Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome

Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated

Immunogenicity of an Electron Beam Inactivated <i>Rhodococcus equi</i> Vaccine in Neonatal Foals

<div><p><i>Rhodococcus equi</i> is an important pathogen of foals that causes severe pneumonia. To date, there is no licensed vaccine effective against <i>R. equi</i> pneumonia of foals. The objectives of our study were to develop an electron beam (eBeam) inactivated vaccine against <i>R. equi</i> and evaluate its immunogenicity. A dose of eBeam irradiation that inactivated replication of <i>R. equi</i> while maintaining outer cell wall integrity was identified. Enteral administration of eBeam inactivated <i>R. equi</i> increased interferon-γ production by peripheral blood mononuclear cells in response to stimulation with virulent <i>R. equi</i> and generated naso-pharyngeal <i>R. equi</i>-specific IgA in newborn foals. Our results indicate that eBeam irradiated <i>R. equi</i> administered enterally produce cell-mediated and upper respiratory mucosal immune responses, in the face of passively transferred maternal antibodies, similar to those produced in response to enteral administration of live organisms (a strategy which previously has been documented to protect foals against intrabronchial infection with virulent <i>R. equi</i>). No evidence of adverse effects was noted among vaccinated foals.</p></div