Decompensated cirrhosis predisposes to infectious diseases and acute-on-chronic liver failure (ACLF) in critically ill patients. Infections like spontaneous bacterial peritonitis (SBP) are frequently ...associated with multi-organ failure and increased mortality. Consequently, reliable predictors of outcome and early diagnostic markers of infection are needed to improve individualized therapy. This study evaluates the prognostic role of ascitic interleukin 6 in 64 patients with cirrhosis admitted to our intensive care unit (ICU). In addition, we analysed the diagnostic ability of ascitic interleukin 6 in a subgroup of 19 patients with SBP. Baseline ascitic interleukin 6 performed well in predicting 3-month mortality in patients with decompensated cirrhosis (area under curve (AUC) = 0.802), as well as in patients fulfilling ACLF-criteria (AUC = 0.807). Ascitic interleukin 6 showed a moderate prognostic advantage compared with common clinical scores and proinflammatory parameters. Moreover, ascitic interleukin 6 had a sufficient diagnostic ability to detect SBP (AUC = 0.901) and was well correlated with ascitic polymorphonuclear neutrophils in SBP (p = 0.002). Interestingly, ascitic interleukin 6 revealed a high predictive value to rule out apparent infections on admission to ICU (AUC = 0.904) and to identify patients with “culture-positive SBP” (AUC = 0.856). Ascitic interleukin 6 is an easily-applicable proinflammatory biomarker with high prognostic and diagnostic relevance in critically ill patients with liver cirrhosis.
Economic restrictions and workforce cuts have continually challenged conventional autopsies. Recently, the COVID-19 pandemic has added tissue quality and safety requirements to the investigation of ...this disease, thereby launching efforts to upgrade autopsy strategies.
In this proof-of-concept study, we performed bedside ultrasound-guided minimally invasive autopsy (US-MIA) in the ICU of critically ill COVID-19 patients using a structured protocol to obtain non-autolyzed tissue. Biopsies were assessed for their quality (vitality) and length of biopsy (mm) and for diagnosis. The efficiency of the procedure was monitored in five cases by recording the time of each step and safety issues by swabbing personal protective equipment and devices for viral contamination.
Ultrasound examination and tissue procurement required a mean time period of 13 min and 54 min, respectively. A total of 318 multiorgan biopsies were obtained from five patients. Quality and vitality standards were fulfilled, which not only allowed for specific histopathological diagnosis but also the reliable detection of SARS-CoV-2 virions in unexpected organs using electronic microscopy and RNA-expressing techniques.
Bedside multidisciplinary US-MIA allows for the fast and efficient acquisition of autolytic-free tissue and offers unappreciated potential to overcome the limitations of research in postmortem studies.
Objective
To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration‐resistant prostate cancer (mCRPC) undergoing treatment with ...abiraterone in a post‐chemotherapy setting.
Patients and Method
Chromogranin A (CGa) and neurone‐specific enolase (NSE) were determined in serum drawn before treatment with abiraterone from 45 patients with mCRPC. Outcome measures were overall survival (OS), prostate‐specific antigen (PSA) response defined by a PSA level decline of ≥50%, PSA progression‐free survival (PSA‐PFS), and clinical or radiographic PFS.
Results
The CGa and NSE serum levels did not correlate (P = 0.6). Patients were stratified in to low‐ (nine patients), intermediate‐ (18) or high‐risk (18) groups according to elevation of none, one, or both neuroendocrine markers, respectively. The risk groups correlated with decreasing median OS (median OS not reached vs 15.3 vs 6.6 months; P < 0.001), decreasing median clinical or radiographic PFS (8.3 vs 4.4 vs 2.7 months; P = 0.001) and decreasing median PSA‐PFS (12.0 vs 3.2 vs 2.7 months; P = 0.012). In multivariate Cox regression analysis the combination of CGa and NSE (≥1 marker positive vs both markers negative) remained significant predictors of OS, clinical or radiographic PFS, and PSA‐PFS. We did not observe a correlation with PSA response (63% vs 35% vs 31%; P = 0.2).
Conclusion
Chromogranin A and NSE did not predict PSA response in patients with mCRPC treated with abiraterone. However, we observed a correlation with shorter PSA‐PFS, clinical or radiographic PFS, and OS. This might be due to an elevated risk of developing resistance under abiraterone treatment related to neuroendocrine differentiation.
Early-onset epileptic encephalopathy (EE) and combined developmental and epileptic encephalopathies (DEE) are clinically and genetically heterogeneous severely devastating conditions. Recent studies ...emphasized de novo variants as major underlying cause suggesting a generally low-recurrence risk. In order to better understand the full genetic landscape of EE and DEE, we performed high-resolution chromosomal microarray analysis in combination with whole-exome sequencing in 63 deeply phenotyped independent patients. After bioinformatic filtering for rare variants, diagnostic yield was improved for recessive disorders by manual data curation as well as molecular modeling of missense variants and untargeted plasma-metabolomics in selected patients. In total, we yielded a diagnosis in ∼42% of cases with causative copy number variants in 6 patients (∼10%) and causative sequence variants in 16 established disease genes in 20 patients (∼32%), including compound heterozygosity for causative sequence and copy number variants in one patient. In total, 38% of diagnosed cases were caused by recessive genes, of which two cases escaped automatic calling due to one allele occurring de novo. Notably, we found the recessive gene SPATA5 causative in as much as 3% of our cohort, indicating that it may have been underdiagnosed in previous studies. We further support candidacy for neurodevelopmental disorders of four previously described genes (PIK3AP1, GTF3C3, UFC1, and WRAP53), three of which also followed a recessive inheritance pattern. Our results therefore confirm the importance of de novo causative gene variants in EE/DEE, but additionally illustrate the major role of mostly compound heterozygous or hemizygous recessive inheritance and consequently high-recurrence risk.
Printing Chemical Gradients Kraus, Tobias; Stutz, Richard; Balmer, Tobias E ...
Langmuir,
08/2005, Letnik:
21, Številka:
17
Journal Article
Recenzirano
We describe a method to exploit the mass-transfer limitations of microcontact printing for the fabrication of surfaces with well-defined, arbitrarily shaped composition variations. An analysis of the ...transport processes reveals that the printing of hexadecanethiol (HDT) from poly(dimethylsiloxane) is purely diffusion-controlled. Stamps with geometries that enhance surface-normal diffusion paths therefore allow not only the contours, but also the local density of self-assembled monolayers to be controlled. We use stamps with variable thickness and uniform ink concentration to print HDT density gradients on gold, depleting the stamps during the process. In the second step, a perfluorinated thiol fills the vacancies in the partial monolayer to form a two-component gradient that we analyze by means of X-ray photoelectron spectroscopy and spectroscopic ellipsometry. Linear and radial gradients are shown here as examples for a wide range of geometries that can be fabricated with high precision using the method.
In eukaryotes, the molecular chaperones Hsp90 and Hsp70 are connected via the co‐chaperone Sti1/Hop, which allows transfer of clients. Here, we show that the basic functions of yeast Sti1 and human ...Hop are conserved. These include the simultaneous binding of Hsp90 and Hsp70, the inhibition of the ATPase activity of Hsp90, and the ability to support client activation in vivo. Importantly, we reveal that both Hop and Sti1 are subject to inhibitory phosphorylation, although the sites modified and the influence of regulatory phosphorylation is species specific. Phospho‐mimetic variants have a reduced ability to activate clients in vivo and different affinity for Hsp70. Hop is more tightly regulated, as phosphorylation affects also the interaction with Hsp90 and induces structural rearrangements in the core part of the protein.
Synopsis
This study shows that Hop and Sti1 are phosphorylated, and the sites and magnitude of the effects are species specific, with Hop being more tightly regulated. Phosphorylation negatively affects interaction with Hsp70.
Yeast Sti1 and human Hop share highly conserved functions.
Human Hsp90 is not inhibited to the same degree as yeast Hsp90 by Sti1/Hop.
Phosphorylation of Hop at a unique position affects its structure.
Phosphorylation of Sti1/Hop negatively affects client maturation.
This study shows that Hop and Sti1 are phosphorylated, and the sites and magnitude of the effects are species specific, with Hop being more tightly regulated. Phosphorylation negatively affects interaction with Hsp70.
The European Spallation Source (ESS), which is under construction in Lund (Sweden), will be the leading and most brilliant neutron source and aims at starting user operation at the end of 2023. Among ...others, two small angle neutron scattering (SANS) machines will be operated. Due to the high brilliance of the source, it is important to minimize the downtime of the instruments. For this, a collaboration between three German universities and the ESS was initialized to develop and construct a unified sample environment (SE) system. The main focus was set on the use of a robust carrier system for the different SEs, which allows setting up experiments and first prealignment outside the SANS instruments. This article covers the development and construction of a SE for SANS experiments with foams, which allows measuring foams at different drainage states and the control of the rate of foam formation, temperature, and measurement position. The functionality under ESS conditions was tested and neutron test measurement were carried out.
A significant number of patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs) present with metastatic disease and with unknown primary in about 15% of cases.
We analyzed 163 primaries ...of GEP NET and 115 metastases for expression of caudal type homebox 2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), somatostatin receptor 2a (SSTR2a) and Ki67.
PR was most often positive in pancreatic NET and only rarely in non-pancreatic NET (p<0.001). ER was more frequently expressed in non-pancreatic NET (p<0.001) and was more often positive in females than males (p=0.019). CDX2 was positive in all primaries of the duodenum, ileum and appendix, but was also detected in 24% of metastases with pancreatic primary. SSTR2a and Ki67 did not differ significantly between primaries and metastases.
Our data substantiate the value of PR, ER and CDX2 in GEP NET, and steroid hormone receptors, being differentially expressed in male and female patients. Differences between primaries and metastases were small but potentially relevant.
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