Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Proximal major limb amputations – a retrospective analysis of 45 oncological cases

<p>Abstract</p> <p>Background</p> <p>Proximal major limb amputations due to malignant tumors have become rare but are still a valuable treatment option in palliation and in some cases can even cure. The aim of this retrospective study was to analyse outcome in those patients, including the postoperative course, survival, pain, quality of life, and prosthesis usage.</p> <p>Methods</p> <p>Data of 45 consecutive patients was acquired from patient's charts and contact to patients, and general practitioners. Patients with interscapulothoracic amputation (n = 14), shoulder disarticulation (n = 13), hemipelvectomy (n = 3) or hip disarticulation (n = 15) were included.</p> <p>Results</p> <p>The rate of proximal major limb amputations in patients treated for sarcoma was 2.3% (37 out of 1597). Survival for all patients was 42.9% after one year and 12.7% after five years. Survival was significantly better in patients with complete tumor resections. Postoperative chemotherapy and radiation did not prolong survival. Eighteen percent of the patients with malignant disease developed local recurrence. In 44%, postoperative complications were observed. Different modalities of postoperative pain management and the site of the amputation had no significant influence on long-term pain assessment and quality of life. Eighty-seven percent suffered from phantom pain, 15.6% considered their quality of life worse than before the operation. Thirty-two percent of the patients who received a prosthesis used it regularly.</p> <p>Conclusion</p> <p>Proximal major limb amputations severely interfere with patients' body function and are the last, albeit valuable, option within the treatment concept of extremity malignancies or severe infections. Besides short survival, high complication rates, and postoperative pain, patients' quality of life can be improved for the time they have remaining.</p

Early diagnosis is associated with improved clinical outcomes in benign esophageal perforation: an individual patient data meta‑analysis

Background Time of diagnosis (TOD) of benign esophageal perforation is regarded as an important risk factor for clinical outcome, although convincing evidence is lacking. The aim of this study is to assess whether time between onset of perforation and diagnosis is associated with clinical outcome in patients with iatrogenic esophageal perforation (IEP) and Boerhaave’s syndrome (BS). Methods We searched MEDLINE, Embase and Cochrane library through June 2018 to identify studies. Authors were invited to share individual patient data and a meta-analysis was performed (PROSPERO: CRD42018093473). Patients were subdivided in early (≤ 24 h) and late (> 24 h) TOD and compared with mixed effects multivariable analysis while adjusting age, gender, location of perforation, initial treatment and center. Primary outcome was overall mortality. Secondary outcomes were length of hospital stay, re-interventions and ICU admission. Results Our meta-analysis included IPD of 25 studies including 576 patients with IEP and 384 with BS. In IEP, early TOD was not associated with overall mortality (8% vs. 13%, OR 2.1, 95% CI 0.8–5.1), but was associated with a 23% decrease in ICU admissions (46% vs. 69%, OR 3.0, 95% CI 1.2–7.2), a 22% decrease in re-interventions (23% vs. 45%, OR 2.8, 95% CI 1.2–6.7) and a 36% decrease in length of hospital stay (14 vs. 22 days, p < 0.001), compared with late TOD. In BS, no associations between TOD and outcomes were found. When combining IEP and BS, early TOD was associated with a 6% decrease in overall mortality (10% vs. 16%, OR 2.1, 95% CI 1.1–3.9), a 19% decrease in re-interventions (26% vs. 45%, OR 1.9, 95% CI 1.1–3.2) and a 35% decrease in mean length of hospital stay (16 vs. 22 days, p = 0.001), compared with late TOD. Conclusions This individual patient data meta-analysis confirms the general opinion that an early (≤ 24 h) compared to a late diagnosis (> 24 h) in benign esophageal perforations, particularly in IEP, is associated with improved clinical outcome.publishedVersio

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

Toward a better understanding of the magnetocaloric effect: An experimental and theoretical study of MnFe4Si3

The intermetallic compound MnFe4Si3 has been studied by high-resolution Time of Flight (TOF) neutron powder diffraction. MnFe4Si3 crystallizes in the hexagonal space group P63/mcm with lattice constants of a=b=6.8043(4) Å and c=4.7254(2) Å at 310 K. Magnetic susceptibility measurements show clearly the magnetic transition from paramagnetism to ferromagnetism at about 302(2) K. Magnetic structure refinements based on neutron powder diffraction data with and without external magnetic field reveal strong evidence on the origin of the large magnetocaloric effect (MCE) in this material as a partial reordering of the spins between ~270 K and 300 K. In addition, electronic structure calculations using the self-consistent, spin-polarized Tight Binding-Linear MuffinTin Orbital (TB-LMTO) method were also accomplished to address the “coloring problem” (Mn/Fe site preference) as well as the unique ferromagnetic behavior of this intermetallic compound

Kidney injury as post-interventional complication of TAVI

Abstract Transcatheter aortic valve implantation (TAVI) is an accepted treatment approach of aortic stenosis. In the beginning, this technique was executed in high-risk patients only. Today, intermediate-risk patients are also amenable for TAVI, as long as the transfemoral approach is chosen. Numerous predictors have been identified that could lead to periprocedural complications and are defined by patient co-morbidities as well as being inherent to the technical approach. Although vascular complications and postinterventional paravalvular regurgitation have been minimized over the past years by revised technologies and techniques, there is a prevailing individual risk brought about by the specific pathophysiology of the cardiorenal syndrome