Morphologic study of the ascending aorta and aortic arch in hypoplastic left hearts: Surgical implications

ObjectivesThe ascending aorta and aortic arch in patients with hypoplasia of the left heart are hypoplastic as a result of diminished blood flow. In this study, the presence and degree of obstruction owing to areas of narrowing or infolding within the diminutive aorta are quantified, and their surgical significance is discussed.MethodsNinety-six specimens with hypoplasia of the left heart were studied and measurements were taken at specified sites to evaluate areas of narrowing. Quantitative assessments of infoldings and their contribution to obstruction of flow are made.ResultsNarrowing of the distal ascending aorta was found in 60 (62.5%) specimens, with a decrease in circumference of the distal ascending aorta (0.72 ± 1.06 mm) present when compared with its midpoint (P < .05). Tissue infolding at the orifice of the brachiocephalic artery and its junction with the distal ascending aorta was observed in 56 (58.3%) hearts, with major infolding in 29 (30.2%) and minor infolding in 27 (28.5%). Tissue infolding at this site correlated with a smaller ascending aorta (P < .001) but not with narrowing in the distal ascending aorta (P = .53). Ductal coarctations were detected in 77 (81.1%) specimens. Their presence correlated with a smaller diameter of the ascending aorta (P < .05), and their severity correlated with the presence of aortic and mitral valvular atresia (P < .05).ConclusionsImportant areas of obstruction in the ascending aorta in patients with hypoplasia of the left heart were found, and their pathogenesis is discussed. The findings highlight the importance of incorporating the ascending aorta into the aortic reconstruction at the time of initial palliation for patients with hypoplasia of the left heart

Revisiting the anatomy of the right ventricle in the light of knowledge of its development

Controversies continue regarding several aspects of the anatomy of the morphologically right ventricle. There is disagreement as to whether the ventricle should be assessed in bipartite or tripartite fashion, and the number of leaflets to be found in the tricuspid valve. In particular, there is no agreement as to whether a muscular outlet septum is present in the normally constructed heart, nor how many septal components are to be found during normal development. Resolving these issues is of potential significance to those investigating and treating children with congenitally malformed hearts. With all these issues in mind, we have revisited our own experience in investigating the development and morphology of the normal right ventricle. To assess development, we have examined a large number of datasets, prepared by both standard and episcopic microscopy, from human and murine embryos. In terms of gross anatomy, we have compared dissections of normal autopsied hearts with virtual dissections of datasets prepared using computed tomography. Our developmental and postnatal studies, taken together, confirm that the ventricle is best assessed in tripartite fashion, with the three parts representing its inlet, apical trabecular, and outlet components. The ventricular septum, however, has only muscular and membranous components. The muscular part incorporates a small component derived from the muscularised fused proximal outflow cushions, but this part cannot be distinguished from the much larger part that is incorporated within the free-standing muscular infundibular sleeve. We confirm that the tricuspid valve itself has three components, which are located inferiorly, septally, and antero-superiorly.<br/

Revisiting the anatomy of the right ventricle in the light of knowledge of its development

Controversies continue regarding several aspects of the anatomy of the morphologically right ventricle. There is disagreement as to whether the ventricle should be assessed in bipartite or tripartite fashion, and the number of leaflets to be found in the tricuspid valve. In particular, there is no agreement as to whether a muscular outlet septum is present in the normally constructed heart, nor how many septal components are to be found during normal development. Resolving these issues is of potential significance to those investigating and treating children with congenitally malformed hearts. With all these issues in mind, we have revisited our own experience in investigating the development and morphology of the normal right ventricle. To assess development, we have examined a large number of datasets, prepared by both standard and episcopic microscopy, from human and murine embryos. In terms of gross anatomy, we have compared dissections of normal autopsied hearts with virtual dissections of datasets prepared using computed tomography. Our developmental and postnatal studies, taken together, confirm that the ventricle is best assessed in tripartite fashion, with the three parts representing its inlet, apical trabecular, and outlet components. The ventricular septum, however, has only muscular and membranous components. The muscular part incorporates a small component derived from the muscularised fused proximal outflow cushions, but this part cannot be distinguished from the much larger part that is incorporated within the free-standing muscular infundibular sleeve. We confirm that the tricuspid valve itself has three components, which are located inferiorly, septally, and antero-superiorly.<br/

The independence of the infundibular building blocks in the setting of double-outlet right ventricle.

It has long been contentious as to whether the presence of bilateral infundibulums, or conuses, is a prerequisite for the diagnosis of double-outlet right ventricle. As the use of such a criterion would abrogate the so-called "morphological method", which correctly states that one variable entity should not be defined on the basis of another entity that is itself variable, it is now accepted that double outlet can exist in the setting of fibrous continuity between the leaflets of the atrioventricular and arterial valves. Although this debate has now been resolved, there are other contentious areas still requiring clarification in the setting of hearts unified because of the presence of this particular ventriculo-arterial connection - for example, it is questionable whether the channel between the ventricles should be described as a "ventricular septal defect", whereas it is equally arguable that the mere presence of fibrous continuity between the leaflets of the arterial valves does not necessarily place the channel in a doubly committed location. In this review, we describe a series of autopsied hearts in which the anatomical features serve to illuminate these various topics. We then discuss recent findings regarding cardiac development that point to the individuality of the building blocks of the ventricular outflow tracts, specifically the outlet septum, the inner heart curvature, or ventriculo-infundibular fold, and the septomarginal trabeculation, or septal band

Assessing the Criteria for Definition of Perimembranous Ventricular Septal Defects in Light of the Search for Consensus

Background: Discussions continue as to whether ventricular septal defects are best categorized according to their right ventricular geography or their borders. This is especially true when considering the perimembranous defect. Our aim, therefore, was to establish the phenotypic feature of the perimembranous defect, and to establish the ease of distinguishing its geographical variants. Methods and results: We assessed unrepaired isolated perimembranous ventricular defects from six historic archives, subcategorizing them using the ICD-11 coding system. We identified 365 defects, of which 94 (26%) were deemed to open centrally, 168 (46%) to open to the outlet, and 84 (23%) to the inlet of the right ventricle, with 19 (5%) being confluent. In all hearts, the unifying phenotypic feature was fibrous continuity between the leaflets of the mitral and tricuspid valves. This was often directly between the valves, but in all instances incorporated continuity through the atrioventricular portion of the membranous septum. In contrast, we observed fibrous continuity between the leaflets of the tricuspid and aortic valves in only 298 (82%) of the specimens. When found, discontinuity most commonly was seen in the outlet and central defects. There were no discrepancies between evaluators in distinguishing the borders, but there was occasional disagreement in determining the right ventricular geography of the defect. Conclusions: The unifying feature of perimembranous defects, rather than being aortic-to-tricuspid valvar fibrous continuity, is fibrous continuity between the leaflets of the atrioventricular valves. While right ventricular geography is important in classification, it is the borders which are more objectively defined

The Atrioventricular Conduction Axis and its Implications for Permanent Pacing

Extensive knowledge of the anatomy of the atrioventricular conduction axis, and its branches, is key to the success of permanent physiological pacing, either by capturing the His bundle, the left bundle branch or the adjacent septal regions. The inter-individual variability of the axis plays an important role in underscoring the technical difficulties known to exist in achieving a stable position of the stimulating leads. In this review, the key anatomical features of the location of the axis relative to the triangle of Koch, the aortic root, the inferior pyramidal space and the inferoseptal recess are summarised. In keeping with the increasing number of implants aimed at targeting the environs of the left bundle branch, an extensive review of the known variability in the pattern of ramification of the left bundle branch from the axis is included. This permits the authors to summarise in a pragmatic fashion the most relevant aspects to be taken into account when seeking to successfully deploy a permanent pacing lead.Sin financiaciónNo data JCR 20211.035 Q1 SJR 2021No data IDR 2021UE

Endogenous production of IL-1B by breast cancer cells drives metastasis and colonisation of the bone microenvironment

Background: Breast cancer bone metastases are incurable highlighting the need for new therapeutic targets. After colonizing bone, breast cancer cells remain dormant, until signals from the microenvironment stimulate outgrowth into overt metastases. Here we show that endogenous production of IL-1B by tumor cells drives metastasis and growth in bone. Methods: Tumor/stromal IL-B and IL-1R1 expression was assessed in patient samples and effects of the IL-1R antagonist, Anakinra or the IL-1B antibody Canakinumab on tumor growth and spontaneous metastasis were measured in a humanized mouse model of breast cancer bone metastasis. Effects of tumor cell-derived IL-1B on bone colonisation and parameters associated with metastasis were measured in MDA-MB-231, MCF7 and T47D cells transfected with IL-1B/control. Results: In tissue samples from >1300 patients with stage II/III breast cancer, IL-1B in tumor cells correlated with relapse in bone (hazard ratio 1.85; 95% CI 1.05-3.26; P=0.02) and other sites (hazard ratio 2.09; 95% CI 1.26-3.48; P=0.0016). In a humanized model of spontaneous breast cancer metastasis to bone, Anakinra or Canakinumab reduced metastasis and reduced the number of tumor cells shed into the circulation. Production of IL-1B by tumor cells promoted EMT (altered E-Cadherin, N-Cadherin and G-Catenin), invasion, migration and bone colonisation. Contact between tumor and osteoblasts or bone marrow cells increased IL-1B secretion from all three cell types. IL-1B alone did not stimulate tumor cell proliferation. Instead, IL-1B caused expansion of the bone metastatic niche leading to tumor proliferation. Conclusion: Pharmacological inhibition of IL-1B has potential as a novel treatment for breast cancer metastasis

Structure, function and diversity of the healthy human microbiome

Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis of the HMPdata was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article