Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier

Stem cell therapy is a promising strategy to treat neurodegenerative diseases, traumatic brain injury, and stroke. For stem cells to progress towards clinical use, the risks associated with invasive intracranial surgery used to deliver the cells to the brain, needs to be reduced. Here, we show that MRI-guided focused ultrasound (MRIgFUS) is a novel method for non-invasive delivery of stem cells from the blood to the brain by opening the blood brain barrier (BBB) in specific brain regions. We used MRI guidance to target the ultrasound beam thereby delivering the iron-labeled, green fluorescent protein (GFP)-expressing neural stem cells specifically to the striatum and the hippocampus of the rat brain. Detection of cellular iron using MRI established that the cells crossed the BBB to enter the brain. After sacrifice, 24 hours later, immunohistochemical analysis confirmed the presence of GFP-positive cells in the targeted brain regions. We determined that the neural stem cells expressed common stem cell markers (nestin and polysialic acid) suggesting they survived after transplantation with MRIgFUS. Furthermore, delivered stem cells expressed doublecortin in vivo indicating the stem cells were capable of differentiating into neurons. Together, we demonstrate that transient opening of the BBB with MRIgFUS is sufficient for transplantation of stem cells from the blood to targeted brain structures. These results suggest that MRIgFUS may be an effective alternative to invasive intracranial surgery for stem cell transplantation

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm2. In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage

The role of beliefs, expectations and values in decision-making favoring climate change adaptation—implications for communications with European forest professionals

Beliefs, expectations and values are often assumed to drive decisions about climate change adaptation. We tested hypotheses based on this assumption using survey responses from 508 European forest professionals in ten countries. We used the survey results to identify communication needs and the decision strategies at play, and to develop guidelines on adequate communications about climate change adaptation. We observed polarization in the positive and negative values associated with climate change impacts accepted by survey respondents. We identified a mechanism creating the polarization that we call the 'blocked belief' effect. We found that polarized values did not correlate with decisions about climate change adaptation. Strong belief in the local impacts of climate change on the forest was, however, a prerequisite of decision-making favoring adaptation. Decision-making in favor of adaptation to climate change also correlated with net values of expected specific impacts on the forest and generally increased with the absolute value of these in the absence of 'tipping point' behavior. Tipping point behavior occurs when adaptation is not pursued in spite of the strongly negative or positive net value of expected climate change impacts. We observed negative and positive tipping point behavior, mainly in SW Europe and N-NE Europe, respectively. In addition we found that advice on effective adaptation may inhibit adaptation when the receiver is aware of effective adaptation measures unless it is balanced with information explaining how climate change leads to negative impacts. Forest professionals with weak expectations of impacts require communications on climate change and its impacts on forests before any advice on adaptation measures can be effective. We develop evidence-based guidelines on communications using a new methodology which includes Bayesian machine learning modeling of the equivalent of an expected utility function for the adaptation decision problem

Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

Immunotherapy for Alzheimer's disease (AD) relies on antibodies directed against toxic amyloid-beta peptide (Aβ), which circulate in the bloodstream and remove Aβ from the brain [1], [2]. In mouse models of AD, the administration of anti-Aβ antibodies directly into the brain, in comparison to the bloodstream, was shown to be more efficient at reducing Aβ plaque pathology [3], [4]. Therefore, delivering anti-Aβ antibodies to the brain of AD patients may also improve treatment efficiency. Transcranial focused ultrasound (FUS) is known to transiently-enhance the permeability of the blood-brain barrier (BBB) [5], allowing intravenously administered therapeutics to enter the brain [6]–[8]. Our goal was to establish that anti-Aβ antibodies delivered to the brain using magnetic resonance imaging-guided FUS (MRIgFUS) [9] can reduce plaque pathology. To test this, TgCRND8 mice [10] received intravenous injections of MRI and FUS contrast agents, as well as anti-Aβ antibody, BAM-10. MRIgFUS was then applied transcranially. Within minutes, the MRI contrast agent entered the brain, and BAM-10 was later found bound to Aβ plaques in targeted cortical areas. Four days post-treatment, Aβ pathology was significantly reduced in TgCRND8 mice. In conclusion, this is the first report to demonstrate that MRIgFUS delivery of anti-Aβ antibodies provides the combined advantages of using a low dose of antibody and rapidly reducing plaque pathology

Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood–brain and blood–spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments

Individual tree basal area increment models suitable for different stand structures in Finland

Forest growth models employed in Fennoscandia have been generally targeted at rotation forestry (RF) stands, relying on age as a key predictor. Uneven aged, irregular stands, such as the ones managed with continuous cover forestry, are becoming of increasingly common. New models suited for all kind of management approaches (i.e., age-independent) have been developed in Fennoscandia. Although the ongoing climate change is projected to strongly affect tree growth in boreal regions, climatic variables included in current models are usually restricted to temperature sum averages with simple links. The objectives of our research were: 1) fitting a new age independent empirical tree basal area increment model (B2023) with inclusion of additional climatic variables for the main Nordic tree species (Norway spruce, Scots pine, and birches); 2) using independent data to validate both the new model and other two age-independent published empirical models (P2013, P2021); and 3) investigating the sensitivity of growth predictions of all the empirical models to climate change. Our results showed that the new model B2023 was as accurate as P2013 when independently validated. Both models performed well in different forest structures and management alternatives (namely rotation forestry, continuous cover forestry, two-storied stands, and old-growth natural forests), although with few differences, and on average slightly better than P2021. At plot level, the new model B2023 showed slight underprediction for the overstorey pine layer in continuous cover forestry and two-storied stands. The predicted climate change scenarios increased simulated growth in all models, although P2021 showed very high values for spruce. We failed to include additional climatic variables than temperature sum in B2023, thus not improving much its accuracy under historical data, nor its sensitivity to future climate. Concluding, the individual tree models here presented can be applied to a wide range of forest structures and managements in Fennoscandia. For long-term simulation scenarios, different approaches to improve the climate sensitivity of empirical, individual tree model should be explored

A 63 element 1.75 dimensional ultrasound phased array for the treatment of benign prostatic hyperplasia

BACKGROUND: Prostate cancer and benign prostatic hyperplasia are very common diseases in older American men, thus having a reliable treatment modality for both diseases is of great importance. The currently used treating options, mainly surgical ones, have numerous complications, which include the many side effects that accompany such procedures, besides the invasive nature of such techniques. Focused ultrasound is a relatively new treating modality that is showing promising results in treating prostate cancer and benign prostatic hyperplasia. Thus this technique is gaining more attention in the past decade as a non-invasive method to treat both diseases. METHODS: In this paper, the design, construction and evaluation of a 1.75 dimensional ultrasound phased array to be used for treating prostate cancer and benign prostatic hyperplasia is presented. With this array, the position of the focus can be controlled by changing the electrical power and phase to the individual elements for electronically focusing and steering in a three dimensional volume. The array was designed with a maximum steering angle of ± 13.5° in the transverse direction and a maximum depth of penetration of 11 cm, which allows the treatment of large prostates. The transducer piezoelectric ceramic, matching layers and cable impedance have been designed for maximum power transfer to tissue. RESULTS: To verify the capability of the transducer for focusing and steering, exposimetry was performed and the results correlated well with the calculated field. Ex vivo experiments using bovine tissue were performed with various lesion sizes and indicated the capability of the transducer to ablate tissue using short sonications. CONCLUSION: A 1.75 dimensional array, that overcame the drawbacks associated with one-dimensional arrays, has been designed, built and successfully tested. Design issues, such as cable and ceramic capacitances, were taken into account when designing this array. The final prototype overcame also the problem of generating grating lobes at unwanted locations by tapering the array elements

Medication Complications in Extracorporeal Membrane Oxygenation.

The need for extracorporeal membrane oxygenation (ECMO) therapy is a marker of disease severity for which multiple medications are required. The therapy causes physiologic changes that impact drug pharmacokinetics. These changes can lead to exposure-driven decreases in efficacy or increased incidence of side effects. The pharmacokinetic changes are drug specific and largely undefined for most drugs. We review available drug dosing data and provide guidance for use in the ECMO patient population

Kotitarveviljely ja hyötyeläimet Suomessa ja kotitarvetuotantoon motivoivat tekijät

Kasvava kiinnostus ruuan alkuperään sekä tuotantoon on näkynyt viime vuosina julkisessa keskustelussa. Kotitarvetuotannosta on kuitenkin olemassa huonosti tietoa. Tässä tutkimuksessa selvitettiin ruuan kotitarvetuotannon eli omaan tarpeeseen viljelyn sekä erilaisten hyötyeläinten kasvattamisen piirteitä keväällä 2017. Kotitarvetuotannolla tarkoitettiin ei-ammattimaista kasvisten kasvattamista tai eläinten pitämistä ruuan tuottamiseksi kotitalouden omaan käyttöön tai pienimuotoisesti myyntiin. Tavoitteena oli selvittää minkälaisesta ilmiöstä kotitarvetuotannossa on kyse, mikä motivoi ihmisiä ruuan tuotantoon kodeissaan sekä minkälaisia vaikeuksia tai esteitä he ovat mahdollisesti kohdanneet kotitarvetuotannossaan. Tutkimus toteutettiin Internet-kyselynä, jonka vastauslinkkiä jaettiin erilaisille ruokaan tai ruuan tuotantoon liittyville järjestöille, yhdistyksille, ruokapiireille ja muille tahoille. Kysely koostui kahdesta osasta. Ensimmäisen kysymykset koskivat sitä, mitä vastaajat tuottivat kotitarpeisiin, mitkä tekijät motivoivat heitä kotitarvetuotantoon, minkälaisia resursseja kotitarvetuotantoon on olemassa ja mitä resursseja puuttuu sekä millaisia rajoituksia kotitarvetuotannossa on. Toisessa osassa selvitettiin vastaajien sosiodemografisia taustatietoja. Kysymykset olivat tutkimusryhmän tätä kyselyä varten kehittämiä. Kyselyyn vastasi 623 henkilöä, joista suurin osa (86 %) oli naisia. Aikuisväestö oli aineistossa hyvin edustettu, sillä kyselyyn vastanneiden henkilöiden iät olivat väliltä 16 ja 79 vuotta. Liki kolmannes vastaajista oli kotoisin Uudeltamaalta, mutta edustettuina olivat kaikki muutkin maakunnat lukuun ottamatta Ahvenanmaata. Suurin osa vastanneista kotitarvetuottajista viljeli vain kasveja. Yleisimmät kasvit olivat erilaiset yrtit, salaatit, marjat ja palkokasvit, mutta myös peruna, juurekset, kurkku olivat yleisiä kasvatettavia. Noin 40 %:lla vastaajista oli sekä eläimiä että kasveja ja vain muutama vastaaja kasvatti pelkästään eläimiä. Eläintenpidossa suosituinta oli munivan siipikarjan kasvattaminen, mutta siipikarjaa kasvatettiin paljon myös lihaksi. Kaneja lihaksi tai villan tuotantoon kasvatettiin melkein yhtä paljon kuin kanoja lihaksi. Isojen tuotantoeläinten kasvatus oli harvinaista, mikä johtunee niiden kasvattamisen vaatimasta isommasta tilantarpeesta. Myös mehiläisiä pidettiin sekä maaseudulla että kaupungissa. Yleisimpiä syitä kotitarvetuotannolle olivat sen kokeminen hyvänä harrastuksena, mahdollisuus nähdä työnsä tulokset tai seurata kasvien ja / tai eläinten kehitystä sekä tieto ruuan alkuperästä. Sen sijaan ryhtyminen oman ravintonsa tuottamiseen rahatilanteen sanelemana selviytymiskeinona oli hyvin harvinaista. Eläinten hyvinvoinnista huolehtiminen, halu ympäristöystävälliseen elämään ja luonnonmukaiseen tuotantoon, vastuuntunnon lisääntyminen ja lasten opettaminen olivat tärkeitä kotitarvetuotannon motivaatiotekijöitä etenkin tuotantoeläimiä kasvattaville. Hallinnollisten esteiden, kuten kaavamääräyksien, rakentamisjärjestyksen, järjestyssääntöjen tai terveyslainsäädännön ei koettu yleisesti haittaavan kotitarvetuotantoa. Tieto-taitoa kotitarvetuotantoon oli vastaajilla vaihtelevasti. Kotitarvetuotantoon tarvittavien tietojen ja taitojen ylläpitäminen ja edistäminen voisi lisätä kansalaisten omaehtoista ruokaturvaa. Joidenkin vastaajien osalta tietämys eläintautien torjunnasta ja elintarviketurvallisuudesta olivat puutteelisia ja kotitarvetuottajille tulisi kertoa selkeämmin, miksi erilaisia vaatimuksia ja sääntöjä on olemassa tuotantoeläinten kasvatukseen.</p