Reassessment of Acarbose as a Transition State Analogue Inhibitor of Cyclodextrin Glycosyltransferase

The binding of several different active site mutants of Bacillus circulans cyclodextrin glycosyltransferase to the inhibitor acarbose has been investigated through measurement of Ki values. The mutations represent several key amino acid positions, most of which are believed to play important roles in governing the product specificity of cyclodextrin glycosyltransferase. Michaelis-Menten parameters for the substrates α-maltotriosyl fluoride (αG3F) and α-glucosyl fluoride (αGF) with each mutant have been determined by following the enzyme-catalyzed release of fluoride with an ion-selective fluoride electrode. In both cases, reasonable correlations are observed in logarithmic plots relating the Ki value for acarbose with each mutant and both kcat/Km and Km for the hydrolysis of either substrate by the corresponding mutants. This indicates that acarbose, as an inhibitor, is mimicking aspects of both the ground state and the transition state. A better correlation is observed for αGF (r = 0.98) than αG3F (r = 0.90), which can be explained in terms of the modes of binding of these substrates and acarbose. Re-refinement of the previously determined crystal structure of wild-type CGTase complexed with acarbose reveals a binding mode consistent with the transition state analogue character of this inhibitor.

SUBMIT: Systemic therapy with or without up front surgery of the primary tumor in breast cancer patients with distant metastases at initial presentation

<p>Abstract</p> <p>Background</p> <p>Five percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis.</p> <p>Design</p> <p>Randomization will take place after the diagnosis of primary distant metastatic breast cancer. Patients will either be randomized to up front surgery of the breast tumor followed by systemic therapy or to systemic therapy, followed by delayed local treatment of the breast tumor if clinically indicated.</p> <p>Patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy are eligible. Important exclusion criteria are: prior invasive breast cancer, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor and synchronous bilateral breast cancer. The primary endpoint is 2-year survival. Quality of life and local tumor control are among the secondary endpoints.</p> <p>Based on the results of prior research it was calculated that 258 patients are needed in each treatment arm, assuming a power of 80%. Total accrual time is expected to take 60 months. An interim analysis will be performed to assess any clinically significant safety concerns and to determine whether there is evidence that up front surgery is clinically or statistically inferior to systemic therapy with respect to the primary endpoint.</p> <p>Discussion</p> <p>The SUBMIT study is a randomized controlled trial that will provide evidence on whether or not surgery of the primary tumor in breast cancer patients with metastatic disease at initial presentation results in an improved survival.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01392586">NCT01392586</a>.</p

Оксид азота и нитритные ионы в энергетике нейронов мозжечка

Зниження вмісту АТФ в нейронах при гіпоксії мозку і гіперстимуляції глутаматних рецепторів здатне порушити систему внутри і міжклітинної сигналізації в нейронах мозку, зокрема іонний обмін, активність ферментів гліколізу і окислювального фосфорилірування, захоплення Са2+ мітохондріями і синтез білків. В даній роботі вивчали дію ендогенного глутамат індукованого NO і дію екзогенний доданих донорів NO – нітриту натрію (NaNO2) і нітрозоцистеїну (SNOC) на вміст АТФ в 7-8 денних культивованих нейронах мозочка.Decrease of content ATPA in neurones at a hypoxia of a brain and a hyperstimulation глутаматных receptors is capable to break system inside and the intercellular signal ystem in neurones of a brain, in particular an ion exchange, activity of enzymes of glycolysis and oxidative phosphorylation, seizure Са 2+ mitochondrions and synthesis of proteins. In the given work studied action endogenic glutamate inducted NO and action of exogenous padding donors NO diazotizing salt (NaNO2) and нитрозоцистеина (SNOC) on content ATPA in 7 8 diurnal cultivated{incubated} neurones of a cerebellum

Organic Matter in Space - an Overview

Organic compounds are ubiquitous in space: they are found in diffuse clouds, in the envelopes of evolved stars, in dense star-forming regions, in protoplanetary disks, in comets, on the surfaces of minor planets, and in meteorites and interplanetary dust particles. This brief overview summarizes the observational evidence for the types of organics found in these regions, with emphasis on recent developments. The Stardust sample-return mission provides the first opportunity to study primitive cometary material with sophisticated equipment on Earth. Similarities and differences between the types of compounds in different regions are discussed in the context of the processes that can modify them. The importance of laboratory astrophysics is emphasized.Comment: Introductory overview lecture presented at IAU Symposium 251, "Organic matter in space", held at Hong Kong, February 2008; to appear in IAU Symposium 251 proceedings, Cambridge University Press, ed. S. Kwok et a

Safety and feasibility of indocyanine green fluorescence angiography in pediatric gastrointestinal surgery:A systematic review

Background: Although ICG-FA may be valuable in assessing anastomotic perfusion, reliable data on its use in pediatric gastrointestinal surgery is lacking. This systematic review analyzes whether ICG is useful for intestinal perfusion assessment in pediatric gastrointestinal surgery and safe to use in neonates. Methods: Systematic searches of PubMed, EMBASE &amp; MEDLINE and CENTRAL were performed (last conducted December 6, 2021). The main inclusion criteria were (1) use of ICG for intestinal perfusion assessment and (2) use of ICG in young infants. Exclusion criteria were lack of an English or Dutch full-text and MINORS quality score &lt;60%. Data was presented in overview tables. The usefulness in pediatric gastrointestinal surgery was assessed by surgical outcome. Safety of ICG in neonates was assessed by complication or adverse event occurrence. Results: Regarding intestinal perfusion assessment, four studies were included, reporting 45 patients (median age 1.5 years). ICG was considered useful for anastomotic blood flow evaluation and intraoperative determination of resection length. Regarding ICG safety in neonates, eight studies were included, reporting 46 infants (median age 24.9 days), of which 18 neonates. All but one studies reported the absence of complications or adverse events. Two studies reported subcutaneous dye retention, which fully disappeared within two weeks. Conclusion: Although the number of available studies is small, ICG might be useful for intraoperative intestinal perfusion assessment, perhaps even more than conventional clinical assessment. Furthermore, its safety profile looks promising in neonates. Larger prospective studies are necessary to confirm these assumptions and seem warranted given the safety profile. Levels of evidence: Since this is a systematic review, a Level of Evidence for clinical studies cannot be determined for this manuscript.</p

A general model for the identification of specific PAHs in the far-IR

Context. In the framework of the interstellar PAH hypothesis, far-IR skeletal bands are expected to be a fingerprint of single species in this class. Aims. A detailed model of the photophysics of interstellar PAHs is required for such single-molecule identification of their far-IR features in the presently available Infrared Space Observatory data and in those of the forthcoming Herschel Space Observatory mission. Methods. We modelled the detailed photophysics of a vast sample of species in different radiation fields, using a compendium of Monte-Carlo techniques and quantum-chemical calculations. This enabled us to validate the use of purely theoretical data and assess the expected accuracy and reliability of the resulting synthetic far-IR emission spectra. Results. We produce positions and intensities of the expected far-IR features which ought to be emitted by each species in the sample in the considered radiation fields. A composite emission spectrum for our sample is computed for one of the most favourable sources for detection, namely the Red Rectangle nebula. The resulting spectrum is compared with the estimated dust emission in the same source, to assess the dependence of detectability on key molecular parameters. Conclusions. Identifying specific PAHs from their far-IR features is going to be a difficult feat in general, still it may well be possible under favourable conditions.Comment: 14 pages, 9 figures + 18 pages of online appendix. Accepted for publication in A&A (09/06/2006

Blood pressure measurements for diagnosing hypertension in primary care:room for improvement

Background: In the adult population, about 50% have hypertension, a risk factor for cardiovascular disease and subsequent premature death. Little is known about the quality of the methods used to diagnose hypertension in primary care. Objectives: The objective was to assess the frequency of use of recognized methods to establish a diagnosis of hypertension, and specifically for OBPM, whether three distinct measurements were taken, and how correctly the blood pressure levels were interpreted. Methods: A retrospective population-based cohort study using electronic medical records of patients aged between 40 and 70 years, who visited their general practitioner (GP) with a new-onset of hypertension in the years 2012, 2016, 2019, and 2020. A visual chart review of the electronic medical records was used to assess the methods employed to diagnose hypertension in a random sample of 500 patients. The blood pressure measurement method was considered complete if three or more valid office blood pressure measurements (OBPM) were performed, or home-based blood pressure measurements (HBPM), the office- based 30-minute method (OBP30), or 24-hour ambulatory blood pressure measurements (24 H-ABPM) were used. Results: In all study years, OBPM was the most frequently used method to diagnose new-onset hypertension in patients. The OBP-30 method was used in 0.4% (2012), 4.2% (2016), 10.6% (2019), and 9.8% (2020) of patients respectively, 24 H-ABPM in 16.0%, 22.2%, 17.2%, and 19.0% of patients and HBPM measurements in 5.4%, 8.4%, 7.6%, and 7.8% of patients, respectively. A diagnosis of hypertension based on only one or two office measurements occurred in 85.2% (2012), 87.9% (2016), 94.4% (2019), and 96.8% (2020) of all patients with OBPM. In cases of incomplete measurement and incorrect interpretation, medication was still started in 64% of cases in 2012, 56% (2016), 60% (2019), and 73% (2020). Conclusion: OBPM is still the most often used method to diagnose hypertension in primary care. The diagnosis was often incomplete or misinterpreted using incorrect cut-off levels. A small improvement occurred between 2012 and 2016 but no further progress was seen in 2019 or 2020. If hypertension is inappropriately diagnosed, it may result in under treatment or in prolonged, unnecessary treatment of patients. There is room for improvement in the general practice setting.</p