Clinical and non-clinical aspects of reimbursement policy for orphan drugs in selected European countries.

Objectives: The aim of the study was to assess the reimbursement policy for orphan drugs (ODs) in selected European countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedures and reimbursement decision-making.

Materials And Methods: A list of authorized ODs was extracted from a web-based registry of the European Medicines Agency, including information on active substance, Anatomical Therapeutic Chemical (ATC) classification code, and therapeutic area. A country-based questionnaire survey was conducted between September 2022 and September 2023 among selected experts from 12 European countries.

Potential of continuous cover forestry on drained peatlands to increase the carbon sink in Finland.

Land-based mitigation measures are needed to achieve climate targets. One option is the mitigation of currently high greenhouse gas (GHG) emissions of nutrient-rich drained peatland forest soils. Continuous cover forestry (CCF) has been proposed as a measure to manage this GHG emission source; however, its emission reduction potential and impact on timber production at regional and national scales have not been quantified.

Myeloma Genome Project Panel is a Comprehensive Targeted Genomics Panel for Molecular Profiling of Patients with Multiple Myeloma.

Purpose: We designed a comprehensive multiple myeloma targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards.

Experimental Design: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNA). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical FISH (translocations), multiplex ligation probe analysis (MLPA; CNAs), whole-genome sequencing (WGS; CNAs, mutations, translocations), or droplet digital PCR (ddPCR) of known standards (mutations).

Mitoxantrone, pixantrone and mitoxantrone (2-hydroxyethyl)piperazine are toll-like receptor 4 antagonists, inhibit NF-κB activation, and decrease TNF-alpha secretion in primary microglia.

Toll-like receptor 4 (TLR4) recognizes various endogenous and microbial ligands and is an essential part in the innate immune system. TLR4 signaling initiates transcription factor NF-κB and production of proinflammatory cytokines. TLR4 contributes to the development or progression of various diseases including stroke, neuropathic pain, multiple sclerosis, rheumatoid arthritis and cancer, and better therapeutics are currently sought for these conditions.

Genetic lack of histamine upregulates dopamine neurotransmission and alters rotational behavior but not levodopa-induced dyskinesia in a mouse model of Parkinson's disease.

The brain histaminergic and dopaminergic systems closely interact, and some evidence also suggests significant involvement of histamine in Parkinson's disease (PD), where dopaminergic neurons degenerate. To further investigate histamine-dopamine interactions, particularly in the context of PD, a genetic lack of histamine and a mouse model of PD and levodopa-induced dyskinesia were here combined. Dopaminergic lesions were induced in histidine decarboxylase knockout and wildtype mice by 6-hydroxydopamine injections into the medial forebrain bundle.

Pharmacy Practice and Education in Finland.

The Pharmacy Education in Europe (PHARMINE) project studies pharmacy practice and education in the European Union (EU) member states. The work was carried out using an electronic survey sent to chosen pharmacy representatives. The surveys of the individual member states are now being published as reference documents for students and staff interested in research on pharmacy education in the EU, and in mobility.

Dyskinesia and brain-derived neurotrophic factor levels after long-term levodopa and nicotinic receptor agonist treatments in female mice with near-total unilateral dopaminergic denervation.

Background: The treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID). Nicotinic acetylcholine receptor agonists can alleviate LID in animal models but may be less effective in conditions of severe dopaminergic denervation. While the mechanisms of LID remain incompletely understood, elevated corticostriatal levels of the brain-derived neurotrophic factor (BDNF) have been suggested to play a role.

Attenuated dopaminergic neurodegeneration and motor dysfunction in hemiparkinsonian mice lacking the α5 nicotinic acetylcholine receptor subunit.

Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of α5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and α5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle.

Effects of antidyskinetic nicotine treatment on dopamine release in dorsal and ventral striatum.

The treatment of Parkinson's disease is often complicated by levodopa-induced dyskinesia (LID), and antidyskinetic treatment options are currently sparse. Nicotinic acetylcholine receptors have been suggested as potential targets for treatment of LID, as nicotinic agonists have been reported to alleviate LID in animal models. We aimed at the first independent replication of an antidyskinetic effect by nicotine using a mouse model of LID, and at investigation of its mechanisms by studying the release of [H]dopamine from synaptosomes prepared from the dorsal and ventral striatum.

Histamine H Receptors Decrease Dopamine Release in the Ventral Striatum by Reducing the Activity of Striatal Cholinergic Interneurons.

Histamine H receptors are widely distributed G-coupled receptors whose activation reduces neuronal activity and inhibits release of numerous neurotransmitters. Although these receptors are abundantly expressed in the striatum, their modulatory role on activity-dependent dopamine release is not well understood. Here, we observed that histamine H receptor activation indirectly diminishes dopamine overflow in the ventral striatum by reducing cholinergic interneuron activity.

Competence-Based Pharmacy Education in the University of Helsinki.

In order to meet the expectations to act as an expert in the health care profession, it is of utmost importance that pharmacy education creates knowledge and skills needed in today's working life. Thus, the planning of the curriculum should be based on relevant and up-to-date learning outcomes. In the University of Helsinki, a university wide curriculum reform called 'the Big Wheel' was launched in 2015.

Is enhanced biodiversity protection conflicting with ambitious bioenergy targets in eastern Finland?

The study describes how qualitative stakeholder feedback can be used in quantitative scenarios to simulate forest resource use under alternative management objectives. In earlier studies in the region of eastern Finland, stakeholders did not see a possible conflict between increased bioenergy use and nature conservation; this finding is contrary to the results of other studies. The aim of this study was to test with a quantitative modelling approach whether the stakeholder expectation holds and whether forest management in eastern Finland can simultaneously increase biomass utilization and biodiversity protection.

Different Hypothalamic Nicotinic α7 Receptor Expression and Response to Low Nicotine Dose in Alcohol-Preferring and Alcohol-Avoiding Rats.

Background: The aim of this study was to examine possible differences in nicotinic acetylcholine receptors and responses in rats with genetic preference or avoidance for alcohol. This was done by using 2 rat lines with high alcohol preference (Alko Alcohol [AA]) or alcohol avoidance (Alko Non-Alcohol [ANA]).

Methods: Locomotor activity was measured following nicotine and histamine H3 receptor (H3R) antagonist treatment.

Methadone's effect on nAChRs--a link between methadone use and smoking?

Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone.

Methadone is a non-competitive antagonist at the α4β2 and α3* nicotinic acetylcholine receptors and an agonist at the α7 nicotinic acetylcholine receptor.

Nicotine-methadone interactions have been studied in human beings and in various experimental settings regarding addiction, reward and pain. Most methadone maintenance treatment patients are smokers, and methadone administration has been shown to increase cigarette smoking. Previous in vitro studies have shown that methadone is a non-competitive antagonist at rat α3β4 nicotinic acetylcholine receptors (nAChR) and an agonist at human α7 nAChRs.

α6β2*-subtype nicotinic acetylcholine receptors are more sensitive than α4β2*-subtype receptors to regulation by chronic nicotine administration.

Nicotinic acetylcholine receptors (nAChR) of the α6β2* subtype (where *indicates the possible presence of additional subunits) are prominently expressed on dopaminergic neurons. Because of this, their role in tobacco use and nicotine dependence has received much attention. Previous studies have demonstrated that α6β2*-nAChR are down-regulated following chronic nicotine exposure (unlike other subtypes that have been investigated - most prominently α4β2* nAChR).

Stakeholder engagement in scenario development process - bioenergy production and biodiversity conservation in eastern Finland.

In this study participatory approaches were used to develop alternative forest resource management scenarios with particular respect to the effects on increased use of forest bioenergy and its effect on biodiversity in Eastern Finland. As technical planning tools, we utilized a forest management planning system (MELA) and the Tool for Sustainability Impact Assessment (ToSIA) to visualize the impacts of the scenarios. We organized a stakeholder workshop where group discussions were used as a participatory method to get the stakeholder preferences and insights concerning forest resource use in the year 2030.

Low micromolar Ba(2+) potentiates glutamate transporter current in hippocampal astrocytes.

Glutamate uptake, mediated by electrogenic glutamate transporters largely localized in astrocytes, is responsible for the clearance of glutamate released during excitatory synaptic transmission. Glutamate uptake also determines the availability of glutamate for extrasynaptic glutamate receptors. The efficiency of glutamate uptake is commonly estimated from the amplitude of transporter current recorded in astrocytes.

A role for α4(non-α6)* nicotinic acetylcholine receptors in motor behavior.

Nicotinic acetylcholine receptors (nAChRs) containing either the α4 and/or α6 subunit are robustly expressed in dopaminergic nerve terminals in dorsal striatum where they are hypothesized to modulate dopamine (DA) release via acetylcholine (ACh) stimulation from cholinergic interneurons. However, pharmacological blockade of nAChRs or genetic deletion of individual nAChR subunits, including α4 and α6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the α4 subunit in modulation of DA in dorsal striatum, we hypothesized that mice expressing a single point mutation in the α4 nAChR subunit, Leu9'Ala, that renders nAChRs hypersensitive to agonist, would exhibit exaggerated differences in motor behavior compared to WT mice.

Nicotine-morphine interactions at α4β2, α7 and α3(⁎) nicotinic acetylcholine receptors.

Nicotine and opioids share several behavioral and rewarding properties. Although both opioids and nicotine have their own specific mechanism of action, there is empirical and experimental evidence of interactions between these drugs. We studied receptor-level interactions of nicotine and morphine at α4β2, α7 and α3(⁎) nicotinic acetylcholine receptors.

[Effect of Catechol-O-methyltransferase deficiency on reinforcing effects of cocaine (experimental study)].

Catechol-O-methyltransferase (COMT) remains an important regulatory element in prefrontal cortex dopamine homeostasis. The literature data suggest that individual differences in COMT activity (Val158Met polymorphism) might have indirect downstream effects on the reward system. The aim of the present study was to examine whether COMT deletion affects reinforcing effects of cocaine in mice.

[Effect of alpha-conotoxin MII and its N-terminal derivatives on Ca2+ and Na+ signals induced by nicotine in neuroblastoma cell line SH-SY5Y].

Nicotinic acetylcholine receptors (nAChRs) are implicated in the regulation ofintracellular Ca2+-dependent processes in cells both in normal and pathological states, alpha-Conotoxins isolated from Conus snails venom are a valuable tool for the study of pharmacological properties and functional role of nAChRs. In the present study the alpha-conotoxin MII analogue with the additional tyrosine attached to the N terminus (Y0-MII) was prepared. Also we synthesized analogs with the N-terminal glycine residue labeled with the Bolton- Hunter reagent (BH-MII) or fluorestsein isothiocyanate (FITC-MII).

Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits.

Introduction: The role of the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25 in the etiology of nicotine dependence (ND) is still being defined. In this study, we included all 15 tagging single nucleotide polymorphisms (SNPs) within the CHRNA5-CHRNA3-CHRNB4 cluster and tested associations with 30 smoking-related phenotypes.

Methods: The study sample was ascertained from the Finnish Twin Cohort study.

Associations of nicotine intake measures with CHRN genes in Finnish smokers.

Introduction: Genetic effects contribute to individual differences in smoking behavior. Persistence to smoke despite known harmful health effects is mostly driven by nicotine addiction. As the physiological effects of nicotine are mediated by nicotinic acetylcholine receptors (nAChRs), we aimed at examining whether single nucleotide polymorphisms (SNPs) residing in nAChR subunit (CHRN) genes, other than CHRNA3/CHRNA5/CHRNB4 gene cluster previously showing association in our sample, are associated with smoking quantity or serum cotinine levels.