Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 μg · kg−1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean ± S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 ± 0.3 μmol · kg−1 and the highest dose (1000 μg · kg−1) produced a 67 ± 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carbboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 μmol · kg−1, i.v.). Compared to sumatriptan (pD2: 6.12 ± 0.15; Emax: 31.3 ± 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 ± 0.2; Emax: 21.0 ± 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects

Bacterial composition in Swedish raw drinking water reveals three major interacting ubiquitous metacommunities

Background Surface raw water used as a source for drinking water production is a critical resource, sensitive to contamination. We conducted a study on Swedish raw water sources, aiming to identify mutually co-occurring metacommunities of bacteria, and environmental factors driving such patterns. Methods The water sources were different regarding nutrient composition, water quality, and climate characteristics, and displayed various degrees of anthropogenic impact. Water inlet samples were collected at six drinking water treatment plants over 3 years, totaling 230 samples. The bacterial communities of DNA sequenced samples (n = 175), obtained by 16S metabarcoding, were analyzed using a joint model for taxa abundance. Results Two major groups of well-defined metacommunities of microorganisms were identified, in addition to a third, less distinct, and taxonomically more diverse group. These three metacommunities showed various associations to the measured environmental data. Predictions for the well-defined metacommunities revealed differing sets of favored metabolic pathways and life strategies. In one community, taxa with methanogenic metabolism were common, while a second community was dominated by taxa with carbohydrate and lipid-focused metabolism. Conclusion The identification of ubiquitous persistent co-occurring bacterial metacommunities in freshwater habitats could potentially facilitate microbial source tracking analysis of contamination issues in freshwater sources

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Rapid Identification of Bio-Molecules Applied for Detection of Biosecurity Agents Using Rolling Circle Amplification

Detection and identification of pathogens in environmental samples for biosecurity applications are challenging due to the strict requirements on specificity, sensitivity and time. We have developed a concept for quick, specific and sensitive pathogen identification in environmental samples. Target identification is realized by padlock- and proximity probing, and reacted probes are amplified by RCA (rolling-circle amplification). The individual RCA products are labeled by fluorescence and enumerated by an instrument, developed for sensitive and rapid digital analysis. The concept is demonstrated by identification of simili biowarfare agents for bacteria (Escherichia coli and Pantoea agglomerans) and spores (Bacillus atrophaeus) released in field

UL 508A standardin ohjeistus teollisuuden sähkökeskusvalmistuksessa

Opinnäytetyön tarkoituksena oli luoda ohjeistukset UL 508A standardista sekä Industrial Machinery lisävaatimuksesta Satmatic Oy:lle. Opinnäyte koostui kolmesta osa-alueesta, jotka olivat projektin lähtötietojen tiedustelu asiakkaalta, suunnittelu-osaston UL-tarkasteludokumentin kehittäminen sekä tuotannon UL-kaappityöselostuksen luonti. Tutkimustyö keskittyi UL 508A standardin sisällön tutkimiseen ja olennaisen tiedon erottamiseen työn eri osa-alueille. Tutkimusta tehtiin myös Satmatic Oy:n suunnitteluosastolla toteuttamalla asiakkaalle virallinen UL-tarkastelu. Asiakkaalle luotiin lähtötietolomake, johon täytetään projektin lähtötiedot ennen varsinaisen työn aloitusta. Lopputuloksessa tärkeimmät ominaisuudet olivat tarvittavien tietojen tiedustelu ja vastausvaihtoehtojen esitys, virallinen ulkoasu, sekä monipuolinen käytettävyys. Satmatic Oy:n suunnitteluosasto käyttää projekteissa UL-tarkasteludokumenttia, joka kehitettiin käytännöllisemmäksi lisäämällä tarkastelussa huomioon otettavia seikkoja, jotka olivat puuttuneet, tai muuttuneet UL 508A standardin päivitysten myötä. UL-kaappityöselitys luotiin Satmatic Oy tuotannon ohjeistukseksi, johon sisällytettiin kaikki huomioon otettavat asiat UL-hyväksytyn keskuksen mekaanisessa ja sähköisessä valmistuksessa. Tarkoituksena oli myös antaa tuotannon työntekijöille enemmän tietoa UL-projekteista ja niiden virallisista valmistus menetelmistä. Lopputulos sisälsi vaadittavat tiedot ja taulukot, mahdollisimman yksinkertaisessa ja tiivistetyssä muodossa.The purpose of this thesis was to create instructions for Satmatic Oy, about the UL 508A standard and Industrial Machinery supplementary demand. The thesis consisted of three different sections, that were the inquiry of the projects background data from the customer, the development of the designing departments UL examination form and the creating an UL cabinet explanation for the manufacturing department. The research work was focused on researching the content of the UL 508A standard and finding the essential information for the different sections. Research work was also made in the Satmatic Oy designing department by carrying out an official UL examination to a customer. The background data form was created for the customer, to fill the projects background data before starting the project. The main features of the outcome were the inquiry of the necessary information and to present answers to choose from, formal appearance as well as versatile availability. The designing department of Satmatic Oy uses the UL examination document, that was developed to be more practical with adding considerable factors, that were missing or changed with the updates of UL 508A standard. The UL cabinet explanation was created as an instruction for the production department of Satmatic Oy, that was included with all considerable matters in the electrical and mechanical manufacturing of an UL listed cabinet. The purpose was also to give more information about the UL projects and the official manufacturing methods used to the workers of the manufacturing department. The outcome contained all required information and tables, in as simple and compact form as possible

Ammatillinen kasvaminen tiiminvetäjänä

Opinnäytetyössä seurataan rahoitusalalla toimivan tiiminvetäjän työtehtäviä kahdeksan viikon seurantajakson ajan 12.9. – 4.11.2022. Opinnäytetyö on toteutettu päiväkirjamuotoisena ja tavoitteena on seurata tiiminvetäjän ammatillista kehittymistä. Opinnäytetyössä seurataan keskisuuren suomalaisen pankin tiiminvetäjän toimintaa asuntokauppojen maailmassa. Tiiminvetäjän tavoite on oppia lisää esihenkilötyöstä ja työssä keskitytään esihenkilötyön ja johtamisen osaamisen kehittämiseen. Päiväkirjamuotoisessa opinnäytetyössä esitetään tekijän lähtötaso, tehdään päiväkohtaisia merkintöjä tiiminvetäjän työtehtävistä ja seurantaviikon päätteeksi analysoidaan tiiminvetäjän kehittymistä kyseisellä viikolla. Lopuksi pohditaan koko seurantajakson aikana saatuja oppeja ja tiiminvetäjän kehitystä. Pohdinnassa analysoidaan tiiminvetäjän ammatillista kehittymistä

Patients’ self-reported nausea : Validation of the Numerical Rating Scale and of a daily summary of repeated Numerical Rating Scale scores

Aim and objectives: To validate the Numeric Rating Scale (NRS) for postoperative nausea assessments, and determine whether a central tendency, median, based on patients’ self-rated nausea is a clinically applicable daily measure to describe patients’ nausea after major surgery. Background: Postoperative nausea causes major discomfort, risks for complications and prolonged hospital stays. The NRS is recommended for the assessment of pain but is little explored for assessing nausea. Design: A repeated measure design was carried out on patients who had undergone major surgery in three Swedish hospitals. Methods: Nonparametric statistical methods were used to analyse (a) associations between the NRS and a verbal scale (no, mild, moderate and severe) and (b) to analyse associations between Measure 1 (nausea scores postoperative Day 1) and Measure 2 (retrospective nausea scores at rest and during activity, postoperative Day 2). Reporting of this research adheres to the Strobe Guidelines. Results: The mean age of the 479 patients (44% women) in the sample was 65 years (range, 22–93 years). Self-assessed nausea scores from the NRS and the verbal scale correlated well (rS pearman= 0.79). Correlation between nausea at rest and nausea during activity was rS pearman= 0.81. The calculated median scores (Measure 1) showed only moderate correlations with retrospective nausea scores (Measure 2); 4–9 ratings, rS pearman= 0.41; 6–9 ratings, rS pearman= 0.54. Conclusions: Numeric Rating Scale scores showed strong associations with a verbal scale; therefore, the NRS seems to be a valid tool to measure nausea intensity. The quality of daily summarised median nausea scores needs to be further explored before clinical use. Relevance to clinical practice: The use of the NRS in assessments of nausea in postoperative care will facilitate communication between patients and health care professionals regarding nausea intensity. When documenting nausea, it seems unnecessary to distinguish nausea at rest from nausea during activity