Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.

Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.

A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk.

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ≈ 20 ng ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16,705 asthmatics and 30,809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

Gastric pneumatosis following cardiac surgery.

Infiltration of the stomach wall by air, first described by Fraenkel in 1889 [3], is a very rare condition. We describe the first reported case of gastric pneumatosis occurring in a child with complex congenital heart disease after cardiac surgery.

Metal complexes of N-tosylamidoporphyrin: cis-acetato-N-tosylimido-meso-tetraphenylporphyrinatothallium(III) and trans-acetato-N-tosylimido-meso-tetraphenylporphyrinatogallium(III).

The crystal structures of acetato-N-tosylimido-meso-tetraphenylporphyrinatothallium(III), Tl(N-NTs-tpp)(OAc) (1), and acetato-N-tosylimido-meso-tetraphenylporphyrinatogallium(III), Ga(N-NTs-tpp)(OAc) (2), were determined. The coordination sphere around the Tl3+ ion is a distorted square-based pyramid in which the apical site is occupied by a chelating bidentate OAc- group, whereas for the Ga3+ ion, it is a distorted trigonal bipyramid with O(3), N(3), and N(5) lying in the equatorial plane. The porphyrin ring in the two complexes is distorted to a large extent. For the Tl3+ complex, the pyrrole ring bonded to the NTs ligand lies in a plane with a dihedral angle of 50.8 degrees with respect to the 3N plane, which contains the three pyrrole nitrogens bonded to Tl3+, but for the Ga3+ complex, this angle is found to be only 24.5 degrees. In the former complex, Tl3+ and N(5) are located on the same side at 1.18 and 1.29 A from its 3N plane, but in the latter one, Ga3+ and N(5) are located on different sides at -0.15 and 1.31 A from its 3N plane. The free energy of activation at the coalescence temperature Tc for the intermolecular acetate exchange process in 1 in CD2Cl2 solvent is found to be delta G++171 = 36.0 kJ/mol through 1H NMR temperature-dependent measurements. In the slow-exchange region, the methyl and carbonyl (CO) carbons of the OAc- group in 1 are separately located at delta 18.5 [3J(Tl-13C) = 220 Hz] and 176.3 [2J(Tl-13C) = 205 Hz] at -110 degrees C.

Crystal and molecular structure of an eight-coodinate N-methyltetraphenylporphyrin complex: diacetato(N-methyl-meso-tetraphenylporphyrinato)thallium(III).

The crystal structure of diacetato(N-methyl-meso-tetraphenylporphyrinato)thallium(III), Tl(N-Me-tpp)(OAc)2 (1), was established, and the coordination sphere around the Tl3+ ion is described as an eight-coordinate square-based antiprism in which two cis chelating bidentate OAc- groups occupy two apical sites. The plane of the three pyrrole nitrogen atoms (i.e., N(1), N(3), N(4)) strongly bonded to Tl3+ is adopted as a reference plane 3N. The pyrrole N(2) ring bearing the methyl group (i.e., C(45)H3) is the most deviated one from the 3N plane, making a dihedral angle of 21.4 degrees, whereas smaller angles of 9.1 degrees, 7.1 degrees, and 0.9 degree occur with pyrroles N(1), N(3), and N(4), respectively. Because of its larger size, the thallium(III) ion Tl3+ is considerably out of the 3N plane; its displacement of 1.17 A is in the same direction as that of the two apical OAc- ligands. The intermolecular acetate exchange process for 1 in THF-d8 solvent is examined through 1H NMR temperature-dependent measurements. In the slow-exchange region, the methyl and carbonyl carbons of the OAc- groups in 1 are separately located at delta 18.6 [3J(Tl-13C) = 405 Hz] and 170.8 [2J(Tl-13C) = 334 Hz] at -80 degrees C, respectively.