Plasma hyaluronan, hyaluronidase activity and endogenous hyaluronidase inhibition in sepsis: an experimental and clinical cohort study

Background Plasma hyaluronan concentrations are increased during sepsis but underlying mechanisms leading to high plasma hyaluronan concentration are poorly understood. In this study we evaluate the roles of plasma hyaluronan, effective plasma hyaluronidase (HYAL) activity and its endogenous plasma inhibition in clinical and experimental sepsis. We specifically hypothesized that plasma HYAL acts as endothelial glycocalyx shedding enzyme, sheddase. Methods Plasma hyaluronan, effective HYAL activity and HYAL inhibition were measured in healthy volunteers (n = 20), in patients with septic shock (n = 17, day 1 and day 4), in patients with acute pancreatitis (n = 7, day 1 and day 4) and in anesthetized and mechanically ventilated pigs (n = 16). Sixteen pigs were allocated (unblinded, open label) into three groups: Sepsis-1 with infusion of live Escherichia coli (E. coli) 1 × 108 CFU/h of 12 h (n = 5), Sepsis-2 with infusion of E. coli 1 × 108 CFU/h of 6 h followed by 1 × 109 CFU/h of the remaining 6 h (n = 5) or Control with no E. coli infusion (n = 6). Results In experimental E. coli porcine sepsis and in time controls, plasma hyaluronan increases with concomitant decrease in effective plasma HYAL activity and increase of endogenous HYAL inhibition. Plasma hyaluronan increased in patients with septic shock but not in acute pancreatitis. Effective plasma HYAL was lower in septic shock and acute pancreatitis as compared to healthy volunteers, while plasma HYAL inhibition was only increased in septic shock. Conclusion Elevated plasma hyaluronan levels coincided with a concomitant decrease in effective plasma HYAL activity and increase of endogenous plasma HYAL inhibition both in experimental and clinical sepsis. In acute pancreatitis, effective plasma HYAL activity was decreased which was not associated with increased plasma hyaluronan concentrations or endogenous HYAL inhibition. The results suggest that plasma HYAL does not act as sheddase in sepsis or pancreatitis.

Rab8 GTPase differentially controls the long-, and short-range activity of the Hedgehog morphogen gradient by regulating Hedgehog apico-basal distribution

The Hedgehog (Hh) morphogen gradient is required for patterning during metazoan development, yet the mechanisms involved in Hh apical and basolateral release and how this influences short- and long-range target induction are poorly understood. We found that depletion of the GTPase Rab8 in Hh producing cells induces an imbalance between the level of apically and laterally released Hh. This leads to a non-cell autonomous differential effects on the expression of Hh target genes, namely an increase in the short-range and a concomitant decrease in the long-range. We further found that Rab8 regulates the endocytosis and apico-basal distribution of Ihog, a transmembrane protein known to bind to Hh and critical for the establishment of the Hh gradient. Our data provide new understandings of morphogen gradient formation, whereby morphogen activity is functionally distributed between apically and baso-laterally secreted pools.

Six-months CrossFit training improves metabolic efficiency in young trained men (Seis meses de CrossFit mejora la eficiencia metabólica en jóvenes entrenados)

The objective was to analyse the effects of 6 months’ CrossFit on physical performance, metabolic efficiency, body composition, and biochemical parameters. Ten trained CrossFit practitioners were assessed before and after CrossFit training. Anthropometric measurements, biochemical parameters and physical performance parameters were assessed with functional and incremental tests. After 6 months of CrossFit, fat oxidation rate and energy percentage obtained from fat significantly increased (+221.43%; p=.043 and +222.39%; p=.043 respectively) with a concomitant decrease in carbohydrate oxidation rate and use of carbohydrates in maximal values (-47.35%; p=.043 and -34.41%; p=.043, respectively). In the maximal fat oxidation zone, maximal oxygen uptake increased (+20.3%; p=.043). Fat oxidation rate significantly increased with a concomitant decrease in carbohydrate oxidation rate (+62.75% vs -27.67%; p=.043). Lactate dehydrogenase values increased significantly (+27.13%; p= .043). In conclusion, 6 months of CrossFit improves the metabolic efficiency of the fat oxidation zone, without muscle damage.

Internal and External Mechanisms of Englishization: Changes in Marked and Unmarked Chinese Passive Constructions

The Chinese language is changing, and like other languages, has been becoming more like English. This article focuses on the Englishization (Europeanization) of certain Chinese passive constructions. Previous research indicates that written Chinese has seen an increase in the use of the 被 bèi passive construction (BEIC) and a concomitant decrease in use of the notional passive construction (NPC) over time. This assertion is supported by a corpus-based analysis. An apparent-time research study shows that, in general, younger, more educated participants (those hypothesized to have more exposure to English) are more likely to use BEIC than are older, less educated participants in the sentence continuation task. However, this difference between groups is not captured in the binary forced choice task due to the increased use of BEIC under a conscious condition by the older, less educated participants. This finding sheds light on the psychological mechanism of internalization involved with Englishization.

Improving recovery after elective degenerative spine surgery: 5-year experience with an enhanced recovery after surgery (ERAS) protocol

OBJECTIVEEnhanced recovery after surgery (ERAS) has led to a paradigm shift in various surgical specialties. Its application can result in substantial benefits in perioperative healthcare utilization through preoperative physical and mental patient optimization and modulation of the recovery process. Still, ERAS remains relatively new to spine surgery. The authors report their 5-year experience, focusing on ERAS application to a broad population of patients with degenerative spine conditions undergoing elective surgical procedures, including anterior lumbar interbody fusion (ALIF).METHODSA multimodal ERAS protocol was applied between November 2013 and October 2018. The authors analyze hospital stay, perioperative outcomes, readmissions, and adverse events obtained from a prospective institutional registry. Elective tubular microdiscectomy and mini-open decompression as well as minimally invasive (MI) anterior or posterior fusion cases were included. Their institutional ERAS protocol contains 22 pre-, intra-, and postoperative elements, including preoperative patient counseling, MI techniques, early mobilization and oral intake, minimal postoperative restrictions, and regular audits.RESULTSA total of 2592 consecutive patients were included, with 199 (8%) undergoing fusion. The mean hospital stay was 1.1 ± 1.2 days, with 20 (0.8%) 30-day and 36 (1.4%) 60-day readmissions. Ninety-four percent of patients were discharged after a maximum 1-night hospital stay. Over the 5-year period, a clear trend toward a higher proportion of patients discharged home after a 1-night stay was observed (p < 0.001), with a concomitant decrease in adverse events in the overall cohort (p = 0.025) and without increase in readmissions. For fusion procedures, the rate of 1-night hospital stays increased from 26% to 85% (p < 0.001). Similarly, the average length of hospital stay decreased steadily from 2.4 ± 1.2 days to 1.5 ± 0.3 days (p < 0.001), with a notable concomitant decrease in variance, resulting in an estimated reduction in nursing costs of 46.8%.CONCLUSIONSApplication of an ERAS protocol over 5 years to a diverse population of patients undergoing surgical procedures, including ALIF, for treatment of degenerative spine conditions was safe and effective, without increase in readmissions. The data from this large case series stress the importance of the multidisciplinary, iterative improvement process to overcome the learning curve associated with ERAS implementation, and the importance of a dedicated perioperative care team. Prospective trials are needed to evaluate spinal ERAS on a higher level of evidence.

Depletion of Mediator Kinase Module Subunits Represses Superenhancer-Associated Genes in Colon Cancer Cells

ABSTRACT In cancer, oncogene activation is partly mediated by acquired superenhancers, which therefore represent potential targets for inhibition. Superenhancers are enriched for BRD4 and Mediator, and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of superenhancer-associated genes in stem cells. Here we show that depletion of Mediator kinase module subunit MED12 or MED13 together with MED13L can be used to reduce expression of cancer-acquired superenhancer genes, such as the MYC gene, in colon cancer cells, with a concomitant decrease in proliferation. Whereas depletion of MED12 or MED13/MED13L caused a disproportional decrease of superenhancer gene expression, this was not seen with depletion of the kinases cyclin-dependent kinase 9 (CDK8) and CDK19. MED12-MED13/MED13L-dependent superenhancer genes were coregulated by β-catenin, which has previously been shown to associate with MED12. Importantly, β-catenin depletion caused reduced binding of MED12 at the MYC superenhancer. The effect of MED12 or MED13/MED13L depletion on cancer-acquired superenhancer gene expression was more specific than and partially distinct from that of BRD4 depletion, with the most efficient inhibition seen with combined targeting. These results identify a requirement of MED12 and MED13/MED13L for expression of acquired superenhancer genes in colon cancer, implicating these Mediator subunits as potential therapeutic targets for colon cancer, alone or together with BRD4.