Anatomy of the interchondral joints and the effects on mobility of ribs.

BACKGROUND: Variations in the anatomy of the anterior rib cage and costal margin have been observed. We sought to evaluate the location of interchondral joints and evaluate their effect on mobility of the rib cage. METHODS: Cadaveric dissections were performed to evaluate the anatomy of the anterior ribs and the composition of the costal margin. Experienced chest wall surgeons and anatomists evaluated this anatomy through a standardized dissection and assessment. The presence of interchondral joints, and morphology and mobility of ribs were quantified. In addition, the movement and interactions of the ribs with upward pressure on the costal margin at the tip of the 10th rib were assessed. RESULTS: Twenty-eight cadavers were evaluated bilaterally. In all patients, the first rib attached to the manubrium, the second rib attached to the sternal/manubrial junction, and ribs 3 to 6 attached directly to the sternum. Interchondral joints were present between ribs 4/5 in 0%, 5/6 in 35%, 6/7 in 96%, and 7/8 in 96%. The eighth/ninth ribs had free tips in 58% and 92%, respectively, and 10th rib was floating in 46%. Upward pressure on the costal margin resulted in compression of the ribs up to, on average, the 5.7 ± 0.6 rib with no compression above this level. This level corresponded to the rib interspace just above the most superior interchondral joint in 98% of evaluation. The transmission of these upward forces demonstrated an articulation of the ribs at the costal cartilage-sternal junction in the lower ribs. CONCLUSION: Bridging interchondral joints are common between ribs 5 to 8 and participate in distributing forces from the costal margin across the chest wall. Upward forces at the costal margin are transmitted across the lower rib cage and result in increased mobility of the lower half of the ribs. The eighth/ninth ribs often have mobile tips, and the 10th is often a floating rib. LEVEL OF EVIDENCE: Diagnostic Test; Level II.

Surgical techniques for aortic valve xenotransplantation.

BACKGROUND: Heart valve replacement in neonates and infants is one of the remaining unsolved problems in cardiac surgery because conventional valve prostheses do not grow with the children. Similarly, heart valve replacement in children and young adults with contraindications to anticoagulation remains an unsolved problem because mechanical valves are thrombogenic and bioprosthetic valves are prone to early degeneration. Therefore, there is an urgent clinical need for growing heart valve replacements that are durable without the need for anticoagulation. METHODS: A human cadaver model was used to develop surgical techniques for aortic valve xenotransplantation. RESULTS: Aortic valve xenotransplantation is technically feasible. Subcoronary implantation of the valve avoids the need for a root replacement. CONCLUSION: Aortic valve xenotransplantation is promising because the development of GTKO.hCD46.hTBM transgenic pigs has brought xenotransplantation within clinical reach.

Left-right analysis of mammary gland development in retinoid X receptor-α+/- mice.

Left-right (L-R) differences in mammographic parenchymal patterns are an early predictor of breast cancer risk; however, the basis for this asymmetry is unknown. Here, we use retinoid X receptor alpha heterozygous null (RXRα+/-) mice to propose a developmental origin: perturbation of coordinated anterior-posterior (A-P) and L-R axial body patterning. We hypothesized that by analogy to somitogenesis-in which retinoic acid (RA) attenuation causes anterior somite pairs to develop L-R asynchronously-that RA pathway perturbation would likewise result in asymmetric mammary development. To test this, mammary glands of RXRα+/- mice were quantitatively assessed to compare left- versus right-side ductal epithelial networks. Unlike wild-type controls, half of the RXRα+/- thoracic mammary gland (TMG) pairs exhibited significant L-R asymmetry, with left-side reduction in network size. In RXRα+/- TMGs in which symmetry was maintained, networks had bilaterally increased size, with left networks showing greater variability in area and pattern. Reminiscent of posterior somites, whose bilateral symmetry is refractory to RA attenuation, inguinal mammary glands (IMGs) also had bilaterally increased network size, but no loss of symmetry. Together, these results demonstrate that mammary glands exhibit differential A-P sensitivity to RXRα heterozygosity, with ductal network symmetry markedly compromised in anterior but not posterior glands. As TMGs more closely model human breast development than IMGs, these findings raise the possibility that for some women, breast cancer risk may initiate with subtle axial patterning defects that result in L-R asymmetric growth and pattern of the mammary ductal epithelium.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.

Regulation of Ncx1 expression. Identification of regulatory elements mediating cardiac-specific expression and up-regulation.

The Na+-Ca2+ exchanger (NCX1) is up-regulated in hypertrophy and is often found up-regulated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. We have previously shown that the 1831-bp Ncx1 H1 (1831Ncx1) promoter directs cardiac-specific expression of the exchanger in both development and in the adult, and is sufficient for the up-regulation of Ncx1 in response to pressure overload. Here, we utilized adenoviral mediated gene transfer and transgenics to identify minimal regions and response elements that mediate Ncx1 expression in the heart. We demonstrate that the proximal 184 bp of the Ncx1 H1 (184Ncx1) promoter is sufficient for expression of reporter genes in adult cardiomyocytes and for the correct spatiotemporal pattern of Ncx1 expression in development but not for up-regulation in response to pressure overload. Mutational analysis revealed that both the -80 CArG and the -50 GATA elements were required for expression in isolated adult cardiomyocytes. Chromatin immunoprecipitation assays in adult cardiocytes demonstrate that SRF and GATA4 are associated with the proximal region of the endogenous Ncx1 promoter. Transgenic lines were established for the 1831Ncx1 promoter-luciferase containing mutations in the -80 CArG or -50 GATA element. No luciferase activity was detected during development, in the adult, or after pressure overload in any of the -80 CArG transgenic lines. The Ncx1 -50 GATA mutant promoter was sufficient for driving the normal spatiotemporal pattern of Ncx1 expression in development and for up-regulation in response to pressure overload but importantly, expression was no longer cardiac restricted. This work is the first in vivo study that demonstrates which cis elements are important for Ncx1 regulation.

Elevated transforming growth factor beta2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor alpha knockout embryos.

Septation of the single tubular embryonic outflow tract into two outlet segments in the heart requires the precise integration of proliferation, differentiation and apoptosis during remodeling. Lack of proper coordination between these processes would result in a variety of congenital cardiac defects such as those seen in the retinoid X receptor alpha knockout (Rxra(-/-)) mouse. Rxra(-/-) embryos exhibit lethality between embryonic day (E) 13.5 and 15.5 and harbor a variety of conotruncal and aortic sac defects making it an excellent system to investigate the molecular and morphogenic causes of these cardiac malformations. At E12.5, before the embryonic lethality, we found no qualitative difference between wild type and Rxra(-/-) proliferation (BrdU incorporation) in outflow tract cushion tissue but a significant increase in apoptosis as assessed by both TUNEL labeling in paraffin sections and caspase activity in trypsin-dispersed hearts. Additionally, E12.5 embryos demonstrated elevated levels of transforming growth factor beta2 (TGFbeta2) protein in multiple cell lineages in the heart. Using a whole-mouse-embryo culture system, wild-type E11.5 embryos treated with TGFbeta2 protein for 24 hours displayed enhanced apoptosis in both the sinistroventralconal cushion and dextrodorsalconal cushion in a manner analogous to that observed in the Rxra(-/-). TGFbeta2 protein treatment also led to malformations in both the outflow tract and aortic sac. Importantly, Rxra(-/-) embryos that were heterozygous for a null mutation in the Tgfb2 allele exhibited a partial restoration of the elevated apoptosis and of the malformations. This was evident at both E12.5 and E13.5. The data suggests that elevated levels of TGFbeta2 can (1) contribute to abnormal outflow tract morphogenesis by enhancing apoptosis in the endocardial cushions and (2) promote aortic sac malformations by interfering with the normal development of the aorticopulmonary septum.