Gestation day 11 (GD11) and 14 (GD14) embryos were cultured for up to 4 hours in the presence of Dofetilide (0.01-0.50 microgram/ml), a potent Class III Antiarrhythmic which selectively inhibits the rapid component of the time dependent outward potassium current (IKr). Significant (P < or = 0.05) reductions in heart rate (HR) as measured over a 4 hour period were dose dependent and reversible. The sensitivity of the GD11 embryos was greater than GD14 embryos (14-64% decrease in HR vs. an 11-43% decrease in HR, respectively) at the same concentrations tested. These in vitro results support the hypothesis that the embryo-lethality of Class III Antiarrhythmics observed in vivo may be a class effect of the IKr subtype potassium channel blockers. The data suggest a possible mechanism of embryotoxicity is to lower embryonic HR resulting in subsequent hypoxia and death. Dofetilide's effects on GD11 HR were partially reversible by the sequential addition of Isoproterenol or Theophylline.

a b s t r a c tObjectives: The objectives of this study were to: (1) explore the proportion of HTx centers that have a multidisciplinary team and (2) assess the relationship between multidisciplinarity and the level of chronic illness management (CIM). Background: The International Society for Heart and Lung Transplantation (ISHLT) recommends a multidisciplinary approach in heart transplant (HTx) follow-up care but little is known regarding the proportion of HTx centers that meet this recommendation and the impact on patient care. HTx centers

Computed tomographic imaging patterns of intracranial hemorrhage in children younger than 3 years help predict whether the injury was intentional.

No abstract

Background Pharmacological antagonism of VLA‐4 (Very Late Antigen 4, α4β1 integrin) has become an attractive target for the treatment of predominantly eosinophil mediated disease states such as asthma, allergic rhinitis, multiple sclerosis, rheumatoid arthritis, diabetes, and inflammatory bowel disease. Gene knockouts of the α4‐integrin subunit of VLA‐4 or its cell surface ligand, VCAM‐1, however, have been shown to result in embryo‐lethality in homozygous null mice due to defects in chorio‐allantoic or epi‐myocardial fusion. Although gene knockout phenotypes are not always manifested by pharmacological antagonism, those studies suggested that VLA‐4 antagonists might cause embryo‐lethality or drug‐induced malformations. Methods To test these concepts, early neurulating rat embryos were cultured by the methods of New ('78) after intra‐coelomic microinjection of a VLA‐4 blocking antibody or in the presence of small molecule VLA‐4 antagonists. Results Defects in chorio‐allantoic fusion were induced after microinjection of VLA4 blocking antibody and after continuous exposure to small molecule antagonists. In a minority of affected embryos chorio‐allantoic fusion was completely blocked whereas the majority of affected embryos had only superficial chorio‐allantoic fusion and the allantois was enlarged and edematous. Although the allantoic mesoderm covered the trophoblasts of the chorionic plate and contained blood vessels there was only minimal invasion of the trophoblasts by the allantoic mesoderm. The lowest observed effect level generally correlated with the IC∼95, as determined in 90% plasma. Discussion Based on these data, VLA‐4 antagonism might represent a significant risk to the developing embryo/fetus. In vitro exposure, however, is “constant” and does not take into account the elimination phase of these xenobiotics in vivo. Given the high concentrations required to elicit an effect, therapeutic blood levels in vivo may be several fold lower than those that affect the conceptus, depending on the tissue penetration of the compound and the route of administration. VLA‐4 also exists in a range of conformations and activation states in vivo and the gene KOs and present studies do not define whether these developmental processes are dependent upon a particular activation state of VLA‐4. Therefore, state‐selective antagonists may have an improved embryonic safety profile. Additional studies will be required to determine potential effects of VLA‐4 antagonists on embryo/fetal development in vivo. Teratology 65:26–37, 2002. © 2002 Wiley‐Liss, Inc.