleep apnea, enuresis, sleepwalking, sleep terrors, familial fatal insomnia, mood disorders, and schizophrenia. A positive family history is present in up to 30% of patients with narcolepsy or restless legs syndrome.

A complete medication list must be obtained. Many medications can cause insomnia or excessive sleepiness, or they can precipitate or aggravate parasomnias or restless legs syndrome.
Model Organisms in the Study of Development and Disease
Authors: Bier Ethan , Mcginnis William
Published: November 2023

The past two decades have brought major breakthroughs in our understanding of the molecular and genetic circuits that control a myriad of developmental events in vertebrates and invertebrates. These detailed studies have revealed surprisingly deep similarities in the mechanisms underlying developmental processes across a wide range of bilaterally symmetric metazoans (bilateralia). Such phylogenetic comparisons have de7ned a common core of genetic pathways guiding development and have made it possible to reconstruct many features of the most recent common ancestor of all bilateral animals, which most likely lived 600–800 million years ago (Shubin et al., 1997; Knoll and Carroll, 1999). As Meshed out in more detail below and reiterated as a major unifying theme throughout the book, the common metazoan ancestor already had in place many of the genetic pathways that are present in modern-day vertebrates and invertebrates. This ancestor can be imagined as an advanced worm-like or primitive shrimp-like creature that had a few distinct body specializations along the nose-to-tail axis and was subdivided into three distinct germ layers (ectoderm, mesoderm, and endoderm). It also had evolved an inductive signaling system to partition the ectoderm into neural versus nonneural components and is likely to have possessed appendages or outgrowths from its body wall with de7ned anterior–posterior, dorsal– ventral, and proximal–distal axes, as well as light-sensitive organs, a sensory system for detecting vibrations, a rudimentary heart, a molecular guidance system for initiating axon outgrowth to the midline of the nervous system, ion channels for conducting electrical impulses, synaptic machinery required for neural transmission, trachea, germ cells, and an innate immune system.
Molecular Regulation of Cardiogenesis
Authors: Nigam Vishal , Srivastava Deepak
Published: November 2023

Congenital heart malformations, the most common of all human birth defects, occur in almost 1% of the population worldwide, regardless of race (Hoffman and Kaplan, 2002). An additional 1%–2% of the population harbor more subtle cardiac developmental anomalies that only become apparent as age-dependent phenomena reveal the underlying pathology. With more than 1 million survivors of congenital heart disease (CHD) in the United States, it is becoming apparent that genetic disruptions which predispose to developmental defects can have ongoing consequences in the maintenance of speci7c cell types and cellular processes over decades (Srivastava, 2004). A more precise understanding of the causes of CHD is imperative for the recognition and potential intervention of progressive degenerative conditions among the survivors of CHD.
The Sex Determination Pathway
Authors: Erickson Robert P
Published: November 2023

Sexual differentiation is a dynamic process that is subject to a sequential program. This program is so ordered that it can be carried to completion in consecutive stages, often described in the literature as (1) the establishment of chromosomal sex at fertilization, (2) the development of gonadal sex, and (3) the development of secondary sexual characteristics, collectively called the sexual phenotype. However, recent research has shown that sex differences are present immediately after fertilization, thus suggesting that sexual development should be considered to include a stage of pregonadal sexual dimorphism (Erickson and Blecher, 2004). This paradigm of a developmental cascade constitutes the central dogma of sexual differentiation, formulated in principle by A. Jost at the end of the 1940s to explain the results of his experiments on fetal castration in rabbits. He observed that the extirpation of the gonads (ovaries or testes) before sexual differentiation had occurred invariably resulting in the development of fetuses in a female-type pattern (Jost, 1953).
WNT3 and Tetra-amelia
Authors: Niemann Stephan
Published: November 2023

Tetra-amelia is an extremely rare congenital disorder in which all four limbs are absent. In the cases reported so far, tetra-amelia occurred with combinations of craniofacial, urogenital, pulmonary, nervous system, and skeletal malformations.
STK11 (LKB1) and Peutz–Jeghers Syndrome
Authors: Antonarakis Stylianos E
Published: November 2023

A family with intestinal polyposis and mucocutaneous pigmentation was first described by the Dutch physician Johannes Peutz from Hague in 1921 (Peutz, 1921). Harold Jeghers from Boston also described additional patients (Jeghers, 1944). He, along with Victor McKusick and Katz, provided a definitive description of the syndrome in 1949 (Jeghers et al., 1949). For an extensive historical account see Keller et al. (2001). This autosomal dominant disease was probably first described in twin sisters with “ink-black pigmentation of the lips and mouth” by Johnathan Hutchinson in 1896 (Hutchinson, 1896). Francis Giardello in 1987 pointed out that patients with this syndrome have an increased risk for the development of cancer at gastrointestinal and other sites (Giardiello et al., 1987). The genomic interval on chromosome 19p13.3 that harbors a responsible gene was mapped by Akseli Hemminki and Lauri Aaltonen in Helsinki in 1997 using comparative genomic hybridization, loss of heterozygosity, and linkage analysis (Hemminki et al., 1997). A year later Hemminki, and independently Dieter Jenne from Martinsried Germany, identified the gene responsible for PJS and characterized several pathogenic mutations (Hemminki et al., 1998; Jenne et al., 1998). The gene that encodes STK11 was first cloned and its sequence deposited in Genbank (U63333) by Jun-ichi Nezu of Chugai Pharmaceuticals in 1996 after a screen to isolate new kinases and was named LKB1 (liver kinase B1). Suggestive evidence for additional PJS-causing genomic regions has been provided (Mehenni et al., 1998).
The RAS Pathway
Authors: Swensen Jeffrey , Viskochil David
Published: November 2023

In the early 1960s, at the London Hospital Research Laboratories, plasma filtrate collected from a leukemic rat during the routine passage of Moloney leukemia retrovirus was injected into newborn mice. Rather than developing signs of leukemia as expected, the mice grew tumors that proved to be sarcomas. Additional mice inoculated with filtrates of these tumors rapidly developed sarcomas themselves (Harvey, 1964). The tumors resulted from an unknown oncogenic virus that was later named Harvey murine sarcoma virus. A group at the University of Chicago obtained similar results while passing Kirsten murine erythroblastosis virus through rats (Kirsten and Mayer, 1967). Their virus became known as Kirsten murine sarcoma virus.
RAS Signaling Defects and Noonan Syndrome
Authors: Tartaglia Marco , Gelb Bruce D
Published: November 2023

Moonan syndrome (OMIM 163950) is a pleomorphic disorder affecting the cardiovascular, craniofacial, skeletal, hematopoietic, lymphatic, and central nervous systems. It can result from mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase (PTP), Src homology 2 (SHP-2), or the KRAS gene, which encodes a RAS GTPase. The disorder is generally transmitted as an autosomal dominant trait, although many cases result from de novo mutations. Defects in the PTPN11 gene, which resides at chromosomal band 12q24.1, account for approximately 50% of cases. The more than 60 mutations that have been reported are mostly missense changes, with the vast majority affecting residues clustering at the interface between the N-terminal SH2 and PTP domains. Mutant SHP-2 proteins have a gain of function, usually through effects on the molecular switching mechanism important for activating/inactivating this enzyme. Missense PTPN11 mutations also recur in LEOPARD syndrome (MIM 151100), which is clinically related to Noonan syndrome. These mutations cause loss of catalytic activity of the phosphatase and are hypothesized to have dominant-negative effect on the wild-type protein. Defects in the KRAS gene account for approximately 2% of Noonan syndrome cases and engender gain of function in RAS signaling through reduced KRAS GTPase activity or increased GDP/GTP dissociation rate. Clinical manifestations of Noonan syndrome include a typical dysmorphic appearance, congenital heart defects [particularly pulmonic stenosis (PS)] or hypertrophic cardiomyopathy (HCM), webbing of the neck, short stature, cryptorchidism, eye abnormalities, and skeletal anomalies such as pectus deformities, cubitus valgus, and vertebral anomalies. A minority of affected individuals has bleeding diathesis, hearing loss, and mental retardation. Diagnosis is made by clinical examination. Prenatal diagnosis of Noonan syndrome may be suspected in the presence of ultrasonographic findings such as nuchal edema or cystic hygroma. Therapy in the neonatal period and infancy involves discovering and treating the cardiac disease and managing the feeding problems. Orchidopexy is indicated for undescended testes. Growth hormone (GH) therapy has been used to ameliorate the short stature. Preventive pediatric care is appropriate for the hematologic and developmental issues.
RASA1 and Capillary Malformation– Arteriovenous Malformation
Authors: Revencu Nicole , Boon Laurence M , Mulliken, John B , Vikkula Miikka
Published: November 2023

RASA1 encodes p120RasGTPase-activating protein (p120RasGAP), an important RAS inhibitor. Mutations in this gene result in capillary malformation–arteriovenous malformation (CM–AVM; OMIM 608354), a newly recognized autosomal dominant disorder (Eerola et al., 2003). Small, multifocal and randomly distributed CMs are the hallmark of the disorder. In addition, about one-third of patients have a fast-How lesion. Forty-seven mutations have been identified until now and most of them would lead to a truncated protein if translated. Thus, the most likely pathogenic mechanism is loss of function.
PAX6 and Aniridia and Related Phenotypes
Authors: Heyningen Veronica Van , Williamson Kathleen
Published: November 2023

The PAX6 gene on chromosome 11p13 was isolated by positional cloning (Ton et al., 1991) as a strong candidate gene for the human eye anomaly aniridia (OMIM 106210) (Fig. 86–1). The gene was identi(ed within the aniridia subregion of the Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation (WAGR, OMIM 194072) contiguous deletion site. Its expression pattern, assessed by RNA in situ hybridization in human and mouse development, is consistent with a role for PAX6 in developmental eye disease, although it is broader than the spectrum of tissues affected in aniridia.
PAX9 and Hypodontia
Authors: Patel Pragna I , Brown Donald T
Published: November 2023

The most common abnormality affecting the formation of the dentition is deviation from the usual number of the human permanent dentition (a total of 32 teeth in both jaws) or the deciduous dentition (20 total teeth in both jaws). When the number of teeth is less than the normal complement of dentition, the condition is known as hypodontia. Other anomalies seen in association with hypodontia include small tooth size (microdontia) and anomalies in tooth shape, most commonly tapering or “peg-shaped” teeth (McKeown et al., 2001; Brook et al., 2002). Frameshift, nonsense, and missense mutations in the human paired box gene 9 (PAX9) gene have been associated with hypodontia involving primarily posterior teeth. Severe hypodontia associated with a submicroscopic deletion involving loss of the entire gene in one family supports a model implicating haploinsuf)ciency of PAX9 as the primary cause for hypodontia involving molar teeth. Both primary and permanent dentitions are affected, with the effects being more prominent in the case of permanent teeth. PAX9 is a member of a family of transcription factors characterized by a common DNAbinding domain called the paired domain. It is highly homologous to PAX1, with which it shares an overlapping pattern of expression. PAX9 is a 342–amino acid protein encoded by a single gene mapping to human chromosome 14q21. Homozygous Pax9 mutant mice die shortly following birth. They lack a thymus, parathyroid glands, and ultimobranchial bodies. Mutant mice have a cleft secondary palate at birth, and tooth development is arrested at the bud stage, resulting in the absence of all teeth. Heterozygous mutants display no discernible defects.
SOX3 and Infundibular Hypoplasia
Authors: Kelberman Daniel , Dattani Mehul T
Published: November 2023

duplications of Xq26–27 encompassing SOX3 [sex-determining region Y (SRY)-box 3] have previously been associated with variable hypopituitarism and learning difculties. More recently, lossof-function polyalanine tract expansion mutations within SOX3 have been associated with essentially similar phenotypes of infundibular hypoplasia and midline defects of the central nervous system (CNS), with anterior pituitary hypoplasia and varying degrees of hypopituitarism. Variable mental retardation or learning difficulties are observed in some cases. Targeted disruption of Sox3 in mice reveals a somewhat analogous phenotype, with mutant mice exhibiting abnormal development of the infundibulum and hypothalamus, which subsequently disrupts necessary inductive signals for correct anterior pituitary development. Correct gene dosage of SOX3 is therefore critical for normal development of the diencephalon and infundibulum and, consequently, the anterior pituitary in humans and mice. The role of SOX3 in the etiology of X-linked hypopituitarism needs further investigation.
SOX18 and the Hypotrichosis–Lymphedema–Telangiectasia Syndrome
Authors: Ghalamkarpour Arash , Devriendt, Koen , Vikkula Miikka
Published: November 2023

The hypotrichosis–lymphedema–telangiectasia syndrome (HLTS; OMIM 607823) is a rare syndrome with autosomal dominant or recessive pattern of inheritance. It is characterized by the triad of sparse hair, (2) lymphatic edema, and (3) cutaneous telangiectasias. The hair has usually a normal appearance at birth but becomes sparse during infancy. Eyebrows and eyelashes are missing and the patients do not develop axillary or pubic hair. Lymphedema mostly affects lower limbs and has a variable age at onset from congenital to puberty. Telangiectasias can be present at palms, soles, scalp, scrotum, or legs; however, it is not observed in all patients. The molecular basis of HLTS was established by considering the murine ragged phenotype as a putative counterpart of the human disorder. Sex determining Y-box 18 (SOX18), the human ortholog of the murine ragged gene, was found to be mutated in patients with HLTS, accounting for both recessive and dominant forms of the disease.
William Faulkner
Authors: Porter Carolyn
Published: November 2023

In this newest volume in Oxford’s Lives and Legacies series, Carolyn Porter, a leading authority on William Faulkner, offers an insightful account of Faulkner’s life and work, with special focus on the breathtaking twelve-year period when he wrote some of the finest novels in American literature. Porter ranges from Faulkner’s childhood in Mississippi to his abortive career as a poet, his sojourn in New Orleans (where he met a sympathetic Sherwood Anderson and wrote his first novel Soldier’s Pay), his short but strategically important stay in Paris, his “rescue” by Malcolm Crowley in the late 1940s, and his winning of the Nobel Prize. But the heart of the book illuminates the formal leap in Faulkner’s creative vision beginning with The Sound and the Fury in 1929, which sold poorly but signaled the arrival of a major new literary talent. Indeed, from 1929 through 1942, he would produce, against formidable odds--physical, spiritual, and financial--some of the greatest fictional works of the twentieth century, including As I Lay Dying, Sanctuary, Light in August, Absalom, Absalom! and Go Down, Moses. Porter shows how, during this remarkably sustained burst of creativity, Faulkner pursued an often feverish process of increasingly ambitious narrative experimentation, coupled with an equally ambitious thematic expansion, as he moved from a close-up study of the white nuclear family, both lower and upper class, to an epic vision of southern, American, and ultimately Western culture. Porter illuminates the importance of Faulkner’s legacy not only for American literature, but also for world literature, and reveals how Faulkner lives on so powerfully, both in the works of his literary heirs and in the lives of readers today.
Anatomy and Physiology of the Optic Nerve
Authors: Morrison John C
Published: November 2023

The optic nerve is unique. It contains approximately 1.2 million axons, each originating from a single retinal ganglion cell, and experiences several “environmental” changes in its course from the eye to the brain. For example, optic nerve fibers are initially unmyelinated, satisfying the optical needs of the retina, but they become myelinated behind the globe, so as to provide rapid and efficient propagation of visual impulses to the lateral geniculate nucleus.
Miscellaneous Optic Neuropathies
Authors: Kline Lanning B
Published: November 2023

Some forms of optic nerve disease do not conform to any of the usual clinical categories. These disorders may be associated with a systemic disease (e.g., diabetes mellitus) or a therapeutic modality (e.g., radiation therapy) or may be of unknown cause (e.g., papillophlebitis). An understanding of these entities is important for the general ophthalmologist. Delayed necrosis of the optic nerves and chiasm is a well-recognized complication of radiotherapy. This was initially described following fractionated external beam radiotherapy and more recently after single-dose stereotactic radiosurgery. Although most frequently seen after radiation for pituitary adenoma, radiation optic neuropathy (RON) has been reported after radiotherapy for a variety of other neoplasms, including meningioma, craniopharyngioma, metastatic carcinoma, hypo- thalamic glioma, and malignant tumors of the paranasal sinuses.
An Overview of Course and Outcome in ISoS
Authors: Hopper Kim , Harrison Glynn , Wanderling Joseph A
Published: November 2023

The International Pilot Study of Schizophrenia (IPSS) demonstrated that large-scale international studies in psychiatric epidemiology were feasible; that, for research purposes, a diagnostic entity (“schizophrenia”) could be identifled cross-culturally, using a standardized diagnostic interview (the Present State Examination); that assessment instruments of proven reliability could be used in settings as widely varying as Ibadan, Nigeria, Cali, Colombia, and Washington, DC; and that respectable proportions of the initial cohorts could subsequently be located and assessed (WHO, 1973). Two- and 5-year follow-up studies of those patients found that those living in nonindustrialized (“developing”) settings had better social and symptomatic outcomes (WHO, 1979; Leff, Sartorius, Jablensky, Korten, and Ernberg, 1992).
Patient, Heal Thyself :How the New Medicine Puts the Patient in Charge
Authors: Veatch Robert M
Published: November 2023

Robert Veatch is one of the founding fathers of contemporary bioethics. In Patient, Heal Thyself, he sheds light on a fundamental change sweeping through the American health care system, a change that puts the patient in charge of treatment to an unprecedented extent. The change is in how we think about medical decision-making. Whereas medicine’s core idea was that medical decisions should be based on the hard facts of science--the province of the doctor--the “new medicine” contends that medical decisions impose value judgments. Since physicians are not trained to make value judgments, the pendulum has swung greatly toward the patient in making decisions about their treatment. Veatch shows how this is presently true only for value-loaded interventions (abortion, euthanasia, genetics) but is coming to be true for almost every routine procedure in medicine--everything from setting broken arms to choosing drugs for cholesterol. Veatch uses a range of fascinating examples to reveal how values underlie almost all medical procedures and to argue that this change is inevitable and a positive trend for patients.
Bang! The dot meets the family
Authors: Humez Alexander Humez Nicholas
Published: November 2023

The dot is an indispensable component of more punctuation marks than just itself alone (the subject of our final chapter). Conventional signs that include a dot are the colon (:), semicolon (;), ellipsis ( . . . ), question mark (?—and, for Spanish, its upside down version, ¿), and exclamation point (!—and its inversion in Spanish, ¡). (There are some unconventional signs as well, current out to the edges of a given epistemic community but not yet in general use beyond the pale; we’ll get to them a little later on. For everything you ever wanted to know about the ellipsis, turn back to “Dot Dot Dot.”)
Introduction to opioids
Authors: Smith Howard S
Published: November 2023

Opioids are among the most versatile and potent analgesics currently available, yet incomplete knowledge, societal views, and irrational fears continue to impede their optimal use. Health-care providers should be comfortable employing opioid therapy in treatment plans when appropriate. Additionally, clinicians should be familiar with risk-management strategies for assessing drug-taking behaviors, adverse effects of opioids, and analgesic and functional therapeutic outcomes. It is hoped that clinical activities embodying the concept of “balance” (i.e., providing medical availability and instructions as to the appropriate use of opioids, as well as risk-management plans designed to prevent the abuse or misuse of these agents) will lead to optimal patient outcomes.
Evidence for the use of long-term opioid therapy in persistent noncancer pain
Authors: Smith Howard S , McCleane Gary
Published: November 2023

Since 1871, the pendulum of “opiophobia” versus “opiophilia” has swung back and forth for health-care providers. Times change, from periods marked by opiophobia, where opioids are withheld from terminally ill cancer patients because of irrational fears of addiction, to others where opiophilia leads to increased opioid abuse and diversion along with an increase in the medical use of opioids for persistent noncancer pain. Recent times have seen a swing toward more extensive use of opioids. Opioid therapy for chronic pain was described as an “extension of the basic principles of good medical practice” in a consensus statement jointly published by the American Pain Society and the American Academy of Pain Medicine (American Academy of Pain Medicine, 2004).
Diagnosis and assessment of pain
Authors: Argoff Charles E
Published: November 2023

More than 50 million Americans suffer from chronic pain, including cancer pain, chronic headache, chronic neuropathic painful states (e.g., painful diabetic neuropathy, postherpetic neuralgia [PHN], and complex regional pain syndrome [CRPS]), and chronic musculoskeletal pain, including soft-tissue pain disorders (e.g., chronic myofascial pain and flbromyalgia). On an annual basis, chronic pain increases health-care costs and disables more people than do heart disease and cancer combined. However, chronic pain is often viewed as a symptom rather than the chronic disease that it can become.
Opioid therapy for cancer pain
Authors: Davis Mellar P , Smith Howard S
Published: November 2023

The classic approach to the use of analgesics in cancer pain was formulated by the World Health Organization (WHO). The core of its guidelines is a three-step analgesic ladder that advises clinicians to match the strength of an analgesic to the patient’ s level of pain. The same three-step analgesic ladder is recommended for nociceptive and neuropathic pain. One can anticipate good pain relief in 76% and satisfactory relief in 12% of patients using the WHO analgesic ladder (Zech et al., 1995; Grond et al., 1999). Despite the reported success of the analgesic ladder, significant undertreatment of chronic pain continues to be experienced by too many patients receiving active treatment for solid tumors; it has been even more of a problem for those adult cancer patients with advanced disease (Higginson and Hearn, 1997).
Identifying patients at risk for pain medication misuse
Authors: Webster Lynn R , Smith Howard S
Published: November 2023

101 Chronic pain impacts the lives of millions of people, and this issue must be addressed. Indeed, issues with pain are the number one reason that patients go to see their physicians. However, increased recognition of the problem has been somewhat tempered by the souring of the regulatory climate and the growth of prescription drug abuse. Because of this, there has been a trend for some clinicians, particularly nonspecialists, to shy away from using high doses of opioids or even using this modality at all in the treatment of chronic pain. Despite these fears and concerns, the use of opioid therapy to treat chronic pain is growing, based in part on evidence from clinical trials and a growing consensus among pain specialists.