Matthew H. Kaufman

Classification of Proliferative Pulmonary Lesions of the Mouse Recommendations of the Mouse Models of Human Cancers Consortium

Rapid advances in generating new mouse genetic models for lung neoplasia provide a continuous challenge for pathologists and investigators. Frequently, phenotypes of new models either have no precedents or are arbitrarily attributed according to incongruent human and mouse classifications. Thus, comparative characterization and validation of novel models can be difficult. To address these issues, a series of discussions was initiated by a panel of human, veterinary, and experimental pathologists during the Mouse Models of Human Cancers Consortium (NIH/National Cancer Institute) workshop on mouse models of lung cancer held in Boston on June 20–22, 2001. The panel performed a comparative evaluation of 78 cases of mouse and human lung proliferative lesions, and recommended development of a new practical classification scheme that would (a) allow easier comparison between human and mouse lung neoplasms, (b) accommodate newly emerging mouse neoplasms, and (c) address the interpretation of benign and preinvasive lesions of the mouse lung. Subsequent discussions with additional experts in pulmonary pathology resulted in the current proposal of a new classification. It is anticipated that this classification, as well as the complementary digital atlas of virtual histological slides, will help investigators and pathologists in their characterization of new mouse models, as well as stimulate further research aimed at a better understanding of proliferative lesions of the lung.

EMAP and EMAGE: a framework for understanding spatially organized data.

The Edinburgh Mouse Atlas Project (EMAP) is a time-series of mouse-embryo volumetric models. The models provide a context-free spatial framework onto which structural interpretations and experimental data can be mapped. This enables collation, comparison, and query of complex spatial patterns with respect to each other and with respect to known or hypothesized structure. The atlas also includes a time-dependent anatomical ontology and mapping between the ontology and the spatial models in the form of delineated anatomical regions or tissues. The models provide a natural, graphical context for browsing and visualizing complex data.The Edinburgh Mouse Atlas Gene-Expression Database (EMAGE) is one of the first applications of the EMAP framework and provides a spatially mapped gene-expression database with associated tools for data mapping, submission, and query. In this article, we describe the underlying principles of the Atlas and the gene-expression database, and provide a practical introduction to the use of the EMAP and EMAGE tools, including use of new techniques for whole body gene-expression data capture and mapping.

An internet-accessible database of mouse developmental anatomy based on a systematic nomenclature

This paper reports an internet-accessible database of mouse developmental anatomy (DMDA) that currently holds a hierarchy of the names and synonyms of the tissues in the first 22 Theiler stages of development (E1-E13.5), together with other appropriate information. The purposes of the database are to provide, first, a nomenclature for analyzing normal and mutant mouse anatomy, and second a language for inputting, storing and querying gene-expression and other spatially organized data. DMDA currently contains some 6900 named and staged tissues (e.g. 360 and 1161 tissues in Theiler stage (TS) 14 (E9) and TS22 (E13.5) embryos). DMDA will be extended to include further lineage and other data when it becomes available. The database can be interactively accessed over the internet using either a Java or a non-Java WWW browser at http://genex.hgu.mrc.ac.uk/.

An ontology of human developmental anatomy

Human developmental anatomy has been organized as structured lists of the major constituent tissues present during each of Carnegie stages 1–20 (E1–E50, ∼8500 anatomically defined tissue items). For each of these stages, the tissues have been organized as a hierarchy in which an individual tissue is catalogued as part of a larger tissue. Such a formal representation of knowledge is known as an ontology and this anatomical ontology can be used in databases to store, organize and search for data associated with the tissues present at each developmental stage. The anatomical data for compiling these hierarchies comes from the literature, from observations on embryos in the Patten Collection (Ann Arbor, MI, USA) and from comparisons with mouse tissues at similar stages of development. The ontology is available in three versions. The first gives hierarchies of the named tissues present at each Carnegie stage (http://www.ana.ed.ac.uk/anatomy/database/humat/) and is intended to help analyse both normal and abnormal human embryos; it carries hyperlinked notes on some ambiguities in the literature that have been clarified through analysing sectioned material. The second contains many additional subsidiary tissue domains and is intended for handling tissue‐associated data (e.g. gene‐expression) in a database. This version is available at the humat site and at http://genex.hgu.mrc.ac.uk/Resources/intro.html/), and has been designed to be interoperable with the ontology for mouse developmental anatomy, also available at the genex site. The third gives the second version in GO ontology syntax (with standard IDs for each tissue) and can be downloaded from both the genex and the Open Biological Ontology sites (http://obo.sourceforge.net/)

GENETIC BACKGROUND EFFECTS ON DENTAL AND OTHER CRANIOFACIAL ABNORMALITIES IN HOMOZYGOUS SMALL EYE (PAX6SEY/PAX6SEY) MICE

Abstract Small eye (Pax6Sey) is a semi-dominant mutation affecting development of the eyes, brain and nasal structures. The mutant phenotype arises from defects within the Pax6 gene and several mutant alleles have been identified. A previous study reported that Pax6Sey/Pax6Sey homozygotes, in a random-bred stock, had a median cartilaginous rod-like structure in the nasal region and 80% had supernumerary upper incisor teeth. In this study we show that supernumerary upper incisor teeth and a previously unreported nasal capsule-derived cartilaginous ’spur’ occur in compound heterozygous Pax6Sey-Neu/Pax6Sey and homozygous Pax6Sey/Pax6Sey fetuses from several strains of mice. The frequencies of the abnormal phenotypes were not related to allele type but showed variable penetrance, which was dependent on genetic background. The median nasal cartilaginous rod-like structure was present in all homozygous small eye fetuses. The Pax6Sey/Pax6Sey homozygote may provide insight into the complex gene interactions involved in eye, nasal and craniofacial morphogenesis.

Computer-generated three-dimensional reconstructions of serially sectioned mouse embryos

We have been involved with a group of computer scientists and anatomists in the development of computer‐based methodologies that not only combine the advantages of scanning electron microscopy and conventional histology, but provide the additional dimension of tissue recognition. The latter is achieved by the appropriate labelling of tissues and structures by delineation or ‘painting’. Individually segmented anatomically defined tissues can be highlighted in a particular colour and viewed either in isolation or in combination with other appropriately labelled tissues and organs. Tissues can be shown in any orientation either as a transparent overlay on computer‐generated histological sections or as 3‐D images without the histological background. An additional feature of the system is that computer graphics technology combined with 3‐D glasses now also allows the viewer to see the object under analysis in stereo. This facility has been found to be particularly helpful in drawing attention to topological relationships that had not previously been readily noted. As the mouse is now the mammalian model of choice in many areas of developmental research, it is of critical importance that a basic level of skill is available in the research community in the interpretation of serially sectioned material, for example, for the rapidly expanding field in which gene expression studies play a significant role. It is equally important that there is an understanding of the dynamic changes that occur in relation to the differentiation of the various organ systems seen in these early stages of development. What we emphasise here is the additional information that it is possible to gain from the use of this tool which, in our view, could not readily have been gained from the analysis of scanning electron micrographs or by studying conventional serial histological sections of similar stages of mouse embryonic development. The methodology has been developed as part of a large project to prepare a database of mouse developmental anatomy covering all stages from fertilisation to birth in order to allow the accurate spatial mapping of gene expression and cell lineage data onto the digital Atlas of normal mouse development. In this paper we show how this digital anatomical Atlas also represents a valuable teaching aid and research tool in anatomy.

Influence of extracellular Ca2+ and Mg2+ ions on the second meiotic division of mouse oocytes: Relevance to obtaining haploid and diploid parthenogenetic embryos☆

Abstract The types of mouse parthenogenones obtained in a medium modified with respect to Ca2+ and/or Mg2+ ions were investigated in “spontaneously” activating eggs after culturing cumulus masses in vitro for 5 hr. The second meiotic division was affected in eggs cultured in medium lacking Ca2+ and Mg2+ or Ca2+ alone, resulting in suppression of second polar body extrusion in a high proportion of cases, giving rise to two pronuclear eggs or eggs that underwent immediate cleavage. Extrusion of the second polar body occurred normally when the cumulus mass was cultured in complete medium and, in a high proportion of eggs, when Mg2+ alone was lacking in the medium. The results are discussed with reference to the second meiotic division. The method provides an efficient way for obtaining a large number of different types of parthenogenetic embryos.

The Mouse Atlas Database: a community resource for mouse development

The Atlas is designed to provide the bioinformatics framework for community databases of mouse development. To facilitate this, we are building a graphical database that can hold 3D information (e.g. data on gene expression, cell properties, mutant phenotype, etc. from whole-mounts or sections) spatially mapped onto the digital models by using the array of voxels as ‘pigeon holes’ in the database. (Guidelines on preparing gene-expression data for entry into this, and similar, databases can be found in 8xSee all References8.) Because the digital models and anatomical vocabulary are linked, it will be possible to query the database using combinations of spatial and textual criteria. It will thus be possible to find genes with expression patterns that are (as defined by user) similar, adjacent or complementary to the expression domain of a given gene, and to display their expression patterns graphically on the digital models.We also plan to facilitate links with other databases, in particular the large amounts of textual gene-expression data in GXD, developed by our colleagues at the Jackson Laboratory. Indeed, we are collaborating with the Jackson Laboratory to create a ‘mouse gene-expression information resource’ that will provide easy and transparent access to both the Mouse Atlas Database and the GXD 9xA database for mouse development. Ringwald, M. et al. Science. 1994; 265: 2033–2034Crossref | PubMedSee all References9. The facility to visualize and combine experimental data with information from this resource will, we hope, provide a powerful analytical tool for gene-function studies.

Hip disarticulation: the evolution of a surgical technique

Introduced in the 18th century, hip disarticulation was considered to be one of the most radical operations performed for trauma or disease of the lower limb. The high morbidity and mortality associated with it ensured that it was a rarely performed procedure. It is fortunate that it remains extremely uncommon to the present day. Since the first successful hip disarticulation was described, a number of important advances have occurred. General medical care has improved dramatically and the development of anaesthesia, analgesics, antibiotics and blood transfusions has resulted in greatly decreased morbidity associated with this dramatic operation. This review on the history of hip disarticulation outlines the surgical evolution of the operation, the indications for its use and the techniques used. It draws on the early experiences and preferred techniques of the surgeons of the 19th century, with some discussion on the methods employed to reduce intraoperative haemorrhage. Further development of techniques in the 20th century is also described together with discussion on the evolution of hindquarter amputation.

John Bell (1763–1820), the ‘father’ of surgical anatomy

John was one of four very talented sons of the Reverend William Bell. Two qualified as advocates and both became professors. John and his younger brother Charles (later Sir Charles) entered medicine. John qualified with the Edinburgh MD degree in 1779, then obtained the FRCS Edin diploma in 1786. As a student, initially he studied anatomy under Professor Alexander Monro secundus, and it was soon evident to him that his teacher did not have any first-hand knowledge of the problems encountered by surgeons. He then decided to teach anatomy, while practising as a surgeon, and was among the first to emphasize the relevance of anatomy to surgical practice. During this period he lectured and wrote on anatomy and surgical anatomy. After 1800 he, like many of his surgical colleagues, was excluded from the Edinburgh Royal Infirmary as a consequence of the activities of Professor James Gregory, one of the most influential of the managers of that institution. When he stopped lecturing, he continued practising as a surgeon and wrote several influential textbooks but he never forgave Gregory for exclusion from the Infirmary. He was soon recognized as one of the foremost surgeons in Scotland. He spent the last few years of his life on the Continent attending to the surgical needs of the numerous expatriate Britons who lived there.