Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology. Despite the increasing expectations of functional selectivity, translating G protein-biased opioid agonists into improved therapeutics is far from being fully achieved, due to the complex, multidimensional pharmacology of opioid receptors. The multifaceted network of signaling events and molecular processes underlying therapeutic and adverse effects induced by opioids is more complex than the mere dichotomy between G protein and arrestin and requires more comprehensive, integrated, network-centric approaches to be fully dissected. Quantitative Systems Pharmacology (QSP) models employing multidimensional assays associated with computational tools able to analyze large datasets may provide an intriguing approach to go beyond the greater complexity of opioid receptor pharmacology and the current limitations entailing the development of biased opioid agonists as improved analgesics

Racial Disparities in Necrotizing Enterocolitis.

Necrotizing enterocolitis (NEC) is a serious disease of the intestinal tract affecting 5-10% of pre-term infants with up to 50% mortality in those that require surgery. There is wide variation in the rates and outcomes of NEC by race and ethnicity, and the reasons for this disparity are poorly understood. In this article, we review the epidemiology and discuss possible explanations for racial and ethnic differences in NEC. Most of the current evidence investigating the role of race in NEC comes from North America and suggests that Hispanic ethnicity and non-Hispanic Black race are associated with higher risk of NEC compared to non-Hispanic White populations. Differences in pre-term births, breastfeeding rates, and various sociodemographic factors does not fully account for the observed disparities in NEC incidence and outcomes. While genetic studies are beginning to identify candidate genes that may increase or decrease risk for NEC among racial populations, current data remain limited by small sample sizes and lack of validation. Complex interactions between social and biological determinants likely underly the differences in NEC outcomes among racial groups. Larger datasets with detailed social, phenotypic, and genotypic information, coupled with advanced bioinformatics techniques are needed to comprehensively understand racial disparities in NEC

Implementation of bowel ultrasound practice for the diagnosis and management of necrotising enterocolitis.

Necrotising enterocolitis (NEC) is a serious inflammatory bowel disease of prematurity with potentially devastating complications and remains a leading cause of morbidity and mortality among premature infants. In recent years, there has been accumulating data regarding benefits of using bowel ultrasound (BUS) in the diagnosis and management of NEC. Despite this, adoption of robust BUS programmes into clinical practice has been slow. As BUS is a relatively new technique, many barriers to implementation exist, namely lack of education and training for sonographers and radiologists, low case volume and unfamiliarity by clinicians regarding how to use the information provided. The aim of this manuscript is to provide a framework and a roadmap for units to implement BUS in day-to-day practice for NEC diagnosis and management

New concepts for light mechanical structures of cylindrical drift chambers

A significant reduction in the amount of material at the end plates of a drift chamber can be obtained by the simple consideration of separating, in the mechanical structure, the gas containment function from the wire tension support function. According to this scheme, the wires are anchored to a self-sustaining light structure ("wire cage") surrounded by a very thin skin ("gas envelope") of suitable profile to compensate for the gas differential pressure with respect to the outside. The "wire cage" is schematically made of a set of radial spokes, constrained into a polygonal shape at the inner ends and extended to the outer endplate rim, thus subdividing the chamber in identical sectors. The drift chamber is, then, built by stacking up radially, in each of the sectors and between adjacent spokes, printed circuit boards, where the ends of the wires are soldered, alternated with proper spacers, to define the cell width. A system of adjustable tie-rods steers the wire tension to the outer endplate rim, where a rigid cylindrical carbon fibre support structure, bearing the total wire load, is attached. Two thin carbon fibre domes, free to deform under the gas pressure without affecting the wire tension and conveniently shaped to minimize the stress at the inner rim, contribute to the "gas envelope" and, together with an inner thin cylindrical foil and with the outer structural support, enclose the gas volume

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

Cholesterol embolization (CE) is a rare and alarming post-transplant complication, responsible for primary non-function (PNF) or delayed graft function (DGF). Its incidence is expected to rise due to increasingly old donors and recipients and the extended criteria for donation. Therapy with statins and steroids has not been shown to be effective, while agonism of prostaglandin I2 has been reported to be useful in systemic CE. We report two cases of acute post-transplant CE in which intravenous iloprost (0.05 mg/kg/day) was added to standard statin and steroid therapy. In the first instance, CE was due to embolization from the kidney artery resulting in embolization of the small vessels; after a long DGF and 15 days of iloprost therapy, renal function recovered. The second instance is a case of embolization from the iliac artery of the recipient, where CE manifested as a partial renal infarction. After 5 days of iloprost administration, creatinine levels improved. Iloprost acts on vasodilation and on different inflammatory pathways, improving the anti-inflammatory profile. Post-transplant CE is difficult to diagnose and, if not treated, can lead to loss of function. Iloprost added to standard therapy could be beneficial in accelerating renal function recovery immediately after transplant

A conserved role for Snail as a potentiator of active transcription

The transcription factors of the Snail family are key regulators of epithelial-mesenchymal transitions, cell morphogenesis, and tumor metastasis. Since its discovery in Drosophila ~25 years ago, Snail has been extensively studied for its role as a transcriptional repressor. Here we demonstrate that Drosophila Snail can positively modulate transcriptional activation. By combining information on in vivo occupancy with expression profiling of hand-selected, staged snail mutant embryos, we identified 106 genes that are potentially directly regulated by Snail during mesoderm development. In addition to the expected Snail-repressed genes, almost 50% of Snail targets showed an unanticipated activation. The majority of "Snail-activated" genes have enhancer elements cobound by Twist and are expressed in the mesoderm at the stages of Snail occupancy. Snail can potentiate Twist-mediated enhancer activation in vitro and is essential for enhancer activity in vivo. Using a machine learning approach, we show that differentially enriched motifs are sufficient to predict Snail's regulatory response. In silico mutagenesis revealed a likely causative motif, which we demonstrate is essential for enhancer activation. Taken together, these data indicate that Snail can potentiate enhancer activation by collaborating with different activators, providing a new mechanism by which Snail regulates development

A 10-3 drift velocity monitoring chamber

The MEG-II experiment searches for the lepton flavor violating decay: mu in electron and gamma. The reconstruction of the positron trajectory uses a cylindrical drift chamber operated with a mixture of He and iC4H10 gas. It is important to provide a stable performance of the detector in terms of its electron transport parameters, avalanche multiplication, composition and purity of the gas mixture. In order to have a continuous monitoring of the quality of gas, we plan to install a small drift chamber, with a simple geometry that allows to measure very precisely the electron drift velocity in a prompt way. This monitoring chamber will be supplied with gas coming from the inlet and the outlet of the detector to determine if gas contaminations originate inside the main chamber or in the gas supply system. The chamber is a small box with cathode walls, that define a highly uniform electric field inside two adjacent drift cells. Along the axis separating the two drift cells, four staggered sense wires alternated with five guard wires collect the drifting electrons. The trigger is provided by two 90Sr weak calibration radioactive sources placed on top of a two thin scintillator tiles telescope. The whole system is designed to give a prompt response (within a minute) about drift velocity variations at the 0.001 level

A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain

BACKGROUND: IgG4-related disease, described around the years 2000 as a form of autoimmune pancreatitis, is now increasingly accepted as a systemic syndrome. The diagnosis is based on both comprehensive and organ-specific criteria. For the kidney, Mayo clinic classification and the guidelines of the Japanese Nephrology Society are used. Ultimately, together with parameters that characterize every organ or apparatus involved, the key element is the confirmation of growing levels of IgG4 in blood or in tissues. CASE PRESENTATION: We describe a male patient with chronic renal failure associated to hypertension without proteinuria. IgG4-related disease was diagnosed through renal biopsy. After an initial positive response to steroids, he presented tinnitus, and histological assessment showed cerebral and subsequently cardiac damage, both IgG4-related. This case appears unique for the type of histologically documented cardiac and neurological parenchymal involvement, and at the same time, exemplifies the subtle and pernicious course of the disease. Frequently, blurred and non-specific signs prevail. Here, kidney damage was associated with minimal urinary findings, slowly progressive renal dysfunction and other factors that can be equivocated in the differential diagnosis. Neurological involvement was represented by tinnitus alone, while cardiac alterations were completely asymptomatic. CONCLUSIONS: This report is representative of the neurological and cardiac changes described in the literature for IgG4-related disease, which may be correlated or not with the renal form and highlights the need, in some cases, of targeted therapeutic approaches. In addition to glucocorticoids, as in this case, rituximab may be necessary

The Tracking performance for the IDEA drift chamber

The IDEA detector concept for a future e+e- collider adopts an ultra-low mass drift chamber as a central tracking system. The He-based ultra-low mass drift chamber is designed to provide efficient tracking, a high-precision momentum measurement, and excellent particle identification by exploiting the cluster counting technique. This paper describes the expected tracking performance, obtained with full and fast simulation, for track reconstruction on detailed simulated physics events. Moreover, the details of the construction parameters of the drift chamber, including the inspection of new material for the wires, new techniques for soldering the wires, the development of an improved schema for the drift cell, and the choice of a gas mixture, will be described

Assessing connectivity between an overlying aquifer and a coal seam gas resource using methane isotopes, dissolved organic carbon and tritium

Coal seam gas (CSG) production can have an impact on groundwater quality and quantity in adjacent or overlying aquifers. To assess this impact we need to determine the background groundwater chemistry and to map geological pathways of hydraulic connectivity between aquifers. In south-east Queensland (Qld), Australia, a globally important CSG exploration and production province, we mapped hydraulic connectivity between the Walloon Coal Measures (WCM, the target formation for gas production) and the overlying Condamine River Alluvial Aquifer (CRAA), using groundwater methane (CH4) concentration and isotopic composition (δ13C-CH4), groundwater tritium (3H) and dissolved organic carbon (DOC) concentration. A continuous mobile CH4 survey adjacent to CSG developments was used to determine the source signature of CH4 derived from the WCM. Trends in groundwater δ13C-CH4 versus CH4 concentration, in association with DOC concentration and 3H analysis, identify locations where CH4 in the groundwater of the CRAA most likely originates from the WCM. The methodology is widely applicable in unconventional gas development regions worldwide for providing an early indicator of geological pathways of hydraulic connectivity