Correlation between the level of evidence and the class of recommendations concerning the pharmacological aspects of the Guidelines of the European Society of Cardiology.

Background The reliability of the recommendations affecting the clinical decisions is being continuously weighed in everyday practice (Gershlick, 2018). The objective of our study was to assess the consistency of the evidence behind the recommendations. Methods We narrowed our focus on the pharmacotherapeutic aspects of the most recent 38 European Society of Cardiology guidelines and analyzed the correlation between the level of evidence (LoE) classified as A, B and C and the class of recommendations (CoR) subdivided into I, IIa, IIb and III. Results Contrary to the majority of recommendations based on a LoE C (43,0%), fewer recommendations were proposed on heavily evidence-supported LoE A (23.8%), which percentage increased with subsequent updates of the guidelines. The most common recommendation was CoR I (44,9%), while the least common recommendation was CoR III (9,2%). While a similar share of A (39,1%) and C (30,1%) LoE shaped the CoR I nearly half (48,8%) of the CoR III were based on LoE C. Conversely, the overwhelming majority of the recommendations within the scope of LoE A were indisputably strong and classified as CoR I (73,7%). Conclusion The pharmacological aspects of the ESC guidelines are predominantly based on LoE C. A greater number of pharmacological recommendations are based on LoE A in comparison to the general ones. Various constraints significantly skew the credibility due to paucity of scientific data. A more nuanced approach is needed, as the guidelines cannot completely substitute the clinical experience and the patient-centered approach in shaping the optimal therapeutic outcome.

Inability to phosphorylate Y88 of p27Kip1 enforces reduced p27 protein levels and accelerates leukemia progression.

The cyclin-dependent kinase (CDK) inhibitor p27Kip1 regulates cell proliferation. Phosphorylation of tyrosine residue 88 (Y88) converts the inhibitor into an assembly factor and activator of CDKs, since Y88-phosphorylation restores activity to cyclin E,A/CDK2 and enables assembly of active cyclin D/CDK4,6. To investigate the physiological significance of p27 tyrosine phosphorylation, we have generated a knock-in mouse model where Y88 was replaced by phenylalanine (p27-Y88F). Young p27-Y88F mice developed a moderately reduced body weight, indicative for robust CDK inhibition by p27-Y88F. When transformed with v-ABL or BCR::ABL1p190, primary p27-Y88F cells are refractory to initial transformation as evidenced by a diminished outgrowth of progenitor B-cell colonies. This indicates that p27-Y88 phosphorylation contributes to v-ABL and BCR::ABL1p190 induced transformation. Surprisingly, p27-Y88F mice succumbed to premature v-ABL induced leukemia/lymphoma compared to p27 wild type animals. This was accompanied by a robust reduction of p27-Y88F levels in v-ABL transformed cells. Reduced p27-Y88F levels seem to be required for efficient cell proliferation and may subsequently support accelerated leukemia progression. The potent downregulation p27-Y88F levels in all leukemia-derived cells could uncover a novel mechanism in human oncogenesis, where reduced p27 levels are frequently observed.

Eyelid skin disinfecting and conjunctival bacteria in cataract surgery.

PURPOSE: To evaluate the effect on conjunctival micro-organisms of chlorhexidine alcohol 0.5% eyelid wash in cataract patients. METHODS: In this single-centre experimental study, 120 patients scheduled to undergo cataract operation were cultured in the conjunctiva before the operation and after the insertion of the intraocular lens. Bacterial samples for aerobic and anaerobic cultures were taken with a polyvinyl alcohol pad and transported in peptone water to the microbiological laboratory where they were analysed in a blinded fashion. Half of the patients received a standardized eyelid scrub with chlorhexidine alcohol 0.5%, while the rest did not. The conjunctiva of all patients was rinsed preoperatively with chlorhexidine solution 0.05%. RESULTS: In all the between-group comparisons, the treated eyelid group had slightly lower bacterial counts than the control group on the postoperative samples, but differences were far from statistically significant. Within-group comparisons revealed statistically significant reduction in colonies and species between the preoperative and postoperative sampling. CONCLUSION: In this experimental culture study, no evidence was found to suggest that preoperative eyelid chlorhexidine alcohol wash is effective in further reducing bacterial counts in the conjunctiva when the conjunctiva itself is rinsed preoperatively with chlorhexidine solution. The present results, however, do not contradict that the wash may be of some marginal help in reducing bacterial contamination of the operation field. Consequently, this part of the prophylactic protocol is still in practice in our institution.

Low immunogenicity allows Staphylococcus epidermidis to cause PD peritonitis.

BACKGROUND: Peritonitis is a common and serious complication of peritoneal dialysis (PD). Coagulase-negative staphylococci from the patient's own skin flora are the most commonly found micro-organisms. OBJECTIVE: In the present study we aim to elucidate the immune response in the early stage of infection and to clarify the importance of bacterial attachment to fibrinogen. METHODS: Clinical Staphylococcus epidermidis isolates collected from PD peritonitis or the residential skin flora of healthy individuals were used to infect monocytes, macrophages, and peripheral blood mononuclear cells (PBMC) in the presence or absence of fibrinogen. The S. epidermidis strain HB (fbe(+)), expressing the fibrinogen-binding protein Fbe, and its isogenic mutant ST056 (fbe(-)) were used to study the impact of Fbe during cell infection. Immune induction was measured as interleukin-8 (IL-8) production determined by ELISA. Modulation of CD11b/CD18 expression in neutrophils incubated in conditioned medium from these experiments was analyzed in order to judge the cellular response. RESULTS: S. epidermidis causing peritonitis was less immunogenic compared to strains belonging to the residential skin flora, as measured by IL-8 induction in monocytes and CD11b/CD18 expression in neutrophils. At low bacterial concentrations, attachment to fibrinogen was a prerequisite for an IL-8 induction in monocytes and PBMC. The fibrinogen-binding protein Fbe did not, however, influence immune induction under this condition. CONCLUSIONS: We suggest that S. epidermidis strains may be able to cause clinical infection by evoking an inadequate immunological response in the early stage of infection. Bacterial attachment to fibrinogen is a relevant event during this phase but independent of the fibrinogen-binding protein Fbe.