Sex differences in transradial access site characteristics and crossover in STEMI

Objective To assess the differences according to sex in radial artery access site characteristics and crossover and it's influence on the success of ST segment elevation myocardial infarction (STEMI) procedures with primary chosen transradial access site in a large series of patients. Background Transradial angiography (TRA) is now the default access site for PPCI, but technically is a more challenging approach mostly due to anatomic challenges connected to the radial artery. Methods All 5092 consecutive STEMI patients from our center, in the period from March 2011 until December 2017 were examined. Patient were divided in two groups according to sex. Preprocedural radial artery angiography was performed in all patients. Clinical and procedure characteristics, type of radial anatomy variants, transfer to other access sites, transfer direction and procedure time were analyzed. Access site bleeding complications and in-hospital mortality were also recorded. Primary end-point of the study was the occurrence of TRA failure and need to crossover to another access site to finish the procedure. Results From the STEMI population in this period the female group had 1326 PPCI treated patients and the male group 3766 patients. The female group of patients was older 65±11 than the male group 59±11 (p<0,0001). BMI was 27 vs. 30 in the male group (p=0.0003). Most common risk factors in both groups were hypertension, smoking and diabetes, with the latter being more frequent in the female group p<0,0001. Radial artery anomalies were more frequent in the female group 8,8% vs 6,5% (p<0,0001), with complex RA loop and tortuous RA having double percentage than in their male counterparts. Primary chosen TRA access site failure occurred in 4.6% (61) vs. 3.5% (97) of STEMI patients (p<0.0001). Most common access site crossover site was right ulnar access in both groups with 57 and 61% accordingly. Access site bleeding complications, were more common in the female group with 4.4% vs. 3.2%, also this difference persisted in EASY score hematoma 3 to 5. Clinical radial artery spasm was significantly more frequent in female patients 5,7% vs. 2.2% (p<0.0001). In-hospital mortality rate was similar in the two group of patients. Conclusion Female sex is a significant risk factor for TRA failure in STEMI usually connected to smaller size of RA and the more common finding of radial artery anomalies and spasm. FUNDunding Acknowledgement Type of funding sources: None.

Spatial and temporal control of targeting Polo-like kinase during meiotic prophase

Polo-like kinases (PLKs) play widely conserved roles in orchestrating meiotic chromosome dynamics. However, how PLKs are targeted to distinct subcellular localizations during meiotic progression remains poorly understood. Here, we demonstrate that the cyclin-dependent kinase CDK-1 primes the recruitment of PLK-2 to the synaptonemal complex (SC) through phosphorylation of SYP-1 in C. elegans. SYP-1 phosphorylation by CDK-1 occurs just before meiotic onset. However, PLK-2 docking to the SC is prevented by the nucleoplasmic HAL-2/3 complex until crossover designation, which constrains PLK-2 to special chromosomal regions known as pairing centers to ensure proper homologue pairing and synapsis. PLK-2 is targeted to crossover sites primed by CDK-1 and spreads along the SC by reinforcing SYP-1 phosphorylation on one side of each crossover only when threshold levels of crossovers are generated. Thus, the integration of chromosome-autonomous signaling and a nucleus-wide crossover-counting mechanism partitions holocentric chromosomes relative to the crossover site, which ultimately defines the pattern of chromosome segregation during meiosis I.

Divergent kleisin subunits of cohesin specify mechanisms to tether and release meiotic chromosomes

We show that multiple, functionally specialized cohesin complexes mediate the establishment and two-step release of sister chromatid cohesion that underlies the production of haploid gametes. In C. elegans, the kleisin subunits REC-8 and COH-3/4 differ between meiotic cohesins and endow them with distinctive properties that specify how cohesins load onto chromosomes and then trigger and release cohesion. Unlike REC-8 cohesin, COH-3/4 cohesin becomes cohesive through a replication-independent mechanism initiated by the DNA double-stranded breaks that induce crossover recombination. Thus, break-induced cohesion also tethers replicated meiotic chromosomes. Later, recombination stimulates separase-independent removal of REC-8 and COH-3/4 cohesins from reciprocal chromosomal territories flanking the crossover site. This region-specific removal likely underlies the two-step separation of homologs and sisters. Unexpectedly, COH-3/4 performs cohesion-independent functions in synaptonemal complex assembly. This new model for cohesin function diverges from that established in yeast but likely applies directly to plants and mammals, which utilize similar meiotic kleisins.

Orchestrating serine resolvases

A remarkable feature of the serine resolvases is their regulation: the wild-type enzymes will catalyse intra- but not inter-molecular recombination, can sense the relative orientation of their sites and can exchange strands directionally, despite the fact that there is no net release of chemical bond energy. The key to this regulation is that they are only active within a large intertwined complex called the ‘synaptosome’. Because substrate topology greatly facilitates (or, in other cases, inhibits) formation of the synaptosome, it acts as a ‘topological filter’. Within the defined topology of the synaptosome, strand exchange releases supercoiling tension, providing an energy source to bias the reaction direction. The regulatory portion of this complex contains additional copies of the recombinase and sometimes other DNA-bending proteins. We are using a combination of X-ray crystallography, biochemistry and genetics to model the full synaptic complex and to understand how the regulatory portion activates the crossover-site-bound recombinases.

A Plasmid-Borne Shewanella algae Gene, qnrA3, and Its Possible Transfer In Vivo between Kluyvera ascorbata and Klebsiella pneumoniae

ABSTRACT The plasmid-borne quinolone resistance gene qnrA1 is prevalent in multidrug-resistant Enterobacteriaceae. A chromosomally encoded homologue in Shewanella algae, qnrA3, has been described. We isolated two qnrA3-positive strains, one of Klebsiella pneumoniae (He96) and one of Kluyvera ascorbata (Kas96), from the feces of an immunocompromised outpatient. The qnrA3 allele was identical to that of S. algae except for 5 nucleotides and differed from qnrA1 by 29 nucleotides affecting three amino acids. The analysis of the qnrA3 genetic environment showed that qnrA3 was inserted downstream from an ISCR1 element at a recombination crossover site described for other resistance genes, including qnrA1, and immediately upstream from IS26, a situation not described before. IS26 preceded an incomplete class 1 integron which contained, among other genes, aac(6′)-Ib-cr, another transferable quinolone resistance gene, and the β-lactamase gene bla OXA-1/30. The 10-kb fragment encompassing qnrA3 was compared to previously described qnrA1-containing plasmids and multidrug-resistant plasmids; it shares identical sequences with pC15a, pHSH2, pQR1, pQKp311H, and pSAL-1 but with rearrangements, deletions, and mutations. Conjugal transfer of qnrA3 was highly efficient (10−2) from K. pneumoniae He96 or K. ascorbata Kas96 to Escherichia coli J53 but less so (10−5) from either donor to a clinical strain of Enterobacter cloacae. This first description of a plasmid-borne copy and of the in vitro transfer of qnrA3 is taken to illustrate its likely in vivo transfer from S. algae to the Enterobacteriaceae.