bluuebunny/crossref_metadata_2025 huggingface dataset:
LEMD3 and Osteopoikilosis, the Buschke–Ollendorff Syndrome and Melorheostosis
Authors: Hellemans Jan , Mortier Geert R
Published: November 2023

LEMD3 is an integral protein of the inner nuclear membrane and has a molecular mass of approximately 100 kDa. It is composed of a nucleoplasmic N-terminal domain, a #rst transmembrane segment, a luminal loop, a second transmembrane segment and a nucleoplasmic C-terminal domain (Fig. 38–1) (Lin et al., 2000). LEMD3 was previously known as MAN1. It was initially identi#ed as a nuclear envelope protein recognized by autoantibodies from a patient (MAN refers to the initials of this patient) with an ill-de#ned collagen vascular disease (Paulin-Levasseur et al., 1996). To avoid confusion with the abbreviations of the different mannosidase enzymes, MAN1 was recently renamed as LEMD3 (LEM domain containing 3), herewith referring to the LEM domain in the N-terminal portion of the protein. The LEM domain is a conserved globular motif of approximately 40 amino acids found in several inner nuclear membrane and nucleoplasmic proteins. “LEM” refers to the three proteins in which the domain was initially characterized: LAP2, emerin, and MAN1.
TGFBR 1/2 and Loeys–Dietz Syndrome
Authors: Loeys Bart L , Dietz Harry C
Published: November 2023

A novel autosomal dominant aortic aneurysm syndrome characterized by the triad of hypertelorism, bifid uvula/cleft palate, and arterial tortuosity with ascending aortic aneurysm/dissection was initially described in 10 families [Loeys–Dietz syndrome (LDS); MIM 609192] (Fig. 39–1) (Loeys et al., 2005). This syndrome also presents with multiple other findings, including craniosynostosis, Arnold Chiari type I malformation, pectus deformity, scoliosis, arachnodactyly, club feet, patent ductus arteriosus, atrial septal defect, bicuspid semilunar valves, and aneurysms/dissections throughout the arterial tree.
FGF Receptor Mutations: Bone Dysplasia, Craniosynostosis, and Other Syndromes
Authors: Wilkie Andrew O M
Published: November 2023

Mutations in three of the four fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3) have been identified in congenital disorders with a very wide variety of phenotypes. Several features make these mutations of particular interest. The associated clinical conditions are, collectively, a common cause of monogenic disease; the mutation rates for several of these disorders are exceptionally high, and are beginning to reveal a novel mechanism of disease through the selection of spermatogonial mutations; FGFR mutations illustrate the close link between developmental disorders and cancer; and the diversity of phenotypes is re)ected in a diversity of mechanisms of molecular pathogenesis, making FGFR mutations a paradigm for understanding the many bases of genetic dominance. The mutant phenotypes have given important clues to the roles of FGFRs in the development of epiphyseal plate, cranial sutures, limb bud and olfactory neurons, amongst other structures. The accompanying chapter gives an introduction to FGFR structure and biology, which is not detailed here.
TEK (TIE2) and Cutaneomucosal Venous Malformation
Authors: wouters Vinciane , Boon laurence M , Mulliken, john B , vikkula miikka
Published: November 2023

Venous anomalies are the most frequent malformations referred to vascular anomalies centers. They are divided into venous malformations (VMs, 95%) and glomuvenous malformations (GVMs, 5%; see Chapter 183). VMs typically involve skin, mucosa, and subcutis, but they also arise in muscle, bones, and internal organs. Lesions can be solitary or multifocal; the latter presentation is likely to be an autosomal dominant familial trait, termed cutaneomucosal venous malformation (VMCM; MIM 600195). VMCM represents approximately 1% of VMs. VMCM is caused by amino acid substitutions in the tyrosine kinase domain of the angiopoietin receptor TEK (now known as TIE2, which is used in this chapter). These gain-of-function mutations increase receptor phosphorylation. VMs can also be part of complex vascular disorders of unknown etiology, for example, Klippel–Trenaunay syndrome, Maffucci syndrome, and Blue Rubber Bleb Nevus syndrome.
HRAS and Costello Syndrome
Authors: Aoki Yoko , Matsubara Yoichi
Published: November 2023

Costello syndrome (MIM 218040) is a multiple congenital anomaly/ mental retardation syndrome originally reported by J.M. Costello in 1971 (Costello, 1971). Patients with Costello syndrome show a coarse face, loose skin, hypermobility of the small joints, heart defects including cardiomyopathy, and predisposition to tumors. In 2005, germline mutations in the Harvey rat sarcoma (HRAS) proto-oncogene were identified in patients with Costello syndrome (Aoki et al., 2005). All patients had mutations in the heterozygous form, indicating autosomal dominant inheritance. Molecular analysis of parents showed that mutations were not inherited, suggesting mutations occurred de novo. Costello syndrome is the first disorder, which has been found to be associated with germline mutations in the RAS subfamily of small guanosine triphosphatases (GTPases). These observations suggest that the proto-oncogene HRAS plays an important role in human development.
HOXA11 and Amegakaryocytic Thrombocytopenia with Radioulnar Synostosis
Authors: Geddis Amy E
Published: November 2023

Congenital thrombocytopenia is associated with radial abnormalities in several disorders, although the genetic basis of this linkage remains poorly understood. These disorders include thrombocytopenia with absent radii (TAR), Fanconi’s anemia (FA), and amegakaryocytic thrombocytopenia with radioulnar synostosis (ATRUS). Although FA is now recognized to be a defect of DNA repair, the etiology of thrombocytopenia and radial defects in TAR and ATRUS remains unclear. The description of two families in which a heterozygous mutation of Homeobox A11 (HOXA11) was inherited with the phenotype of thrombocytopenia and radioulnar synostosis provided the (rst insights into the molecular mechanism of ATRUS.
PITX2 and PITX3 and the Axenfeld–Rieger Syndrome, Peters Anomaly, Anterior Segment Ocular Dysgenesis, Ring Dermoid of the Cornea, Posterior Polar Congenital Cataract (CPP4), and Microphthalmia with Neurologic Impairment
Authors: Semina Elena V
Published: November 2023

PITX2 and PITX3 represent members of the PITX family of homeobox-containing transcription factor genes that was shown to play an important role in embryonic development in different species. Humans with mutations in the PITX2 or PITX3 genes were found to exhibit a variety of ocular phenotypes such as glaucoma, cataracts, corneal anomalies, and microphthalmia that in many cases are accompanied by other developmental defects. In animal models, Pitx2 gene was shown to be essential to normal development of multiple organs such as eyes, teeth, brain, heart, lungs, liver, and body wall. Pitx3 gene was found to be involved in the development of lens and the mesencephalic dopaminergic system. Therefore, these PITX genes represent key components of the network of genes directing development of multiple organs in various species. Studies of the PITX roles in embryogenesis and cell fate decisions will lead to further exploration of the disorders associated with alterations in these genes. This will provide new insight into mechanisms of normal embryonic development, allow identification of other disease genes, and inevitably lead to the better diagnosis and treatment of the associated conditions.
LMX1B and the Nail Patella Syndrome
Authors: Morello Roy , Lennington, Jennifer N , Lee Brendan
Published: November 2023

Nail patella syndrome (NPS) is a dominantly inherited skeletal malformation syndrome. Patients have characteristic features including nail and patella hypoplasia, elbow and knee deformities, nephropathy, and ocular defects. The condition is characterized by high penetrance, variable expressivity, and signi)cant intrafamilial variability. Diagnosis is based on clinical criteria. Morbidity is associated with functional limitations caused by joint abnormalities, risk of developing nephrotic syndrome [which may progress to end-stage renal disease (ESRD)], and risk of developing glaucoma and ocular hypertension. NPS is caused by loss-of-function mutations in the LIM homeodomain (LHX) transcription factor LMX1B. LMX1B speci)es a transcriptional network important in pattern formation of the limb as well as cell maturation and differentiation in both the kidney and the central nervous system (CNS). In the limb, LMX1B is a unique mesenchymal determinant of dorsal cell fate. In the kidney, it regulates podocyte-speci)c expression of glomerular basement membrane (GBM) type IV collagen. Moreover, it speci)es morphogenesis of secondary foot processes and directs the expression of unique components of a specialized cell–cell adhesion complex, the slit diaphragm. Finally, it has important roles during CNS formation, including the survival of mesencephalic dopaminergic neurons, the development of all serotonergic neurons, and the differentiation of periocular mesenchyme. The pathogenesis of NPS re%ects a loss of dorsal speci)cation of soft tissues of the limb and disrupted proliferation of anterior relative to posterior skeletal elements. The nephropathy arises in part owing to an architectural defect in a primary component of the )ltration barrier of the kidney, the GBM. Glaucoma is likely secondary to anterior segment dysgenesis in the eye. How the function of LMX1B in other developmental programs impacts the pathogenesis of the NPS phenotype is still unclear.
PAX3 and Waardenburg Syndrome Type 1
Authors: Corry Gareth N , Underhill D Alan
Published: November 2023

The human PAX genes encode a group of sequence-specific transcription factors that play important roles in development and cell differentiation (Underhill, 2000; Chi and Epstein, 2002). Pax proteins are characterized by a 128–amino acid DNA-binding paired domain (PD) and are highly conserved in metazoans. Four of nine mammalian Pax proteins also contain a homeodomain (HD), and six are directly implicated in congenital syndromes or cancer in humans.
FOXC1 and FOXL2 and the Axenfeld–Rieger Malformations and the Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome
Authors: Saleem Ramsey A , Berry Fred B , Huang, Lijia , Walter Michael A
Published: November 2023

The complex process of embryogenesis proceeds through molecular signaling and regulation by developmentally important transcription factors. Of the regulatory molecules known, members of the evergrowing forkhead family of transcription factors are known to play key roles in the development of a wide range of organisms (Kaufmann and Knochel, 1996). Forkhead transcription factors are characterized by the presence of a conserved, 110-amino acid, DNA-binding domain; the forkhead domain (FHD). This DNA-binding motif is a variant of the helix–turn–helix motif, consisting of one minor and three major α-helices, two β-sheets, and two large loops that form “wing-like” structures. Consequently, FHDs are often referred to as winged-helix domains. Increasingly, winged-helix or FOX (Forkhead Box) genes have been shown to be involved in human heritable disorders. FOXC1 and FOXL2 are two of four FOX genes known to be involved with diseases possessing an ocular phenotype. FOXC1 mutations underlie ocular anterior segment dysgenesis with an increased risk of glaucoma and systemic defects, while FOXL2 mutations cause blepharophimosis ptosis and epicanthus inversus syndrome (BPES) (MIM 110100), an autosomal dominant disorder affecting the eyelids and tissues surrounding the eye. In this chapter, we discuss the involvement of FOXC1 and FOXL2 in development as well as describe the pathology when alterations to these genes are present.
TBX3 and TBX5 and the Ulnar–Mammary and Holt–Oram Syndromes
Authors: Bamshad Michael J , Jorde Lynn B
Published: November 2023

Ulnar–mammary syndrome (UMS) and Holt–Oram syndrome (HOS) are rare, autosomal dominant, multiple malformation disorders. UMS is characterized by apocrine abnormalities including breast defects and malformations of the posterior elements of the upper limb. In contrast, HOS is typi)ed by heart malformations, most commonly an atrial septal defect (ASD) or ventricular septal defect (VSD), conduction abnormalities, and defects of the anterior elements of the upper limb. UMS and HOS are caused by myriad mutations in TBX3 and TBX5, respectively, two members of the T-box gene family linked together on chromosome 12q24. There is little evidence to support a genotype–phenotype correlation for either condition. The long-term care of patients with UMS or HOS can be challenging, but in general, most patients do well. In the heart, TBX5 physically activates atrial natriuretic factor (ANF), connexin-40 (cx40), and GATA4 to play an important role in formation of the septa, chambers, and conduction system. In the limb, Tbx5 appears to activate )broblast growth factor-10 (Fgf10) directly to initiate forelimb bud outgrowth and to in%uence, in part, forelimb identity. Tbx3 acts as a negative repressor of p19ARF and p53 and interferes with apoptosis. Tbx3 is essential for formation of the mammary glands and plays multiple roles in limb development including the speci)cation of digit identity. In vitro studies demonstrate that substitutions in the DNA-binding domain of TBX3 and TBX5 or truncations in the C terminus of the TBX3 and TBX5 proteins fail to bind DNA and lose their transcriptional properties. Loss of Tbx3 repressor activity may promote a pro-apoptotic path that results in a diminished number of mesodermal cells in the developing limb and breast. Loss of Tbx5 activity appears to result in the down-regulation of several genes critical for normal heart development.
SOX2 and Malformations of the Eye, Brain, Foregut, and Male Genital Tract
Authors: Fitzpatrick David R
Published: November 2023

Heterozygous loss-of-function mutations in the high mobility group (HMG) domain-containing transcription factor SOX2 are associated with a complex spectrum of malformations. The most characteristic malformations are absent (anophthalmia) or small (microphthalmia) eyes, which are usually bilateral, severe, and apparent at birth or by prenatal ultrasound examination. Other commonly associated malformations involve the brain, pituitary gland, trachea, esophagus, and male genital tract (hypospadias, cryptorchidism, and micropenis). Postnatal growth failure, delayed motor development, seizures, and learning disability are other common associations. SOX2 mutations are usually de novo although parental germline mosaicism has been seen. SOX2 appears to function as a transcriptional regulator of developmentally critical genes both in vivo and in embryonic stem (ES) cell culture. Homozygous loss of Sox2 in mouse embryos results in early lethality and failure to establish any of the normal early cell lineages. In contrast to humans, the heterozygous null mice show no major malformations.
SOX9 and Campomelic Dysplasia and Sex Reversal
Authors: Mansour Sahar
Published: November 2023

Campomelic dysplasia (also known as camptomelic dysplasia) (CMD) is a rare, usually lethal skeletal dysplasia. Unlike other forms of skeletal dysplasia, it is frequently associated with XY sex reversal. The gene for this condition, SOX9, was identified in 1994. As suggested by the phenotype in CMD, SOX9 is an important gene, not only in the sex determination pathway but also in chondrogenesis. In this chapter, I discuss SOX9 and its role in both the sex determination pathway and the cartilage and collagen pathway. The clinical and radiological features of CMD are described, including the phenotype and complications in survivors with this condition.
MITF and the Waardenburg Type II and Albinism–Deafness (Tietz) Syndromes
Authors: Hornyak Thomas J , Chung, Nancy M , Tachibana Masayoshi
Published: November 2023

Microphthalmia-associated transcription factor (MITF) is a member of a large family of proteins with basic helix–loop–helix leucine zipper (bHLHZip) domains. Mutations in this transcription factor initially have been described in mice showing microphthalmia, variable pigmentary loss, and hearing deficit. Similar phenotypes can be seen in humans with Waardenburg Type II Syndrome (WS2) and Albinism–Deafness (Tietz) Syndrome with mutations in MITF. The manifestations of MITF mutations result from loss of melanocytes in the eyes, skin, and cochlea emphasizing the importance of this protein in the differentiation and maintenance of melanocytes.
SALL4 and the Okihiro/Duane Radial-Ray and Acro–Renal–Ocular Syndromes
Authors: BI WEIMIN , LUPSKI JAMES R
Published: November 2023

Okihiro/Duane-radial-ray syndrome (DRRS) is a rare autosomal dominant condition characterized by radial-ray defects and Duane anomaly (a form of strabismus). Other abnormalities recognized in this condition are anal, renal, cardiac, ear and foot malformations, hearing loss, postnatal growth retardation, and facial asymmetry. The disease is caused by a mutation in SAL-like 4 ( SALL4) a human gene related to the developmental regulator sal of Drosophila melanogaster. SALL4 mutations may also cause acro–renal–ocular syndrome (AROS), which differs from DRRS by the presence of structural eye anomalies, and phenotypes similar to thalidomide embryopathy and Holt–Oram syndrome (HOS). The SALL4 gene product is a zinc-)nger protein thought to act as a transcription factor. It contains three highly conserved C2H2 double zinc-)nger domains, which are evenly distributed. A single C2H2 motif is attached to the second domain, and at the amino terminus SALL4 contains a C2HC motif. Of the SALL4 mutations known to date, 20 out of 27 are located in exon 2 and 7 in exon 3; and unlike SALL1 mutations causing Townes–Brocks syndrome (see Chapter 25), the mutations do not cluster in a hotspot region. These are nonsense mutations, short insertions/duplications, and short deletions, as well as one missense mutation. All truncating mutations lead to preterminal stop codons and are thought to cause the phenotype via haploinsuf)ciency with the exception of one nonsense mutation, which is associated with a striking intrafamilial phenotypic variability and predicted to escape nonsense-mediated messenger RNA (mRNA) decay. The missense mutation is associated with cranial midline defects, in addition to Okihiro syndrome (OS) features, and predicted to result in an increased DNA-binding af)nity of the mutated zinc-)nger domain. The detection of larger deletions involving the whole SALL4 gene or single exons in patients with OS or AROS provided proof for haploinsuf)ciency as the cause of the malformations.
TCF2 (HNF-1_) and MODY5 and Urogenital Malformations
Authors: BI WEIMIN , LUPSKI JAMES R
Published: November 2023

The clinical entity discussed here was recognized in the early 1970s in a Norwegian family, with the combination of congenital renal disease and glucose intolerance in infancy. Mutations in hepatocyte nuclear factor (HNF)-1, encoded by the transcription factor-2 (TCF2) gene, were demonstrated in Japanese patients with cystic renal disease and early onset diabetes mellitus (Horikawa et al., 1997; Nishigori et al., 1998).
RECQL4 and the Rothmund–Thomson, RAPADILINO, and Baller–Gerold Syndromes
Authors: Maldergem Lionel Van , Siitonen H Annika , Jabs, Ethylin Wang , Gordillo Miriam
Published: November 2023

Disease-causingmutationsinthe RECQL4 genehavebeenassociated with three apparently distinct clinical entities: Rothmund– Thomson syndrome (RTS, OMIM 268400), RAPADILINO syndrome (OMIM 266280) and Baller–Gerold syndrome (BGS, OMIM 218600). RECQL4 belongs to the highly conserved RecQ helicase family com- posed of five members in humans. It has an important role in genomic stability and functions at the interface of DNA replication and DNA repair. Mutations in two other human RecQ helicases, WRN and BLM are implicated in Werner syndrome (WS; OMIM 277700) and Bloom syndrome (BS; OMIM 210900), respectively. RTS, BLM, and BS are associated in varying degrees to premature aging, skin and skeletal abnormalities, and cancer predisposition. All the RECQL4-related syndromes are rare autosomal recessive disorders that have in common growth retardation, radial ray hypo/aplasia, patellar hypo/aplasia, and infantile diarrhea. Poikilodermatous skin change with a characteristic pattern is the hallmark of RTS while craniosynostosis is associated more frequently with BGS. Predisposition to osteosarcoma is also a feature of RTS. The specific function of RECQL4 and mechanism by which it induces pleiotropic manifestations in these syndromes are largely unknown. However, recent studies support its role in initiation of DNA replication and in cell proliferation. In addition, the expression pattern of mouse Recql4 during embryo development and findings relating RECQL4 to osteoprogenitor proliferation suggest a role for RECQL4 during skeleton development.
GPC3 and the Simpson–Golabi–Behmel Syndrome
Authors: Saunders Scott , Martin, Rick A , Debaun Michael R
Published: November 2023

Most genetically characterized cases of Simpson–Golabi–Behmel syndrome (SGBS) in humans have been linked with mutations in the GPC3 gene located at Xq26 (Pilia et al., 1996), a gene encoding for glypican-3, a glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycan (Fig. 164–1). However, a severe form of SGBS has also been reported that maps to Xp22 (Brzustowicz et al., 1999), and many patients with the clinical diagnosis of SGBS have as yet no detectable mutations identified within their GPC3 gene. These data suggest that not all cases of SGBS result solely from GPC3 mutations. Six distinct glypican genes have been identified in vertebrates, all encoding heparan sulfate proteoglycans with structural features similar to those shown in Figure 164–1 (Paine-Saunders et al., 1999; Veugelers et al., 1999). Interestingly, the GPC4 gene is located immediately centromeric to GPC3 in both humans (Huber et al., 1998; Veugelers et al., 1998) and mice (Matsuki et al., 1998), and at least one patient with SGBS has been identi2ed with a deletion involving both GPC3 and GPC4 (Veugelers et al., 1998). However, isolated GPC4 mutations have not been identi2ed in any patients with SGBS, and there is no evidence to suggest that patients with mutations involving both GPC3 and GPC4 have any distinct alteration or enhancement of their phenotype. Furthermore, none of the remaining glypican genes have been mapped to loci linked either specifically with SGBS or, more generally, with overgrowth phenotypes in humans, and mutant alleles of other glypican genes in mice do not seem to phenocopy SGBS (S. Saunders, unpublished data). Therefore, cases of SGBS not arising from GPC3 mutations are unlikely to be due to mutations in genes encoding other members of the glypican gene family.
TRPS1 and the Tricho-rhino-phalangeal Syndromes*
Authors: Lüdecke Hermann-Josef , Horsthemke Bernhard
Published: November 2023

Tricho-rhino-phalangeal syndromes (TRPSs) is an autosomal dominant malformation syndrome which is characterized by craniofacial and skeletal abnormalities. The main features of all three subtypes, TRPS I, II, and III, are caused by mutations in or deletions of the TRPS1 gene on human chromosome 8. TRPS1 encodes a protein featuring an unusual combination of different zinc finger motifs, including GATA-type and IKAROS-like domains. The protein is a potent repressor of GATA-mediated gene expression.
Physiological Bonds
Authors: Lab Mullers
Published: November 2023

Like Müller, du Bois-Reymond spent much of his life longing for friends who shared his scientific outlook. In his twenties, he was far luckier than his mentor, finding in Berlin a group of talented physicists and physiologists with whom he could work. Among them was Ernst Brücke (1819–1892), a painter’s son who had hoped to become an artist but after meeting Müller had shifted his allegiance to experimental physiology.1 In March 1841, du Bois-Reymond organized a group of several young scientists who supported active experimentation and opposed the notion of life force. In January 1845, this group became the Berlin Physical Society, meeting weekly at the physicist Gustav Magnus’s house to exchange ideas about experiments.2 Later that year, they were joined by Hermann von Helmholtz and the engineer Werner von Siemens (1816–1892), who designed Prussia’s telegraph network. Because all of these scientists built their own innovative equipment, the Physical Society provided a forum for technical discussions among physicists, physiologists, and mechanics. In addition to university lecturers, the society included instrument makers and technicians from the Prussian military who wanted to collaborate with physicists.3 As they shared technical tips, these young experimenters inspired each other and formed passionate scientific bonds.
A Boy and His Books
Authors: Hayes Kevin J
Published: November 2023

The chapman was a familiar figure along the byways of colonial America. With a pack on his back filled with a variety of inexpensive goods both useful and entertaining, the chapman crisscrossed the colonies selling his wares. Men and women, boys and girls, all came to know the chapman and eagerly anticipated his visits. Among his wares, he usually kept a stock of books. They were known not only as Chapman’s books, but also as “little books,” “small books,” or, regardless of their largely fictional nature, “small histories.” Some people just called them “histories.” The most ambitious chapmen stocked a good selection of titles. Chapbook texts popular in eighteenth-century America included Dr. Faustus, The Famous History of the Seven Champions of Christendom, The History of Fortunatus, The History of Parismus, The History of Tom Thumb, Jack the Giant Killer, Reynard the Fox, Valentin and Orson, and The Wise Men of Gotham. These entertaining storybooks captured the attention of numerous young readers in colonial America—Thomas Jefferson included.
The Pen and the Tomahawk
Authors: Hayes Kevin J
Published: November 2023

As the mild winter came to a close in March 1775—”the most favorable winter ever known in the memory of man,” Jefferson called it—men from all parts of Virginia began wending their way toward Richmond, where they would gather at St. John’s Church for the second Virginia Convention, rather than at Williamsburg. As the colonial capital, Williamsburg was becoming increasingly uncomfortable for local citizens who were challenging the British administration. Delegates to the Virginia Convention had been elected by voters across the colony from the counties or corporations where they made their homes. This group of over a hundred men included nearly all of Virginia’s foremost leaders. Some, like Peyton Randolph, were old hands at Virginia governance, while others were fairly green. Their youth fueled their enthusiasm and their ardor.
The First Inaugural Address
Authors: Hayes Kevin J
Published: November 2023

At daybreak on Wednesday, March 4, 1801, cannon fire sounded from Capitol Hill as an artillery company discharged its weapons to welcome the day. Those within earshot were reminded that this was no ordinary Wednesday morning. Today was the day Thomas Jefferson would be inaugurated third president of the United States, the first to be inaugurated in Washington, D.C.
“Life of Captain Lewis”
Authors: Hayes Kevin J
Published: November 2023

History of the Expedition under the Command of Captains Lewis and Clark, the most substantial work of American literature to appear in the first two decades of the nineteenth century, was based on journals Meriwether Lewis and William Clark kept during their transcontinental expedition. Eight years would pass between their return in 1806 and the publication of History of the Expedition. During that time Nicholas Biddle began preparing their unwieldy journals for publication but wearied of the task before its completion. Paul Allen took over as editor and saw the work through the press.
The University of Virginia from Dream to Reality
Authors: Hayes Kevin J
Published: November 2023

The last week of November 1821, Jefferson wrote an eloquent letter to William Short, conveying his hopes for the University of Virginia: “It will be a splendid establishment, would be thought so in Europe, and for the chastity of its architecture and classical taste leaves everything in America far behind it.” These words convey the profound satisfaction Jefferson felt at the moment. Finally, his dream of the ideal university was becoming a reality. It had been a long time coming. Construction of the Rotunda had yet to begin, but the rest of the campus was definitely showing signs of progress. Six pavilions, eighty-two dormitories, and two hotels had been completed. Once built, the Rotunda would be the university’s centerpiece. It would unify the campus in terms of both its architecture and its function: Jefferson had designed the Rotunda as the library. Just as he had imagined how Monticello would appear before it was finished, he could now imagine how the University of Virginia would appear when it welcomed its first class of students. Maybe not the next year and maybe not even the year after that, but soon it would open, soon it would emerge as a great university.
Letters to Doubting Thomas
Authors: Layman C Stephen
Published: November 2023

When people encounter an argument for or against God's existence, it often raises more questions than it answers. In Letters to Doubting Thomas, C. Stephen Layman offers a fresh, insightful approach to the issue of God's existence--a way to organize what can seem like a blizzard of claims and concepts--bringing clarity to a debate often mired in confusion. Layman explores the evidence for the existence of God in a series of fictionalized letters between two characters--Zachary, a philosopher, and Thomas, an old college friend who appeals to Zach for help in sorting out his thoughts about God. As their correspondence grows, Zachary leads Thomas through an informal and highly readable comparison of Naturalism (the belief that there is no God and that ultimate reality is physical reality), and Theism (the idea that there is an almighty, perfectly good God). In engaging letters that break down complex philosophical arguments into easily digestible bits, the two friends delve into such weighty topics as the reliability of religious experience, various arguments for God's existence (such as the cosmological, design, and moral arguments), the question of free will, and the problem of evil. A piece at a time, they build an argument that shows that Theism, on balance, provides a better explanation of the world and human life than does Naturalism. Here then is a highly accessible account of the major arguments for and against the existence of God, capturing some of the best new insights of modern philosophy in a marvelously clear and engaging format.
Religious Experience and Interpretation
Authors: Layman C Stephen
Published: November 2023

Dear Thomas, Thanks for your recent post on religious traditions and religious experience. Agreed: Many horrible things have been done in the name of religion. Once you get large numbers of people living within a religious tradition-or claiming to do so, such things are likely to occur sooner or later, aren’t they? But I don’t see that this lamentable fact disproves the official teachings of the traditions.
Nutritional Interventions in Cancer
Authors: Block Keith I
Published: November 2023

Single vitamins, minerals, or antioxidants, in the absence of a comprehensive diet intervention, have very limited ability to prevent cancer or retard its progression. To control cancer-promoting inflammation, intake of animal fat andomega-6 fatty acidsshould belimited, whileintakeofomega-3 fatty acids and monounsaturated fats should be emphasized. To control insulin levels, carbohydrates should come from whole grain products, vegetables, and fruits, while refined flours and added sugars should be limited or eliminated. Plant proteins, egg whites, and fish are the safest protein sources for cancer patients.
The Antioxidant Debate
Authors: ladas Elena , Kelly kara M
Published: November 2023

Patients with cancer are taking antioxidant supplements in combination with conventional chemotherapy and radiotherapy to enhance the anticancer activity and to reduce the side effects of conventional treatment. Many oncologists are concerned that the protective mechanisms of antioxidants may not distinguish between normal and malignant cells, so that supplements may interfere with the anticancer activity of the conventional therapies. Not all antioxidant supplements are equivalent; antioxidants counteract free radical activity through multiple mechanisms of action.
Tending the Spirit in Cancer
Authors: Remen Rachel Naomi
Published: November 2023

Perhaps it is useful to say that spirit is accessed as often through life experience as it is through formal religion. Falling in love, marriage, the birth of a child; these moments may initiate a revolution in personal values and spiritual perspective. The spiritual is really a human birthright; it is the dimension of our being that is the meeting place which underlies human diversity and which creates a genuine connection among all people. Religion attempts to make this real for us through community, practice, and belief, and may become a bridge to the spiritual; but the lived experience of spiritual realities lies beyond all beliefs and practices; it is the all-inclusive ground of being.
Integrative Medicine in Colorectal Cancer
Authors: Jacobson Judith s. , Neugut Alfred I
Published: November 2023

Colorectal cancer may be especially well suited to an integrative approach, which may benefit patients with high risk or precursor conditions as well as those with the disease. A diet rich in fruits and vegetables and regular physical activity may help both to prevent colorectal cancer and to improve survival among patients with colorectal cancer. Two studies have found associations between adverse life events and increased risk of colorectal cancer. Although not conclusive, these data support exploration of stress management measures for individuals at risk.
CAM Therapies to Mitigate the Toxicities of Cancer Therapy
Authors: Lawenda Brian D , Johnstone peter A S
Published: November 2023

Numerous complementary and alternative medicine (CAM) modalities have been demonstrated, through well-designed clinical trials, to be effective in the management and prevention of side effects of conventional oncologic treatments. Acupuncture and certain mind–body therapies (like music therapy and guided imagery) can be successfully employed in patients suffering from chemotherapy-induced nausea and vomiting. In addition to pharmacologic interventions, acupuncture, mas- sage, and other mind–body therapies are useful adjuncts in the management of cancer pain.
Integrative Oncology: The Future
Authors: Rosenthal David s.
Published: November 2023

Integrative care is collaborative care—consolidating the many disciplines of support services. Best overall cancer treatment incorporates the patient’s individual profile including family history, ethnic origin, prior health habits, nutrition, and physical activity. most cancer patients require and seek assistance navigating the healthcare system and addressing their complex and unmet needs. The practice of integrative oncology helps the clinical team better address the patient’s total care.
Twenty-five Years of WHO-Coordinated Activities Concerning Schizophrenia
Authors: Sartorius Norman
Published: November 2023

Some 20 million people in the world suffer from schizophrenia. The disease usually starts early and often has a chronic, disabling course. Treatment, unless rationalized, can be expensive, and the losses in terms of working capacity are staggering. Family members of patients experience disadvantages because of the stigma attached to both the diseased person and his or her relatives. Schizophrenia is a major public health problem. Despite advances in our knowledge about schizophrenia in the past few decades, nothing allows us to surmise that the causes of schizophrenia will soon become known, or that the prevention of the disorder will become possible in the immediate future. Nor is it likely that it will become easier to help people with schizophrenia: The increasing complexity of human society and the disruption of social networks often accompanying economic growth raise the probability that despite progress in treatment, schizophrenia will continue to result in disability and in diminished quality of life.
Study Methodology
Authors: Siegel Carole , Laska Eugene M , Wanderling Joseph A , Baker Sherryl , Harrison Glynn , Bank Rheta , Meisner Morris
Published: November 2023

Isos is a follow-up study on the course of illness and outcomes of a subset of subjects who had been in previous WHO-coordinated research studies of schizophrenia— the International Pilot Study of Schizophrenia (IPSS), the study on the Determinants of Outcome of Severe Mental Disorders (DOSMeD), and the study on Reduction and Assessment of Psychiatric Disability (RAPyD or Disability)—and additionally, subjects who had been in studies conducted locally at three other centers (Retrospective Analysis or Invited). Throughout this volume, these four distinct long-term follow-up cohorts (IPSS, DOSMeD, RAPyD, and Retrospective Analysis) are referred to as the “subsamples” of ISoS.
IPSS: Cali, Colombia
Authors: León Carlos A , León Agatha
Published: November 2023

The Cali World Health Organization (WHO) Collaborating Center for Research and Training in Mental Health originally selected the metropolitan district of the city as its catchment area for the IPSS. However, after June 1969, this area was expanded to include the neighboring town of Palmira. The city of Cali is the capital city of the Departamento del Valle and lies on one side of the long, fertile Cauca valley on the southwest side of Colombia, hemmed in by two of the three parallel ranges of the Andes mountains which edge the western coast of Colombia. Palmira lies across the valley, 25 km north of Cali; the Pacific Ocean is a mere 120 km to the west. Steep terrain and dense jungle vegetation to the west and high mountains to the east have effectively isolated Cali from the capital city of Bogotá. Although Cali lies just 3.5 degrees north of the Equator, its altitude of 1,000 meters insures a mild, semitropical climate all year round, with alternating rainy and dry seasons and small variations in temperature.
IPSS: Prague, Czech Republic
Authors: Skoda Ctirad , Baudis Pavel , Dragomirecká Eva
Published: November 2023

In the fifth and sixth centuries, the Slavs migrated into Prague, founding Prague Castle, which became a cultural and spiritual center. Prague was the capital of Bohemia from the ninth century on. In the 14th century under King Charles IV, it became the capital of the “Holy Empire of the German Nation,” boasting the first university center in Europe (founded in 1348), and ranking as its third largest city after Constantinople and Rome. With the overthrow of the Austro-Hungarian Empire in 1918, Prague became the capital of Czechoslovakia. Since 1900, its population has increased fourfold. By 1967, the start of the IPSS, Prague had 1,102,060 inhabitants.
Dublin, Ireland
Authors: Finnerty Aine , Keogh Fiona , Walshe Anne O’Grady , Walsh Dermot
Published: November 2023

Since the late 19th century, there has been preoccupation with major functional psychotic illness in the Irish because of high hospitalization rates for mental illness and because of reportedly similar high rates among the emigrant Irish, particularly in North America. Speculation has centered on whether incidence is higher among the Irish than in other populations and, if so, whether this is due to a high incidence rate and/ or to an abnormally poor outcome. In the 1960s, these concerns led to considerable research through both fleldwork and improved mental health information systems in Ireland. To begin with, critical examination of hospitalization figures revealed artifactual difficulties indicating that hospital-derived data were unreliable; for example, the term first admission was not rigorously defined, so that there was a substantial over reporting of first admissions. Thus, as an incidence indicator, first admission was invalid perhaps to a greater degree than in other jurisdictions. Second, traditions and practices established in the 19th century and continued into the 20th ensured that Irish mental hospitals became an indiscriminate repository for social problems.
Honolulu, Hawai’i
Authors: Marsella Anthony J , Suarez Edward , Leland Thomas , Morse Heather , Digman Barbara , Scheuer Alice , Katz Martin M
Published: November 2023

Hawai’i consists of eight major volcanic islands and more than 200 small islets totaling 6450 square miles in the middle of the Pacific Ocean, approximately 2100 miles southwest of San Francisco, California. Volcanic activity continues to add landmass from eruptions that flow from the Kilauea Crater to the ocean. The Hawaiian Islands are a lush tropical paradise of flora and fauna that thrived because of their isolation from other lands and people (Nordyke, 1989). According to the 1990 census, Hawai’i has more than 1,150,000 people with ethnocultural minorities making up more than 75% of the population; there are Caucasians, Japanese, Filipinos, Chinese, AfricanAmericans, Koreans, pure and part-Hawaiians, Samoans, Hispanic/ Latinos, and other mixed races.
Moscow, Russia
Authors: Tsirkin Sergey
Published: November 2023

In the late 1970s, an administrative district of Moscow was chosen to participate in the Determinants of Outcome of Severe Mental Disorders study (DOSMeD), a WHO-coordinated epidemiological study of new cases of schizophrenia. The population of this district was then approximately 400,000, of whom about 230,000 were aged 18 to 54, the age of inclusion in the study. (The population of the City of Moscow, now about 9 million, was then about 8 million.) The selected catchment area does not include historic central Moscow, but is a relatively new area that has more factories and fewer offices, theaters, and museums. The population, having migrated to the catchment area during the last decades to improve their living conditions, is accordingly more numerous and younger. Most of the houses, erected in the sixties, are much larger than those in other parts of the city. Several hostels house relatively young workers from the provinces who came with the obligation of taking menial jobs in specific factories with manpower shortages.
Nagasaki, Japan
Authors: Nakane Yoshibumi , Takada Koichi , Yoshitake Kazuyasu , Hatada Keiko
Published: November 2023

Located in the western part of Kyushu Island of the Isles of Japan and in the southern part of Nagasaki Prefecture, Nagasaki City is home of the prefectural government of Nagasaki and a center of economic activity: industry, business, and trade. It extends 25 km from east to west and 25.9 km from north to south, for a total area of 240.43 sq km. According to the October 1995 census (Statistical Bureau, Prime Minister’s Office), the population of Nagasaki City is 438,724 (204,252 men and 234,472 women), and the population of Nagasaki prefecture is about 1,545,000. In the 17th century, an isolationist policy closed Japan to the outside world. Only the Dutch and the Chinese were allowed to carry on very restricted trade with Japan and only through Nagasaki harbor. Thus, for nearly 250 years, Nagasaki was Japan’s only window to foreign culture. Even after the opening of Japan in the mid-19th century, Nagasaki remained an important entry point for foreign culture and technology. Among its innovations were a training school for sailors and the first steel ingot factory, which marked the beginning of modern technological industry in Japan and set the stage for the development of Japan’s major industries.
Groningen, The Netherlands
Authors: Wiersma Durk , Nienhuis Fokko J , Slooff Cees J , Giel Robert , Jong Ate de
Published: November 2023

While population growth of the Netherlands (from about 13.8 million in 1976 to over 15 million in 1990) will continue into the 21st century because of age distribution (the aging of people and the lengthening of average life expectancy which is already amongst the highest in Europe), the birthrate has been decreasing since 1963 and, in 1973, dropped below replacement level. The decrease accompanied by a high divorce rate can be regarded as an indication of a changed lifestyle in which marriage and family became less important. Since the mid-1980s, however, a growing number of marriages and a recent reduction in divorces may indicate a return to more traditional ways. The educational system is greatly accessible, and there is a very high degree of active participation by the young. Dutch is spoken and understood everywhere, although almost every region or province has a dialect or vernacular. Foreign nationals (refugees, asylum seekers, second-generation immigrants) are a small but growing (less than 5%) proportion of the Dutch population.
Sofia, Bulgaria
Authors: Ganev Kimon , Onchev Georgi , Ivanov Plamen
Published: November 2023

Bulgaria, with a total population of nearly 9 million, is situated in the middle of the Balkan peninsula on a territory of 110,000 sq km. The population is largely Bulgarian; Turks, the largest minority, account for about one-tenth of the population. There are also Gypsies, Jews, Armenians, and other minorities. The dominant religion is Eastern Orthodox Christianity. The official language is Bulgarian, which is also spoken by most minority group members. The WHO Collaborating Center is located in Sofla, the largest city and the administrative and academic center of Bulgaria, comprising about 1.2 million inhabitants. The largest proportion of the population is engaged in service activities. There are also various industries, and some neighborhoods of the city are inhabited exclusively by the families of industrial workers. A significant portion of older people practices seasonal migration: They move to the villages in spring and summer, growing food and raising animals, and come back to the city during the winter. Fifty years ago, Bulgaria was a traditional patriarchal society with extensive kinship networks as a constant source of support throughout life. Despite significant changes in this pattern during the past half-century, old traditions still have their influence, and kinship obligations can be described as strong.
RA: Chennai (Madras), India
Authors: Thara R , Rajkumar S , Joseph A Albert
Published: November 2023

Chennai (Madras) is the fourth largest city in India, the second most populous country in the world, with a population of nearly 980 million. Chennai and its suburbs contain about 5.5 million people. A port city, Chennai is the seat of south Indian culture and the capital of the state of Tamil Nadu bordering the southeast coast of the country. For the past 30 years, the state has been ruled only by regional political parties that have no base outside the state. A matter of political contention has been the relationship between the central government and the states, and the struggle for greater autonomy for states continues. Hindus constitute about 80% of the population with Christians and Muslims accounting for the rest; religious groups generally coexist in harmony. There is an air of cultural homogeneity.
Impediments That Prevent Physicians And Therapists From Making Valid Inferences
Authors: Bausell R Barker
Published: November 2023

It’s one thing to hypothesize how someone like Sarah can be tricked into believing that a CAM therapy is helping her when nothing is operating except placebo effects, the natural history of pain, and a few Psych 101 concepts such as cognitive dissonance. It’s still another to explain how a highly trained, skilled, and compassionate physician can be tricked into believing a placebo is really a miraculous panacea. Here is one scenario demonstrating how such a state of affairs could come to pass.