Introduction Women or girls with haemophilia (WGH) represent a group of female symptomatic carriers who experience bleeding events more frequently than non‐carriers. Bleeding events include spontaneous/traumatic bleeds and prolonged bleeding related to surgery, menstruation and pregnancy. Challenges for the treatment of WGH include lack of screening, diagnosis and treatment guidelines. Aim Evaluate clinical characteristics, haemostasis management and clinical outcomes regarding menstruation, childbirth, dental procedures, surgeries and other bleeding events in WGH. Methods A retrospective, non‐interventional review of medical records from WGH among three haemophilia treatment centres (HTCs) was conducted in the United States (2012–2018). Patients with ≥2 visits to the HTC and who had undergone intervention for haemostasis management with the outcome documented were included. Descriptive statistics were used. Results Of 47 women and girls included in the chart review (37 with factor VIII deficiency, 10 with factor IX deficiency), median age at diagnosis was 22.6 years. Approximately 79% (n = 37) were diagnosed with mild haemophilia. Events of interest were primarily managed by factor concentrates or antifibrinolytics. Most treatment approaches were successful across clinical scenarios, except for heavy menstrual bleeding being insufficiently controlled in 8 (57%) of the 14 patients who experienced it. Conclusions Bleeding events in WGH, such as excessive and prolonged bleeding during menstruation, demonstrate a unique burden and require specific medical intervention. These results highlight the importance of assessing the need for haemostasis management in WGH and may contribute to future prospective study designs.
6S RNA is a noncoding RNA that inhibits bacterial transcription by sequestering RNA polymerase holoenzyme (Eσ 70 ) in lownutrient conditions. This transcriptional block can be relieved by the synthesis of a short product RNA (pRNA) using the 6S RNA as a template. Here, we selected a range of 6S RNA release-defective mutants from a high diversity in vitro pool. Studying the release-defective variant R9-33 uncovered complex interactions between three regions of the 6S RNA. As expected, mutating the transcriptional start site (TSS) slowed and partially inhibited release. Surprisingly, additional mutations near the TSS were found that rescued this effect. Likewise, three mutations in the top strand of the large open bubble (LOB) could considerably slow release but were rescued by the addition of upstream mutations found between a highly conserved "-35" motif and the LOB. Combining the three top strand LOB mutations with mutations near the TSS, however, was particularly effective at preventing release, and this effect could be further enhanced by inclusion of the upstream mutations. Overexpressing R9-33 and a series of milder release-defective mutants in Escherichia coli resulted in a delayed entry into exponential phase together with a decrease in cell survival that correlated well with the severity of the in vitro phenotypes. The complex crosstalk observed between distinct regions of the 6S RNA supports a scrunching type model of 6S RNA release, where at least three regions of the 6S RNA must interact with Eσ 70 in a cooperative manner so as to ensure effective pRNAdependent release.
Small RNAs, defined as noncoding 20-30-nt-long RNAs, are instrumental regulators of cellular processes in most eukaryotes. In this chapter we describe three methods for extracting small RNA from cells: a general method, one plant specific and a third particular to conifers. Further, protocols are given for the analysis and quantification of small RNAs using polyacrylamide gel-based approaches. A native streptavidin gel-shift assay, useful for measuring the relative amounts of multiple small RNAs simultaneously, is presented. To further characterize small RNAs biochemically, a sodium periodate assay probing for 2', 3' hydroxyl groups on the 3' terminus of small RNAs is outlined.
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