Mustarotan (Rattus rattus) esiintyminen ja mahdolliset vaikutukset kotoperäisille jyrsijöille Kaakkois-Madagaskarilla

Native faunas and floras are especially susceptible to negative effects of invasive alien species in islands. The world´s fourth largest island, Madagascar, has very unique biota with high level of endemism. The black rat, Rattus rattus, is claimed to cause more extinctions of insular vertebrates than any other introduced rodent in the world. On Madagascar, R. rattus is suggested to competete with native rodents belonging to the endemic subfamily Nesomyinae. Extensive deforestation and fragmentation also threatens Malagasy forest-dwelling species. The aims of this thesis were to 1) study the occurence of native and introduced species and the different kind of factors determining occurence in southeastern Madagascar and 2) help to target future studies by estimating which native rodents are the most potential competitors with introduced rodents on Madagascar. Habitat use data of black rat and endemic rodents were collected both in fragmented and in unfragmented forest in Ranomafana National Park in southeastern Madagascar. A total of 698 rodent individuals were captured in 6204 trap nights. Logistic and Poisson regression models were used to determine the factors that influence the presence and abundance of rodent species and to investigate how sensitive one variable can be to other variables in regression models. This led to the introduction of a new approach called explanatory framework based regression analysis (EFRA) which rests on the social science based elaboration technique. EFRA enables systematization of the link between ecological knowledge and statistical analysis. From the point of it multicollinearity is more source of information than a problem for data analysis. The abundance of R. rattus increased with increasing forest disturbance. The spread of R. rattus was suggested to be associated with deforestation but not directly with fragmentation. It is not surprising when remembering that R. rattus utilizes open areas too. The measured value of the size of the fragment can be viewed as an index capturing certain features of the forest fragment. For Malagasy native rodents, clear-cutting is disastrous and forest fragmentation may have a diminishing effect on populations of Nesomys audeberti. However, none of the native species was more abundant in un-logged than in selectively logged forest. There was no evidence that Eliurus webbi suffers directly from forest fragmentation but it may be more susceptible to interactions with R. rattus in fragments than in continuous forest. In the last paper, the comparison of morphological measurements leads to the conclusion that there is a high probability of competition between introduced R. rattus and the following native taxa: all species of Nesomys, larger semiarboreal Eliurus species (e.g. E. tanala, E. webbi), and especially Gymnuromys roberti.Saarien alkuperäinen eliöstö on erityisen altis tulokaslajien haitallisille vaikutuksille. Maailman neljänneksi suurimman saaren Madagaskarin eliölajistosta suurinta osaa ei tavata missään muualla maailmassa. Kaikista maailman tulokasjyrsijöistä mustarotan (Rattus rattus) on väitetty aiheuttavan eniten selkärankaisten eläinlajien sukupuuttoja saarilla. Madagaskarilla mustarotan on epäilty kilpailevan alkuperäisten jyrsijälajien kanssa, jotka kaikki kuuluvat samaan kotoperäiseen alaheimoon madagaskarinrotat (Nesomyinae). Myös metsien häviäminen ja pirstoutuminen uhkaavat Madagaskarin metsien eläinlajeja. Väitöskirjan tavoitteina oli 1) tutkia Kaakkois-Madagaskarin alkuperäis- ja tulokasjyrsijöiden esiintymistä ja siihen vaikuttavia tekijöitä sekä 2) antaa suuntaviivoja tuleville tutkimuksille arvioimalla, mitkä Madagaskarin alkuperäisistä jyrsijälajeista todennäköisimmin kilpailevat tulokasjyrsijöiden kanssa. Aineistoa mustarotan ja kotoperäisten jyrsijöiden habitaatin käytöstä kerättiin sekä yhtenäiseltä että pirstoutuneelta metsäalueelta Ranomafanan kansallispuiston ympäristössä Kaakkois-Madagaskarilla. Yhteensä 698 jyrsijäyksilöä pyydystettiin 6204 loukkuvuorokautena. Poisson- ja logistisia regressiomalleja käytettiin määrittämään jyrsijälajien runsauteen ja läsnäoloon vaikuttavia tekijöitä sekä osoittamaan, kuinka herkkä yksittäinen muuttuja voi olla regressiomalleissa. Se johti ekologialle uuden EFRA: ksi (explanatory framework based regression analysis) kutsuttavan lähestymistavan esittelemiseen. EFRA pohjautuu yhteiskuntatieteissä käytettyyn elaboraatioteknikkaan, jonka avulla ekologista tietoa pystytään paremmin hyödyntämään tilastollisessa käsittelyssä. EFRAn näkökulmasta eri muuttujien korreloiminen keskenään ei ole ongelma vaan pikemminkin tiedonlähde. Tutkimusaineistossa mustarotta oli sitä runsaampi mitä enemmän metsää oli käsitelty. Mustarotan leviämisen esitettiin olevan yhteydessä metsien häviämisen mutta ei suoraan pirstoutumisen kanssa. Se ei ole yllättävää, kun muistetaan, että mustarotta viihtyy myös avoimilla alueilla. Mustarotan esiintymistä tarkasteltaessa metsälaikun koko pitäisikin nähdä vain eräänlaisena metsälaikun ominaispiirteitä ilmentävänä indeksinä. Madagaskarin kotoperäisille jyrsijälajeille avohakkuut ovat vahingollisia ja metsien pirstoutuminen saattaa heikentää madagaskarinpunarottiin kuuluvan Nesomys audeberti lajin populaatioita. Kuitenkaan mikään Madagaskarin alkuperäisistä jyrsijälajeista ei ollut runsaampi koskemattomissa kuin harvennushakatuissa metsissä. Madagaskarinrannikkotupsukkaan (Eliurus webbi) ei todettu suoraan kärsivän metsien pirstoutumisesta, mutta se saattaa olla alttiimpi mahdolliselle kilpailulle mustarotan kanssa metsälaikuilla kuin yhtenäisillä metsäalueilla. Morfologisten mittatietojen perusteella mustarotta todennäköisimmin kilpailee voalavoanalan (Gymnuromys roberti), mutta todennäköisesti myös kaikkien madagaskarinpunarottalajien (Nesomys) sekä suurikokoisten ja harvemmin kiipeilevien madagaskarintupsukkaiden (esim. Eliurus tanala, Eliurus webbi) kanssa

The Quest for New Approaches in Myocarditis and Inflammatory Cardiomyopathy

Myocarditis is a diverse group of heart-specific immune processes classified by clinical and histopathological manifestations. Up to 40% of dilated cardiomyopathy is associated with inflammation or viral infection. Recent experimental studies revealed complex regulatory roles for several microribonucleic acids and T-cell and macrophage subtypes. Although the prevalence of myocarditis remained stable between 1990 and 2013 at about 22 per 100,000 people, overall mortality from cardiomyopathy and myocarditis has decreased since 2005. The diagnostic and prognostic value of cardiac magnetic resonance has increased with new, higher-sensitivity sequences. Positron emission tomography has emerged as a useful tool for diagnosis of cardiac sarcoidosis. The sensitivity of endomyocardial biopsy may be increased, especially in suspected sarcoidosis, by the use of electrogram guidance to target regions of abnormal signal. Investigational treatments on the basis of mechanistic advances are entering clinical trials. Revised management recommendations regarding athletic participation after acute myocarditis have heightened the importance of early diagnosis. (C) 2016 by the American College of Cardiology Foundation.Peer reviewe

Congestive heart failure : more common as well as an important cardiovascular outcome: reply

Non peer reviewe

Optimization of Cavity-Based Negative Images to Boost Docking Enrichment in Virtual Screening

Molecular docking is a key in silico method used routinely in modern drug discovery projects. Although docking provides high-quality ligand binding predictions, it regularly fails to separate the active compounds from the inactive ones. In negative image-based rescoring (R-NiB), the shape/electrostatic potential (ESP) of docking poses is compared to the negative image of the protein’s ligand binding cavity. While R-NiB often improves the docking yield considerably, the cavity-based models do not reach their full potential without expert editing. Accordingly, a greedy search-driven methodology, brute force negative image-based optimization (BR-NiB), is presented for optimizing the models via iterative editing and benchmarking. Thorough and unbiased training, testing and stringent validation with a multitude of drug targets, and alternative docking software show that BR-NiB ensures excellent docking efficacy. BR-NiB can be considered as a new type of shape-focused pharmacophore modeling, where the optimized models contain only the most vital cavity information needed for effectively filtering docked actives from the inactive or decoy compounds. Finally, the BR-NiB code for performing the automated optimization is provided free-of-charge under MIT license via GitHub (https://github.com/jvlehtonen/brutenib) for boosting the success rates of docking-based virtual screening campaigns. </p

Ligand-Enhanced Negative Images Optimized for Docking Rescoring

Despite the pivotal role of molecular docking in modern drug discovery, the default docking scoring functions often fail to recognize active ligands in virtual screening campaigns. Negative image-based rescoring improves docking enrichment by comparing the shape/electrostatic potential (ESP) of the flexible docking poses against the target protein's inverted cavity volume. By optimizing these negative image-based (NIB) models using a greedy search, the docking rescoring yield can be improved massively and consistently. Here, a fundamental modification is implemented to this shape-focused pharmacophore modelling approach-actual ligand 3D coordinates are incorporated into the NIB models for the optimization. This hybrid approach, labelled as ligand-enhanced brute-force negative image-based optimization (LBR-NiB), takes the best from both worlds, i.e., the all-roundedness of the NIB models and the difficult to emulate atomic arrangements of actual protein-bound small-molecule ligands. Thorough benchmarking, focused on proinflammatory targets, shows that the LBR-NiB routinely improves the docking enrichment over prior iterations of the R-NiB methodology. This boost can be massive, if the added ligand information provides truly essential binding information that was lacking or completely missing from the cavity-based NIB model. On a practical level, the results indicate that the LBR-NiB typically works well when the added ligand 3D data originates from a high-quality source, such as X-ray crystallography, and, yet, the NIB model compositions can also sometimes be improved by fusing into them, for example, with flexibly docked solvent molecules. In short, the study demonstrates that the protein-bound ligands can be used to improve the shape/ESP features of the negative images for effective docking rescoring use in virtual screening

Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator

Background: Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown. Methods: We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up. Results: Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (chi(2)=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; chi(2)=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; chi(2)=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation. Conclusions: Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.Peer reviewe

Hydroxychloroquine reduces interleukin-6 levels after myocardial infarction : The randomized, double-blind, placebo-controlled OXI pilot trial

Objectives: To determine the anti-inflammatory effect and safety of hydroxychloroquine after acute myocardial infarction. Method: In this multicenter, double-blind, placebo-controlled OXI trial, 125 myocardial infarction patients were randomized at a median of 43 h after hospitalization to receive hydroxychloroquine 300 mg (n = 64) or placebo (n = 61) once daily for 6 months and, followed for an average of 32 months. Laboratory values were measured at baseline, 1, 6, and 12 months. Results: The levels of interleukin-6 (IL-6) were comparable at baseline between study groups (p = 0.18). At six months, the IL-6 levels were lower in the hydroxychloroquine group (p = 0.042, between groups), and in the on-treatment analysis, the difference at this time point was even more pronounced (p = 0.019, respectively). The high-sensitivity C-reactive protein levels did not differ significantly between study groups at any time points. Eleven patients in the hydroxychloroquine group and four in the placebo group had adverse events leading to in-terruption or withdrawal of study medication, none of which was serious (p = 0.10, between groups). Conclusions: In patients with myocardial infarction, hydroxychloroquine reduced IL-6 levels significantly more than did placebo without causing any clinically significant adverse events. A larger randomized clinical trial is warranted to prove the potential ability of hydroxychloroquine to reduce cardiovascular endpoints after myocar-dial infarction. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Peer reviewe

Incidence of Sudden Cardiac Death and Life-Threatening Arrhythmias in Clinically Manifest Cardiac Sarcoidosis With and Without Current Indications for an Implantable Cardioverter Defibrillator

Background:Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown.Methods:We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up.Results:Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%-15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%-19.1%) in those without (chi(2)=1.834, P=0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%-21.0%) versus 6.3% (95% CI, 0.7%-54.0%; chi(2)=0.814, P=0.367) in definite CS and 7.6% (95% CI, 3.8%-15.1%) versus 3.3% (95% CI, 0.5%-22.9%; chi(2)=0.680, P=0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis (P=0.033) but not by Class I or IIa ICD indications (P=0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%-71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation.Conclusions:Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.</p

Manifestations and Outcome of Cardiac Sarcoidosis and Idiopathic Giant Cell Myocarditis by 25-Year Nationwide Cohorts

Background Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) share many histopathologic and clinical features. Whether they are parts of a one-disease continuum has been discussed.Methods and Results We compared medical record data of 351 CS and 28 GCM cases diagnosed in Finland since the late 1980s and followed until February 2018 for a composite end point of cardiac death, aborted sudden death, and heart transplantation. Heart failure was the presenting manifestation in 50% versus 15% (PP=0.044), of GCM and CS, respectively. At presentation, left ventricular ejection fraction was P=0.004). The median (interquartile range) of plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) was 5273 (2782-11309) ng/L on admission in GCM versus 859 (290-1950) ng/L in CS (PPPConclusions GCM differs from CS in presenting with more extensive myocardial injury and having worse long-term outcome. Yet the key determinant of prognosis appears to be the extent of myocardial injury rather than the histopathologic diagnosis.</p