Anatomical Laser Microdissection of the Ileum Reveals mtDNA Depletion Recovery in A Mitochondrial Neuro-Gastrointestinal Encephalomyopathy (MNGIE) Patient Receiving Liver Transplant

mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE) is a rare genetic disorder characterized by thymidine phosphorylase (TP) enzyme defect. The absence of TP activity induces the imbalance of mitochondrial nucleotide pool, leading to impaired mitochondrial DNA (mtDNA) replication and depletion. Since mtDNA is required to ensure oxidative phosphorylation, metabolically active tissues may not achieve sufficient energy production. The only effective life-saving approach in MNGIE has been the permanent replacement of TP via allogeneic hematopoietic stem cell or liver transplantation. However, the follow-up of transplanted patients showed that gut tissue changes do not revert and fatal complications, such as massive gastrointestinal bleeding, can occur. The purpose of this study was to clarify whether the reintroduction of TP after transplant can recover mtDNA copy number in a normal range. Using laser capture microdissection and droplet-digital-PCR, we assessed the mtDNA copy number in each layer of full-thickness ileal samples of a naive MNGIE cohort vs. controls and in a patient pre- and post-TP replacement. The treatment led to a significant recovery of gut tissue mtDNA amount, thus showing its efficacy. Our results indicate that a timely TP replacement is needed to maximize therapeutic success before irreversible degenerative tissue changes occur in MNGIE.     

L-Carnitine Functionalization to Increase Skeletal Muscle Tropism of PLGA Nanoparticles

Muscular dystrophies are a group of rare genetic pathologies, encompassing a variety of clinical phenotypes and mechanisms of disease. Several compounds have been proposed to treat compromised muscles, but it is known that pharmacokinetics and pharmacodynamics problems could occur. To solve these issues, it has been suggested that nanocarriers could be used to allow controlled and targeted drug release. Therefore, the aim of this study was to prepare actively targeted poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the treatment of muscular pathologies. By taking advantage of the high affinity for carnitine of skeletal muscle cells due to the expression of Na⁺-coupled carnitine transporter (OCTN), NPs have been actively targeted via association to an amphiphilic derivative of L-carnitine. Furthermore, pentamidine, an old drug repurposed for its positive effects on myotonic dystrophy type I, was incorporated into NPs. We obtained monodispersed targeted NPs, with a mean diameter of about 100 nm and a negative zeta potential. To assess the targeting ability of the NPs, cell uptake studies were performed on C2C12 myoblasts and myotubes using confocal and transmission electron microscopy. The results showed an increased uptake of carnitine-functionalized NPs compared to nontargeted carriers in myotubes, which was probably due to the interaction with OCTN receptors occurring in large amounts in these differentiated muscle cells.     

NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.     

Chronic Hyperkaliemia in Chronic Kidney Disease: An Old Concern with New Answers

Increasing potassium intake ameliorates blood pressure (BP) and cardiovascular (CV) prognoses in the general population; therefore the World Health Organization recommends a high-potassium diet (90–120 mEq/day). Hyperkalaemia is a rare condition in healthy individuals due to the ability of the kidneys to effectively excrete dietary potassium load in urine, while an increase in serum K⁺ is prevalent in patients with chronic kidney disease (CKD). Hyperkalaemia prevalence increases in more advanced CKD stages, and is associated with a poor prognosis. This scenario generates controversy on the correct nutritional approach to hyperkalaemia in CKD patients, considering the unproven link between potassium intake and serum K⁺ levels. Another concern is that drug-induced hyperkalaemia leads to the down-titration or withdrawal of renin-angiotensin system inhibitors (RASI) and mineralocorticoids receptors antagonists (MRA) in patients with CKD, depriving these patients of central therapeutic interventions aimed at delaying CKD progression and decreasing CV mortality. The new K⁺-binder drugs (Patiromer and Sodium-Zirconium Cyclosilicate) have proven to be adequate and safe therapeutic options to control serum K⁺ in CKD patients, enabling RASI and MRA therapy, and possibly, a more liberal intake of fruit and vegetables.     

Lipidomic Approaches to Study HDL Metabolism in Patients with Central Obesity Diagnosed with Metabolic Syndrome

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated “omics” approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the “lysophosphatidylcholines to phosphatidylcholines” and “cholesteryl ester to free cholesterol” ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated “omics” approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis.     

Modular experimental setup for real‐time analysis of emergent behavior in networks of Chua's circuits

This paper describes the design, realization and use of an analogical, fully reconfigurable experimental setup to analyze the complex dynamics of networks of chaotic circuits. It reports details of the implementation and characterization of the setup, together with representative results, showing its flexibility and potential. The setup allows to choose arbitrarily the coupling strength and interconnection structure among the circuits, the type of link and to select the parameters of the node dynamics. It has a modular structure, and it can accommodate up to 32 nodes interconnected by at most 32 links. The collective dynamics of a relatively large set of different network structures and configurations has been investigated using the setup. Synchronization, pattern formation and other interesting collective phenomena were observed experimentally, their evidence being reported here as an illustration of the potential of the proposed setup. Copyright © 2015 John Wiley & Sons, Ltd.     

达涅利厚板坯连铸新技术和样板生产厂

达涅利戴维·迪斯汀顿是达涅利集团中负责板坯连铸机设备设计和供货的一家专业公司,通过与用户密切合作,开发了许多创新设备,如获得专利的INMO结晶器和OPTIMUM最优化扇形段,推出许多先进的连铸技术,如动态轻压下等,极大地促进了连铸技术的发展.正是由于这些先进技术,才有可能使达涅利在近些年来为世界上最先进的连铸板坯生产厂家提供连铸设备,其中包括韩国浦项、德国蒂森克虏伯、中国宝钢和法国阿赛洛米塔尔.介绍了达涅利的这些创新设备和它们在2006年12月份几乎同时试车投产的两家著名钢厂,宝钢(中国)和阿赛洛米塔尔(法国敦克尔克)的使用情况.     

达涅利薄板坯连铸连轧设备最新技术成果

给出达涅利薄板坯连铸连轧技术的最新应用成果.这些成果表明,达涅利技术不仅用于生产普通钢种,还可用于生产质量要求严格的优质钢种和高附加值产品.由达涅利在尼兹尼.诺夫戈罗德区Vyksa建设1套CRC(连铸连轧)设备.这是在俄罗斯建设的第1套薄板坯连铸连轧设备,也是世界上第1套利用薄板坯连铸连轧工艺路线生产北极高寒地区用API管线钢的生产设备.另外2套设备已在中国唐山钢铁集团有限公司和本溪钢铁集团有限公司进入满负荷生产阶段,前者一直保持着设备生产能力世界纪录,后者则成为中国第一家利用薄板坯连铸连轧工艺生产硅钢的厂家.     

Sodium and ultrafiltration profiling in hemodialysis: A long-forgotten issue revisited

Sodium and ultrafiltration profiling are method of dialysis in which dialysate sodium concentration and ultrafiltration rate are altered during the course of the dialysis session. Sodium and ultrafiltration profiling have been used, commonly simultaneously, to improve hemodynamic stability during hemodialysis. Sodium profiling is particularly effective in decreasing the incidence of intradialytic hypotension, while ultrafiltration profiling is suggested to decrease subclinical repeated end organ ischemia during dialysis. However, complications such as increased interdialytic weight gain and thirst due to sodium excess have prevented widespread use of sodium profiling. Evidence suggest that different sodium profiling techniques may lead to different clinical results, and preferring sodium balance neutral sodium profiling may mitigate adverse effects related to sodium overload. However, evidence is lacking on the long-term clinical outcomes of different sodium profiling methods. Optimal method of sodium profiling as well as the utility of sodium/ultrafiltration profiling in routine practice await further clinical investigation.