Hemodynamic and anti-inflammatory effects of early esmolol use in hyperkinetic septic shock. a pilot study

Background: Several studies have shown that heart rate control with selective beta-1 blockers in septic shock is safe. In these trials, esmolol was administered 24 h after onset of septic shock in patients who remained tachycardic. While an earlier use of beta-blockers might be beneficial, such use remains challenging due to the difficulty in distinguishing between compensatory and non-compensatory tachycardia. Therefore, the Esmosepsis study was designed to study the effects of esmolol aimed at reducing the heart rate by 20% after the initial resuscitation process in hyperkinetic septic shock patients on (1) cardiac index and (2) systemic and regional hemodynamics as well as inflammatory patterns. Methods: Nine consecutive stabilized tachycardic hyperkinetic septic shock patients treated with norepinephrine for a minimum of 6 h were included. Esmolol was infused during 6 h in order to decrease the heart rate by 20%. The following data were recorded at hours H0 (before esmolol administration), H1–H6 (esmolol administration) and 1 h after esmolol cessation (H7): systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, central venous pressure, heart rate, PICCO transpulmonary thermodilution, sublingual and musculo-cutaneous microcirculation, indocyanine green clearance and echocardiographic parameters, diuresis, lactate, and arterial and venous blood gases. Results: Esmolol was infused 9 (6.4–11.6) hours after norepinephrine introduction. Esmolol was ceased early in 3 out of 9 patients due to a marked increase in norepinephrine requirement associated with a picture of persistent cardiac failure at the lowest esmolol dose. For the global group, during esmolol infusion, norepinephrine infusion increased from 0.49 (0.34–0.83) to 0.78 (0.3–1.11) µg/min/kg. The use of esmolol was associated with a significant decrease in heart rate from 115 (110–125) to 100 (92–103) beats/min and a decrease in cardiac index from 4.2 (3.1–4.4) to 2.9 (2.5–3.7) l/min/m−2. Indexed stroke volume remained unchanged. Cardiac function index and global ejection fraction also markedly decreased. Using echocardiography, systolic, diastolic as well as left and right ventricular function parameters worsened. After esmolol cessation, all parameters returned to baseline values. Lactate and microcirculatory parameters did not change while the majority of pro-inflammatory proteins decreased in all patients. Conclusion: In the very early phase of septic shock, heart rate reduction using fast esmolol titration is associated with an increased risk of hypotension and decreased cardiac index despite maintained adequate tissue perfusion (NCT02068287)

GReEn: a tool for efficient compression of genome resequencing data

Research in the genomic sciences is confronted with the volume of sequencing and resequencing data increasing at a higher pace than that of data storage and communication resources, shifting a significant part of research budgets from the sequencing component of a project to the computational one. Hence, being able to efficiently store sequencing and resequencing data is a problem of paramount importance. In this article, we describe GReEn (Genome Resequencing Encoding), a tool for compressing genome resequencing data using a reference genome sequence. It overcomes some drawbacks of the recently proposed tool GRS, namely, the possibility of compressing sequences that cannot be handled by GRS, faster running times and compression gains of over 100-fold for some sequences. This tool is freely available for non-commercial use at ftp://ftp.ieeta.pt/∼ap/codecs/GReEn1.tar.gz

Associations of Type 2 Diabetes with Common Variants in PPARD and the Modifying Effect of Vitamin D among Middle-Aged and Elderly Chinese

BACKGROUND: Previous studies have identified that variants in peroxisome proliferator-activated receptor PPAR-δ (PPARD), a target gene of vitamin D, were significantly associated with fasting glucose and insulin sensitivity in European populations. This current study sought to determine (1) whether the genetic associations of PPARD variants with type 2 diabetes and its related traits could be replicated in Chinese Han population, and (2) whether the associations would be modified by the effect of vitamin D status. METHODS AND FINDINGS: We genotyped 9 tag single nucleotide polymorphisms (SNPs) that cover the gene of PPARD (rs2267664, rs6902123, rs3798343, rs2267665, rs2267668, rs2016520, rs2299869, rs1053049, and rs9658056) and tested their associations with type 2 diabetes risk and its related traits, including fasting glucose, insulin and HbA1c in 3,210 Chinese Hans. Among the 9 PPARD tag SNPs, rs6902123 was significantly associated with risk of type 2 diabetes (odds ratio 1.75 [95%CI 1.22-2.53]; P = 0.0025) and combined type 2 diabetes and impaired fasting glucose (IFG) (odds ratio 1.47 [95%CI 1.12-1.92]; P = 0.0054). The minor C allele of rs6902123 was associated with increased levels of fasting glucose (P = 0.0316) and HbA1c (P = 0.0180). In addition, we observed that vitamin D modified the effect of rs6902123 on HbA1c (P for interaction = 0.0347). CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that common variants in PPARD contribute to the risk of type 2 diabetes in Chinese Hans, and provided suggestive evidence of interaction between 25(OH)D levels and PPARD-rs6902123 on HbA1c

Endothelial function and urine albumin levels among asymptomatic Mexican-Americans and non-Hispanic whites

<p>Abstract</p> <p>Background-</p> <p>Mexican-Americans (MA) exhibit increases in various cardiovascular disease (CVD) risk factors compared to non-Hispanic Whites (NHW), yet are reported to have lower CVD mortality rates. Our aim was to help explain this apparent paradox by evaluating endothelial function and urine albumin levels in MA and NHW.</p> <p>Methods-</p> <p>One hundred-five MA and 100 NHW adults were studied by brachial artery flow-mediated dilatation (FMD), blood and urine tests. Participants were studied by ultrasound-determined brachial artery flow-mediated dilatation (FMD), blood and urine tests, at a single visit.</p> <p>Results-</p> <p>Despite higher BMI and triglycerides in MA, MA demonstrated higher FMD than did NHW (9.1 ± 7.3% vs. 7.1 ± 6.3%, p < 0.04). Among MA, urinary albumin was consistently lower in participants with FMD ≥ 7% FMD versus < 7% FMD (p < 0.006). In multivariate analyses in MA men, urinary albumin was inversely related to FMD (r = -0.26, p < 0.05), as were BMI and systolic blood pressure. In MA women, urinary albumin:creatinine ratio was an independent inverse predictor of FMD (p < 0.05 ).</p> <p>Conclusion-</p> <p>To our knowledge, this is the first study to analyze, in asymptomatic adults, the relation of MA and NHW ethnicity to FMD and urine albumin levels. The findings confirm ethnic differences in these important subclinical CVD measures.</p

Plague: past, present and future

[Introduction] Recent experience with SARS (severe acute respiratory syndrome) [1] and avian flu shows that the public and political response to threats from new anthropozoonoses can be near-hysteria. This can readily make us forget more classical animal-borne diseases, such as plague (Box 1). Three recent international meetings on plague (Box 2) concluded that: (1) it should be re-emphasised that the plague bacillus (Yersinia pestis) still causes several thousand human cases per year [2,3] (Figure 1); (2) locally perceived risks far outstrip the objective risk based purely on the number of cases [2]; (3) climate change might increase the risk of plague outbreaks where plague is currently endemic and new plague areas might arise [2,4]; (4) remarkably little is known about the dynamics of plague in its natural reservoirs and hence about changing risks for humans [5]; and, therefore, (5) plague should be taken much more seriously by the international community than appears to be the case

STAT3 regulated ARF expression suppresses prostate cancer metastasis.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.Lukas Kenner and Jan Pencik are supported by FWF, P26011 and the Genome Research-Austria project “Inflammobiota” grants. Helmut Dolznig is supported by the Herzfelder Family Foundation and the Niederösterr. Forschungs-und Bildungsges.m.b.H (nfb). Richard Moriggl is supported by grant SFB-F2807 and SFB-F4707 from the Austrian Science Fund (FWF), Ali Moazzami is supported by Infrastructure for biosciences-Strategic fund, SciLifeLab and Formas, Zoran Culig is supported by FWF, P24428, Athena Chalaris and Stefan Rose-John are supported by the Deutsche Forschungsgemeinschaft (Grant SFB 877, Project A1and the Cluster of Excellence --“Inflammation at Interfaces”). Work of the Aberger lab was supported by the Austrian Science Fund FWF (Projects P25629 and W1213), the European FP7 Marie-Curie Initial Training Network HEALING and the priority program Biosciences and Health of the Paris-Lodron University of Salzburg. Valeria Poli is supported by the Italian Association for Cancer Research (AIRC, No IG13009). Richard Kennedy and Steven Walker are supported by the McClay Foundation and the Movember Centre of Excellence (PC-UK and Movember). Gerda Egger is supported by FWF, P27616. Tim Malcolm and Suzanne Turner are supported by Leukaemia and Lymphoma Research.This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms873

A Toll-Like Receptor 2 Pathway Regulates the Ppargc1a/b Metabolic Co-Activators in Mice with Staphylococcal aureus Sepsis

Activation of the host antibacterial defenses by the toll-like receptors (TLR) also selectively activates energy-sensing and metabolic pathways, but the mechanisms are poorly understood. This includes the metabolic and mitochondrial biogenesis master co-activators, Ppargc1a (PGC-1α) and Ppargc1b (PGC-1β) in Staphylococcus aureus (S. aureus) sepsis. The expression of these genes in the liver is markedly attenuated inTLR2−/− mice and markedly accentuated in TLR4−/− mice compared with wild type (WT) mice. We sought to explain this difference by using specific TLR-pathway knockout mice to test the hypothesis that these co-activator genes are directly regulated through TLR2 signaling. By comparing their responses to S. aureus with WT mice, we found that MyD88-deficient and MAL-deficient mice expressed hepatic Ppargc1a and Ppargc1b normally, but that neither gene was activated in TRAM-deficient mice. Ppargc1a/b activation did not require NF-kβ, but did require an interferon response factor (IRF), because neither gene was activated in IRF-3/7 double-knockout mice in sepsis, but both were activated normally in Unc93b1-deficient (3d) mice. Nuclear IRF-7 levels in TLR2−/− and TLR4−/− mice decreased and increased respectively post-inoculation and IRF-7 DNA-binding at the Ppargc1a promoter was demonstrated by chromatin immunoprecipitation. Also, a TLR2-TLR4-TRAM native hepatic protein complex was detected by immunoprecipitation within 6 h of S. aureus inoculation that could support MyD88-independent signaling to Ppargc1a/b. Overall, these findings disclose a novel MyD88-independent pathway in S. aureus sepsis that links TLR2 and TLR4 signaling in innate immunity to Ppargc1a/b gene regulation in a critical metabolic organ, the liver, by means of TRAM, TRIF, and IRF-7

Spectroscopy Of Ncncs At The Canadian Light Source: The Far-infrared Spectrum Of The Ν7 Region From 60-140 Cm−1

We report on the analysis of our spectrum from 60-140 \wn\ of the $\nu_7$ bending fundamental and associated hot band sequence of NCNCS, obtained on the far-infrared beamline at the Canadian Light Source synchrotron. The data were collected in May 2013, building upon what we learned conducting experiments in May 2011 and 2012 on this molecule. Calculations indicated that the $\nu_7$ system was very weak (one of the four weakest fundamental bands, all of comparable strength), but its spectrum became evident when 30 mTorr of NCNCS was admitted into the 2-m-long sample cell, through which the synchrotron beam passed 40 times. The best spectrum so far has been obtained with 121 mTorr of gas. Loomis-Wood plots reveal many branches, some of which were unambiguously assignable to $\Delta \nu_7 = +1$ subbands for $\nu_7^{\prime\prime} = 0, 1, 2, 3$ and for $K_a = 0, 1,2$ with $\Delta K_a = 0$ (a-type subbands) by comparison of lower-state combination differences with those obtained from the published pure-rotational data. We will continue the analysis by assigning as many a-type subbands as possible and by searching for b-type subbands with $\Delta K_a = \pm 1$ so that the connections between $K_a$-stacks can be measured. Finally, we will simultaneously fit the infrared and rotational data with a generalized semi-rigid bender Hamiltonian

Economic Analysis of Knowledge: The History of Thought and the Central Themes

Following the development of knowledge economies, there has been a rapid expansion of economic analysis of knowledge, both in the context of technological knowledge in particular and the decision theory in general. This paper surveys this literature by identifying the main themes and contributions and outlines the future prospects of the discipline. The wide scope of knowledge related questions in terms of applicability and alternative approaches has led to the fragmentation of research. Nevertheless, one can identify a continuing tradition which analyses various aspects of the generation, dissemination and use of knowledge in the economy