Dysregulated Choline, Methionine, and Aromatic Amino Acid Metabolism in Patients with Wilson Disease: Exploratory Metabolomic Profiling and Implications for Hepatic and Neurologic Phenotypes.

Wilson disease (WD) is a genetic copper overload condition characterized by hepatic and neuropsychiatric symptoms with a not well-understood pathogenesis. Dysregulated methionine cycle is reported in animal models of WD, though not verified in humans. Choline is essential for lipid and methionine metabolism. Defects in neurotransmitters as acetylcholine, and biogenic amines are reported in WD; however, less is known about their circulating precursors. We aimed to study choline, methionine, aromatic amino acids, and phospholipids in serum of WD subjects. Hydrophilic interaction chromatography-quadrupole time-of-flight mass spectrometry was employed to profile serum of WD subjects categorized as hepatic, neurologic, and pre-clinical. Hepatic transcript levels of genes related to choline and methionine metabolism were verified in the Jackson Laboratory toxic milk mouse model of WD (tx-j). Compared to healthy subjects, choline, methionine, ornithine, proline, phenylalanine, tyrosine, and histidine were significantly elevated in WD, with marked alterations in phosphatidylcholines and reductions in sphingosine-1-phosphate, sphingomyelins, and acylcarnitines. In tx-j mice, choline, methionine, and phosphatidylcholine were similarly dysregulated. Elevated choline is a hallmark dysregulation in WD interconnected with alterations in methionine and phospholipid metabolism, which are relevant to hepatic steatosis. The elevated phenylalanine, tyrosine, and histidine carry implications for neurologic manifestations and are worth further investigation

A Literature Review for Identification of Performance Measures for Establishing a Framework for Performance Measurement in Supply Chains

Supply Chain Management (SCM) has gained significance as one of the 21st century manufacturing paradigms for improving organizational competitiveness. Supply chain ensures improved efficiency and effectiveness of not only product transfer, but also information sharing between the complex hierarchies of all the tiers. The literature on SCM that deals with strategies and technologies for effectively managing a supply chain is quite vast. In recent years, organizational performance measurement (PM) and metrics have received much attention from researchers and practitioners. Performance measurement and metrics have an important role to play in setting objectives, evaluating performance, and determining future courses of actions. Performance measurement and metrics pertaining to SCM have not received adequate attention from researchers or practitioners. There is no systematic grouping of the different performance measures in the existing literature. The development of a framework for PM in supply chains requires generalised performance measures. This paper seeks to provide an extensive literature review for identification of performance measures, which in turn forms a basis for establishing a framework for performance measurements in supply chains

Intensive care doctors and nurses personal preferences for intensive Care, as compared to the general population: a discrete choice experiment

Background To test the hypothesis that Intensive Care Unit (ICU) doctors and nurses differ in their personal preferences for treatment from the general population, and whether doctors and nurses make different choices when thinking about themselves, as compared to when they are treating a patient. Methods Cross sectional, observational study conducted in 13 ICUs in Australia in 2017 using a discrete choice experiment survey. Respondents completed a series of choice sets, based on hypothetical situations which varied in the severity or likelihood of: death, cognitive impairment, need for prolonged treatment, need for assistance with care or requiring residential care. Results A total of 980 ICU staff (233 doctors and 747 nurses) participated in the study. ICU staff place the highest value on avoiding ending up in a dependent state. The ICU staff were more likely to choose to discontinue therapy when the prognosis was worse, compared with the general population. There was consensus between ICU staff personal views and the treatment pathway likely to be followed in 69% of the choices considered by nurses and 70% of those faced by doctors. In 27% (1614/5945 responses) of the nurses and 23% of the doctors (435/1870 responses), they felt that aggressive treatment would be continued for the hypothetical patient but they would not want that for themselves. Conclusion The likelihood of returning to independence (or not requiring care assistance) was reported as the most important factor for ICU staff (and the general population) in deciding whether to receive ongoing treatments. Goals of care discussions should focus on this, over likelihood of survival

A REVIEW ON FUNCTIONAL COMPARISON OF 5-HT1A AND 5-HT2C RECEPTORS

5-HT neurotransmission system is targeted by drugs useful in behavioural disorders, including anxiety, depression, psychosis and eating disorders. 5-HT1A autoreceptors, located on 5-HT neurones of the midbrain raphe nuclei, are coupled to K channels through a pertusis toxin-sensitive G-protein. 5-HT1A receptor agonists inhibit adenylyl cyclase, while 5-HT2C receptor agonists activate two signal transduction pathways coupled with these receptors. 5-HT1A and 5-HT2C receptors have lots potential in treating the disorders with less or no side effects. Keywords: 5-HT1A, 5-HT2C, Receptor

Status report on the folded tandem ion accelerator at BARC

The folded tandem ion accelerator (FOTIA) facility set up at BARC has become operational. At present, it is used for elemental analysis studies using the Rutherford backscattering technique. The beams of 1H, 7Li, 12C, 16O and 19F have been accelerated up to terminal voltages of about 3 MV and are available for experiments. The terminal voltage is stable within ±2 kV. In this paper, present status of the FOTIA and future plans are discussed

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. Summary: Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic\ue2\u80\u93uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP

Bypassing adverse injection reactions to nanoparticles through shape modification and attachment to erythrocytes

Intravenously injected nanopharmaceuticals, including PEGylated nanoparticles, induce adverse cardiopulmonary reactions in sensitive human subjects, and these reactions are highly reproducible in pigs. Although the underlying mechanisms are poorly understood, roles for both the complement system and reactive macrophages have been implicated. Here, we show the dominance and importance of robust pulmonary intravascular macrophage clearance of nanoparticles in mediating adverse cardiopulmonary distress in pigs irrespective of complement activation. Specifically, we show that delaying particle recognition by macrophages within the first few minutes of injection overcomes adverse reactions in pigs using two independent approaches. First, we changed the particle geometry from a spherical shape (which triggers cardiopulmonary distress) to either rod- or disk-shape morphology. Second, we physically adhered spheres to the surface of erythrocytes. These strategies, which are distinct from commonly leveraged stealth engineering approaches such as nanoparticle surface functionalization with poly(ethylene glycol) and/or immunological modulators, prevent robust macrophage recognition, resulting in the reduction or mitigation of adverse cardiopulmonary distress associated with nanopharmaceutical administration

The clinical application of electrical impedance technology in the detection of malignant neoplasms: a systematic review

Background: Electrical impedance technology has been well established for the last 20 years. Recently research has begun to emerge into its potential uses in the detection and diagnosis of pre-malignant and malignant conditions. The aim of this study was to systematically review the clinical application of electrical impedance technology in the detection of malignant neoplasms. Methods: A search of Embase Classic, Embase and Medline databases was conducted from 1980 to 22/02/2018 to identify studies reporting on the use of bioimpedance technology in the detection of pre-malignant and malignant conditions. The ability to distinguish between tissue types was defined as the primary endpoint, and other points of interest were also reported. Results: 731 articles were identified, of which 51 reported sufficient data for analysis. These studies covered 16 different cancer subtypes in a total of 7035 patients. As the studies took various formats, a qualitative analysis of each cancer subtype’s data was undertaken. All the studies were able to show differences in electrical impedance and/or related metrics between malignant and normal tissue. Conclusions: Electrical impedance technology provides a novel method for the detection of malignant tissue, with large studies of cervical, prostate, skin and breast cancers showing encouraging results. Whilst these studies provide promising insights into the potential of this technology as an adjunct in screening, diagnosis and intra-operative margin assessment, customised development as well as multi-centre clinical trials need to be conducted before it can be reliably employed in the clinical detection of malignant tissue

Structure and Morphology of Silver Nanoparticles on the (111) Surface of Cerium Oxide

The structure of Ag nanoparticles of different size, supported on the cerium oxide (111) surface, was investigated by X-ray absorption fine structure at the Ag K-edge. The results of the data analysis in the near and extended energy range are interpreted with the help of the results obtained by X-ray photoelectron spectroscopy and scanning tunneling microscopy measurements and allow to obtain a detailed atomic scale description of the model system investigated. The Ag nanoparticles have an average size of a few tens of angstroms, which increases with increasing deposited Ag amount. The nanoparticles show a slight tendency to nucleate at the step edges between different cerium oxide layers and they have a face centered cubic structure with an Ag-Ag interatomic distance contracted by 3-4% with respect to the bulk value. The interatomic distance contraction is mainly ascribed to dimensionality induced effects, while epitaxial effects have a minor role. The presence of Ag-O bonds at the interface between the nanoparticles and the supporting oxide is also detected. The Ag-O interatomic distance decreases with decreasing nanoparticle size