Poststroke survival and ischemic stroke recurrence : the cerebral small-vessel disease perspective

The aim of the present study was to investigate the influence of different manifestations of cerebral SVD on poststroke survival and ischemic stroke recurrence in long-term follow-up. The core imaging features of small-vessel disease (SVD) are confluent and extensive white matter changes (WMC) and lacunar infarcts. These are associated with minor motor deficits but a major negative influence on cognition, mood, and functioning in daily life, resulting from small-vessel lesions in the fronto-subcortical brain network. These sub-studies were conducted as part of the Helsinki Stroke Aging Memory (SAM) study. The SAM cohort consisted of 486 consecutive patients aged 55 to 85 years who were admitted to Helsinki University Central Hospital with acute ischemic stroke. The study included comprehensive clinical, neuropsychological, psychiatric and radiological assessment three months poststroke. The patients were followed up up for 12 years using extensive national registers. The effect of different manifestations of cerebral SVD on poststroke survival and stroke recurrence was analyzed controlling for factors such as age, education, and cardiovascular risk factors. Poststroke dementia and cognitive impairment relate to poor long-term survival. In particular, deficits in executive functions as well as visuospatial and constructional abilities predict poor outcome. The predictive value of cognitive deficits is further underlined by the finding that depression-executive dysfunction syndrome (DES), but not depression in itself, is associated with poor poststroke survival. Delirium is not independently associated with increased risk for long-term poststroke mortality, although it is associated with poststroke dementia. Furthermore, acute index stroke attributable to SVD is associated with poorer long-term survival and a higher risk for cardiac death than other stroke subtypes. Severe WMC, a surrogate of SVD, is independently related to an increased risk of stroke recurrence at five years. In summary, cognitive poststroke outcomes reflecting changes in the executive network brain, and the presence of cerebral SVD are important determinants of poststroke mortality and ischemic stroke recurrence, regardless of whether SVD is the cause of the index stroke or a condition concurrent to some other etiology.

Maidontuottajatila ja ravinnepolitiikka: Tilan toimintamekanismit, politiikan tarve ja ohjauskeinojen vaikuttavuus

Tutkielman tarkoituksena on rakentaa malli, jolla voidaan arvioida maitotilan toimintaa monipuolisesti ravinnehuuhtouman kannalta. Tavoitteena on ennen muuta analyyttinen tarkastelu siten, että kuitenkin huomioiden maidontuotannon ominaispiirteet, keskeisinä esimerkkeinä ravinnon, maidontuotannon ja lannan ominaisuuksien väliset riippuvuudet. Analyysissa tarkastellaan tilanomistajan yksityisen hyödynmaksimoinnin ja yhteiskunnan tavoitteiden eroavaisuutta. Lisäksi johdetaan optimaaliset ohjauskeinot ja arvioidaan eräiden yksinkertaisten ohjauskeinojen vaikuttavuutta. Mallin analysoinnin perusteella yksityinen ja yhteiskunnallinen optimiratkaisu eroavat toisistaan kaikkien päätösmuuttujien osalta. Ei voida kuitenkaan yleispätevästi sanoa muutosten merkittävyyttä tai suuntaa ottamatta kantaa mallin funktiomuotoihin ja parametriarvoihin. Optimaaliset ohjauskeinot tulisi asettaa keinolannoitteen ja lannan levitykselle, väkirehuruokinnalle ja säilörehun viljelylle, mutta ei eläinten määrälle. Toisaalta optimaaliset ohjauskeinot ovat hyvin monimutkaisia. Tarkasteltujen yksinkertaisempien ohjauskeinojen vaikuttavuutta ei voida tarkasti arvioida analyyttisella tasolla. Numeeristen tulosten perusteella yhteiskunnallisessa optimissa eläinmäärä olisi hieman yksityistä optimia pienempi, väkirehun käyttö vähäisempää, enemmän peltoa allokoitaisiin säilörehun viljelyyn ja lannoitustasot olisivat kautta linjan hieman pienemmät. Lannanlevitykset eroavat etäisyyden suhteen: molemmissa tapauksissa lannanlevityksen intensiteetti kasvaa kohti tilan keskusta kuljettaessa, mutta yksityisessä optimissa lähimmälle pellolle dumpataan kaikki ylimääräinen lanta, kun taas yhteiskunnallisessa optimissa lanta levitetään tasaisemmin eri pelloille. Ero kokonaishyvinvoinnissa jää pieneksi, mutta eläinmäärän kasvu kärjistäisi lannan dumppauksen aiheuttamia huuhtoumahaittoja. Yksinkertaisista ohjauskeinoista lannoitusrajoitus sekä ravinne- ja keinolannoitevero osoittautuivat kohtalaisen käyttökelpoisiksi numeeristen tulosten perusteella. Sen sijaan eläinmäärän rajoittaminen ja lannan kuljetuskustannuksia kompensoivat tuet vaikuttavat tulosten perusteella huonoilta ratkaisuilta.

Literature Review: Investigating Drug Transport at the Blood-Brain Barrier and the Effects of P-glycoprotein on the Brain Distribution of Drugs.

The blood-brain barrier (BBB) is a unique barrier that strictly regulates the entry of endogenous substrates and xenobiotics into the brain. This is due to its tight junctions and the array of transporters and metabolic enzymes that are expressed. The determination of brain concentrations in vivo is difficult, laborious and expensive which means that there is interest in developing predictive tools of brain distribution. Predicting brain concentrations is important even in early drug development to ensure efficacy of central nervous system (CNS) targeted drugs and safety of non-CNS drugs. The literature review covers the most common current in vitro, in vivo and in silico methods of studying transport into the brain, concentrating on transporter effects. The consequences of efflux mediated by p-glycoprotein, the most widely characterized transporter expressed at the BBB, is also discussed. The aim of the experimental study was to build a pharmacokinetic (PK) model to describe p-glycoprotein substrate drug concentrations in the brain using commonly measured in vivo parameters of brain distribution. The possibility of replacing in vivo parameter values with their in vitro counterparts was also studied. All data for the study was taken from the literature. A simple 2-compartment PK model was built using the Stella™ software. Brain concentrations of morphine, loperamide and quinidine were simulated and compared with published studies. Correlation of in vitro measured efflux ratio (ER) from different studies was evaluated in addition to studying correlation between in vitro and in vivo measured ER. A Stella™ model was also constructed to simulate an in vitro transcellular monolayer experiment, to study the sensitivity of measured ER to changes in passive permeability and Michaelis-Menten kinetic parameter values. Interspecies differences in rats and mice were investigated with regards to brain permeability and drug binding in brain tissue. Although the PK brain model was able to capture the concentration-time profiles for all 3 compounds in both brain and plasma and performed fairly well for morphine, for quinidine it underestimated and for loperamide it overestimated brain concentrations. Because the ratio of concentrations in brain and blood is dependent on the ER, it is suggested that the variable values cited for this parameter and its inaccuracy could be one explanation for the failure of predictions. Validation of the model with more compounds is needed to draw further conclusions. In vitro ER showed variable correlation between studies, indicating variability due to experimental factors such as test concentration, but overall differences were small. Good correlation between in vitro and in vivo ER at low concentrations supports the possibility of using of in vitro ER in the PK model. The in vitro simulation illustrated that in the simulation setting, efflux is significant only with low passive permeability, which highlights the fact that the cell model used to measure ER must have low enough paracellular permeability to correctly mimic the in vivo situation.