Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis.

BACKGROUND: Previous work in our laboratory showed reduced myocardium and dilated ventricular chambers in gestation day (GD) 17 hearts that were collected from hyperglycemic CD1 mouse dams. Pre-breeding maternal immune stimulation, using Freund's complete adjuvant (FCA), diminished the severity of these fetal heart lesions. The following experiments were performed to detect possible changes in fetal heart apoptotic cell death, under hyperglycemic conditions and with or without maternal immune stimulation. METHODS: Female CD1 mice were injected with 200 mg/kg of streptozocin (STZ) to induce insulin-dependent diabetes mellitus. Half of these mice received prior FCA injection. Fetal hearts were collected on GD 17 and myocardial apoptotic cells were quantified using flow cytometry. A panel of apoptosis regulatory genes (Bcl2, p53, Casp3, Casp9, PkCe) was then examined in the fetal myocardium using RT-PCR. RESULTS: Early apoptotic cells and late apoptotic/necrotic cells were significantly increased in fetal hearts from STZ or STZ+FCA dams. Pre-treatment with FCA reduced late apoptotic/necrotic cells to control level, suggesting some cell death protection was rendered by FCA. Paradoxically in the face of such increased cell death, the expression of pro-apoptotic genes Casp3 and Casp9 was decreased by diabetes, while the anti-apoptotic gene Bcl2 was increased. CONCLUSIONS: Maternal hyperglycemia causes dys-regulated apoptosis of fetal myocardial cells. Such effect may be prevented by maternal immune stimulation.

Heart changes in 17-day-old fetuses of diabetic ICR (Institute of Cancer Research) mothers: improvement with maternal immune stimulation.

Maternal diabetes mellitus is associated with increased fetal teratogenesis, including cardiovascular defects. Non-specific maternal immune stimulation with Freund's complete adjuvant (FCA) or interferon gamma (IFNgamma) has been associated with protection against birth malformations. Using a diabetic mouse model, late-gestation fetal heart and great vessel morphology were analyzed. Four groups of mice were used: non-diabetic females as a control group, hyperglycemic females induced by streptozotocin as a diabetic group, and diabetic females injected either with FCA or IFNgamma. At day 17 of gestation, females were euthanized and one fetus was arbitrarily selected per litter for fixation and sectioning. Treatment-induced changes in cardiac development were assessed from digital images of serial sections taken at standardized levels in the thorax. One-way parametric and non-parametric ANOVA and ordinal logistic regression were performed to compare the difference among groups (P<0.05). Maternal hyperglycemia altered morphology of the late-gestation fetal mouse heart by causing ventricular chamber dilation, sectional myocardial reduction, and an increase in transversal aortic area. FCA protected the fetal heart from cavitary dilation in diabetic mothers. FCA and IFNgamma protected the fetal heart against reduction of myocardial area, and ascending thoracic aorta dilation. Consequences of late gestation heart chamber dilation and myocardial reduction are not yet known. Maternal immune stimulation partially protected against these developmental defects by mechanisms that remain unclear.

My thoughts on teaching.

The Pfizer Distinguished Teacher Award, presented annually to a faculty member at each college or school of veterinary medicine in the United States, is the most prestigious teaching award in veterinary medicine. Originally this award was known as the Norden Award, named in honor of Carl J. Norden, founder of Norden Laboratories, but since 1963 it has been sponsored by Pfizer Animal Health. Awardees are selected by their individual colleges and schools based on the following criteria: teaching excellence in lectures, laboratories, and/or clinical settings; support of student learning and development outside of traditional venues, such as by counseling, advising of specialty clubs, and so on (extracurricular activities); and character and leadership. Students, peers, and administrators provide input into the various criteria. Each of the 28 colleges or schools of veterinary medicine in the United States is invited to submit the dossier of their awardee to a national selection committee sponsored by the Association of American Veterinary Medical Colleges (AAVMC). It gives me great pleasure to note that the committee has awarded the 2008 Pfizer Teaching Award to Dr. Bonnie Smith, Associate Professor of Anatomy, Embryology, and Physiology at the Virginia-Maryland Regional College of Veterinary Medicine (VMRCVM) at Virginia Tech. Dr. Smith began her faculty service at VMRCVM in 1991, and previous to that spent four years on the faculty at North Carolina State University. Her ability to make a positive impact in the lives of students and their learning has become legendary over the years. Likewise, as a member of the Curriculum Board (Committee) and serving on various course design teams, Dr. Smith has been a steadying force in guiding the curriculum through various iterations. Helping students and faculty keep a sense of balance throughout these changes has been one of her major contributions. As a testament to her long-term teaching excellence, Dr. Bonnie Smith has received at least 22 different awards and citations for teaching excellence, two of which came very early in her career while she was at North Carolina State University. Most notable among these many awards is the fact that she is now a three-time recipient of the Pfizer Teaching Award. Dr. Smith has also been nominated by Student AVMA for a Teaching Excellence Award in Basic Sciences and has received an Honorable Mention, Teacher of the Year Award from the AVMA. Additionally, she has received an Alumni Teaching Award and a University Award for Teaching Excellence, and she has been elected to the Virginia Tech Academy of Teaching Excellence. Each of these three awards recognizes the best educators on Virginia Tech's faculty. Students have been very articulate in their praise of Dr. Smith's teaching. The comments received include "She has developed a unique teaching style that infuses traditional lectures with her unrelenting energy while never sacrificing content or complexity" and "She approaches the material from many angles, with clear verbalization of concepts, creatively utilizing stories and metaphors for clarification." Finally, a very fitting comment that illustrates her impact on her students: "Outside the classroom, Dr. Smith also influences many of us by serving as a strong female role model. In the face of life's hardships, she perseveres with an unshakably positive spirit. She encourages us to excel in all we do within the walls of our school and in our own lives." Peers have likewise been most complimentary of Dr. Smith's abilities as an educator. Examples from her nomination packet include the following: "Dr. Smith is truly a Master Teacher of the college. She has consistently demonstrated exemplary qualities of teaching, dedication and work ethic. She has received every teaching award the College has to offer and is consistently recognized by students, peers and the University" and "She epitomizes the qualities we have come to associate with teaching excellence. First and foremost is her dedication and commitment to student learning. Second, Dr. Smith's rapport with her students is outstanding because she invests the time necessary to gain their trust so she knows exactly what they are struggling with in her course. Third, she has the uncommon ability and desire to reach into students' minds and hearts to tailor instruction to meet individual learning styles and needs. Indeed, Dr. Smith is extremely gifted in being able to take complex details and concepts, and simplify, organize and present them in a very clear, understandable fashion." Other peer comments include: "Dr. Smith's animated and enthusiastic style was very effective and well-received"; "She is commended for her very good use of metaphors, examples and humor"; and "We all agree that attending Dr. Smith's lectures was beneficial to us as well as to the students! Keep up the fine work." In summary, Dr. Smith is to be sincerely congratulated on receiving this prestigious award. It is well deserved, based on her long history of teaching excellence and on the positive impact she has had in the lives of her students. -J. Blair Meldrum, Professor of Toxicology, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, and Chair, VMRCVM Pfizer Teaching Award Selection Committee.

Study of the vasculature of the caprine reproductive organs using the tissue-clearing technique, with special reference to the angioarchitecture of the utero-ovarian vessels and the adaptation of the ovarian and/or vaginal arteries to multiple pregnancies.

Arteries of the reproductive tracts of nonpregnant does and does at 4, 7, 10, 13, 16, and 18 weeks of gestation were injected in situ with Microfil. The tracts were fixed, dehydrated, and rendered transparent to reveal the paths of arteries. The tortuous ovarian artery lay in close apposition to the uterine tributary of the ovarian vein, an arrangement that may serve as a local utero-ovarian pathway for the corpus luteum (CL) luteolysis at the end of nonfertile estrous cycle. During pregnancy, this arteriovenous arrangement might transfer luteotropic substances from uterus to ovary, which might serve in maternal recognition of pregnancy and fit the fact that the goat is CL-dependent throughout gestation. In some cases of triplets, the size of the uterine branch of the ovarian artery was equal to or even larger than that of its parent artery and/or the ipsilateral uterine artery, and the vaginal artery contributed a connecting branch to the uterine artery. These physiological adaptations of the ovarian and/or vaginal arteries, which have not previously been described, correlate well with the increasing nutrient demands of the growing multiple fetuses.

Aortic and ventricular dilation and myocardial reduction in gestation day 17 ICR mouse fetuses of diabetic mothers.

BACKGROUND: Maternal diabetes mellitus is associated with increased fetal teratogenesis, including cardiovascular defects. Information regarding cardiovascular changes in late-gestation fetal mice, related to maternal hyperglycemia, is not present in the literature. METHODS: Late-gestation fetal heart and great vessel morphology were analyzed in fetuses from control and diabetic mice. Female ICR mice were injected with streptozocin (200 mg/kg IP) prior to mating to induce diabetes (n = 8). Nonhyperglycemic females were used as controls (n = 8). At day 17 of gestation, females were euthanized and one fetus was arbitrarily selected per litter to analyze the heart and great vessels. Six additional fetuses from different litters, showing external malformations (spina bifida and/or exencephaly), were also evaluated from the diabetic group. Fetal thoraxes were processed using routine histopathologic techniques, and 7-mum transversal sections were stained with hematoxylin-eosin. Digital images of sections were made and analyzed using NIH Image J software to compare regional cardiac development. Student's t tests for means were performed to determine differences between groups (p < .05). RESULTS: Maternal hyperglycemia caused a dilation of late-gestation fetal ventricular chambers, a reduction of total ventricular myocardial area, and an increase in transversal ascending thoracic aortic area. Three of six fetuses that displayed external malformations showed an overt cardiac defect, beyond the ventricular and myocardial changes. CONCLUSIONS: Maternal hyperglycemia altered morphology of the late-gestation fetal mouse heart. Postnatal persistence or consequences of late-gestation heart chamber dilation and myocardial reduction are not yet known.