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The eponymous term torcular Herophili has been used for the confluence of sinuses. Although no original writings of Herophilus are extant, his accomplishments and descriptions live on in the writings of such authors as Galen. However, in regard to the torcular Herophili, there are some inconsistencies in the secondary sources and their translations regarding what was actually originally described by Herophilus. Herein, we review the history of the term torcular Herophili, which is so often used in clinical medicine.

The modern view that the human body is composed of tissues and body fluids, and that there are four basic tissue types, may be a more significant departure from Artistotle's homoeomeres, and from Bichat's membranes and tissues, than commonly appreciated. The older concepts described these body parts as structural and functional parts of organs, whereas it is now commonplace to consider a tissue to be a grouping of similar cells with a variable amount of extracellular matrix. The development of the microscope as a useful tool in human anatomy shifted focus from tissues to cells and led to changes in the definition of tissue and the classification of tissues. Not all of these changes have been consistent with observable facts: many tissues contain diverse cell types, not all "connective tissues" are proper connective tissues, and some specialized tissues are not easily classified as subtypes of one of the four basic types. Here we propose corrective measures, including re-recognition of compound tissues, cataloging all adult human tissue types, and increasing the emphasis on function during the construction of a complete taxonomy of human adult tissues. Specific problems in the current scheme and a preliminary reclassification of human adult tissues are discussed.

Most of the terms in Terminologia Anatomica are arranged by organ systems (systemata); however, the names for these systems are often used by physiologists and other biomedical scientists for related functional systems. These functional systems may differ in their composition from the anatomist's organ systems. In addition, many functional systems have been described that do not correspond to organ systems. Similarly, the non-standard anatomical terms alimentary tract, respiratory tract, urinary tract and reproductive tract lack a consistent meaning in the biomedical sciences. For clear communication, one should be cautious when using terms that may have other meanings in other disciplines. This appears to be particularly true for high level terms in the nomenclature of systematic anatomy.

Introduction Communication in the biomedical sciences and clinical practice would be clearer if everyone used the same set of technical terms. Technical vocabularies, such as international standard terminologies, are attempts to avoid common linguistic problems, such as synonymy (many names for a single entity) and polysemy (many meanings for a single term). Materials and methods Efforts made in human anatomical nomenclature since the late 19th century to deal with these issues were reviewed. Results The new designations official term, equivalent term, synonym and related term are defined, and current challenges (e.g., eponyms) are identified. Discussion The addition of synonyms and related terms to the international standard anatomical terminology allows indexing of these terms to the official terms and evaluation of the relationships between terms.

Revision of the international standard anatomical terminology is required periodically to add names for new entities, delete archaic terms, and correct errors in existing terms. In addition to a small set of nomenclature rules, three principles have guided revisions: names should not be changed unless they are wrong; corrections of perceived errors should not be pedantic; and inclusion of every minor structure should not be attempted. These principles have served well, and are expected to continue to do so, but they have also proven to be subjective because their application through the history of the international terminology has varied. Specific efforts to deal with existing problems and new organizational initiatives to prevent future issues are presented. Clin. Anat. 33:327-331, 2020. © 2019 Wiley Periodicals, Inc.

Textbooks frequently report that there are 206 human bones, or 200 bones and 6 auditory ossicles. The human bone counts in history and within adulthood were reviewed. Tallies of 197 to 307 bones have been reported over the past several centuries. The relatively low modern reckoning of 206 was due to exclusion of teeth and sesamoid ossicles, and to reassessments of the hyoid, sacrum, coccyx, and sternum as unitary bones. An audit of bone counts during adulthood failed to confirm a rational justification for the total of 206. The number is higher in young adults and lower in the elderly. Difficulties in establishing a definitive bone count include individual differences and the inconsistency of viewing the adult cranium as a collection of 21 bones. Clin. Anat. 33:187-191, 2020. © 2019 Wiley Periodicals, Inc.

The rules of the anatomical nomenclature are sometimes in conflict with the principles of revision of the nomenclature. This is possibly most obvious is the debate about the use of the Latin words pudendus ("shameful") and sacer ("holy") in the anatomical nomenclature. The principles of revision stress preservation of traditional terms even if there are etymological concerns. On the other hand, the nomenclature rules state that anatomical names should, preferably, have informative or descriptive value and that the official Latin terms are the basis for translations of the international standard terminology into modern, vernacular languages. This issue of Clinical Anatomy contains responses to the removal of the noun pudendum and the replacement of the adjective pudendus with pudendalis in the second edition of Terminologia Anatomica.

The frequency of diminutives in anatomical Latin has often been noted to be high, but that is not unusual in postclassical Latin. Although the connotation of "little" is well known, many of the diminutives in anatomical Latin do not have that meaning. The morphology of regular, irregular, and secondary diminutives is presented, along with that of adjectival forms of diminutives. Several transgendered and malformed diminutives are discussed. Clin. Anat. 31:1100-1103, 2018. © 2018 Wiley Periodicals, Inc.

Future revisions of anatomical terminologies will have to give more consideration to the relationships between terms and referents, and the relationships between referents, because computer applications require greater precision. Median anatomical entities and paired entities that closely flank the median plane present common problems in nomenclature, semantics, and ontology. Some of these problems represent vestiges of usage in classical Latin. For example, the use of plural words for polite names of some body parts, and singular words for euphemisms for naughty words. Clin. Anat. 32:22-24, 2019. © 2019 Wiley Periodicals, Inc.

Spelling variants are common in Latin anatomical terms. Some of these variants cause confusion with respect to the meaning of the word by altering the base of the word to resemble a different word base. Thus these variants should be considered errors, comparable to errors in declension of nouns and adjectives, and errors in the formation of neologisms. Use of correct Latin words in Latin anatomical terms should increase the rigor, stability, and universality of the nomenclature. Clin. Anat. 31:77-80, 2018. © 2017 Wiley Periodicals, Inc.

This is the first in a short series about orthography in anatomical Latin. Although phonology is an important aspect of diphthongs and digraphs, the focus here is on spelling, not the more complicated topic of pronunciation. Recommendations are made for standard spellings of words that contain or may appear to contain diphthongs in Latin anatomical words or their ancient Greek sources. Ligatures and diaereses (typographical symbols that were developed after the classical period) are not recommended for use in anatomical Latin terms. Clin. Anat. 30:1013-1016, 2017. © 2017 Wiley Periodicals, Inc.

Here, new rules of Latin anatomical nomenclature are proposed to deal with cases not covered by existing or other recommended rules. Determiners (e.g., numerals, letters, alphanumeric strings, and Latin names of Greek letters) should follow the noun they specify or limit, just as it is recommended that adjectives should follow the noun they modify. In general, Roman numerals, Latin letters, and Latin names of Greek letters are preferable to Arabic numerals and Greek letters in Latin anatomical terms. It is also noted that the word typus (type) appears to be superfluous and unnecessary in the Latin anatomical nomenclature. Clin. Anat. 30:700-702, 2017. © 2017Wiley Periodicals, Inc.

Twice in fifteen months the popular press has published reports of the discovery of a new human organ. The claims that the mesentery and interstitium are organs come from medical practitioners, not from anatomical scientists. Although both of these anatomical entities are important in the functioning of the body, neither satisfies the requirements that an organ be composed of two or more tissues and perform a special function. Also missing in the recent claim that the interstitium, that is, connective tissues with fluid-filled spaces, is an organ, is a statement to that effect in the original research report. Alas, it appears to be much ado about nothing. Clin. Anat. 31:648-649, 2018. © 2018 Wiley Periodicals, Inc.

Information systems are increasing in importance in biomedical sciences and medical practice. The nomenclature rules of human anatomy were reviewed for adequacy with respect to modern needs. New rules are proposed here to ensure that each Latin term is uniquely associated with an anatomical entity, as short and simple as possible, and machine-interpretable. Observance of these recommendations will also benefit students and translators of the Latin terms into other languages. Clin. Anat. 30:300-302, 2017. © 2016 Wiley Periodicals, Inc.

The anatomical nomenclature rules require that terms be as short and simple as possible. One common exception to that rule is Latin terms that contain two nouns in nominative case, for example, Musculus masseter and Os ischium. Although these may appear to speakers of other languages to be compound nouns, they are appositions, grammatical structures in which one noun renames, defines or describes the entity named by the other noun. More than 125 terms in Terminologia Anatomica can be simplified, without loss of clarity, by prohibiting use of more than one noun in nominative case in Latin anatomical terms (e.g., Masseter and Os ischii). Clin. Anat., 2016. © 2016 Wiley Periodicals, Inc.

Although disparaged by philologists, hybrid words enrich technical and scientific vocabularies. They are common, so, like it or not, they are here to stay. On the other hand, where there are pre-existing purebred compound or affixed words, they should generally be given preference over hybrids. Some adjectives (e.g., laryngeus and sphenoideus) are discussed to illustrate these recommendations. Clin. Anat. 31:771-773, 2018. © 2018 Wiley Periodicals, Inc.

This is the first in a short series about orthography in anatomical Latin. Although phonology is an important aspect of diphthongs and digraphs, the focus here is on spelling, not the more complicated topic of pronunciation. Recommendations are made for standard spellings of words that contain or may appear to contain diphthongs in Latin anatomical words or their ancient Greek sources. Ligatures and diaereses (typographical symbols that were developed after the classical period) are not recommended for use in anatomical Latin terms. Clin. Anat. 30:1013-1016, 2017. © 2017 Wiley Periodicals, Inc.

Here, new rules of Latin anatomical nomenclature are proposed to deal with cases not covered by existing or other recommended rules. Determiners (e.g., numerals, letters, alphanumeric strings, and Latin names of Greek letters) should follow the noun they specify or limit, just as it is recommended that adjectives should follow the noun they modify. In general, Roman numerals, Latin letters, and Latin names of Greek letters are preferable to Arabic numerals and Greek letters in Latin anatomical terms. It is also noted that the word typus (type) appears to be superfluous and unnecessary in the Latin anatomical nomenclature. Clin. Anat. 30:700-702, 2017. © 2017Wiley Periodicals, Inc.

Twice in fifteen months the popular press has published reports of the discovery of a new human organ. The claims that the mesentery and interstitium are organs come from medical practitioners, not from anatomical scientists. Although both of these anatomical entities are important in the functioning of the body, neither satisfies the requirements that an organ be composed of two or more tissues and perform a special function. Also missing in the recent claim that the interstitium, that is, connective tissues with fluid-filled spaces, is an organ, is a statement to that effect in the original research report. Alas, it appears to be much ado about nothing. Clin. Anat. 31:648-649, 2018. © 2018 Wiley Periodicals, Inc.

To the Editor, Clinical Anatomy:Amidst medical curricula that are undergoing radical reform,there is concern that anatomy teaching may be inadequatefor the standards of postgraduate residency programs (Princeet al., 2005; Fitzgerald et al., 2008). With the decreasingnumber of hours spent in anatomy and embryology laborato-ries (Craig et al., 2010), there also emerges a need for defin-itive and accessible illustrations for the education of medicalstudents. The illustrations contained in modern textbooksoften lack comprehensive detail, and are occasionally in needof correction. Moreover, the simplified style of modern medi-cal illustration has been described as a desired compromisebetween the professional and initiate (Strong, 2011).Medical students will often heavily utilize online resourcesprovided to them, given the portability of the material andthe ability to utilize it at their own convenience and pace(Nieder and Nagy, 2002). There are myriad potential difficul-ties with copyright in modern medical education, and anincreasing number of institutions have been subject to litiga-tion as a result of unauthorized use of copyrighted materialsin their printed and online modules (Gutman, 2011). We pro-pose that modernization efforts involving older, out-of-copyright material may represent a viable solution for thecreation of high-quality teaching resources.As digital archiving on Internet databases rapidly grows,there has been an unprecedented expansion in the availabil-ity of scanned out-of-copyright text and illustrations accessi-ble online. Consequently, there is an opportunity to utilizeand modify exceptionally-detailed, accurate medical illustra-tions. Here, we attempt to modernize these images for usein contemporary digital databases.Two scanned images were selected for modernization.The first, “Cloaca of human embryo from twenty-five totwenty-seven days old” from the 1918 edition of Gray’s Anat-omy (Gray and Lewis, 1918), was downloaded from Wikime-dia Commons (2014, September 6). The second, “Theforebrain section” from the 1920 edition of Ranson’s Anat-omy of the Nervous System (Ranson, 1920), was copiedfrom the Internet Archive (2010).Digitally-scanned online versions of the illustrations werecompared with hard copies to ensure correct attribution.Adobe Photoshop CS4 was used to clean up and sharpen thesource images, as well as remove the original label lines andbackground to yield an unlabeled base image. Subsequently,modernized labels were added, with improved positioning,clearer typeset and lines. In addition, additional hues wereadded behind the existing linework to define additional struc-tures. Legends were updated in keeping with changes in ter-minology and age estimates of embryonic stages. Thesemodernized images are presented (see Figures 1 and 2). Theillustrations are both enhanced with regards to clarity anddetail, while preserving the original focus. The figure legendsand labels were brought up to date with current conceptsand terms.There are no known copyright restrictions for the use ofthe human cloaca or the forebrain section illustrations in theUnited States and Canada as the original books were pub-lished before 1923 and the authors died [mt]50 years ago.Furthermore, as per Bridgeman Art Library v. Corel Corp(Bangle, 1999), the human cloaca illustration may be not besufficiently original to merit copyright in the U.S. because itis a drawing of a wax model by Keibel.Both images were made available under a Creative Com-mons licence. Four components of such a license exist, eachof which must be included or excluded. These are Attributon,ShareAlike, Noncommercial, and No Derivative Works. In thecase of our images, the former two were stipulated. Attribu-tion requires that one must give appropriate credit, provide alink to the license, and indicate if changes were made. Onemay do so in any reasonable manner, but not in any waythat suggests the licensor endorses them or their use of thematerial. Share Alike requires that if one remixes, trans-forms, or builds upon the material, this party must distributethe new work under the same or similar license as the origi-nal. For instance, we would be unable to apply legal termsthat restricted others from doing anything the license per-mits. Since Noncommercial and No Derivative Works condi-tions do not apply, one is free to copy and distribute thematerial in any medium or format, and remix, transform andbuild upon the material. This is legitimate for any purpose,even commercial.The availability of out-of-copyright materials from vener-ated medical texts represents a unique opportunity to mod-ernize old illustrations while preserving their high level ofaccuracy and detail. Updating of terminology that has sincechanged is feasible and worthwhile in service of the best pos-sible education in anatomy and embryology. The images con-tained within many anatomy and embryology texts of theearly 20th century were painstakingly prepared by physi-cians, scientists, and illustrators with an unparalleled appre-ciation for these domains.

Exceptions to the anatomical nomenclature rule that names must be in proper Latin include a few terms that contain borrowed Greek adjectives that are not declined like Latin words. Adoption of these adjectives into Latin would change about a half-dozen terms, e.g., vena azyga, vena hemiazyga, and fascia darta. The anatomical nomenclature rules apply only to the Latin terms, so there is no requirement to alter the way azygos, hemiazygos, and dartos are used in equivalent terms in other languages. Clin. Anat. 30:450-451, 2017. © 2017 Wiley Periodicals, Inc.

The definition of an organ is vague, so that listing and classifying human organs is problematic. The classical Greek definition of an organ as an instrumental part of the body has been supplemented in modern biology by stating that organs occupy a hierarchical level between systems and tissues. Not all anatomical entities on that level meet the requirement of a special function. Thus it appears that systems are composed of organs and connecting (or linking) structures, such as some connective tissues, various tubular entities, and nerves. Clin. Anat. 30:288-289, 2017. © 2017 Wiley Periodicals, Inc.

Item does not contain fulltext This article deals with a recent revision of the terminology of the Sections Central Nervous System (CNS; Systema nervosum centrale) and Peripheral Nervous System (PNS; Systema nervosum periphericum) of the Terminologia Anatomica (TA, 1998) and the Terminologia Histologica (TH, 2008). These sections were extensively updated by the Federative International Programme for Anatomical Terminology (FIPAT) Working Group Neuroanatomy of the International Federation of Associations of Anatomists (IFAA). After extensive discussions by FIPAT, and consultation with the IFAA Member Societies, these parts were merged to form a Terminologia Neuroanatomica (TNA). After validation at the IFAA Executive Meeting, September 22, 2016, the TNA has been placed on the open part of the FIPAT website (http://FIPAT.library.dal.ca) as the official FIPAT Terminology. This article outlines the major differences between the TNA and the TA. Clin. Anat. 30:145-155, 2017. (c) 2016 Wiley Periodicals, Inc.

Information systems are increasing in importance in biomedical sciences and medical practice. The nomenclature rules of human anatomy were reviewed for adequacy with respect to modern needs. New rules are proposed here to ensure that each Latin term is uniquely associated with an anatomical entity, as short and simple as possible, and machine-interpretable. Observance of these recommendations will also benefit students and translators of the Latin terms into other languages. Clin. Anat. 30:300-302, 2017. © 2016 Wiley Periodicals, Inc.

The anatomical nomenclature rules require that terms be as short and simple as possible. One common exception to that rule is Latin terms that contain two nouns in nominative case, for example, Musculus masseter and Os ischium. Although these may appear to speakers of other languages to be compound nouns, they are appositions, grammatical structures in which one noun renames, defines or describes the entity named by the other noun. More than 125 terms in Terminologia Anatomica can be simplified, without loss of clarity, by prohibiting use of more than one noun in nominative case in Latin anatomical terms (e.g., Masseter and Os ischii). Clin. Anat. 30:156-158, 2017. © 2016 Wiley Periodicals, Inc.

For over 20 years, interventional methods have improved the outcomes of patients with cardiovascular disease or stroke. However, these procedures require an intricate combination of visual and tactile feedback and extensive training periods. An essential part of this training relates to catheter or guidewire manipulation. In this paper, we propose a composite model to realistically simulate a catheter, a guidewire or a combination of both. Where a physics-based simulation of both devices would be computationally prohibitive and would require to deal with a large number of contacts, we propose to address this problem by replacing both objects by a composite model. This model has a dual visual representation and can dynamically change its material properties to locally describe a combination of both devices. Results show that the composite model exhibits the same characteristics of a catheter/guidewire combination while maintaining real-time interaction.

C57BL/6J and DBA/2J inbred mice differ in aspects of maternal behavior and in the morphology of the medial preoptic nucleus (MPO), suggesting a possible association. DBA/2J mice have a compact subnucleus in the MPO, the MPOpc, that is sexually dimorphic and absent in C57BL/6J mice. To determine whether MPOpc cells are activated by maternal behavior, FOS and FOSB immunohistochemistry was performed on brain sections of C57BL/6J and DBA/2J mothers following the return of their pups after a separation of 2 days. In both light and dark phases of the daily cycle, stimulation of DBA/2J mothers evoked an increase in FOS- and FOSB-immunoreactivity in the MPOpc. Stimulated C57BL/6J mice, which lack the MPOpc, did not show an increase in cellular activity in the corresponding MPO region. Cells immediately lateral to the MPOpc were activated by pup stimulation, in both strains. These results suggest that MPOpc cells are active during maternal behavior, and that strain differences in maternal behavior are related to anatomical differences in the MPO.

Rocker (gene symbolrkr), a new neurological mutant phenotype, was found in descendents of a chemically mutagenized male mouse. Mutant mice display an ataxic, unstable gait accompanied by an intention tremor, typical of cerebellar dysfunction. These mice are fertile and appear to have a normal life span. Segregation analysis reveals rocker to be an autosomal recessive trait. The overall cytoarchitecture of the young adult brain appears normal, including its gross cerebellar morphology. Golgi-Cox staining, however, reveals dendritic abnormalities in the mature cerebellar cortex characterized by a reduction of branching in the Purkinje cell dendritic arbor and a “weeping willow” appearance of the secondary branches. Using simple sequence length polymorphism markers, therockerlocus was mapped to mouse chromosome 8 within 2 centimorgans of the calcium channel α1a subunit (Cacna1a,formerly known astottering) locus. Complementation tests with theleanermutant allele (Cacna1ala) produced mutant animals, thus identifyingrockeras a new allele ofCacna1a(Cacna1arkr). Sequence analysis of the cDNA revealedrockerto be a point mutation resulting in an amino acid exchange: T1310K between transmembrane regions 5 and 6 in the third homologous domain. Important distinctions betweenrockerand the previously characterized alleles of this locus include the absence of aberrant tyrosine hydroxylase expression in Purkinje cells and the separation of the absence seizures (spike/wave type discharges) from the paroxysmal dyskinesia phenotype. Overall these findings point to an important dissociation between the seizure phenotypes and the abnormalities in catecholamine metabolism, and they emphasize the value of allelic series in the study of gene function.

Niemann-Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13-cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232-235) recently demonstrated that one of these ESTs is the Niemann-Pick type C (NPCI) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097-->T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1-cM (1.3-1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5-cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.

PURPOSE: To investigate the retinal function in aniridic patients with documented PAX6 mutations to determine the range of electroretinogram abnormalities in aniridic patients and to relate electroretinogram findings with specific PAX6 mutations. METHODS: Eleven patients with typical aniridia and fully characterized PAX6 mutations underwent electroretinography. RESULTS: In all 11 patients, electroretinogram recordings were abnormal, ranging from mild to severe. Rod-related and cone-related activities were equally affected. The amplitude of the oscillatory potentials was the most reduced, followed by the b-wave, then to a milder degree the a-wave. Mutations affecting the paired domain of the PAX6 protein had the biggest impact on the electroretinogram amplitudes. Implicit times were increased in a subgroup with mutations affecting only the homeodomain. CONCLUSION: Patients with aniridia have varying degree of retinal dysfunction, ranging from severely abnormal to almost normal. The paired domain appears to have more impact on retinal function than other regions of the PAX6 protein. It is unclear whether mutations affecting the homeodomain lead to alteration of the photoreceptor function.

Audiogenic seizure (AGS) susceptibility in mice is a multifactorial behavioral disorder that involves severe generalized convulsions in response to loud, high-frequency sound. The inheritance of AGS susceptibility was examined in crosses between AGS-susceptible DBA/2J (D2) mice and epilepsy-prone (EP) mice. The EP mice were selected for high AGS susceptibility in a BALB/c-derived line. The AGS phenotype was similar in the EP and D2 mice at 30 days of age. The frequency of generalized clonic–tonic AGS was high in both the D2 and the EP mice (53 and 83%, respectively) but was low in the reciprocal EPD2F1 and D2EPF1 hybrids (14 and 19%, respectively). In the backcross to the EP parent, no significant associations were found between AGS susceptibility and microsatellite markers linked to Asp1 or Asp2, AGS genes located on Chromosomes 12 and 4, respectively. Significant associations were found for markers linked to Asp3, which is located in the proximal region of Chromosome 7. The influence of Asp3 on AGS susceptibility was seen in the EP × EPD2F1 backcross but not in the reciprocal EPD2F1 × EP backcross, suggesting that Asp3 expression is influenced by genomic imprinting. A model is proposed where genomic imprinting represses the maternal Asp3 allele, providing an influence largely from the paternal allele.

By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial “response to novelty” ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit1 16; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, >2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phe-notypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.

Recombinant inbred (RI) strains derived from the C57BL/6J and A/J mouse strains were used for behavioral studies designed to estimate the number and location of chromosomal loci responsible for anxiety-related behaviors and differential sensitivity to agonists and inverse agonists of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor complex. The phenotypes of the parental inbred strains and of 28 RI strains were characterized for the number of transitions in the light--dark exploratory model, anxiolytic response to diazepam, vertical and ambulatory activities in an open field, and sensitivity to the convulsant properties of methyl-beta-carboline-3-carboxylate (beta-CCM). The strain distribution patterns and estimates of the minimal number of loci obtained for each trait suggest that multiple chromosomal loci contribute to differences in anxiety-related behavioral phenotypes and the behavioral responses to diazepam and beta-CCM between C57BL/6J and A/J mice. The best probabilities of linkage were found between the variables characterizing response to diazepam and loci on chromosomes 1 (Xmv-41) and 10 (D10Mit2) and between the sensitivity to the convulsant actions of beta-CCM and locus D15Mit5 on chromosome 15.

Neural tube defects (NTD) in humans have been considered to have a multifactorial aetiology, however the participating genes have not been identified. The curly-tail (ct) mutant mouse develops NTD that resemble the human malformations in location, pathology and associated abnormalities. Moreover, there appears to be multifactorial influence on the incidence of NTD in offspring of curly-tail mice. We now describe a linkage analysis that localizes the ct gene to distal chromosome 4 in mice. Further analysis using recombinant inbred strains demonstrates the presence of at least three modifier loci that influence the incidence of NTD. This study provides definitive evidence for multifactorial inheritance in a mouse model of human NTD.

Glutamate neurotransmission is an essential component of many forms of neuronal plasticity, however, the intracellular mechanisms that mediate plasticity are only beginning to be elucidated. The emerging image of the NMDA receptor complex reminds us that the similarity between mechanisms of plasticity in various model systems is greater than their apparent differences. For example, the cAMP-dependent protein kinase A signalling pathway is crucial for plasticity in a variety of neuronal systems and across a wide variety of species.

Recombinant inbred strains have been shown to be important tools for segregation and linkage analysis of multifactorial traits. Tests of association have been used as robust methods of linkage detection, however, guidelines for forming inferences from significance levels have not been generally available. In this paper, lessons learned from a Bayesian statistical approach to linkage analysis of Mendelian traits have been applied to studies of multifactorial traits. Criteria for detection of linkage based on Bonferroni's correction for multiple testing are also discussed.

Mice homozygous for the recessive mutation swaying (sw) are characterized by ataxia and hypertonia, attributed to the malformation of anterior regions of the cerebellum. We show that sw is a deletion of a single base pair from the proto-oncogene Wnt-1. The deletion is predicted to cause premature termination of translation, eliminating the carboxy-terminal half of the Wnt-1 protein. Histological examination shows that sw is phenotypically identical to a previously described wnt-1 mutation introduced into mice by gene targeting. Although both mutations in Wnt-1 disrupt primarily the development of the anterior cerebellum, they also exhibit a variability in expressivity such that rostrally adjacent structures in the midbrain and caudally adjacent structures in the posterior cerebellum can also be affected.

Approximately 89 markers have been mapped to Chromosome (Chr) 15 (Table 1) by a combination of methods including in situ hybridization, analysis of somatic cell hybrids, recombinant inbred (RI) strains, backcrosses and intercrosses. Sixty of these markers are cloned sequences and 29 of them are assayed by examination of their phenotype. The bulk of these phenotypes are morphological mutations with visible effects, which have been described in depth by Green (1989). Additional phenotypic markers include: (1) Afr-1, which regulates the level of expression of a-fetoprotein (Alp), which is located on Chr 5 (Olsson et al. 1977; Blankenhorn et al. 1988); (2) Mupm-1, which modifies the expression of mouse major urinary protein (Mup-1), which is located on Chr 4 (Duncan et al. 1988); and (3) Ril-l, a tumor susceptibility gene involved in radiation-induced leukemia (Meruelo et al. 1981, 1987).

Pulsed-field gel electrophoresis (PFGE) and deletion mapping are being used to construct a physical map of the long arm of human chromosome 13. The present study reports a 2700-kilobase (kb) Not I long-range restriction map encompassing the 13q14-specific loci D13S10, D13S21, and D13S22, which are detected by the cloned DNA markers p7D2, pG24E2.4, and pG14E1.9, respectively. Analysis of a panel of seven cell lines that showed differential methylation at a Not I site between D13S10 and D13S21 proved physical linkage of the two loci to the same 875-kb Not I fragment. D13S22 mapped to a different Not I fragment, precluding the possibility that D13S22 is located between D13S10 and D13S21. PFGE analysis of Not I partial digests placed the 1850-kb Not I fragment containing D13S22 immediately adjacent to the 875-kb fragment containing the other two loci. The proximal rearrangement breakpoint in a cell line carrying a del13(q14.1q21.2) was detected by D13S21 but not by D13S10, demonstrating that D13S21 lies proximal to D13S10. Quantitative analysis of hybridization signals of the three DNA probes to DNA from the same cell line indicated that only D13S10 was deleted, establishing the order of these loci to be cen-D13S22-D13S21-D13S10-tel. Surprisingly, this order was estimated to be 35,000 times less likely than that favored by genetic linkage analysis.

For over 20 years, interventional methods have improved the outcomes of patients with cardiovascular disease. However, these procedures require an intricate combination of visual and tactile feedback and extensive training. In this paper, we describe a series of novel approaches that have led to the development of a high-fidelity simulation system for interventional neuroradiology. In particular, we focus on a new approach for real-time deformation of devices such as catheters and guidewires during navigation inside complex vascular networks. This approach combines a real-time incremental Finite Element Model (FEM), an optimization strategy based on substructure decomposition, and a new method for handling collision response in situations where the number of contact points is very large. We also briefly describe other aspects of the simulation system, from patient-specific segmentation to the simulation of contrast agent propagation and fast volume-rendering techniques for generating synthetic X-ray images in real time. Although currently targeted at stroke therapy, our results are applicable to the simulation of any interventional radiology procedure.

The somatosensory (SI) cortex of mice displays a patterned, nonuniform distribution of neurons in layer IV called the 'barrelfield' (ref. 1). Thalamocortical afferents (TCAs) that terminate in layer IV are segregated such that each barrel, a readily visible cylindrical array of neurons surrounding a cell-sparse center, represents a distinct receptive field. TCA arbors are confined to the barrel hollow and synapse on barrel-wall neurons whose dendrites are oriented toward the center of the barrel. Mice homozygous for the barrelless (brl) mutation, which occurred spontaneously in ICR stock at Université de Lausanne (Switzerland), fail to develop this patterned distribution of neurons, but still display normal topological organization of the SI cortex. Despite the absence of barrels and the overlapping zones of TCA arborization, the size of individual whisker representations, as judged by 2-deoxyglucose uptake, is similar to that of wild-type mice. We identified adenylyl cyclase type I (Adcy1) as the gene disrupted in brl mutant mice by fine mapping of proximal chromosome 11, enzyme assay, mutation analysis and examination of mice homozygous for a targeted disruption of Adcy1. These results provide the first evidence for involvement of cAMP signalling pathways in pattern formation of the brain.

Summary Niemann-Pick type D (NPD) disease is a progressive neurodegenerative disorder characterized by the accumulation of tissue cholesterol and sphingomyelin. This disorder is relatively common in southwestern Nova Scotia, because of a founder effect. Our previous studies, using classic linkage analysis of this large extended kindred, defined the critical gene region to a 13-cM chromosome segment between D18S40 and D18S66. A recently isolated gene from this region, NPC1, is mutated in the majority of patients with Niemann-Pick type C disease. We have identified a point mutation within this gene (G 3097 →T; Gly 992 →Trp) that shows complete linkage disequilibrium with NPD, confirming that NPD is an allelic variant of NPC1.

Previous reports concerning the location of D18S44 with respect to the centromere have been ambiguous. Also, it has not been possible, based on formerly reported markers, to show that contigs WC18.0 and WC18.1 overlap. However, the data presented here definitively show, using FISH technology, that D18S44 (located on WC18.0) maps to proximal 18q. Furthermore, inter-Alu fingerprinting shows a clear overlap between WC18.0 and WC18.1, thereby establishing a complete contig between D18S44 and markers from WC18.1.Key words: FISH mapping, inter-Alu, fingerprinting, human chromosome 18.

Purpose To identify the mutation responsible for lattice corneal dystrophy type 1 in an extended Canadian kindred. Methods A search for a mutation in the candidate gene, kerato-epithelin, was carried out by single-strand conformation polymorphism and sequencing analyses. Results A C → T mutation at position 417 was detected in exon 4 of the kerato-epithelin gene, which is expected to cause an Arg 124 → Cys change. This is the same nucleotide change described previously in two Swiss families with lattice corneal dystrophy type 1. Conclusion Although the possibility that the three families (two previously described Swiss families and this Canadian kindred) are related has not been excluded, it appears that the unique phenotype of lattice corneal dystrophy type 1 is caused by this particular amino acid change.

Patterning of the mouse somatosensory cortex is unusually evident because of the presence of a “barrel field.” Presynaptic serotonin and postsynaptic glutamate receptors regulate barrel formation, but little is known of the intracellular signaling pathways through which they act. To determine whether protein kinase A (PKA) plays a role in the development of the barrel field, we examined five viable PKA subunit-specific knock-out (KO) mouse lines for barrel field abnormalities. Barrels are present in these mice, but those lacking the RIIβ subunit display significantly reduced contrast between the cell densities of barrel hollows and sides compared with wild-type animals. Thalamocortical afferent segregation in the posterior medial barrel subfield appeared normal, suggesting a postsynaptic site of gene action for the RIIβ protein. Immunoelectron microscopy confirmed that RIIβ was selectively localized to dendrites and dendritic spines. Mice lacking RIIβ show reduced glutamate receptor A (GluRA) subunit insertion into the postsynaptic density in postnatal day 7 somatosensory cortex; however, GluRA KO mice developed normal barrels. Our results clearly demonstrate a role for postsynaptic PKA signaling pathways in barrel differentiation. They also demonstrate a clear dissociation between the regulation of GluRA trafficking by PKA and its role in barrel formation. Finally, although a role for PKA downstream of cAMP cannot be ruled out, these data suggest that PKA may not be the principle downstream target because none of the mutants showed a barrelless phenotype similar to that observed in adenylate cyclase type 1 KO mice. These results give insight into activity-dependent mechanisms that regulate barrel formation.

Cortical map formation requires the accurate targeting, synaptogenesis, elaboration and refinement of thalamocortical afferents. Here we demonstrate the role of Ca2+/calmodulin–activated type-I adenylyl cyclase (AC1) in regulating the strength of thalamocortical synapses through modulation of AMPA receptor (AMPAR) trafficking using barrelless mice, a mutant without AC1 activity or cortical 'barrel' maps. Barrelless synapses are stuck in an immature state that contains few functional AMPARs that are rarely silent (NMDAR-only). Long-term potentiation (LTP) and long-term depression (LTD) at thalamocortical synapses require postsynaptic protein kinase A (PKA) activity and are difficult to induce in barrelless mice, probably due to an inability to properly regulate synaptic AMPAR trafficking. Consistent with this, both the extent of PKA phosphorylation on AMPAR subunit GluR1 and the expression of surface GluR1 are reduced in barrelless neurons. These results suggest that activity-dependent mechanisms operate through an AC1/PKA signaling pathway to target some synapses for consolidation and others for elimination during barrel map formation.

C57BL/6J (B6) and DBA/2J (D2) mice differ in maternal behavior and nest building, but previous observations on nest building appear to be contradictory. Lactating B6 females spent more time nest building than lactating D2 females [Physiol. Behav. 67 (1999) 599.]; however, pregnant D2 females have been reported to build better nests than pregnant B6 females [Physiol. Behav. 29 (1982) 153.]. To resolve this apparent discrepancy, virgin B6 and D2 females were mated, and the nest quality of nulligravid, primigravid and lactating primiparous females was compared between groups and with that of virgin females. There were no strain differences in the nest ratings of virgin or mated nulligravid females, nor did these groups differ within strains. Pregnant and lactating females of both strains built better nests than nonpregnant females. There was an increase in nest ratings in both strains on the day of parturition. The nest ratings of pregnant and lactating females were higher in B6 than D2 females. The largest strain differences were observed between pregnant B6 and D2 females. One hypothesis to account for these results is that females of these two strains differ in their levels of or sensitivity to hormones during pregnancy and parturition.