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Developmental Imaging Workshop
A complete account of the Workshop held on September 18 and 19 1997, including the Agenda, Abstracts, Speaker List, and links to Project Web Pages. The title of each talk is linked to its abstract; the speaker name is linked to their address.
- Session I
- Embryological Collections
- Chair: Elaine Young, Comparative Medicine Branch, National Center for Research Resources, NIH
- The Human Developmental Anatomy Center; History
and Current Initiatives
- Adrianne Noe, Director, National
Museum of Health and Medicine, Armed Forces Institute of Pathology
- The Patten Embryology Research Collection
- Alphonse R. Burdi, Director, University
of Michigan Medical School
- Collecting Human Embryos and Fetuses: Thirty-five
Years of Experience
- Alan G. Fantel, Department of Pediatrics,
University of Washington
- Embryo Sections on CD-ROM for Studies of Human
- Raymond F. Gasser, Director, Computer
Imaging Lab, Department of Cell Biology and Anatomy, Louisiana State University Medical Center
- Heart Imaging in Human Embryos
- Kent L. Thornburg and Jeffrey Pentecost, Congenital Heart Research Center, Oregon Health Sciences University
- Session II
- Resources on the Web
- Chair: Louise Ramm, Deputy Director, National Center for Research Resources, NIH
- Imaging and Distribution of Embryo Images and Models.
- Elizabeth C. Lockett, Imaging Specialist, Human Developmental Anatomy Center, National Museum of Health and Medicine, AFIP
- Magnetic Resonance Imaging and Volume Rendering for Three-Dimensional Analysis of Embryos.
- Bradley R. Smith, Center for InVivo
Microscopy, Duke University
- Gene Expression Information Resource for Mouse
Development: Concept, Current Status and Future Goals.
- Martin Ringwald,, Gene Expression Information Resource Project, The Jackson Laboratory
- Session III
- Computers and Imaging in Embryology Teaching and Training
- Chair: Robert S. Ledley, Medical Computing and Biophysics Division, Georgetown University Medical Center
- Multimedia Anatomy Tutorial: Animating Developmental Concepts in Three Dimensions
- Carmen L. Arbona, MouseWorks, The Visible Embryo, UC San Francisco
- Basic Embryology Review Program, An Effort in Collaborative Development.
- Albert O. Shar, Executive Director, Computing and Educational Technology, Basic Embryology Review Program, University of PA School of Medicine
- The Muritech Internet Atlas of Mouse Embryology.
- B.S. Williams, MuriTech, Inc
- Embryo Images: Normal and Abnormal Mammalian
- Tim Poe, University of North Carolina, Chapel Hill
- Computerized 3-D Visualization of Embryonic
- David Damassa, Envision Development
Corporation and Tufts University Schools of Medicine, Dental Medicine and Veterinary Medicine
- Moving to a Digital Library for Medical Research and Education
- Brian Athey, University of Michigan Medical School
- Computer Applications for Fetal Imaging: Ultrasound
Education and Training
- Wesley Lee, Fetal Imaging Resources, Division of Fetal Imaging,
William Beaumont Hospital
- The Visible Human Project: A Public Resource for Anatomical Imaging
- Michael J. Ackerman, Assistant Director
for High Performance Computing and Communications, National Library of
- Session IV
- Imaging in Embryology Research
- Chair: Sally A. Moody, Programs in Neuroscience and in Genetics, George Washington University Medical Center
- Development and Application of a 3-Dimensional
Dynamic Image Analysis System
- David Soll, Department of Biological
Sciences, University of Iowa
- Using microMR Imaging in Developmental Biology
- Fish, Frogs, Mice, & Monkeys
- Russell E. Jacobs, Biological Imaging
Center, Caltech www.gg.caltech.edu/~rjacobs/rjacobs.html
- Analysis and Manipulation of Mouse Embryonic Brain and Heart Development with High Frequency Ultrasound Imaging
- Daniel H. Turnbull, Skirball Institute
of Biomolecular Medicine, New York University Medical Center
- Imaging Techniques For Studying The Embryology Of Epididymal-Testicular Descent
- Dale S. Huff, Director, Developmental-Perinatal Pathology, The University Of Pittsburgh And Magee-Womans Hospital
- Fast Volume Visualization with T-Vox.
- Michele Ursino & Gregory L. Merril, HT Medical
- Fitting 3D Imaging Data Using Orthogonal Distance Regression
- Janet Rogers, Mathematical and Computational Sciences Division, National Institute of Standards and Technology
- Session V
- Imaging in Diagnosis and Treatment
- Chair: Felix de la Cruz, Chief, Mental Retardation & Developmental Disabilities Branch, NICHD, NIH
- 3-Dimensional Ultrasound Imaging of the Fetus
- Dolores Pretorius, UCSD 3D Ultrasound Imaging Group, University of California, San Diego
- The Impact of Fetal Echocardiography on Early Intervention of Congenital Heart Disease
- Ernerio T. Alboliras, Director, Non-Invasive Imaging and Fetal Cardiology, Rush Children's Heart Center
- Ultrafast MRI in the Evaluation of the Abnormal Fetus During the Second and Third Trimesters
- Anne M. Hubbard, The Department of
Radiology and the Center for Fetal Diagnosis and Treatment, The Children's
Hospital of Philadelphia
- The Current Status and Future Potential of Fetal
Intervention - Image is Everything
- Alan W. Flake, Director, Children's
Institute of Surgical Science, Childrens Hospital of Philadelphia
- Quantitative Assessment of Mouse Fetal Cardiac
Anatomy by Magnetic Resonance Imaging
- Harvey Hensley, Susan Schachtner,
Anne Hubbard, John Haselgrove & Scott Baldwin, Childrens Hospital of Philadelphia
- Power Doppler in the Assessment of Normal and
Abnormal Fetal Vascularity
- Beverly G. Coleman, Director of Ultrasound Imaging, University of Pennsylvania Medical Center
- Session VI
- Funding Opportunities
- Chair: A. Tyl Hewitt, Chief, Developmental Biology Genetics & Teratology Branch, NICHD, NIH
- Towards an Information Infrastructure for Healthcare:
Funding Opportunities Through The Advanced Technology Program
- Bettijoyce Lide, Technology Administration, National Institute of Standards and Technology
- NSF support for research and infrastructure in
- Christopher Platt, Division of Integrative
Biology & Neuroscience, National Science Foundation
- Support Mechanisms for Technology Development at
- Abraham Levy, Biomedical Technology
Branch, National Center for Research Resources, NIH
- Funding Mechanisms and Opportunities at the NICHD
- Steven Klein, Program Official, Developmental Biology, Genetics & Teratology Branch, NICHD, NIH
THE HUMAN DEVELOPMENTAL ANATOMY CENTER,
NATIONAL MUSEUM OF HEALTH AND MEDICINE, ARMED FORCES INSTITUTE OF PATHOLOGY:
HISTORY AND CURRENT INITIATIVES
Adrianne Noe, Director, National Museum of Health and
Medicine, Armed Forces Institute of Pathology
This presentation will introduce the origins, present work, and future
plans of the Human Developmental Anatomy Center of the National Museum
of Health and Medicine, Armed Forces Institute of Pathology. Within the
context of an overview of nineteenth and early twentieth century developmental
anatomy, the Carnegie Human Embryology Collection's history will be presented
and its role in advancing knowledge in the field will be offered. With
that collection as its core, the Human Developmental Anatomy Center has
amassed a number of other significant collections; they will be identified
Several types of work are on-going in the Center. They fall into several
categories: research projects, image distribution and modeling projects,
publication projects, conservation and collections management projects,
and exhibitions. Examples of each will be described. Future plans for the
Center as a national research resource and as a component of the National
Museum of Health and Medicine will be discussed, as will its role in the
National Health Exhibitions Consortium. Finally, procedures for gaining
access to the collections by qualified scholars will be addressed and explained.
THE PATTEN EMBRYOLOGY RESEARCH COLLECTION
Alphonse R. Burdi, Curator, Patten Embryological Collection,
The University of Michigan Medical School
Historical Perspectives. The Patten Embryology Research Collection
was established at Michigan in the early 1900s due to the need for accurate
descriptions of human embryos at critical developmental stages. While the
Carnegie Collection featured a world-renown collection of human embryos
at their very youngest stages, it seemed both desirable and strategic for
Michigan's collection to focus on the later stages of embryonic, second
trimester, and early third trimester human specimens. The University of
Michigan Collection is thought to be largest collection of human embryos
and fetuses found within the United States today, and is a national resource
available to investigators throughout the world.
New Goals and Foci. Since 1972, strategic planning involving
past, present, and potential users of the Michigan Embryology Collection
pointed toward the essentiality of much-needed medical or teratologic flavor
for the Collection whereby newly acquired human embryos and fetuses would
be documented with medical and familial histories. Since that time, the
acquisition of new specimens (approximately 150-200 per year) has been
ongoing due largely to cooperative enterprise between the Department of
Anatomy & Cell Biology and obstetricians, pediatric dysmorphologists,
and pathologists in the University of Michigan Hospitals. This consortium
is known as the University of Michigan Teratology Unit. In addition, our
Teratology Unit regularly takes first call on receipt of the specimens
from throughout Michigan, conducts the necropsies, and provides reports
to the referring physicians. Specimens are subsequently received by the
Patten Embryology Collection and accounted for as required by anatomical
A Shared Resource. Every effort is made to share the collection
specimens and derived information with responsible investigators from within
and outside the university. A computerized data base catalog has
been designed for the easy retrieval of such information dealing with specimen
histories (always handled confidentially) that include vital statistics
of each specimen, and maternal and familial histories.
A specimen dossier (coded for confidentiality purposes) is then maintained
for each of the specimens collected since 1972 and made available to investigators
who wish to assess normal and abnormal human morphogenesis using dependent
variables that go beyond such traditionally-used measures as crown-rump
and crown-heel lengths. Thus, users of the Michigan Collection from throughout
the world are able to study prenatal morphogenesis along population lines
as are carried out in animal teratologic studies and clinical studies of
human birth defects. Investigators contribute to the dossiers with data
from their specific studies so that new information might be shared with
other users of the same specimens. Specimens and facilities of the Patten
Embryology Collection continue to be available to visiting scientists with
formalized research protocols.
The currently available human embryos and fetuses, especially the 3500
plus documented specimens collected since 1972 are chiefly second and third
trimester aborti. This group is a part of the 1,750 specimens that are
currently available as serially-sectioned specimens. While the Patten Embryology
Collection continues with its longstanding focus on human morphogenesis,
an adjunct collection of serially-sectioned animal (e.g., chick, rats,
mice) embryos and fetuses is also available for comparative studies. Every
effort is made to accommodate visiting investigators. Located in the Department
of Anatomy & Cell Biology, space and equipment are available for the
study of specimens within the research facility.
Researchers are welcomed to work in the Patten Embryology Collection
by appointment and are invited to submit to the Collection's director a
request to work with the collection. The information should include a description
of the specimens needed in terms of age or size, population characteristics,
type of sectioning, space and equipment needed, and approximate duration
of the proposed visit. Submission of the protocol is requested early enough
for purposes of scheduling and advising the prospective investigator on
the availability of desired materials.
COLLECTING HUMAN EMBRYOS AND FETUSES:
THIRTY-FIVE YEARS OF EXPERIENCE
Alan G. Fantel, Department of Pediatrics, University
The Central Laboratory for Human Embryology has collected, studied and
analyzed human conceptal tissue for nearly 35 years. During that time,
changes in laws, practice, funding and medical technology have significantly
affected the condition, types and stages of embryonic and fetal tissues
available for research. We will discuss these changing relationships, detailing
tissue availability today and present information on obtaining material
for biomedical research, including imaging. During the 1960s, most tissue
collected by the laboratory was delivered by spontaneous abortion. Despite
this designation, the percentage that was actually induced could not be
determined. While these specimens enabled studies of abortus morphology
and cytogenetics, they were generally too autolyzed for imaging, biochemical
or molecular studies. Tissue available for research was largely derived
from hysterotomy and hysterectomy and to a lesser extent, from surgical
intervention in ectopic pregnancy. Hysterotomy specimens tended to date
from mid second through third trimesters and preservation was generally
poor. They were often nonviable in utero for days or were exposed to KCl
prior to delivery, inducing rapid and severe autolysis. Specimens derived
from hysterectomy tended to be in excellent condition but generally dated
from relatively late gestation. Ectopic specimens served as a primary source
of embryos but massive bleeding and tubal rupture commonly limited successful
retrieval. These rare specimens remain an important source of intact, early
In the 1970s Washington enacted therapeutic abortion on demand. Most
terminations were performed by dilatation and manual curettage and it became
possible to obtain increasing amounts of well preserved tissue. Embryos
tended to be relatively intact and most organs and tissues could be collected.
Increasing use of vacuum extraction in the late 1970s made tissue retrieval
challenging, since specimens tended to be severely fragmented by exposure
to pressure gradients and passage through fine cannulas, long runs of tubing
and collection in gauze bags. Most of these specimens date from late first
and early second trimesters with increasing availability of late second
and third trimester fetuses. In the late 1980s and early 90s, they were
often pretreated with KCl, rendering them useless for detailed study.
Today, the Central Laboratory for Human Embryology supplies university
and institute-based investigators nationwide with embryonic tissues processed
according to the requirements of individual studies. Technicians collect
at clinic sites where specimens are obtained within minutes of passage,
rapidly assessed and staged. Individual tissues are then identified, separated,
processed and delivered to the laboratory from which they are shipped by
overnight air express. Information on obtaining embryonic or fetal tissue
can be obtained at 800-583-0668.
EMBRYO SECTIONS ON CD-ROM FOR STUDIES
OF HUMAN DEVELOPMENT
Raymond F. Gasser, Director, Computer Imaging Lab, Department
of Cell Biology and Anatomy, Louisiana State University Medical Center,
New Orleans, Louisiana.
The serial sections of human embryos were captured digitally and stored
on CD-ROM, making them available to investigators and instructors at minimal
expense. All of the sections of three human embryos from the Carnegie Collection
were captured at 1024 X 768 pixels (16 or 32 bits/pixel) in targa format.
Image processing was used to delete debris, repair tears and folds, color
enhance faded stains and sharpen contrast. Each section was placed in alignment,
given a scale bar, section number and slide location number, then stored
on CD-ROM in TIFF format with LZW compression for distribution. The enhanced
sections can be viewed in sequence with most WWW browsers (e.g., Netscape)
or any image viewer (e.g., Photoshop) on an inexpensive PC 486 computer.
Besides preservation and distribution of valuable reference material, examples
will be presented on how the data can be utilized by investigators (determination
of 3D growth movements from reconstructions) and instructors (construction
of interactive atlases of sectional morphology).
HEART IMAGING IN HUMAN EMBRYOS
Kent L. Thornburg and Jeffrey Pentecost, Congenital
Heart Research Center, Oregon Health Sciences University
The Congenital Heart Research Center (CHRC) at Oregon Health Sciences University
has directed construction of 3D computer models of embryonic human hearts
with the intention of 1) devising a mechanism for researchers to store,
retrieve, and visualize physiologic, molecular, and genetic data pertinent
to cardiogenesis, and 2) improving methods for teaching normal/abnormal
cardiac embryology. Using serial sections of human embryos from the
Carnegie Collection at the Armed Forces Institute of Pathology, contours
are manually traced, then re-stacked into three-dimensional, wire frame
models. A surface connecting the layers provides the appearance of a solid
Because of its versatility and ease of manipulation, the resultant structure
is an ideal tool for visualizing structural and experimental data. For
example, 3D simulations of embryologic hemo-dynamics and internal/external
heart development based on real data provide a new means of analyzing influences
of mechanical forces on cardiogenesis. Consequences of genetic expression
affecting heart formation can be mapped in these models, showing exactly
which tissues are involved at specific stages of development. As an educational
tool, this system of viewing the embryonic heart in all of its developmental
stages surpasses any currently used method. The user can view the developing
heart in cross-section from any angle, observe 'morphing' from stage to
stage, and 'fly' through the computerized model.
Human model construction: The CHRC is currently collecting more
data from the Carnegie Collection of Embryos; by the end of the summer
of 1997, the CHRC plans to have data for six additional embryos of different
Mouse model construction: An image database is being developed
for similar reconstruction of the embryonic mouse heart. The process of
specimen preparation, capturing digital photomicrographs, transferring
images to the computer, and tissue segmentation for reconstruction has
been established at CHRC. Modeling of congenitally malformed mouse hearts
is one of our next steps. An examination of the influences of hemodynamic
forces and blood flow patterns on cardiogenesis is being planned. This
project addresses one of the most exciting new theories of heart development,
and will depend on the physical heart models created
by the CHRC.
Stereolithography: CHRC computerized heart models are being converted
to physical models using a process by which computer data directs the production
of physical models using laser beams and resin-based materials. The accuracy
and precision of such a process is exceptional. This technology has not
been applied previously to anatomical modeling at this level. The National
Museum of Health and Medicine in Washington, DC, has requested our first
model for permanent display in their collection. These physical models
will be used by CHRC scientists for analysis of embryonic hemodynamics.
They will also serve as an invaluable teaching tool for medical and scientific
IMAGING AND DISTRIBUTION OF EMBRYO
MODELS FROM THE HUMAN DEVELOPMENTAL ANATOMY CENTER, NATIONAL MUSEUM OF
HEALTH AND MEDICINE, ARMED FORCES INSTITUTE OF PATHOLOGY
E. C. Lockett, Human Developmental Anatomy Center, National
Museum of Health and Medicine, Armed Forces Institute of Pathology
This presentation will discuss current strategies for imaging histologic
information from the Carnegie Collection, modeling techniques, and distribution
mechanisms for both models and histologic information. A re-evaluation
of the target audience for models and images prompted by recent challenges
to distribution methods has required changes in storage and distribution
methods. Long term logistical goals for the distribution of information
from the Center will be discussed, as well as steps taken toward achieving
MAGNETIC RESONANCE IMAGING AND VOLUME
RENDERING FOR THREE-DIMENSIONAL ANALYSIS OF EMBRYOS
Bradley R. Smith, Department of Radiology, Duke University,
The difficulty in obtaining well-documented and well-preserved human embryo
specimens presents an important challenge to understanding normal and abnormal
development. There is a need to minimize the number of embryos of all species
used during research and to maximize the distribution of information obtained
from the embryos that are used. A complete source of distributable, three
dimensional image data representing the human embryological time period
is not yet available. The Multidimensional Human Embryo project, will generate
three-dimensional image data sets representing most of the human embryonic
time period, and will make these data easily accessible. The data will
be generated by magnetic resonance imaging with specimens from the Carnegie
Collection of Human Embryos. Embryos from stage 12 through stage 23 will
be scanned three times each to produce T1, T2, and Diffusion weighted data
sets. Each data set will be isotropic with 256 x 256 x 256 voxels. The
image data will be made available at the conclusion of the project by CD-ROM
and via a Web site. Sample images will also be available via the web site
throughout the project to document progress of the work.
Magnetic resonance imaging is also being used to characterize the three
dimensional structure of normal and abnormal animal embryonic hearts. The
vasculature is represented as three-dimensional digital models that can
be measured, rotated to any orientation, and digitally sectioned to permit
rapid comparison of normal and abnormal hearts. Genetically manipulated
mouse embryos (gap junction gene Cx43 knockouts and CMV43 overexpression)
and surgically altered chick embryos were investigated by MR microscopy
after vascular infusion with the MR contrast agent Gd-DTPA-BSA. Blood flow
was altered in chick embryos by partial left atrial ligation with nylon
suture. MR imaging of the mouse and chick embryos was performed at 9.4
T to produce 128 image slices each with 2562 pixels at 54.7µm resolution.
Three-dimensional spin warp encoding produced T1-weighted datasets in 3.5
hours per embryo. MR imaging demonstrated the morphological changes in
the right ventricle, conotruncus, and ductus arteriosus associated with
altered expression of the Cx43 gap junction gene in mouse embryos. It also
demonstrated the altered aortic arch morphogenesis due to the changing
blood flow pattern in the left atrial ligated chick.
GENE EXPRESSION INFORMATION RESOURCE
FOR MOUSE DEVELOPMENT: CONCEPT, CURRENT STATUS AND FUTURE GOALS
M. Ringwald, R. Baldock*, J. Bard#, D. Begley, G. Davis,
D. Davidson*, C. Dubreuil*, J.T. Eppig, K. Frazer, P. Johnson, M. Kaufman#,
M. Mangan, J. Richardson, L. Trepanier. The Jackson Laboratory, Bar Harbor;
*MRC Human Genetics Unit, Edinburgh; #Edinburgh University, Edinburgh.
The process of differential gene expression generates extraordinarily complex
spatio-temporal networks of gene and protein interactions. A major thrust
of current biomedical research is elucidating these networks to understand
the molecular basis of human development, health, and disease. The laboratory
mouse serves as a pivotal animal model in these studies. To cope with the
shear volume and complexity of gene expression data, we, the Gene Expression
Database (GXD) group at The Jackson Laboratory and our collaborators at
the MRC Human Genetics Unit and the University in Edinburgh, Scotland,
are developing a comprehensive Gene Expression Information Resource for
Mouse Development. The resource will link the following components:
(1) GXD, which stores and integrates many types of expression data and
provides comprehensive links to the Mouse Genome Database (MGD) and to
other databases containing DNA and protein sequence information, genetic
and physical mapping data, and descriptions of disease states and mutant
mice to place the gene expression data into the larger biological and analytical
context. GXD describes expression patterns by a controlled anatomical dictionary
that is part of the Anatomy Database and includes 2D images of original
in situ data that are indexed via terms from the dictionary.
(2) The Anatomy Database, which provides the standard nomenclature for
textual queries relating gene expression to developmental anatomy.
(3) the 3D Atlas of Mouse Development, high resolution digital 3D models
of mouse embryos at representative developmental stages reconstructed from
serial sections, which enable 3D graphical storage, display and analysis
of expression patterns. The major anatomical structures in the 3D atlas
are labeled using the anatomy nomenclature. This assignment provides an
important link between the graphical and the text based query systems.
The Gene Expression Information Resource will provide the research community
with a tool to store and analyze gene expression data in the appropriate
context using the full power of combined text and image-based methods.
The current status of the project will be presented and future applications
of the resource for biomedical research will be discussed.
The GXD Project is supported by NIH grant HD33745. Work at Edinburgh
is supported by the MRC, the BBSRC, and by the European Science Foundation.
MULTIMEDIA ANATOMY TUTORIAL: ANIMATING
DEVELOPMENTAL CONCEPTS IN THREE DIMENSIONS
Carmen Arbona, MouseWorks,
San Francisco, CA
The Visible Embryo (http://visembryo.ucsf.edu)
is an interactive early anatomy program for medical student training delivered
via the internet as a project of the Multimedia Anatomy Tutorial (MAT).
The Visible Embryo illustrates the first four weeks of in-utero development
and is being expanded to illustrate organ development in 3D specifically
1) the processes of gastrulation and neurulation, 2) development of the
heart tube illustrating congenital heart defects, and 3) the formation
of organ systems. The Visible Embryo program is based on evidence that
visualization in 3D assists in the understanding of difficult concepts.
A correct understanding of the early embryonic concepts is essential to
medical education and practice and useful to a lay audience in understanding
infertility and birth defects. MAT is an outcome-based teaching curriculum
developing delivery of medical education on-line.
BASIC EMBRYOLOGY REVIEW PROGRAM (BERP),
AN EFFORT IN COLLABORATIVE DEVELOPMENT
Albert O. Shar, Computing and Educational Technology,
University of Pennsylvania School of Medicine
In 1990, the University of Pennsylvania School of Medicine had a well developed
program of medical software development funded by a contribution of hardware
from Apple Computer and for programming from the Pew Charitable Trust.
The program was based upon the use of technical staff for the development
of core software (programs, templates, training, special purpose equipment,
standards, etc.), medical students to provide the actual combination of
text and images and limited programming as needed and faculty as the content
experts. One of the most successful programs developed under this effort
was BERP(c), the Basic Embryology Review Program. This Macintosh-only program
has been extensively used at the U of P and other locations.
Shortly after this program was developed, funding for education software
development became essentially unavailable. By 1995, the power of the World
Wide Web as a method for delivering, platform independent multimedia was
becoming clear and, as a proof of concept, an attempt at moving BERP to
the web was started. This still unfinished and relatively naive program
was largely ignored for two years, with only occasional attempts to refine
the product. Even with this minimal attention, this application is consistently
among the most popular areas visited on the entire UPHS web.
In May of 1997, in part because of the funding for a new curriculum,
funds were made available to refine and complete the web version of BERP(c).
This effort is scheduled for completion by the end of September 1997.
THE MURITECH INTERNET ATLAS OF MOUSE
B.S. Williams*, M.J. Pescitelli,* and M.D.
Doyle*# MuriTech Inc., Cambridge, MA* and Eolas Technologies
Inc., Chicago, IL#
The Muritech Internet Atlas of Mouse Embryology allows visualization of
the anatomy of the mouse embryo with linkage to information about the developing
structures. The system uses the resources of the World Wide Web. It provides
educators, students and researchers with an easy-to-access interface to
an interactive online reference system that correlates textual information
with 2-dimensional and 3-dimensional microscopic images of mouse embryos
at various stages. These images were obtained by digitizing paraffin serial
sections of mouse embryos. The high-resolution multidimensional image data
were precisely mapped using the patented MetaMAP(R) Web imagemap system,
allowing standard Web browsers to be used to view the images and interactively
query the knowledge base. By clicking on any part of the mapped image datasets,
relevant information can be retrieved and viewed in an adjacent frame of
the Web browser. An applet-based 3-D imagemap browser is also demonstrated
that allows the user to rotate and slice through an embryo image dataset,
and query the knowledge base by clicking directly on voxels in the 3-D
dataset from within the Web browser page.
EMBRYO IMAGES: NORMAL AND ABNORMAL MAMMALIAN
Kathleen K. Sulik, Peter Bream, and Tim Poe, The University
of North Carolina, Chapel Hill, North Carolina 27599-7090
Embryo Images: Normal and Abnormal Development is an interactive
tutorial based on scanning electron micrographs (SEMs) of mammalian embryos
(mouse and human). The original CD-ROM has been available since 1994 and
is currently in use in the majority of the medical schools in this country.
The program has enjoyed popularity, in part, because the SEMs provide a
three dimensional-like image of actual embryos. Embryo Images was created
using Macromedia's Director. Director is the industry standard for multimedia
authoring, allowing products to be ported to multiple platforms and the
Internet. Text and graphics have been carefully combined in a manner that
is both interactive and easy to use. Digitized movies, animations, and
morphs (in this case, movies simulating embryo growth) have been added
to illustrate key concepts. Removable semi-transparent color overlays are
often included to identify embryo anatomy and a "Help" section is available
to introduce users to the features of Embryo Images. We are completing
revisions and additions to this program, with major emphasis being placed
on inclusion of concepts and illustrations related to abnormal development.
The student has the option of looping out at indicated points from study
of the sequence of normal embryonic development to view abnormal sequences
and consequences. Abnormal sequences of development are typically illustrated
in scanning electron micrographs and consequences are typically color patient
photographs. Music has been added as a user option for the more narrative
components of Embryo Images. The program can be used as an independent
resource or as a complement to embryology textbooks. Although the target
audience is largely medical students, it is also a valuable resource for
developmental biologists and toxicologists, biology students and clinicians.
The CD-ROM will run on both Windows '95 and the Mac OS.
COMPUTERIZED 3-D VISUALIZATION OF
R.L.Simon, D.A. Damassa, R.F. Willson, A.W. Gustafson,
and E.W. Overstrom. Envision Development Corporation, Marlboro, MA and
Tufts University Schools of Medicine, Dental Medicine and Veterinary Medicine,
The overall goal of this project is to generate a database of 3-D digital
embryonic images of pig development and, using this database, create low-cost
software products for the study of mammalian embryology. Applications are
being tailored for medical, dental and veterinary curricula. Reconstructed
3-D datasets of pig embryos are generated from serial digital images obtained
by confocal and conventional microscopy. From these datasets, both three-dimensional
and slice views of the embryo are produced. A Silicon Graphics Indy workstation
running InterVision's 3-D software is used to generate specific views and
also produce video clips of rotations of the 3-D images. The ultimate design
of these software products will allow users to visualize 3-D images of
embryos, view the formation of specific organs and organ systems, and access
related hyper-media, including text, histological sections and clinical
cases. Key features in product design include direct access to the various
databases for customization of program content and network/web-based implementation.
MOVING TO A DIGITAL LIBRARY FOR MEDICAL
RESEARCH AND EDUCATION
Brian Athey, University of Michigan Medical School
COMPUTER APPLICATIONS FOR FETAL ULTRASOUND
Wesley Lee, Fetal Imaging Resources, Inc
Birth defects are a leading cause for infant mortality in the United States.
Prenatal detection can improve outcome in selected cases but, some studies
suggest that improved diagnostic training is necessary to improve the detection
rate of fetal anomalies. Fetal Imaging Resources, Inc. is collaborating
with the American College of Obstetricians and Gynecology and the Acuson
Corporation for developing a CD-ROM product that addresses this need.
The multimedia-based software prototype will allow the user to learn
about fetal ultrasound anomalies in a Research Library. Diagnostic skills
can then be tested through an interactive learning environment called the
Examination Room. Advanced users may take the Ultrasound Challenge where
a variety of problem-oriented scenarios are presented. User responses will
be tracked by time and accuracy.
The presentation will include a demonstration of this prototype product
and discussion about how interactive multimedia can offer advantages for
prenatal ultrasound training. Possible multimedia delivery scenarios across
the Internet will also be examined.
Another project involves simulation of embryonic heart development by
three-dimensional animation. Developmental sequences were created with
the assistance of Dr. Keith Moore, Professor Emeritus from the University
of Toronto. Examples of conotruncal abnormalities (transposition of the
great arteries, double outlet right ventricle, and tetralogy of Fallot)
will be demonstrated with Quicktime VR technology. This technique allows
the user to completely rotate a virtual fetal heart model for close inspection
and comparison with digital ultrasound video examples.
Finally, the potential role of three-dimensional fetal ultrasound for
medical education will be discussed. Examples of fetal volume reconstructions
will be presented to illustrate the application of this technology for
prenatal ultrasound training.
THE VISIBLE HUMAN PROJECTTM:
A PUBLIC RESOURCE FOR ANATOMICAL IMAGING
Michael J. Ackerman, National Library of Medicine, Office
of High Performance Computing and Communications
The National Library of Medicine (NLM) has long been a world leader in
the archiving and distribution of the print-based images of biology and
medicine. NLM has also been a pioneer in the use of computer systems to
encode and distribute textual knowledge of the life sciences. NLM's Long
Range Planning effort of 1985-86 foresaw a coming era where NLM's Bibliographic
and factual database services would be complemented by libraries of digital
images, distributed over high speed computer networks and by high capacity
physical media. The NLM Planning Panel on Electronic Imaging recommended
that NLM should undertake the building of a digital image library consisting
of computer assisted tomography (CAT), magnetic resonance imaging (MRI),
and cryosection images of a representative, carefully selected and prepared
male and female cadaver -- the "Visible Human ProjectTM."
The male Visible Human data set became available on November 28, 1994.
The Female Visible Human data set became available one year later. The
Visible Human data sets are being made available through a license agreement
with the NLM.
The Visible Human Project data sets are designed to serve as a common
reference point for the study of human anatomy, as a set of common public
domain data for testing medical imaging algorithms, and as a test bed and
model for the construction of image libraries that can be accessed through
networks. The data sets are being applied to a wide range of educational,
diagnostic, treatment planning, virtual reality, artistic, mathematical
and industrial uses by over 800 licensees in 26 countries.
The data sets are having their greatest effect on health care and health
education. They are used as a normal reference and as an aid in the diagnostic
process. Programs under development will be used to educate patients about
the need for and purpose of surgery and other medical procedures as well
as to permit physicians to plan surgery and radiation therapy. The images
from the Visible Human data sets are used in several prototype virtual
reality surgical simulators. Educational materials that make use of the
Visible Human data sets are beginning to be used by students from kindergarten
to practicing health care professionals.
But key issues remain in the development of methods to link such image
data to symbolic text-based data comprised of names, hierarchies, principles
and theories. Standards do not currently exist for such linkages. Generalizable
methods like the use of hypermedia where words can be used to find pictures
and pictures can be used as an index into relevant text are being experimented
with. Basic research is needed in the description and representation of
structures, and the connection of structural-anatomical to functional-physiological
knowledge. This is the larger, long-term goal of the Visible Human Project:
to transparently link the print library of functional-physiological knowledge
with the image library of structural-anatomical knowledge into one unified
resource of health information.
DEVELOPMENT AND APPLICATION OF A 3-DIMENSIONAL
DYNAMIC IMAGE ANALYSIS SYSTEM (3D-DIAS)
David R. Soll, Department of Biological Sciences, University
Because we traditionally view living cells through microscopes in 2 dimensions
as they move along a flat substratum, we tend to conceptualize both their
behavior and organization in 2 dimensions. In reality, however, both a
cell's behavior in vivo and in vitro, and a cell's organization is 3-dimensional.
We have, therefore, developed the 3- dimensional Dynamic Image Analysis
System (3D-DIAS) to study the behavior of a cell in 3 dimensions. In this
system, a migrating cell is optically sectioned through differential interference
contrast optics during a period short enough so that cell movement does
not cause a reconstruction artifact between the first and last section.
Optical sectioning of the entire cell is repeated every second. The optical
sections at each time point are then digitized into the 3D-DIAS database,
image processed, and the edges of the cell image detected by an invention
referred to as the "pixel complexity measurement". Each continuous edge
is then converted into a beta-spline model, and filled with the in-focus
portion of the original image. This results in the subtraction of all out
of focus and extracellular information in the original optical section.
The optical sections at each time point are stacked and pixel intensity
averaged between optical sections in the Z-axis. This results in the genesis
of a complete 3D digitized image every second. 3D-DIAS software then allows
computer-generated movies to be produced in which a crawling cell can be
viewed by means of a 3D workstation at any angle. Because the 3D-surface
of the cell is converted to a beta-spline model, 140 parameters of motility,
based on the 3D path of the cell centroid, and of dynamic cell morphology,
based on the 3D encapsulating surface, can be computed at one-second intervals.
The cell can also be peeled or gouged at any angle to any depth, and the
dynamics of the nucleus and intracellular organelles viewed and quantitated.
The system also color codes the particulate and nonparticulate cytoplasm
of a crawling cell, which is useful in monitoring the 3D dynamics of F-actin
filled pseudopods. 3D-DIAS has been applied to a number of developmentally
relevant systems, most notably the chemotaxis and aggregation processes
in the cellular slime mold Dictyostelium discoideum and mitosis in fibroblast
cell lines. In both cases, the power of the system has been in describing
aberrant behavioral phenotypes of specific cytoskeletal mutants. 3D-DIAS
has been underutilized primarily because it has been continuously under
development at Iowa during the last six years and no version has been commercialized.
Its potential application to embryogenesis and many other aspects of cell
motility are self-evident. A second-generation 3D-DIAS system is now under
development that will include near-real time reconstruction speeds, high-speed
(250 frame per second) analysis of intracellular vesicles, a confocal front
end and virtual reality software. Through funds from the W.M Keck Foundation,
visitors can now access 3D-DIAS.
Soll, D.R. 1995. The use of computers in understanding
how cells crawl. Int. Rev. of Cytology, 163, 43-104.
Shutt, D., Wessels, D., Chandrasekhar, A., Luna, B., Hitt,
A. and Soll, D.R. 1995. Ponticulin plays a role in the spatial stabilization
of pseudopods. J. Cell Biol., 131, 1495-1506.
Wessels, D., Titus, M., and Soll, D.R. 1996. A Dictyostelium
myosin I plays a crucial role in regulating the requency of pseudopods
formed on the substratum. Cell Motil. Cytoskel., 33, 64-79.
Soll, D.R. and Voss, E. 1997. Two and three dimensional
computer systems for analyzing how cells crawl. In "Motion Analysis of
Living Cells", ed. D.R. Soll, D. Wessels. John Wiley, Inc. In press.
USING mMR IMAGING
IN DEVELOPMENTAL BIOLOGY - FISH, FROGS, MICE, & MONKEYS
Russell E. Jacobs, Biological Imaging Center,
California Institute of Technology
This work is a collaboration among a number of disciplines at Caltech,
including neuroscience, developmental biology, computer science, chemistry,
and electrical engineering. The long-term goal of this work is to refine
and apply a goal-directed interactive paradigm for data collection and
analysis in the neurosciences. We are applying it to Magnetic Resonance
Micro-Imaging in several contexts: the generation of in vivo atlases
of brain development; studies of transgenic mice model systems; and the
design of new MR contrast agents. The specific aim of the computational
aspect of this work is to create a "teleological pipeline" for making datasets,
models, and images. By "teleological pipeline" we mean a computational
and instrumental device in which the user's goals (i.e. the qualities
they wish the final image to possess) guide the data collection and processing
Preliminary results obtain using our current 11.7T vertical bore MRI
instrument will be used to illustrate this melding of disciplines. We focus
on five topics using : MRI as a methodology
to examine embryonic development in vivo and in vitro in
š mMRI of developing frog embryos
š in vitro and in vivo :
MRI of mouse embryos
š in vitro : MRI of a small
primate (Microcebus murimus)
š diffusion tensor MR imaging of a transgenic MS mouse model system
š bi-functional & 'smart' MR contrast agents
We begin with a discussion of 3 dimensional MR imaging of fixed mouse specimens
which demonstrates the excellent image quality, resolution, and contrast
that can be obtained on immobile samples in a several hour experiment.
Preliminary diffusion tensor imaging of a transgenic mouse model for multiple
sclerosis illustrates the wealth of information inherent in this imaging
modality and its ability to delineate nerve tracts and abnormalities in
the mouse spinal cord. Finally, we show some recent in vivo MR and
fluorescence images demonstrating the feasibility of employing such bi-functional
agents in the developmental studies.
This work was funded by the Human Brain Project with contributions from
the National Institute of Drug Abuse, the National Institute of Mental
Health, and the National Science Foundation; by the National Institute
of Child Health & Human Development; and by the Beckman Institute.
ANALYSIS AND MANIPULATION OF MOUSE
EMBRYONIC BRAIN AND HEART DEVELOPMENT WITH HIGH FREQUENCY ULTRASOUND IMAGING
Daniel H. Turnbull, Skirball Institute of Biomolecular
Medicine New York University Medical Center
The availability of genetic analysis and transgenic techniques in the mouse
have led to its widespread acceptance as the preferred animal model for
studying mammalian development and many human diseases. We have developed
a high frequency (40-100 MHz) ultrasound backscatter microscope (UBM),
capable of high resolution (~50µm) noninvasive imaging of mouse embryos,
in utero. The most obvious features in the real time UBM images
of early mouse embryos are the beating heart and the fluid-filled neural
tube cavity, which appears echo-free in contrast to the surrounding embryonic
tissues. Both of these features have been utilized to perform in vivo
analysis of early embryonic brain and heart development.
Cardiac activity can be identified with UBM as early as gestational
age 8.5 days (E8.5, equivalent to human day 21). By E9.5 the common atrium
and ventricle can be identified, and cardiac chamber dimensions can be
traced on UBM images through the early stages of morphogenesis and ventricular
septation (E10.5-13.5). UBM imaging is also useful for cardiac imaging
of neonatal mice, and has recently been used to characterize functional
differences between normal and a-myosin heavy
chain (Arg403Gln) mutant mice which die of congestive heart failure in
the first week of life. At the high ultrasound frequencies used in UBM
imaging, moving blood produces a high signal. As a result, blood flow through
umbilical, vitteline and other major blood vessels can be easily delineated
as a hyperechoic streaming pattern. Quantitative data on heart rate and
blood flow velocities in the embryonic heart and umbilical vessels are
collected using a 40 MHz Doppler ultrasound system, recently implemented
on the UBM. The ultimate goal of this project is to develop noninvasive
methods to assess cardiovascular function in normal and mutant mouse embryos.
We have shown that cardiac defects associated with a null mutation of VCAM-1
can be identified in utero with UBM imaging, and are currently quantifying
umbilical Doppler waveforms in order to characterize putative placental
defects in the same mutant embryos.
The shape of the neural tube cavity, evident from in utero UBM
images can be used to detect and analyze neural tube defects such as the
mid-hindbrain deletions associated with null mutations of the Wnt-1
and En-1 genes. Three-dimensional UBM images have been used to characterize
volumetric differences in the neural tube endoluminal space between E10.5
mutant embryos and normal littermates. In addition, specific brain structures
are readily identified with UBM, especially those which appear in contrast
to the venticular fluid, including the forebrain basal ganglion and septum,
thalamus, midbrain tectum and cerebellum. Similarly, non-neural structures
such as the developing limbs can be followed in utero, and the initial
formation of digits visualized with UBM.
We have recently modified the UBM system to allow cells, retroviruses
and other agents to be injected into early mouse embryos, in utero.
The ability to manipulate embryos through transplantation and injections
has been widely used in lower vertebrate species such as frog, zebrafish
and chick, but has been difficult or impossible in mammalian embryos due
to their inaccessibility, enclosed in the maternal uterus. We have used
UBM as a guidance system, allowing image-directed, targeted injections
into the embryonic neural tube as early as E9.5, and into specific parenchymal
target regions in the developing limbs and brain as early as E11.5. The
UBM-guided embryo injection system is being used in a number of projects:
using retroviruses to study cell lineages in the mouse forebrain and limb,
transplantation of neural cells to determine the developmental potential
and fate of cells placed in ectopic regions of the brain, and the effects
of gene misexpression using both retroviruses and transfected cell lines
expressing secreted proteins. The availability of mouse mutants opens up
the possibility to study cell lineage and fate and the effects of altered
gene expression using UBM-guided injections in mice lacking specific genes,
as well as normal animals. In particular, it should be possible to test
cell replacement and gene therapy strategies by injecting cells or retroviruses
expressing specific genes into defined mutant embryos.
In summary, UBM can be used to analyze noninvasively a variety of developmental
processes, and to manipulate mouse embryos through UBM-guided injections
over a wide range of embryonic stages. The combination of recent breakthroughs
in mouse genetics together with this new high resolution ultrasound imaging
technology is providing a powerful system for studying mammalian embryogenesis
and human disease models in the mouse.
IMAGING TECHNIQUES, OLD AND NEW, IN
THE STUDY OF EPIDIDYMAL-TESTICULAR DESCENT IN HUMAN EMBRYOS
Dale S. Huff, MD, Magee-Womens Hospital and the University
of Pittsburgh; Elizabeth Lockett, William Discher, and Adrianne Noe, PhD,
The Human Developmental Anatomy Center of the National Museum of Health
and Medicine, Armed Forces Institute of Pathology.
In 1912, Felix cited overwhelming embryological evidence against the universally
accepted concept of transabdominal testicular descent. He apparently had
a talent, which other embryologists lacked, for reconstructing in his mind
an accurate three-dimensional image of an embryo from two-dimensional serial
microscopic sections and graphic reconstructions of that embryo and further
for reconstructing in his mind an accurate four-dimensional movie loop-like
visual image from multiple mental three-dimensional visual images of a
series of progressively more mature embryos. In the century since Felix
first rejected the concept of transabdominal testicular descent, multiple
imaging techniques applied to human embryos have confirmed his position.
These techniques have included high quality serial microscopic sections
from many more well preserved human embryos, detailed graphic reconstructions,
models of whole embryos and of organ systems, photographs of gross dissections,
stereo photographs both gross and microscopic, scanning electromicrography,
and transmission electromicrography. Despite a century of solid imaging
evidence to the contrary, the concept of transabdominal testicular descent
in humans has persisted and has recently been used as the foundation upon
which theoretical strategies for the treatment of cryptorchidism have been
based. Only in the last few years have the modern imaging technologies
of computer-assisted three-dimensional reconstruction and morphing provided
the potential for reproducing on computer, video, and movie screens what
Felix probably saw in his mindās eye one hundred year ago. These reconstruction
and morphing techniques are being applied to the historic Carnegie Collection
of Embryology in an effort to confirm Felixās position. To date, the mesonephros
of three embryos, Carnegie Collection numbers 5072 (Stage II, 17 somites),
6097 (Stage 12, 25 somites) and 1380 (Stage 14) have been completed. The
results support the concepts that the development of the mesonephros begins
and is completed during the fourth post-ovulatory week as part of the cranio-caudal
developmental gradient of blastogenesis now known to be under the control
of homeobox genes; that the relationship between what will become the tail
of the epididymis and what will become the inguinal ring is established
by the 28th post-ovulatory day; and that transabdominal testicular descent
does not occur in humans. It is hoped that reconstructions of the mesonephros
from a complete series of embryos will conclusively demonstrate that Felix
was correct in his rejection of transabdominal testicular descent in humans.
FAST VOLUME VISUALIZATION WITH T-VOX
Michele Ursino, Ph.D. and Gregory L.
Merril, HT Medical, Rockville, Maryland
Embryonic development is a dynamic, three-dimensional process, posing significant
challenges for the research and teaching communities that disseminate current
research findings. We have developed software, called T-Vox (Teleos Voxel
Visualizer), that facilitates the transformation of 2D data into 3D models
and the manipulation of 3D models for the visualization of dynamic processes
that occur during embryogenesis. This has involved the development of specific
software features, including volume rendering and interactive look-up table
manipulation through five editors to isolate bones, skin, and other tissues.
T-Vox also can generate animation files in MPEG or QuickTime formats. This
feature pre-renders complex voxel images for distribution on PCs and Macintosh
To perform volume rendering with update speeds from 3 to over 30 frames
per second, T-Vox uses a special technique based on hardware capable of
managing volumetric textures. A volumetric texture is a region where texture
values, called texels, are stored in a 3-D grid in a particular position
and orientation in space. When the volumetric texture is active, each polygon
inside the texture space assumes the color of the texture values. For example,
when T-Vox loads data in the texture space of a set of images and draws
a polygon through it, users can obtain an arbitrary section of the data.
When many polygons are drawn through the texture space and the alpha blending,
or transparence effect, is applied, the single polygons disappear and the
volume becomes visible. This technology provides a powerful interactive
algorithm to display volume data and enables fast rendering speeds.
FITTING 3D IMAGING DATA USING ORTHOGONAL
Janet Rogers, Mathematical and Computational Sciences
Division, National Institute of Standards and Technology
Orthogonal Distance Regression methods provide meaningful least squares
estimates for distance calibration problems such as are required for biomedical
image processing. A major characteristic of these problems is the prevalence
of non-uniformly distributed noise in the data to be fitted. A NIST developed
software package, ODRPACK, specifically designed for these circumstances,
has been successfully employed to identify parameters and characteristics
of such biotechnology models.
This talk will discuss how Image Guided Technologies (IGT) in Boulder,
CO, used ODRPACK to locate significant calibration discrepancies within
their coordinate measuring machine. This instrument is employed in the
design and manufacture of 3D optical localizers that enable surgeons to
track the location of a probe inserted into a patient's skull. The development
of novel optical property models was efficiently facilitated by application
of ODRPACK, and accuracy testing and certification of new IGT systems are
presently performed using procedures based on ODRPACK. Some specific features
of ODRPACK that make it especially relevant for high precision measurements
and uniquely well-suited for modeling 3D image data will be described.
THREE-DIMENSIONAL ULTRASOUND OF
Dolores H. Pretorius, and Thomas R. Nelson, Department
of Radiology, University of California, San Diego, California
Interest in 3DUS has been building as equipment performance and user experience
has increased. Scientific papers are being presented at numerous national
and international scientific meetings describing clinical results imaging
specific organs, trials of new equipment and determination of optimal methods
of acquisition and interactive display of volume. 3DUS imaging can be performed
using commercially available ultrasound equipment or in combination with
clinical scanners and additional data acquisition and graphics workstations.
Since patient imaging geometry often precludes obtaining the optimal image
plane, a key feature of 3DUS which is essential to clinical utility, is
that the diagnostician may review the volume data interactively, evaluating
the relevant anatomy from orientations besides those used to acquire the
data. Such flexibility provides an increased understanding of underlying
anatomic relationships. 3DUS evaluation of fetuses from various angles
permits complex anatomic relationships to be more easily understood. Inclusion
of color Doppler imaging facilitates identification of vascular anatomy
leading to direct visualization of vessel organization and spatial relationships
of the fetus, cord, and placenta. We have shown that volume rendering of
fetal structures such as the face provides a more understandable picture
of anatomy and that curved bony structures such as the skull and spine
can be evaluated in more detail than with 2DUS due to the inclusion of
the entire structure rather than a single plane. Interactive display methods
are essential to provide the physician with the means to observe and evaluate
patient anatomy. Several techniques are used to enhance comprehension,
including volume rendering, rotation of volume data, viewing in a standardized
orientation and stereoscopic viewing.
The feasibility of 3DUS in the clinical setting is nearby. Benefits
of 3DUS include allowing the physician to evaluate arbitrary planes not
available with 2DUS due to patient body habitus or fetal position; measure
organ dimensions and volumes; obtain anatomic and blood flow information;
improve assessment of complex anatomic anomalies; confirm normalcy; standardize
the ultrasound exam procedures; enhance understanding of physicians in
primary care facilities and communicate volume data over networks for consultation
at tertiary facilities. Standardization of the ultrasound examination protocols
potentially can lead to uniformly high quality examinations and decreased
health care costs.
ADVANCES IN DIAGNOSING FETAL CARDIAC
DISEASES BY ULTRASONOGRAPHY
Ernerio T. Alboliras, M.D. and Anthony F. Cutilletta,
M.D. Rush Childrenās Heart Center Rush-Presbyterian-St. Lukeās Medical
Center, Chicago, IL.
Advancing expertise in obstetric ultrasound techniques allowed diagnosis
of an increasing array of fetal anatomic defects, and has resulted in an
interdependent relationship between obstetrician/perinatologist and pediatric/fetal
cardiologist. During the past decade, major advances in pediatric cardiology
have occurred, including a greater understanding of pathology and natural
history of congenital heart disease, superior results in neonatal heart
surgery, and finer imaging capability, particularly with color flow Doppler
and high-resolution two-dimensional echocardiography.
Almost every form of congenital heart disease recognizable by ultrasound
in the infant or child can be detected in fetal life. The incidence of
congenital heart disease in the general population is 8 per 1,000 live
births. As experience in fetal echocardiography develops, it is clearly
being learned that the incidence of congenital heart disease among high-risk
pregnancies rises to 75-80 per 1,000 fetuses. Even if consecutive non-high
risk pregnancies are scanned, the incidence is still high, at 25 per 1,000
fetuses. Certain maternal, paternal and fetal risk factors have been identified
as strong indications for performing fetal echocardiography. These include
sibling or parental (either mother or father) congenital heart disease,
familial or genetic syndromes, maternal diabetes and collagen vascular
disease, exposure to cardiac teratogens, and some maternal infections.
Fetal risk factors may appear, including abnormal appearance of the heart
during an obstetric scan, extracardiac fetal anomaly, fetal arrhythmia
and nonimmune hydrops fetalis. Trans-abdominal fetal echocardiography may
be ideally performed from anywhere between 16-20 weeks age of gestation,
with a confirmational study occasionally needed before 24 weeks. If an
indication arises during the pregnancy, the procedure may be performed
anytime. Transvaginal echocardiography may even be performed to as early
as 12 weeks age of gestation.
The detection of cardiac abnormalities in utero has increased our knowledge
of the natural history of certain pregnancies. There is a strong association
between occurrence of heart defects with anomalies of other organ systems.
Among pregnancies associated with cardiac defects, there is a high incidence
of spontaneous intrauterine death (11.2%), high incidence of chromosomal
anomalies (17%) and increased fetal loss associated with chromosomal anomalies
(20%). The spectrum of congenital heart disease in the fetus is different
from that seen after birth. There is a greater chance of seeing a serious
cardiac disease in the former (i.e. hypoplastic left heart syndrome, atrioventricular
canal, single ventricle, Ebstein anomaly), oftentimes resulting in fetal
demise. Also, some abnormalities change or progress during fetal life (i.e.
valvar stenosis, arterial hypoplasia, certain ventricular septal defect
types, hypertrophic cardiomyopathy).
When an anomaly is detected, parents are counseled concerning the type
of cardiac anomaly present and their options explained in a nondirective
manner. The options are usually dependent on the gestational age at diagnosis
and the presence or absence of other fetal anomalies. The prognosis of
naturally carrying to term the pregnancy and the surgical options available
after birth is explained. Parents are supported in their decision whatever
Knowledge of the presence of a fetal anomaly with echocardiography has
been shown to allow the mother to emotionally better cope with the sick
child. For the caregivers (obstetricians, perinatologists, neonatologists
and pediatric cardiologists), detection of fetal cardiac anomaly allows
for optimal chance of infant survival, with the expectant delivery of a
high risk baby and speedy transfer to a tertiary center. Because of the
high accuracy of echocardiography in detecting fetal cardiac malformations
if done by experienced fetal echocardiographers, medicolegal implications
may arise if parents are not allowed the chance to learn of the presence
of a problem in the fetus and be given the choice of medical intervention
during pregnancy. Therefore, fetuses suspected to have cardiac disease
should have a fetal echocardiogram. A referral to an experienced fetal
echocardiographer may allow optimal outcome. The detection of a healthy
fetus or one with a heart defect would nevertheless result in proper workup
ULTRAFAST MRI IN THE EVALUATION OF
THE ABNORMAL FETUS DURING THE SECOND AND THIRD TRIMESTERS
Anne M. Hubbard, The Department of Radiology and the
Center for Fetal Diagnosis and Treatment, The Children's Hospital of Philadelphia
With the development of ultrafast scan techniques, MRI has the potential
to add valuable information to the evaluation of an abnormal pregnancy.
Sequences have been developed in which an image is obtained in less than
.5 sec. These include echo planar, single shot turbo spin echo, and single
shot gradient echo sequences.
Prenatal MRI is useful in evaluation of the fetus with a suspected chest
mass. Congenital diaphragmatic hernia (CDH) in the most common mass in
the fetal chest. MRI can confirm the diagnosis by demonstrating the defect
in the diaphragm and the abnormal position of the bowel. More important
is the ability of MRI to determine the position of the liver, as the prognosis
for survival decreases when liver is herniated into the chest. US relies
on indirect signs of vessel displacement to determine the position of the
liver. On MRI the liver is conspicuously seen on gradient echo images.
MRI can help to diagnosis cystic adenomatiod malformation (CAM) of the
lung and bronchopulmonary sequestration. The pattern of lobar involvement,
the size of the lung tumor, and the amount of normal lung tissue present
is more easily seen than with US. CAM and CDH may be confused on US but
are easily differentiated with MRI. Lung volumes can be determined with
MRI, which in the future may help determine prognosis.
Neck tumors are important to evaluate because of the potential to cause
life-threatening airway obstruction at birth. MRI can differentiate teratomas
and lymphangiomas, the most common neck masses, and further define the
anatomy of the mass with respect to the airway and the vessels of the neck
allowing advanced planning for intervention at the birth.
The fetal brain is well visualized on prenatal MRI. With US, visualization
of the brain depends on the age, fetal position, and amount of amniotic
fluid present. The posterior fossa is the most difficult area to see. The
diagnosis of Dandy Walker malformation can easily be confirmed or excluded
with MRI. Abnormalities of the corpus callosum can also be seen. Ventricular
dilation is easily detected with US but the cause may be difficult to see.
With MRI, the third and forth ventricles and the extra-axial spaces can
be seen. Abnormalities of the brain parenchyma such as infarcts, hemorrhage,
and some disorders of neuronal migration can be seen. MRI can help in prenatal
diagnosis, counseling, and delivery planning.
The Current Status and Future Potential
of Fetal Intervention - Image is Everything!
Alan W. Flake, M.D., Director, The Center for Fetal
Diagnosis and Treatment, Childrenās Hospital of Philadelphia.
Fetal imaging is integral to the past, present, and future of fetal intervention.
In the early history of fetal intervention, the role of prenatal ultrasound
was primarily to identify a fetal lesion, provide a correct anatomic diagnosis,
and exclude other anatomic defects. We now depend on ultrasound, and other
imaging studies, to not only provide anatomic information, but to provide
prognostic, physiologic and functional information prior to surgery for
optimal selection of patients for fetal intervention. Perioperative imaging
allows optimal planning of the approach to the fetus and real time monitoring
of fetal well being during the procedure. After fetal surgery, imaging
studies allow assessment of ongoing fetal well being as well as determination
of positive or negative physiologic response to fetal interventions. Prior
to open fetal surgery we routinely obtain a level II ultrasound assessment
augmented by power ultrasound, fetal echocardiography, and a fetal MRI.
Preoperative assessment for fetuses with Congenital Diaphragmatic Hernia
includes determination of the presence or absence of liver in the chest,
determination of the contralateral lung area to head circumference ratio
(LHR), and assessment of lung volumes by MRI to determine suitability for
prenatal tracheal occlusion. Physiologic information is the primary focus
for prenatal evaluation of fetuses with Congenital Cystic Adenomatoid Malformation
and Sacrococcygeal Teratoma (SCT). Appropriate fetal intervention for these
anomalies requires accurate early assessment of the presence or absence
of hydrops and in the case of SCT, evolution of high output physiology
as determined by serial Doppler blood flow measurements. The increasing
use of fetoscopy for surgical interventions through small scopes with a
limited field of vision requires imaging to assume an operative as well
as a diagnostic role. The use of combined modalities for ultrasound guided
fetoscopic interventions is being increasingly applied for procedures such
as fetoscopic twin seperations, cord ligations, cystoscopic laser ablation
of posterior urethral valves, and other procedures. In the future, imaging
will play a progressively larger role in fetal intervention. Bronchoscopic
or ultrasound guided tracheal occlusion and imaging guided tumor destruction
or embolization should replace current open fetal surgery techniques. With
improved resolution and technology, early gestational interventions including
delivery of stem cells to the fetus and organ-directed gene therapy will
undoubtedly be entirely performed under image guidance. In the past, prenatal
diagnosis allowed fetal intervention to evolve. In the future, improvements
in imaging and non-invasive technology will drive further expansion of
indications and therapeutic options for fetal intervention.
QUANTITATIVE ASSESSMENT OF MOUSE
FETAL CARDIAC ANATOMY BY MAGNETIC RESONANCE IMAGING
Harvey Hensley, Susan Schachtner, Anne Hubbard, John
Haselgrove & Scott Baldwin, Childrens Hospital of Philadelphia
While the heart and cardiovascular systems have proven to be particularly
vulnerable to genetic manipulations, current techniques for quantitative
analysis of cardiovascular development are limited. Recent advances in
the use of magnetic resonance imaging (MRI), with three dimensional volume
acquisition, have demonstrated that this modality might prove particularly
efficacious in the assessment of embryonic development. To this end, we
have begun to test the feasibility of magnetic resonance microscopy in
the quantitative evaluation of normal and abnormal development of the heart
in mouse. Initially, embryos at 14 and 16 days post conception were injected
with a contrast agent (Gd-DTPA conjugated to albumin), fixed in paraformaldehyde
and then imaged at a field strength of 9.4 Tesla. T1 and T2 weighted three-dimensional
data sets were acquired with a voxel size of 60x60x60 microns. The T1 weighted
data sets permitted the observation of the contrast material in the vasculature
and cardiac chambers, while the T2 weighted data sets allow us to distinguish
the exterior of the heart from the pericardium. Registration of the data
sets therefore allows us to measure ventricular wall thickness. Other quantities
measured include ventricular and atrial volumes and the thickness of the
ventricular septum. Image resolution and reproducibility of measurements
suggests that this approach might prove valuable in evaluation of subtle
as well as gross defects in cardiac development.
POWER DOPPLER IN THE ASSESSMENT OF
NORMAL AND ABNORMAL FETAL VASCULARITY
Beverly G. Coleman, Director, Ultrasound Imaging University
of Pennsylvania Medical Center
Doppler sonography is a unique, noninvasive modality for the assessment
of normal and abnormal vasculature. The most widely available instruments
incorporate simultaneous real-time imaging with Doppler display, which
permits easy and rapid identification of vessels to be interrogated. Conventional
color Doppler (CD) systems present velocity information in a color format
such that flowing blood virtually serves as its own contrast agent. CD
is generally based on the mean Doppler frequency shift and is a measure
of directionality component of the velocity of blood moving through a volume
of tissue. Changes in frequency and flow direction that occur in vascular
structures in response to physiologic or pathologic states can be indirectly
assessed. CD depicts areas of vascularity which are typically red or blue,
although color selection is quite arbitrary. Blood flow toward the transducer
is often displayed in red and flow away from the transducer in blue.
Power Doppler (PD) is a new technique in which the color map displays
the strength or power inherent in blood cell motion. It has recently been
described as a potential useful alternative to CD and several advantages
have been reported which include the following: 1) PD does not alias because
the integral of the Doppler power spectrum remains constant, which allows
imaging at lower color velocity ranges thereby increasing sensitivity 3-5
times greater than CD; 2) noise on PD has a very low power signal and is
displayed as soft background color; and, 3) PD is relatively angle independent.
The disadvantages of PD are that it is unable to give information about
velocity or flow direction and it is extremely sensitive to tissue motion.
The identification of vessels with power facilitates placement of the sample
volume in an area of blood flow. The identification of vessels with power
facilitates placement of the sample volume in an area of blood blow. The
resulting waveform obtained from pulsed Doppler can be characterized as
arterial or venous and analyzed for quantitative information.
The obstetric applications of PD in the 2nd and 3rd trimester of pregnancy
includes: 1) depiction of normal and abnormal fetal vascular anatomy; 2)
assessment of placental pathology including previa, abruption and velamentous
cord insertion; 3) evaluation of umbilical cord anomalies including single
umbilical artery and nuchal cord; and, 4) investigation of flow dynamics
in multiple gestations. This presentation will focus on the utility of
PD in the depiction of normal and abnormal fetal vascular anatomy in structural
TOWARD AN INFORMATION INFRASTRUCTURE
FOR HEALTH CARE: FUNDING OPPORTUNITIES THROUGH THE ADVANCED TECHNOLOGY
Bettijoyce Lide, Technology Administration, National
Institute of Standards and Technology, Department of Commerce.
The Advanced Technology Program (ATP), managed by the National Institute
of Standards and Technology (NIST), works with U.S. industry to advance
the nation's competitiveness and economy by helping to fund the development
of high-risk but powerful new technologies that underlie a broad spectrum
of potential new applications, commercial products, and services. Through
cooperative agreements with individual companies or groups of companies,
large and small, the ATP invests in industrial projects to develop technologies
with high-payoff potential for the nation. The ATP accelerates technologies
that - because they are risky - are unlikely to be developed in time to
compete in rapidly changing world markets without such a partnership of
industry and government. By sharing the cost of such projects, the ATP
catalyzes industry to pursue promising technologies.
Within the ATP, the Information Infrastructure for Healthcare (IIH)
focused program will develop critical information infrastructure technologies
to enable enhanced, more fully integrated medical information systems across
the healthcare industry, greatly reducing costs and errors in handling
medical information. In response to the first two solicitations, 26 awards
were made (out of 127 proposals submitted). These awards include over 75
participants from 24 states, and represent a commitment of $135M from the
government and $142M from the private sector. Businesses of all sizes are
participating, from small start-up companies to very large joint ventures.
There is also heavy participation on the part of universities and non-profits.
The first solicitation funded projects to pursue infrastructure development
technologies; the second addressed user-interface and efficiency-enhancement
technologies. A third solicitation this year yielded 94 additional proposals
in these areas.
Results of this competition should be announced shortly. The original
program plan calls for an additional solicitation in the area of healthcare
NSF SUPPORT FOR RESEARCH AND INFRASTRUCTURE
IN DEVELOPMENTAL BIOLOGY
Christopher Platt, Division of Integrative
Biology & Neuroscience, National Science Foundation
FUNDING OPPORTUNITIES AT THE NCRR
Abraham Levy, Biomedical Technology Branch, National
Center for Research Resources, NIH
The National Center for Research Resources (NCRR) has the primary responsibility
at the National Institutes of Health (NIH) to develop critical research
technologies and to provide cost- effective, multidisciplinary resources
to biomedical investigators across the spectrum of research activities
supported by the NIH. This infrastructure underpins biomedical research
and enables advances that improve the health of our Nation=s
citizens. In this presentation, the various funding mechanisms available
from the Biomedical Technology area of NCRR are described. These mechanisms
include: Resource Center Grant (P41); Investigator-Initiated Research Grant
(R01); Innovative Approaches to Developing New Technologies (R21); First
Independent Research Support and Transition (FIRST) Award (R29); Conference
Grant (R13); Academic Research Enhancement Award (AREA) (R15); Small Business
Innovation Research (SBIR) Grant (R43; R44); Small Business Technology
Transfer Grant (STTR) (R41; R42); and Contract and Cooperative Agreement
mechanisms. An overview of the varied technology developments under the
current Biomedical technology program is given with special emphasis on
imaging technologies. Finally, recent Biomedical Technology budgets and
trends are presented.
FUNDING MECHANISMS AND OPPORTUNITIES
AT THE NICHD
Steven L. Klein, Ph.D. Developmental Biology, Genetics
& Teratology Branch, National Institute of Child Health and Human Development,
The NICHD currently supports individual projects on developmental imaging
via regular research grants (R01s), grants to small businesses (SBIRs and
STTRs) and contracts. We are interested in expanding research in this topic
by motivating interactions between individuals working in different components
of the field (e.g., education, research, diagnosis and treatment, computer
science, embryology, etc.). Accordingly, we will consider applications
from several investigators for projects that perform research, and provide
training, in multiple components of computer-assisted imaging of development.
Specifically, we encourage submission of applications for scientific meetings
(R13s) and recurring annual courses (T15s), Program Project Grants (P01s),
Interactive Research Project Grants (IRPGs), and Institutional pre- and
postdoctoral training programs (T32s). We believe that research and training
activities that encompass several components will stimulate this emerging
Speakers and Chairs
|Michael Ackerman, Ph.D.
Assistant Director for High Performance Computing and Communications
National Library of Medicine
8600 Rockville Pike Bethesda, MD 20894
|Abraham Levy, Ph.D.
Biomedical Technology Branch,
National Center for Research Resources,
|Ernerio T. Alborilas, MD
Director Non-Invasive Imaging and Fetal Cardiology
Rush Children's Heart Center
Advanced Technology Program, National Institute of Standards and Technology,
Technology Administration, Department of Commerce
166 Madrone Avenue
San Francisco, CA 94217
|Elizabeth Lockett, M.F.A.
Human Developmental Anatomy Center
National Museum of Health and Medicine
Armed Forces Institute of Pathology
|Brian Athey, Ph.D.
Director, Biomedical Imaging Programs
The Environmental Research Institute of Michigan (ERIM)
University of Michigan Medical School
Ann Arbor, Michigan 48409-0616
|Gregory L. Merril
President and CEO,
6001Montrose Road, Suite 902
Rockville, MD 20852-4874
(301) 984-3706 x 224
|Scott Baldwin, M.D.
The Childrenās Hospital of Philadelphia Department of Cardiology
Philadelphia, PA 19104
|Sally A. Moody, Ph.D.
George Washington University Medical Center, Programs in Neuroscience
and in Genetics
|Alphonse Burdi , Ph.D.
Curator, Patton Embryological Collection
University of Michigan
Department of Anatomy & Cell Biology
Ann Arbor, Michigan 48104
313-764-4358 or 313-764-9534
|Adrianne Noe, Ph. D.
Director, National Museum of Health and Medicine, Armed Forces Institute
Washington, DC 20306-6000
|Beverly G. Coleman, M.D,
Director of Ultrasound Imaging,
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania.
|Christopher Platt, Ph.D.
Division of Integrative Biology & Neuroscience
National Science Foundation
4201 Wilson Blvd. Arlington VA 22230
|David A. Damassa, Ph.D.
Department of Anatomy and Cellular Biology
University of North Carolina
106 Oak Street, Carrboro, NC, 27510
Chief, Mental Retardation & Developmental Disabilities Branch,
National Institute of Child Health and Human Development, NIH
|Dolores H. Pretorius, M.D.
Department of Radiology, University of California, San Diego
9500 Gilman Dr., 0610
La Jolla, CA 92093-0610
|Michael D. Doyle, Ph.D.
Chairman and CEO, Eolas Technologies Incorporated
|Louise E. Ramm, Ph. D.
Deputy Director, National Center for Researech Resources
|Alan G. Fantel, Ph.D.
Department of Pediatrics, School of Medicine University of Washington,
Seattle, WA 98195
|Martin Ringwald, Ph.D.
The Jackson Laboratory
600 Main Street
Bar Harbor, ME 04609
|Alan W. Flake, M.D.
Department of Surgery and Obstetrics University of Pennsylvania
& Director, Children's Institute of Surgical Science, Childrens
Hospital of Philadelphia
|Janet E. Rogers
Mathematical and Computational Sciences Division
National Institute of Standards and Technology
Boulder, CO 80303-3328
|Raymond F.Gasser, Ph.D.
Director, Computer Imaging Labs, Department of Cell Biology and Anatomy,
Louisiana State University Medical Center, New Orleans, Louisiana
|Albert Shar, Ph.D.
Executive Director, Computing and Educational Technology
University of PA School of Medicine
|Harvey Hensley, Ph. D.
Department of Cardiology, Childrenās Hospital of Philadelphia
Philadelphia, PA 19104
Envision Development Corporation
|A. Tyl Hewitt
Chief, Developmental Biology, Genetics & Teratology Branch, National
Institute of Child Health and Human Development,
|Bradley R. Smith, Ph.D.
Department of Radiology
Room 141D Bryan Research Building
Duke University Medical Center
Durham, NC 27710
|Anne M. Hubbard, M.D.
The Department of Radiology and the Center for Fetal Diagnosis and
Treatment, The Children's Hospital of Philadelphia
The University of Pennsylvania School of Medicine, Philadelphia, PA
|David R. Soll, Ph.D.
Director, WM Keck Dynamic Image Analysis Facility, Department of Biological
Sciences, University of Iowa
138 Biology Build.
Iowa City, IA 52242
|Dale S Huff, M.D.
Director Of Developmental-Perinatal Pathology
The University Of Pittsburgh and Magee-Womans Hospital,
Pittsburg, PA 15213
|Kent L. Thornburg, Ph.D.
Director, Congenital Heart Research Center
Professor of Physiology & Pharmacology
Oregon Health Sciences University
|Russell Jacobs, Ph.D.
Biological Imaging Center, Beckman Institute 139-74, Caltech
Pasadena, CA 91125
|Dan Turnbull, Ph.D.
Skirball Institute, NYU Medical Center
540 First Ave, New York, NY 10016
|Steven L. Klein, Ph.D.
Developmental Biology, Genetics & Teratology Branch, National Institute
of Child Health and Human Development, NIH
HT Medical 6001 Montrose Road, Suite 902
Rockville, MD 20852-4874
National Biomedical Research Foundation, Georgetown University Medical
& Editor-in-Chief, Computerized Medical Imaging and Graphics
FAX (202) 687-1662
|Betsey Williams, Ph.D.
President, Muritech Inc.
100 Inman St.,Cambridge MA, 02139
|Wesley Lee , M.D.
Division of Fetal Imaging, William Beaumont Hospital, Detroit, Michigan
and President, Fetal Imaging Resources, Inc.
|Elaine Young, Ph.D.
Comparative Medicine Branch
National Center for Research Resources
- Links to Ten Cool Projects
- Human Developmental Anatomy Center, National Museum of Health and Medicine, AFIP
- UC San Diego 3D Ultrasound Imaging Group
- The Multi-Dimensional Human Embryo, Center for In Vivo Microsocopy, Duke University
- Volume Visualization, HT Medical, Inc.
- The Visible Embryo, UC San Francisco
- Basic Embryology Review Program, University of PA School of Medicine
- The Visible Human Project, National Library of Medicine, NIH
- Internet Atlas of Mouse Embryology, MuriTech, Inc.
- Gene Expression Information Resource Project, The Jackson Laboratory
- Fetal Imaging Resources, Division of Fetal Imaging, William Beaumont Hospital
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SOCIETY FOR DEVELOPMENTAL BIOLOGY
Posted Tuesday, November 18, 1997