Bisphosphonates as antimyeloma drugs

In patients with symptomatic multiple myeloma (MM), bisphosphonate (BP) treatment has been widely used to prevent bone loss and preserve skeletal health because of its proven effects on inhibiting osteoclast-mediated bone resorption. In addition to their effects on osteoclasts, it is becoming increasingly evident that BPs may have additional effects on the bone microenvironment and cells other than osteoclasts that may potentially inhibit the development and progression of MM. This review focuses on the pathophysiology of MM with an emphasis on the events that drive MM progression within the bone and the mechanisms by which BPs may inhibit specific processes. The underlying molecular mechanisms that drive the modulation of cellular fate and function and consequent physiological outcomes are described. Direct effects on myeloma cell growth and survival and the interactions between myeloma cells and the bone microenvironment are discussed. Clinical evidence of the antimyeloma effects of BPs is emerging and is also reviewed

Long Term Cyclic Pamidronate Reduces Bone Growth by Inhibiting Osteoclast Mediated Cartilage-to-Bone Turnover in the Mouse

Bisphosphonates, used to treat diseases exhibiting increased osteoclast activity, reduce longitudinal bone growth through an as yet undefined mechanism. Pamidronate, an aminobisphosphonate, was given weekly to mice at 0, 1.25, or 2.50 mg/kg/wk beginning at 4 weeks of age. At 12 weeks of age, humeral length, growth plate area, regional chondrocyte cell numbers, chondrocyte apoptosis, TRAP stained osteoclast number, and osteoclast function assessed by cathepsin K immunohistochemistry were quantified. Humeral length was decreased in pamidronate treated mice compared to vehicle control mice, and correlated with greater growth plate areas reflecting greater proliferative and hypertrophic chondrocyte cell numbers with fewer hypertrophic cells undergoing apoptosis. Pamidronate treatment increased TRAP stained osteoclast numbers yet decreased cathepsin K indicating that pamidronate repressed osteoclast maturation and function. The data suggest that long term cyclic pamidronate treatment impairs bone growth by inhibition of osteoclast maturation thereby reducing cartilage-to-bone turnover within the growth plate

Analysis of cosmic radio noise absorption measured by the SGO riometer network

This thesis was made in collaboration with the Sodankylä Geophysical Observatory (SGO) and the Ionospheric Physics group in Oulu University. In my work I analysed data from the SGO riometer network. The data I used is from years 1997–2013, and seven stations located at different latitudes. The stations are located in Hornsund, Abisko, Ivalo, Sodankylä, Rovaniemi, Oulu and Jyväskylä. In the analysis I concentrated on comparing the effect of different quiet-day curve (QDC) methods to the statistics of absorption events. In my thesis I study the yearly number of absorption events and their diurnal variation in magnetic local time (MLT). In my work I used absorption data calculated by two different QDC methods. The first method is based on automatic determination of the QDC and the second is based on manual determination. We decided to concentrate on using the data calculated by the automatic method, but I also compare our results to the manual data. In the beginning of this project I determined a simple method for finding absorption events from the riometer data. In collaboration with my supervisors and SGO staff we chose the criteria for an absorption event. I wrote a Matlab-script that was used to find the times and magnitudes of events from the data using the criteria. With this information I made the yearly and MLT-distributions to the automatic and manual data. We found a problem in the atomatic QDC method during the winter months of the maximum years of the solar cycle. We decided to manually remove the problematic periods. The automatic data set where the interfered periods are removed from forms the third data set used in this study, called the corrected automatic data. The yearly distributions of absorption events in the corrected automatic and manual data set have similarities with the yearly average Kp index, which is the index of geomagnetic activity. The Kp maximum year, 2003, and the minimum year, 2009, are visible at most of the stations. Correlation with the yearly average sunspot number is less obvious, even though the 11-year cycle is visible in the absorption. Common features in the MLT-distribution are the morning maximum around 9 MLT and the evening minimum around 18 MLT. This is visible in the automatic and manual data to some extent at all stations. The MLT-distributions are slightly different each year, and during the minimum years of absorption it is significantly different. The morning maximum and evening minimum are not clearly visible. Most of our results are also visible in the uncorrected automatic data, excluding the years 2000–2003 and certain stations. The data sets acquired from different QDC methods produced similar results, which gives credibility to them. There still are many interferences in the data, and it would require more work to remove them. The automatic QDC method should be refined so that it doesn’t take into account data from times when the riometer has saturated. Our goal is to publish these results after some further analysis.Tein Pro Gradu-tutkielmani yhteistyössä Sodankylän Geofysiikan Observatorion (SGO) ja Oulun yliopiston Ionosfäärifysiikan tutkimusryhmän kanssa. Työssäni analysoin SGO:n riometriverkoston dataa. Käyttämäni data on peräisin seitsemältä eri leveysasteilla sijaitsevalta asemalta vuosilta 1997–2013. Asemat sijaitsevat Hornsundissa, Abiskossa, Ivalossa, Sodankylässä, Rovaniemellä, Oulussa ja Jyväskylässä. Analyysissäni keskityin vertailemaan erilaisten hiljaisen päivän käyrän (Quiet Day Curve, QDC) määritysmenetelmien vaikutusta absorptioeventtien statistiikkaan. Tutkielmassani teen vertailua absorptioeventtien vuosittaisista määristä sekä niiden jakaumista magneettisen paikallisajan (Magnetic Local Time, MLT) funktiona. Käytin työssäni kahdella eri menetelmällä määritettyä absorptiodataa. Ensimmäinen menetelmä perustuu QDC:n automaattiseen määritykseen ja toinen manuaaliseen määritykseen. Päätimme keskittyä käyttämään automaattisella menetelmällä määritettyä dataa, mutta työssäni vertailen tuloksia myös manuaaliseen dataan. Työni alussa kehitin yksinkertaisen tavan etsiä absorptioeventtejä riometridatasta. Yhdessä ohjaajieni ja SGO:n henkilökunnan avulla valitsimme kriteerit absorptioeventille. Kirjoittamani Matlab-ohjelma etsi datasta näillä kriteereillä absorptioeventtien ajankohdat sekä magnitudit. Näiden tietojen avulla tein vuosijakaumat ja MLT-jakaumat sekä manuaaliselle että automaattiselle datalle. Automaattisessa QDC-määritysessä ilmeni kuitenkin ongelmia auringonpilkkusyklin maksimivuosien talvikuukausina. Päätimme poistaa nämä ajanjaksot joilla ongelma ilmeni. Tämä automaattinen data josta häiriöitä oli poistettu muodosti kolmannen käyttämäni datasetin, korjatun automaattisen datan. Absorptioeventtien vuosijakaumat automaattisessa ja manuaalisessa datassa noudattavat hyvin Kp-indeksiä, joka on geomagneettisen aktiivisuuden indeksi. Kp-indeksin maksimivuosi 2003 on havaittavissa monilla asemilla, kuin myös minimi vuonna 2009. Korrelaatio auringonpilkkuluvun vuosittaisen keskiarvon kanssa on vähemmän selkeä, vaikkakin 11 vuoden sykli on absorptiossa havaittavissa. MLT-jakaumissa yhdistävä piirre on aamumaksimi noin 9 MLT ja iltaminimi noin 18 MLT. Tämä on havaittavissa automaattisessa datassa ja manuaalisessa datassa jossain määrin kaikilla asemilla. MLT-jakauman muoto vaihtelee vuosittain, ja absorption minimivuosina se on hyvin erilainen, eivätkä aamumaksimi ja iltaminimi erotu selkeästi. Suuri osa saaduista tuloksista on myös nähtävissä korjaamattomassa datassa, lukuunottamatta vuosia 2000–2003 ja tiettyjä asemia. Eri QDC-menetelmillä määritetyt datat, korjattu automaattinen ja manuaalinen data, tuottivat samanlaisia tuloksia ja kasvattavat tulosten luotettavuutta. Häiriöitä on kuitenkin edelleen datassa mukana, ja niiden tarkempi poistaminen vaatii vielä lisätyötä. QDC:n automaattista määritystä pitäisi myös kehittää niin, että se ei ottaisi huomioon ajanjaksoja jolloin riometri on saturoitunut. Tarkoituksemme on julkaista saamamme tulokset jatkoanalyysin jälkeen

Three principal components describe the spatiotemporal development of mesoscale ionospheric equivalent currents around substorm onsets

Substorms are a commonly occurring but insufficiently understood form of dynamics in the coupled magnetosphere–ionosphere system, associated with space weather disturbances and auroras. We have used principal component analysis (PCA) to characterize the spatiotemporal development of ionospheric equivalent currents as observed by the International Monitor for Auroral Geomagnetic Effects (IMAGE) magnetometers during 28 substorm onsets identified by Frey et al. (2004). Auroral observations were provided by all-sky cameras. We found that the equivalent currents can typically be described by three components: a channel of poleward equivalent current (wedgelet), a westward electrojet (WEJ) associated with an auroral arc, and a vortex. The WEJ and vortex are located at the equatorward end of the channel, which has been associated with bursty bulk flows (BBFs) by previous studies. Depending on its polarity, the vortex either indents the WEJ and arc equatorward or bulges the WEJ poleward while winding the arc into an auroral spiral. In addition, there may be a background current system associated with the large-scale convection. The dynamics of the WEJ, vortex, and channel can describe up to 95 % of the variance of the time derivative of the equivalent currents during the examined 20 min interval. Rapid geomagnetic variations at the substorm onset location, which can drive geomagnetically induced currents (GICs) in technological conductor networks, are mainly associated with the oscillations of the WEJ, which may be driven by oscillations of the transition region between dipolar and tail-like field lines in the magnetotail due to the BBF impact. The results contribute to the understanding of substorm physics and to the understanding of processes that drive intense GICs.</p

Drivers of rapid geomagnetic variations at high latitudes

We have examined the most intense external (magnetospheric and ionospheric) and internal (induced) |dH/dt| (amplitude of the 10gs time derivative of the horizontal geomagnetic field) events observed by the high-latitude International Monitor for Auroral Geomagnetic Effects (IMAGE) magnetometers between 1994 and 2018. While the most intense external |dH/dt| events at adjacent stations typically occurred simultaneously, the most intense internal (and total) |dH/dt| events were more scattered in time, most likely due to the complexity of induction in the conducting ground. The most intense external |dH/dt| events occurred during geomagnetic storms, among which the Halloween storm in October 2003 featured prominently, and drove intense geomagnetically induced currents (GICs). Events in the prenoon local time sector were associated with sudden commencements (SCs) and pulsations, and the most intense |dH/dt| values were driven by abrupt changes in the eastward electrojet due to solar wind dynamic pressure increase or decrease. Events in the premidnight and dawn local time sectors were associated with substorm activity, and the most intense |dH/dt| values were driven by abrupt changes in the westward electrojet, such as weakening and poleward retreat (premidnight) or undulation (dawn). Despite being associated with various event types and occurring at different local time sectors, there were common features among the drivers of most intense external |dH/dt| values: preexisting intense ionospheric currents (SC events were an exception) that were abruptly modified by sudden changes in the magnetospheric magnetic field configuration. Our results contribute towards the ultimate goal of reliable forecasts of dH/dt and GICs

Osteoanabolic effect of alendronate and zoledronate on bone marrow stromal cells (BMSCs) isolated from aged female osteoporotic patients and its implications for their mode of action in the treatment of age-related bone loss

In the present study, we evaluated the potential for aminobisphosphonates to enhance the development of bone-forming osteoblasts from progenitor cells isolated from aged female osteoporotic patients. The aminobisphosphonates tested significantly enhanced osteoblast formation and thus lend further insights into their possible mode of action in the treatment of osteoporosis. INTRODUCTION: The primary aim of this study was to evaluate the influence of aminobisphosphonates on the osteogenesis of human bone marrow stromal cells (hBMSCs) and mineralization of differentiating bone-forming cells isolated from osteoporotic patients. METHODS: The influence of aminobisphosphonate treatment on hBMSC osteogenesis was assessed by the quantitative measurement of alkaline phosphatase (ALP) activity, in addition to quantitative reverse transcription polymerase chain reaction and Western blot analysis of known osteogenic markers. Mineralized matrix formation by hBMSC-derived osteoblasts was visualized and quantified using Alizarin red staining. RESULTS: hBMSC cultures treated with osteogenic medium supplemented with zoledronate demonstrated a significant increase in Alizarin red staining after 3 weeks as compared to cells cultured in osteogenic medium alone. Similarly, cultures of differentiating hBMSCs isolated from patients receiving alendronate treatment also demonstrated an increased propensity for mineralization, even in the absence of further in vitro stimulation by zoledronate. The stimulatory effects of aminobisphosphonate treatment on hBMSC-derived osteoblast-mediated mineralization were independent of any alterations in ALP activity, although significant decreases in the expression levels of osteopontin (SPP1) were evident in hBMSCs following exposure to aminobisphosphonates. Further analysis including Western blotting and loss-of-function studies revealed osteopontin as having a negative influence on the mineralization of differentiating osteoporotic bone-forming cells. CONCLUSIONS: The results presented here demonstrate for the first time that aminobisphosphonate treatment of osteoporotic hBMSCs enhances their capacity for osteoblast formation and subsequent mineral deposition, thus supporting the concept of aminobisphosphonates as having an osteoanabolic effect in osteoporosis

Thermospheric wind response to a sudden ionospheric variation in the trough:event at a pseudo-breakup during geomagnetically quiet conditions

Abstract The thermospheric wind response to a sudden westward turning of the ion velocity at a high latitude was studied by analyzing data obtained with a Fabry–Perot interferometer (FPI; 630 nm), Dynasonde, and Swarm A &amp; C satellites during a conjunction event. The event occurred during a geomagnetically quiet period (Kp = 0 +) through the night, but some auroral activity occurred in the north. The collocated FPI and Dynasonde measured the thermospheric wind (U) and ionospheric plasma velocity (V), respectively, in the F region at the equatorward trough edge. A notable scientific message from this study is the possible role of thermospheric wind in the energy dissipation process at F-region altitude. The FPI thermospheric wind did not instantly follow a sudden V change due to thermospheric inertia in the F region. At a pseudo-breakup during the event, V suddenly changed direction from eastward to westward within 10 min. U was concurrently accelerated westward, but its development was more gradual than that of V, with U remaining eastward for a while after the pseudo-breakup. The delay of U is attributed to the thermospheric inertia. During this transition interval, U∙V was negative, which would result in more efficient generation of frictional heating than the positive U∙V case. The sign of U∙V, which is related to the relative directions of the neutral wind and plasma drift, is important because of its direct impact on ion-neutral energy exchange during collisions. This becomes especially important during substorm events, where rapid plasma velocity changes are common. The sign of U∙V may be used as an indicator to find the times and locations where thermospheric inertia plays a role in the energy dissipation process

An ephemeral red arc appeared at 68° MLat at a pseudo breakup during geomagnetically quiet conditions

Abstract Various subauroral optical features have been studied by analyzing data collected during periods of geomagnetic disturbances. Most events have been typically found at geomagnetic latitudes of 45–60°. In this study, however, we present a red arc event found at geomagnetic 68° north (L ≈ 7.1) in the Scandinavian sector during a period of geomagnetically quiet conditions within a short intermission between two high‐speed solar wind events. The red arc appeared to coincide with a pseudo breakup at geomagnetic 71–72°N and a rapid equatorward expansion of the polar cap. However, the red arc disappeared in approximately 7 min. Simultaneous measurements with the Swarm A/C satellites indicated the appearance of the red arc at the ionospheric trough minimum and a conspicuous enhancement of the electron temperature, suggesting the generation of the arc by heat flux. Since there are meaningful differences in the red arc features from already‐known subauroral optical features such as the stable auroral red (SAR) arc, we considered that the red arc is a new phenomenon. We suggest that the ephemeral red arc may represent the moment of SAR arc birth associated with substorm particle injection, which is generally masked by bright dynamic aurorae