LIN28 is an RNA-binding protein that is expressed in many developing tissues. It can block let-7 (Mirlet7) microRNA processing and help promote pluripotency. We have observed LIN28 expression in the ...developing mouse neural tube, colocalizing with SOX2, suggesting a role in neural development. To better understand its normal developmental function, we investigated LIN28 activity during neurogliogenesis in vitro, where the succession of neuronal to glial cell fates occurs as it does in vivo. LIN28 expression was high in undifferentiated cells, and was downregulated rapidly upon differentiation. Constitutive LIN28 expression caused a complete block of gliogenesis and an increase in neurogenesis. LIN28 expression was compatible with neuronal differentiation and did not increase proliferation. LIN28 caused significant changes in gene expression prior to any effect on let-7, notably on Igf2. Furthermore, a mutant LIN28 that permitted let-7 accumulation was still able to completely block gliogenesis. Thus, at least two biological activities of LIN28 are genetically separable and might involve distinct mechanisms. LIN28 can differentially promote and inhibit specific fates and does not function exclusively by blocking let-7 family microRNAs. Importantly, the role of LIN28 in cell fate succession in vertebrate cells is analogous to its activity as a developmental timing regulator in C. elegans.
Syncope and collapse in acute pulmonary embolism Keller, Karsten, MD; Beule, Johannes, MD; Balzer, Jörn Oliver, MD ...
The American journal of emergency medicine,
07/2016, Letnik:
34, Številka:
7
Journal Article
Recenzirano
Abstract Background Syncope and collapse (= presyncope) are 2 symptoms of pulmonary embolism (PE), which are suspected of being connected with poorer outcome, regardless of haemodynamic instability. ...However, pathomechanisms are not completely understood. We aimed to investigate these pathomechanisms in regard to blood pressure and heart rate of syncope/collapse in PE. Methods We performed a retrospective study of consecutive PE patients, who were treated in the Internal Medicine Department. Patients with and without syncope/collapse were compared. Regression models for associations between syncope/collapse and blood pressure, heart rate and shock index (SI) were computed. Moreover we calculated ROC analyses and Youden indices for effectiveness and cut-off-values of these parameters for the probability of syncope/collapse. Results 182 patients (mean-age 68.5 ± 15.3 years; 61.5% female) with confirmed PE were included in this study. 20 PE patients (11.0%) showed a syncope/collapse. PE patients with syncope/collapse were in median 7.5 years older (78.5 (72.0/82.3) vs. 71.0 (61.0/80.0) years, P = .0575), had lower systolic (132.0 (108.8/154.0) vs. 145.5 (127.0/166.0) mmHg, P = .0845) and diastolic (70.0 ± 27.0 vs. 78.4 ± 18.4 mmHg, P = .0740) blood pressure, whereas heart rate (103.5 (87.8/116.0) vs. 90.0 (76.0/102.0)beats/min, P = .0518), SI (0.78 (0.65/1.01) vs. 0.60(0.50/0.79), P = .0127) and frequency of right ventricular dysfunction (RVD) (88.2% vs. 55.8%, P = .0294) were higher in PE patients with syncope/collapse than in those without. Hypotension (systolic blood pressure < 90 mmHg), tachycardia and SI > 1.0 were connected with 6.4-fold, 2.5-fold and 5.8-fold higher probability of syncope/collapse, respectively. ROC analyses revealed cut-off values of ≤ 110 mmHg, ≥ 107beats/min and > 0.62 for systolic blood pressure, heart rate and SI with low AUC values, respectively. Conclusions The pathomechanism of syncope/collapse in patients with acute PE seems to be connected with blood pressure fall, heart rate increase and RVD, in terms of cardiovascular syncope with reduced cardiac output and vasovagal reflex.
Glycosyl isoquinoline‐1‐carboxylate was developed as a novel benchtop stable and readily available glycosyl donor. The glycosylation reaction was promoted by the inexpensive Cu(OTf)2 salt under mild ...reaction conditions. The copper isoquinoline‐1‐carboxylate salt was precipitated from the solution and thus rendered a traceless leaving group. Surprisingly, the proton from the acceptor was absorbed by the precipitated metal complex and the reaction mixture remained at neutral pH. The copper‐promoted glycosylation was also proven to be completely orthogonal to the gold‐promoted glycosylation, and an iterative synthesis of oligosaccharides from benchtop stable anomeric ester building blocks becomes possible under mild reaction conditions.
Generous donor: A new glycosyl ester donor was developed. It is readily available, benchtop stable, reactive upon chelation to inexpensive copper salts under mild and neutral reaction conditions, orthogonal to other glycosyl esters, serves as a traceless leaving group, and facilitates a broad substrate scope. Tf=trifluoromethanesulfonyl.
In addition to right ventricular dysfunction (RVD) and myocardial injury, impaired renal function is connected with poorer prognosis in pulmonary embolism (PE). We aimed to investigate renal function ...as a cofactor for risk stratification in PE.
Data from 182 patients with PE, treated between May 2006 and June 2011, were analysed retrospectively. PE patients with elevated creatinine were compared with those with normal values. Logistic regression models were calculated to investigate associations between creatinine and myocardial necrosis, RVD and in-hospital death. Prognostic performance of creatinine for prediction of myocardial necrosis and RVD were computed.
Overall, 182 patients (61.5% females,aged 68.5±15.3years) with confirmed PE were included in this study; 142 patients(78.0%) showed normal creatinine, and 40(22.0%) had an elevated creatinine. Patients with elevated creatinine were older (75.9±10.7 vs. 66.5±15.7years, P=0.0003), more frequently female (77.5% vs. 57.0%,P=0.019), and had higher cardiac troponin I (0.19±0.23 vs. 0.11±0.29ng/ml,P=0.0004), systolic pulmonary artery pressure (43.18±16.69 vs. 30.83±17.53mmHG,P=0.0006) and percentage of RVD (77.1% vs. 54.1%,P=0.040).
Creatinine was significantly and independently associated with myocardial necrosis (OR 10.192, 95%CI 2.850–36.452, P=0.0004), shock-index≥1.0 (OR 3.265, 95%CI 1.067–9.992, P=0.0381) and RVD (OR 5.172, 95%CI 1.387–19.295, P=0.014).
Creatinine>1.25mg/dl indicated for myocardial necrosis (AUC 0.680) and RVD (AUC 0.663).
Additionally, to RVD and myocardial necrosis, impaired renal function could give further information for risk stratification in PE. Cardio-pulmonary-renal interactions in PE seem to be multi-factorial.
•PE patients with elevated serum creatinine levels at admission had an increased risk for myocardial necrosis and right ventricular dysfunction.•Creatinine values >1.25mg/dl indicated for myocardial necrosis and right ventricular dysfunction with moderate effectiveness.•Impaired renal function at the admission for PE gives additional information for risk stratification.•Cardio-pulmonary-renal interactions in PE seem to be multifactorial.
Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI) in critically ill patients while the ...CFH-scavenger haptoglobin might play a protective role. We evaluated the association of CFH and haptoglobin with AKI in patients with an acute respiratory distress syndrome (ARDS) requiring therapy with VV ECMO.
Patients with CFH and haptoglobin measurements before initiation of ECMO therapy were identified from a cohort of 1044 ARDS patients and grouped into three CFH concentration groups using a risk stratification. The primary objective was to assess the association of CFH and haptoglobin with KDIGO stage 3 AKI. Further objectives included the identification of a target haptoglobin concentration to protect from CFH-associated AKI.
Two hundred seventy-three patients fulfilled the inclusion criteria. Of those, 154 patients (56.4%) had AKI at ECMO initiation. The incidence of AKI increased stepwise with increasing concentrations of CFH reaching a plateau at 15 mg/dl. Compared to patients with low < 5 mg/dl CFH concentrations, patients with moderate 5-14 mg/dl and high ≥ 15 mg/dl CFH concentrations had a three- and five-fold increased risk for AKI (adjusted odds ratio OR moderate vs. low, 2.69 95% CI, 1.25-5.95, P = 0.012; and OR high vs. low, 5.47 2.00-15.9, P = 0.001). Among patients with increased CFH concentrations, haptoglobin plasma levels were lower in patients with AKI compared to patients without AKI. A haptoglobin concentration greater than 2.7 g/l in the moderate and 2.4 g/l in the high CFH group was identified as clinical cutoff value to protect from CFH-associated AKI (sensitivity 89.5% 95% CI, 83-96 and 90.2% 80-97, respectively).
In critically ill patients with ARDS requiring therapy with VV ECMO, an increased plasma concentration of CFH was identified as independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI and should be subject of future research.
Developing electrospun nanofiber/nanoparticle composites (ENNCs) is an emerging strategy for immobilizing functional particles for a variety of applications. The radial location of the particle along ...the fiber, either at the surface or in the bulk, has implication into the resulting properties. To explore particle location along fibers, ZIF-8 impregnated poly(ethylene oxide) (PEO) nanofibers are formed by electrospinning particle suspensions. Fibers impregnated with two different ZIF-8 particle sizes (200 nm and 12.5 μm) were electrospun and shown by nitrogen porosimetry to be nearly completely wrapped by PEO in each case at loadings near 10 wt %. This was favorably compared to developed theory of polymeric membrane encapsulated particles and extended to other electrospun fiber/particle composites through a brief literature review. ENNCs with varying loadings of nanosized ZIF-8 particles were then fabricated and tested with nitrogen porosimetry to find that the particles became available for adsorption at the surface of the fibers starting from 25 wt % (28 vol %) loading. This suggests that the particles are kinetically trapped at this loading level since, if allowed to exhibit random close-packing, the ZIF-8 would be expected to fully imbedded inside the fibers up to 56 vol % loading.
Human immunodeficiency virus (HIV) treatment reduces tuberculosis (TB) disease and mortality; however, the population-level impact of universal HIV-test-and-treat interventions on TB infection and ...transmission remain unclear.
In a sub-study nested in the SEARCH trial, a community cluster-randomized trial (NCT01864603), we assessed whether a universal HIV-test-and-treat intervention reduced population-level incident TB infection in rural Uganda. Intervention communities received annual, population-level HIV testing and patient-centered linkage. Control communities received population-level HIV testing at baseline and endline. We compared estimated incident TB infection by arms, defined by tuberculin skin test conversion in a cohort of persons aged 5 and older, adjusting for participation and predictors of infection, and accounting for clustering.
Of the 32 trial communities, 9 were included, comprising 90 801 participants (43 127 intervention and 47 674 control). One-year cumulative incidence of TB infection was 16% in the intervention and 22% in the control; SEARCH reduced the population-level risk of incident TB infection by 27% (adjusted risk ratio = 0.73; 95% confidence interval CI: .57-.92, P = .005). In pre-specified analyses, the effect was largest among children aged 5-11 years and males.
A universal HIV-test-and-treat intervention reduced incident TB infection, a marker of population-level TB transmission. Investments in community-level HIV interventions have broader population-level benefits, including TB reductions.
We address the task of adjusting a surface to a vector field of desired surface normals in space. The described method is entirely geometric in the sense, that it does not depend on a particular ...parametrization of the surface in question. It amounts to solving a nonlinear least-squares problem in shape space. Previously, the corresponding minimization has been performed by gradient descent, which suffers from slow convergence and susceptibility to local minima. Newton-type methods, although significantly more robust and efficient, have not been attempted as they require second-order Hadamard differentials. These are difficult to compute for the problem of interest and in general fail to be positive-definite symmetric. We propose a novel approximation of the shape Hessian, which is not only rigorously justified but also leads to excellent numerical performance of the actual optimization. Moreover, a remarkable connection to Sobolev flows is exposed. Three other established algorithms from image and geometry processing turn out to be special cases of ours. Our numerical implementation founds on a fast finite-elements formulation on the minimizing sequence of triangulated shapes. A series of examples from a wide range of different applications is discussed to underline flexibility and efficiency of the approach.
The impact of algorithms on everyday life is ever increasing. Medicine and public health are not excluded from this development – algorithms in medicine do not only challenge, change and inform ...research (methods) but also clinical situations. Given this development, questions arise concerning the competency level of prospective physicians, thus medical students, on algorithm related topics. This paper, based on a master's thesis in library and information science written at Humboldt‐Universität zu Berlin, gives an insight into this topic by presenting and analysing the results of a knowledge test conducted among medical students in Germany. F. J.
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