Long-Term Depression at Parallel Fiber to Golgi Cell Synapses

Golgi cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule cells is central to operate the relay of excitatory inputs to the cerebellar cortex. Parallel fibers (PFs) establish synapses to the GoCs in the molecular layer; these synapses contain AMPA, N-methyl-d-aspartate (NMDA), and mostly group II metabotropic glutamate receptors. Long-term changes in the efficacy of synaptic transmission at the PF-GoC synapse have not been described previously. We used whole cell patch-clamp recordings of GoCs in acute rat cerebellar slices to study synaptic plasticity. We report that high-frequency burst stimulation of PFs, using a current-clamp or voltage-clamp induction protocol, gave rise to long-term depression (LTD) at the PF-GoC synapse. This form of LTD was not associated with persistent changes of paired-pulse ratio, suggesting a postsynaptic origin. Furthermore, LTD induction was not dependent on activation of NMDA receptors. PF-GoC LTD does require activation of specifically group II metabotropic glutamate receptors and of protein kinase A

Histological and stable isotope analysis of archeological bones from St. Rombout's cemetery (Mechelen, Belgium): Intrasite, intraindividual, and intrabone variability

Funder: Greek Archaeological Committee UK (GACUK)Funder: Leventis Foundation; Id: http://dx.doi.org/10.13039/501100004117Abstract: This study compares histological preservation in archeological bones from different burial types to unravel the histotaphonomy‐to‐funerary practices relationship. Αn intraskeletal approach is also adopted to explore intraindividual (inner ear part of the petrous bone vs. upper/lower limb long bones) and intrabone (proximal vs. distal diaphysis) variability in bone collagen preservation, δ13C, and δ15N. The aim is to (a) target bones that likely retain higher amounts of collagen, (b) better understand the inner ear bone collagen isotopic signature and remodeling, and (c) assess intrabone isotopic and histological homogeneity. For the histological analysis, the data have been collected from 61 specimens (20 individuals) from the medieval/postmedieval cemetery of St. Rombout, Belgium. Thin sections have been studied using optical and scanning electron microscopy. For the collagen and isotopic data, 101 samples have been collected from 21 individuals. Distinct histological patterns are observed only in bones from single coffin burials; however, bone histology can display intraindividual and intrabone variability, which are important to account for interpretations. Collagen wt.%, δ13C, and δ15N show significant intraindividual differences but insignificant intrabone variability. This study also confirms the extraordinary nature of the petrous bone, as the inner ear bone collagen δ13C and δ15N values reflect the dietary input of the first approximately 2–3 years of life

Medication Review: What’s in a Name and What Is It about?

Background: Medication review is a multifaceted service aimed at optimizing the use of medicines and enhancing the health outcomes of patients. Due to its complexity, it is crucial to clearly describe the service, its variants, and its components to avoid confusion and ensure a better understanding of medication review among healthcare providers. Aim: This study aims to bring clarity to the origins, definitions, abbreviations, and types of medication reviews, together with the primary criteria that delineate key features of this service. Method: A narrative review approach was employed to clarify the diverse terminology associated with “medication review” services. Relevant references were initially identified through searches on PubMed and Google Scholar, complementing the existing literature known to the authors. Results: The study uncovers a complicated and sometimes convoluted history of “medication review” in different regions around the world. The initial optimization of medicine use had an economic purpose before evolving subsequently into a more patient-oriented approach. A selection of abbreviations, definitions, and types were outlined to enhance the understanding of the service. Conclusions: The study underscores the urgent need for comprehensive information and standardization regarding the content and quality of the services, collectively referred to as “medication review”

Rhinovirus-16 induced temporal interferon responses in nasal epithelium links with viral clearance and symptoms

Background: The temporal in vivo response of epithelial cells to a viral challenge and its association with viral clearance and clinical outcomes has been largely unexplored in asthma. Objective: To determine gene expression profiles over time in nasal epithelial cells (NECs) challenged in vivo with rhinovirus-16 (RV16) and compare to nasal symptoms and viral clearance. Methods: Patients with stable mild to moderate asthma (n = 20) were challenged intranasally with RV16. Nasal brush samples for RNA sequencing were taken 7 days prior to infection and 3, 6 and 14 days post-infection, and blood samples 4 days prior to infection and day 6 post-infection. Viral load was measured in nasal lavage fluid at day 3, 6 and 14. Results: Top differentially (>2.5-fold increase) expressed gene sets in NECs post-RV16 at days 3 and 6, compared with baseline, were interferon alpha and gamma response genes. Patients clearing the virus within 6 days (early resolvers) had a significantly increased interferon response at day 6, whereas those having cleared the virus by day 14 (late resolvers) had significantly increased responses at day 3, 6 and 14. Interestingly, patients not having cleared the virus by day 14 (non-resolvers) had no enhanced interferon responses at any of these days. The daily Cold Symptom Scores (CSS) peaked at days 3 to 5 and correlated positively with interferon response genes at day 3 (R = 0.48), but not at other time-points. Interferon response genes were also enhanced in blood at day 6 after RV16 challenge. Conclusion and Clinical Relevance: This study shows that viral load and clearance varies markedly over time in mild to moderate asthma patients exposed to a fixed RV16 dose. The host's nasal interferon response to RV16 at day 3 is associated with upper respiratory tract symptoms. The temporal interferon response in nasal epithelium associates with viral clearance in the nasal compartment

Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3

Purpose: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. Methods: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. Findings: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. Implications: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002). © 2018 Elsevier HS Journals, Inc