The most impressive phenotypic appearance of sirenomelia is the presence of a 1808-rotated, axially positioned, single lower limb. Associated gastrointestinal and genitourinary anomalies are almost always present. This rare anomaly is still the subject of ongoing controversies concerning its nosology, pathogenesis, and possible genetic etiology. Sirenomelia can be part of a syndromic continuum, overlapping with other complex conditions including caudal dysgenesis and VATER/VACTERL/VACTERL-H associations, which could all be part of a heterogeneous spectrum, and originate from an early defect in blastogenesis. It is imaginable that different "primary field defects," whether or not genetically based, induce a spectrum of caudal malformations. In the current study, we review the contemporary hypotheses and conceptual approaches regarding the etiology and pathogenesis of sirenomelia, especially in the context of concomitant conditions. To expand on the latter, we included the external and internal dysmorphology of one third trimester sirenomelic fetus from our anatomical museum collection, in which multiple concomitant but discordant anomalies were observed compared with classic sirenomelia, and was diagnosed as VACTERL-H association with sirenomelia. Key words: blastogenesis; caudal dysgenesis; mermaid syndrome; anatomical museum; sirenomelia; teratology; VACTERL; VACTERL-H; VATER IntroductionThe most obvious phenotypic characteristic in sirenomelia (also called: symmelia or mermaid syndrome) is the single axially positioned lower limb. However, sirenomelia can be seen as a (lethal) multi-system condition based on a polytopic field defect with a wide phenotypical variability and frequently observed co-occurring with musculoskeletal, central nervous system, cardiopulmonary and other visceral anomalies, in addition to the almost always present gastrointestinal and genitourinary anomalies (reviewed by Gabriele and Gianpaolo, 2013). Sirenomelia is still the subject of debate, due to its ongoing controversies regarding its etiopathogenesis. Sirenomelia shows a heterogeneous phenotypic variability and overlap with caudal regression syndrome/sacro-coccygeal dysgenesis (Duhamel, 1961;Stocker and Heifetz, 1987;Adra et al., 1994), small pelvic outlet syndrome (Currarino and Weinberg, 1991), VATER/ VACTERL (Young et al., 1986;Sch€ uler and Salzano, 1994;Jain et al., 2002;Moosa et al., 2012), and VACTERL-H associations (Onyeije et al., 1998). There have been several attempts to classify these receptacles of caudal malformations, unfortunately without satisfying results. Clearly, diagnostic overlap exists between these conditions and the interpretation of their etiopathogenetic origin.The purpose of this study is to give an overview of multiple facets of this dysmorphological puzzle and review what is known about the co-occurrence of sirenomelia and other birth defects, in particular those assigned to the VACTERL(-H) spectrum. The existing literature on these conditions is supplemented by one additional case of sirenomelia with ...

In this article, we provide a comprehensive overview of multiple facets in the puzzling genesis of symmetrical conjoined twins. The etiopathogenesis of conjoined twins remains matter for ongoing debate and is currently cited—in virtually every paper on conjoined twins—as partial fission or secondary fusion. Both theories could potentially be extrapolated from embryological adjustments exclusively seen in conjoined twins. Adoption of these, seemingly factual, theoretical proposals has (unconsciously) resulted in crystallized patterns of verbal and graphic representations concerning the enigmatic genesis of conjoined twins. Critical evaluation on their plausibility and solidity remains however largely absent. As it appears, both the fission and fusion theories cannot be applied to the full range of conjunction possibilities and thus remain matter for persistent inconclusiveness. We propose that initial duplication of axially located morphogenetic potent primordia could be the initiating factor in the genesis of ventrally, laterally, and caudally conjoined twins. The mutual position of two primordia results in neo‐axial orientation and/or interaction aplasia. Both these embryological adjustments result in conjunction patterns that may seemingly appear as being caused by fission or fusion. However, as we will substantiate, neither fission nor fusion are the cause of most conjoined twinning types; rather what is interpreted as fission or fusion is actually the result of the twinning process itself. Furthermore, we will discuss the currently held views on the origin of conjoined twins and its commonly assumed etiological correlation with monozygotic twinning. Finally, considerations are presented which indicate that the dorsal conjunction group is etiologically and pathogenetically different from other symmetric conjoined twins. This leads us to propose that dorsally united twins could actually be caused by secondary fusion of two initially separate monozygotic twins. An additional reason for the ongoing etiopathogenetic debate on the genesis of conjoined twins is because different types of conjoined twins are classically placed in one overarching receptacle, which has hindered the quest for answers. Clin. Anat. 32:722–741, 2019. © 2019 Wiley Periodicals, Inc.

The structure-activity relationships (SAR) of 8-phenyl-1,3-dipropylxanthine derivatives in binding to recombinant human A 2B adenosine receptors were explored, in order to identify selective antagonists. Based on the finding of receptor selectivity in MRS 1204, containing an N-hydroxysuccinimide ester attached through the p-position of the 8-phenyl substituent [7-amino-2-{furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazin-5-ylamino-ethyl)phenol). The initial screening utilized rat A 1 /A 2A receptors and human A 3 receptors, and selected compounds were examined at the human A 1 /A 2A subtypes. A 1,2-dimethylmaleimide derivative, 14 (MRS 1595), bound to human A 2B receptors with a K i of 19 nM and proved to be selective vs. human A 1 /A 2A /A 3 receptors by 160-, 100-, and 35-fold, respectively. Enprofylline (3-propylxanthine) is slightly selective for A 2B receptors, suggesting removal of the 1-propyl group; however, combination of the 1-H-3-Pr and 8-phenyl substituents eliminated the selectivity. Other potent and moderately selective A 2B antagonists were a tetrahydrophthaloyl derivative 18b (MRS 1614, K i value 10 nM) and amino acid conjugates of the XCC-hydrazide, i.e., the glutarimide 24b (MRS 1626, K i value 13 nM), and protected dipeptide 27 (MRS 1615, K i value 11 nM). Drug Dev. Res. 47:178-188, 1999. : 8-[4-[[[[(2-aminoethyl As an approach to finding selective antagonists for the A 2B receptor, we synthesized novel 8-phenyl-1,3-dialkylxanthines related structurally to 4d, in most of which the active ester bond has been replaced by a more stable acyl-hydrazide bond, and screened them for receptor affinity and selectivity in binding to the recombinant human A 2B receptor and other adenosine receptor subtypes. In order to identify potent adenosine receptor subtype-selective antagonists, in this study we utilized radioligand binding assays based on the use of membranes derived from HEK-293 cells that overexpress recombinant human A 2B ARs.

m 6 A RNA methyltransferase (METTL3-14) catalyzes the methylation of adenosine in mRNA and plays important roles in mRNA functions, and it has been implicated in the progression of multiple cancers, including acute myeloid leukemia (AML). In this study, we describe the discovery of the first allosteric inhibitor of the METTL3-14 complex based on structure-activity relationship (SAR) and optimization studies ofoxy]benzoic acid (CDIBA). Compound 43n was optimized throughout the modifications of 4 different regions of the structure, and it displayed potent enzyme inhibitory activity of the METTL3-14 complex (IC 50 = 2.81 μM) and an antiproliferative effect in the AML cell lines by suppressing the m 6 A level of mRNA. The inhibition mechanism and binding mode of 43n were based on the interaction of the reversible and noncompetitive inhibitory profile at the allosteric site along with selectivity for the METTL3-14 complex relative to each subunit enzyme or truncated complex enzyme.

Shared anomalies, always located close to the area of coalescence and observable in virtually every type of conjoined twinning, are currently seen as separate anomalies caused by mostly unknown and seemingly unrelated pathways rather than being connected to the twinning mechanism itself. Therefore, most (case) reports about conjoined twins are mere descriptions of (external) dysmorphologies lacking reflections on the possible origin of their concomitant anomalies. As we will demonstrate in this article, shared anomalies are influenced, and in some cases solely and sequentially explained, by interaction aplasia and neo-axial orientation; two embryological mechanisms to which each set of conjoined twins is subjected and are responsible for their ultimate phenotypical fate.In this review, we consider how the ventral, lateral and caudal conjunction types and their intermediates determine the phenotypic presentation of the twins, including patterns of shared malformations and anomalies, which in themselves can be indistinguishable from those encountered in singleton cases. Hence, it can be hypothesized that certain anomalies in singletons originate in a fashion similar to that in conjoined twins.