Sems Sensibility: Biliary Stent Migration into the Oesophagus.

Endoprostheses are commonly used in the treatment of biliary and pancreatic disorders. Fully-covered metal stents are intended for the palliation of malignant strictures in the biliary tree. We report a case of a patient affected by cancer of the pancreas who was treated with a proximal metallic biliary stent. The stent migrated to the oesophagus and was endoscopically removed. Proximal migration, although rare, should be kept in mind as a potential complication of the procedure.

Mood State Detection in Handwritten Tasks Using PCA-mFCBF and Automated Machine Learning.

In this research, we analyse data obtained from sensors when a user handwrites or draws on a tablet to detect whether the user is in a specific mood state. First, we calculated the features based on the temporal, kinematic, statistical, spectral and cepstral domains for the tablet pressure, the horizontal and vertical pen displacements and the azimuth of the pen's position. Next, we selected features using a principal component analysis (PCA) pipeline, followed by modified fast correlation-based filtering (mFCBF). PCA was used to calculate the orthogonal transformation of the features, and mFCBF was used to select the best PCA features. The EMOTHAW database was used for depression, anxiety and stress scale (DASS) assessment. The process involved the augmentation of the training data by first augmenting the mood states such that all the data were the same size. Then, 80% of the training data was randomly selected, and a small random Gaussian noise was added to the extracted features. Automated machine learning was employed to train and test more than ten plain and ensembled classifiers. For all three moods, we obtained 100% accuracy results when detecting two possible grades of mood severities using this architecture. The results obtained were superior to the results obtained by using state-of-the-art methods, which enabled us to define the three mood states and provide precise information to the clinical psychologist. The accuracy results obtained when detecting these three possible mood states using this architecture were 82.5%, 72.8% and 74.56% for depression, anxiety and stress, respectively.

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics.

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

Structure-Activity Relationship Study of a Potent α-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides.

The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172-TH 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life. The anticoagulant activity of the modified oligonucleotide was also found to be slightly preferable to NU172. Overall, these results confirm the potential of hexitol nucleotides as biomimetic agents, while laying the foundations for the development of NU172-inspired α-thrombin-binding aptamers.

A Stereoconvergent Tsuji-Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides.

A highly regio- and stereoselective route to d- and l-cyclohexenyl nucleosides has been devised, using the Tsuji-Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.

Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars.

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars 10a-b and 11a-b based on the one-pot conjugation of both enantiomeric forms of N-butyldeoxynojirimycin (NBDNJ) and N-nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I2/ImH activating system, which provided the desired compounds in high yields (94-96%) by a one-pot procedure. The substantial increase in the lipophilicity of 10a-b and 11a-b is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties. However, assays are currently hampered by solubility problems; therefore, alternative administration strategies will need to be devised.

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes.

Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1 hr after oxidative stress induction and a return to basal level at 48 hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity.

Discriminative Power of Handwriting and Drawing Features in Depression.

This study contributes knowledge on the detection of depression through handwriting/drawing features, to identify quantitative and noninvasive indicators of the disorder for implementing algorithms for its automatic detection. For this purpose, an original online approach was adopted to provide a dynamic evaluation of handwriting/drawing performance of healthy participants with no history of any psychiatric disorders ([Formula: see text]), and patients with a clinical diagnosis of depression ([Formula: see text]). Both groups were asked to complete seven tasks requiring either the writing or drawing on a paper while five handwriting/drawing features' categories (i.e. pressure on the paper, time, ductus, space among characters, and pen inclination) were recorded by using a digitalized tablet. The collected records were statistically analyzed. Results showed that, except for pressure, all the considered features, successfully discriminate between depressed and nondepressed subjects. In addition, it was observed that depression affects different writing/drawing functionalities. These findings suggest the adoption of writing/drawing tasks in the clinical practice as tools to support the current depression detection methods. This would have important repercussions on reducing the diagnostic times and treatment formulation.

Assessing the Potential of N-Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent.

Over the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar N-butyl-l-deoxynojirimycin (l-NBDNJ, ent-1), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of Pseudomonas aeruginosa chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells. Mechanistic insights into the observed activity revealed that l-NBDNJ interferes with the expression of proteins regulating cytoskeleton assembly and organization of the host cell, downregulates the main virulence factors of P. aeruginosa involved in the host response, and affects pathogen adhesion to human cells. These findings along with the observation of the absence of an in vitro bacteriostatic/bactericidal action of l-NBDNJ suggest the potential use of this glycomimetic as an antivirulence agent in the management of CF lung disease.

A Dynamic Probabilistic Model for Heterogeneous Data Fusion: A Pilot Case Study from Computer-Aided Detection of Depression.

The present paper, in the framework of a search for a computer-aided method to detect depression, deals with experimental data of various types, with their correlation, and with the way relevant information about depression delivered by different sets of data can be fused to build a unique body of knowledge about individuals' mental states facilitating the diagnosis and its accuracy. To this aim, it suggests the use of a recently introduced «limiting form¼ of the kinetic-theoretic language, at present widely used to describe complex systems of objects of the most diverse nature. In this connection, the paper mainly aims to show how a wide range of experimental procedures can be described as examples of this «limiting case¼ and possibly rendered by this description more effective as methods of prediction from experience. In particular, the paper contains a simple, preliminary application of the method to the detection of depression, to show how the consideration of statistical parameters connected with the analysis of speech can modify, at least in a stochastic sense, each diagnosis of depression delivered by the Beck Depression Inventory (BDI-II).

PYED-1 Overcomes Colistin Resistance in Acinetobacter baumannii.

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome.

Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist. Here, we report the ability of N-substituted l-iminosugars to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype. Particularly, we found that they increase the levels of defective α-N-acetylglucosaminidase and correct its proper sorting toward the lysosomal compartment. Furthermore, l-iminosugars reduce HS accumulation by downregulating protein levels of exostosin glycosyltransferases. These results highlight an interesting pharmacological potential of these glycomimetics in Sanfilippo syndrome, paving the way for the development of novel therapeutic approaches for the treatment of such incurable disease.

The Risk of Malignant Degeneration of Müllerian Derivatives in PMDS: A Review of the Literature.

Persistent Müllerian Duct Syndrome (PMDS) is a rare autosomal recessive disorder of sex development characterized by the presence of fallopian tubes, uterus and upper one-third of the vagina in individuals with XY genotype and normal male phenotype. The main complications of PMDS are infertility and the rare risk of malignant degeneration of both testicular and Müllerian derivatives. We report the case of a 49-year-old man who, during repair of an incisional hernia, was incidentally found to have a uterine-like structure posterior to the bladder. In the past at the age of 18 months, he had undergone bilateral orchidopexies for bilateral cryptorchidism. The intraoperative decision was to preserve the uterine-like structure and make a more accurate diagnosis postoperatively. Evaluation revealed an XY chromosome and imaging consistent with PMDS. The patient was informed about the risk of neoplastic transformation of the residual Müller ducts and was offered surgical treatment, which he declined. Subsequent follow-up imaging studies, including testicular and pelvic ultrasound, were negative for findings suggestive of malignant testicular and Mullerian derivative degeneration. A review of the international literature showed that, when a decision is taken to remove the Mullerian derivatives, laparoscopy and especially robotic surgery allow for the successful removal of Müllerian derivatives. Whenever the removal of these structures is not possible or the patient refuses to undergo surgery, it is necessary to inform the patient of the need for adequate follow-up. Patients should undergo regular pelvic imaging examination and MRI might be a better method for that purpose.

On the recognition of emotional vocal expressions: motivations for a holistic approach.

Human beings seem to be able to recognize emotions from speech very well and information communication technology aims to implement machines and agents that can do the same. However, to be able to automatically recognize affective states from speech signals, it is necessary to solve two main technological problems. The former concerns the identification of effective and efficient processing algorithms capable of capturing emotional acoustic features from speech sentences. The latter focuses on finding computational models able to classify, with an approximation as good as human listeners, a given set of emotional states. This paper will survey these topics and provide some insights for a holistic approach to the automatic analysis, recognition and synthesis of affective states.

Reciprocity versus Self-Interest in a Competitive Interaction Context: An Experimental Study.

In social interactions, the reciprocity norm implies to adjust one's behavior to that of the other agents. Conversely, behaving according to self-interest involves taking into account the reciprocity principle only if it does not hinder the achievement of one's goals. However, reciprocity and self-interest may conflict with each other, as when returning a kind action involves sacrificing the possibility to achieve a personal objective. The conflict could be exacerbated by some contextual factors, such as competitive pressures. This study investigated, in a competitive interaction context, which principle prevails when the two conflict. To this end, 276 unpaid participants (M = 138) took part in a two-stage experiment entailing a simulated interaction with a fictitious opponent, which behaved selfishly, fairly or altruistically toward them during the first stage. Participants had to decide whether or not to reciprocate the opponent's previous behavior, which in the critical experimental conditions conflicted with the goal to successfully complete the experiment. So, they were faced with a moral dilemma. Competition degree was manipulated to make the conflict between reciprocity and self-interest more or less harsh. Moreover, we tested whether the putative effect of experimental manipulation was mediated by changes in context-related affective states and personal beliefs about morality. Results showed that decision-making was principally influenced by reciprocity. Regardless of the competition degree, participants preferred to engage in reciprocal behavior even when this compromised their personal interest. Affective states and beliefs changed in response to the experimental manipulation, but they did not mediate the effect of the independent variable on decision-making.

Digging into protein metalation differences triggered by fluorine containing-dirhodium tetracarboxylate analogues.

The catalytic and biological properties of dirhodium tetracarboxylates ([Rh2(µ-O2CR)4L2], L = axial ligand and R = CH3-, CH3CH2-, etc.) largely depend on the nature of bridging carboxylate equatorial µ-O2CR ligands, which can be easily exchanged by solvent molecules when R is CF3 (i.e. µ-O2CR is trifluoroacetate, tfa). Here, we prepared the [Rh2(OAc)(tfa)3] compound and investigated its interaction with bovine pancreatic ribonuclease and lysozyme under the same conditions used to study the reactivity of these proteins with [Rh2(OAc)4] and [cis-Rh2(OAc)2(tfa)2]. UV-vis absorption spectroscopy and 19F nuclear magnetic resonance studies indicate that [Rh2(OAc)(tfa)3] rapidly loses tfa ligands and interacts with the proteins. Crystallographic data demonstrate that the reaction of [Rh2(OAc)(tfa)3] with proteins can lead to products that are significantly different when compared to those obtained with [Rh2(OAc)4] and [cis-Rh2(OAc)2(tfa)2]: the dirhodium centre can bind the side chain of His residues at both axial and equatorial sites, at variance with what is found in the case of [Rh2(OAc)4] and [cis-Rh2(OAc)2(tfa)2]. These data indicate that the hydrolysis of dirhodium tetracarboxylates plays a significant role in defining their reaction with proteins allowing the formation of unexpected reaction products. These results suggest that [cis-Rh2(OAc)2(tfa)2] and [Rh2(OAc)(tfa)3] can be used to obtain different dirhodium/peptide and dirhodium/protein adducts with distinct catalytic properties and can explain the different cytotoxicity exhibited by tfa-containing dirhodium tetracarboxylates.

Reactivity of a fluorine-containing dirhodium tetracarboxylate compound with proteins.

Dirhodium complexes of general formula [Rh2(O2CR)4]L2 are a well-known class of bimetallic compounds that are used as efficient catalysts for a variety of reactions and have been shown to be potent antibacterial and anticancer agents. The catalytic and biological properties of these complexes largely depend on the nature of the bridging carboxylate ligands. Trifluoroacetate (tfa)-containing dirhodium compounds have been used to build artificial metalloenzymes upon reaction with peptides and have been shown to be more cytotoxic than dirhodium tetraacetate. However, there is no structural information on the interaction between these compounds and proteins. Here, cis-Rh2(µ-O2CCH3)2(µ-O2CCF3)2 ([cis-Rh2(OAc)2(tfa)2]) has been synthesized and its reaction with bovine pancreatic ribonuclease (RNase A) and hen egg white lysozyme (HEWL) was analyzed using a combination of different techniques, including Fluorine-19 nuclear magnetic resonance spectroscopy and macromolecular X-ray crystallography, with the aim to unveil the differences in the reactivity of tfa-containing dihrodium complexes with proteins when compared to [Rh2(OAc)4]. [cis-Rh2(OAc)2(tfa)2] and [Rh2(OAc)4] bind the N atoms of His side chains of RNase A at the axial position; however the fluorine-containing compound rapidly loses its tfa ligands, while [Rh2(OAc)4] can retain the acetate ligands upon protein binding. The reactivity of [cis-Rh2(OAc)2(tfa)2] with HEWL is slightly distinct when compared to that of [Rh2(OAc)4] under the same experimental conditions; however, both [cis-Rh2(OAc)2(tfa)2] and [Rh2(OAc)4] degrade when soaked within HEWL crystals. These results provide a structural-based guide for the design of new heterogenous chiral dirhodium/peptide and dirhodium/protein adducts with application in the fields of organic synthesis and asymmetric catalysis.

Alarm fatigue in nurses working in intensive care units: A multicenter study.

BACKGROUND: Technological progress improves health care efficiency, quality, safety, and cost, supporting clinical activity in various scenarios, such as Intensive Care Unit (ICU). A timely response to alarms from monitors and other ICU electromedical devices is therefore crucial. The number of false alarms tend to desensitize care providers increasing the risk of experiencing alarm fatigue and, at times, lead to severe consequences for patients. OBJECTIVES: To assess the psychometric properties of the Italian version of the Alarm Fatigue Questionnaire and to explore the phenomenon of alarm fatigue among nurses working in intensive care settings. METHODS: The CVI-I was calculated to evaluate the validity of the content of the tool. Construct validity was investigated through exploratory factor analysis. Cronbach's alpha coefficient (α) was used to examine the internal consistency of the scale and Spearman's rho coefficient to test for stability.We designed a multicentre cross-sectional survey. A convenience sample of nurses from 4 Major Italian hospitals was recruited. The nurses completed the Italian version of the Alarm Fatigue Questionnaire. RESULTS: The content validity index CVI-S of the scale (CVI-S) was 91.11%; Cronbach's alpha coefficient was 0.71. The Italian version of the tool explained 67.18%of the overall variance. 396 nurses were enrolled (79.84%). The overall level of alarm fatigue was Me = 29 [22;30]. 42.17%of the sample reported prior experience with alarm fatigue incidents. CONCLUSIONS: The extension of alarm fatigue requires the adoption of a preventive intervention plan. The Italian version of the Alarm Fatigue Questionnaire shows promising psychometric properties.

Synthesis and antiviral properties of biomimetic iminosugar-based nucleosides.

Herein we report the synthesis, conformational analysis and the evaluation of the antiviral activity of six-membered nucleoside analogues having a piperidine ring as the preorganized (deoxy)ribose bioisostere. Mutagenic nucleobase-containing nucleosides 1 and 2 were obtained by appropriate manipulation of the well-known glycomimetic agent deoxynojirimycin as easily accessible starting material. In vitro assays revealed activity of 5-iododeoxyuridine analogue 1 against all DNA viruses tested. As suggested by DFT analysis and pH-dependent NMR experiments, antiviral activity was correlated to the biomimetic character of the piperidine ring, as it is able to resemble the deoxyribose conformations adopted by natural nucleosides when interacting with viral enzymes.