How can antiepileptic drugs affect bone mass, structure and metabolism? Lessons from animal studies

SummaryPatients with epilepsy, treated with antiepileptic drugs (AEDs) are at increased risk of fractures. Although several commonly used AEDs reduce bone mass in patients, the mechanisms are only scarcely known. In this review, we focus on the usefulness of animal models to explore the skeletal effects of AEDs. Moreover, we report our findings from a recent study comparing the effect of levetiracetam (LEV), phenytoin (PHT) and valproate (VPA) on various aspects of bone health in actively growing female rats. Our data indicate that these AEDs act differently on bone mass, structure and metabolism. A novel finding is that LEV reduces bone strength and bone formation without altering bone mass. Based on these results we propose that epidemiological fracture studies of patients treated with LEV are needed, and that these patients should be evaluated regularly to identify possible bone-related side effects

Gene Expression and Distribution of Key Bone Turnover Markers in the Callus of Estrogen-Deficient, Vitamin D-Depleted Rats

An experimental rat model was used to test the hypothesis that in osteoporosis (OP) the molecular composition of the extracellular matrix in the fracture callus is disturbed. OP was induced at 10 weeks of age by ovariectomy and a vitamin D3-deficient diet, and sham-operated animals fed normal diet served as controls. Three months later a closed tibial fracture was made and stabilized with an intramedullary nail. After 3 and 6 weeks of healing, the animals were killed and the fracture calluses examined with global gene expression, in situ mRNA expression, and ultrastructural protein distribution of four bone turnover markers: osteopontin, bone sialoprotein, tartrate-resistant acid phosphatase, and cathepsin K. Global gene expression showed a relatively small number of differently regulated genes, mostly upregulated and at 3 weeks. The four chosen markers were not differently regulated, and only minor differences in the in situ mRNA expression and ultrastructural protein distribution were detected. Gene expression and composition of fracture calluses are not generally disturbed in experimental OP

Matrix Metalloproteinase 9 and Vascular Endothelial Growth Factor Are Essential for Osteoclast Recruitment into Developing Long Bones

Bone development requires the recruitment of osteoclast precursors from surrounding mesenchyme, thereby allowing the key events of bone growth such as marrow cavity formation, capillary invasion, and matrix remodeling. We demonstrate that mice deficient in gelatinase B/matrix metalloproteinase (MMP)-9 exhibit a delay in osteoclast recruitment. Histological analysis and specialized invasion and bone resorption models show that MMP-9 is specifically required for the invasion of osteoclasts and endothelial cells into the discontinuously mineralized hypertrophic cartilage that fills the core of the diaphysis. However, MMPs other than MMP-9 are required for the passage of the cells through unmineralized type I collagen of the nascent bone collar, and play a role in resorption of mineralized matrix. MMP-9 stimulates the solubilization of unmineralized cartilage by MMP-13, a collagenase highly expressed in hypertrophic cartilage before osteoclast invasion. Hypertrophic cartilage also expresses vascular endothelial growth factor (VEGF), which binds to extracellular matrix and is made bioavailable by MMP-9 (Bergers, G., R. Brekken, G. McMahon, T.H. Vu, T. Itoh, K. Tamaki, K. Tanzawa, P. Thorpe, S. Itohara, Z. Werb, and D. Hanahan. 2000. Nat. Cell Biol. 2:737–744). We show that VEGF is a chemoattractant for osteoclasts. Moreover, invasion of osteoclasts into the hypertrophic cartilage requires VEGF because it is inhibited by blocking VEGF function. These observations identify specific actions of MMP-9 and VEGF that are critical for early bone development

Hedgehog Signaling in Tumor Cells Facilitates Osteoblast-Enhanced Osteolytic Metastases

The remodeling process in bone yields numerous cytokines and chemokines that mediate crosstalk between osteoblasts and osteoclasts and also serve to attract and support metastatic tumor cells. The metastatic tumor cells disturb the equilibrium in bone that manifests as skeletal complications. The Hedgehog (Hh) pathway plays an important role in skeletogenesis. We hypothesized that the Hh pathway mediates an interaction between tumor cells and osteoblasts and influences osteoblast differentiation in response to tumor cells. We have determined that breast tumor cells have an activated Hh pathway characterized by upregulation of the ligand, IHH and transcription factor GLI1. Breast cancer cells interact with osteoblasts and cause an enhanced differentiation of pre-osteoblasts to osteoblasts that express increased levels of the osteoclastogenesis factors, RANKL and PTHrP. There is sustained expression of osteoclast-promoting factors, RANKL and PTHrP, even after the osteoblast differentiation ceases and apoptosis sets in. Moreover, tumor cells that are deficient in Hh signaling are compromised in their ability to induce osteoblast differentiation and consequently are inefficient in causing osteolysis. The stimulation of osteoblast differentiation sets the stage for osteoclast differentiation and overall promotes osteolysis. Thus, in the process of developing newer therapeutic strategies against breast cancer metastasis to bone it would worthwhile to keep in mind the role of the Hh pathway in osteoblast differentiation in an otherwise predominant osteolytic phenomenon

Osteopenia, decreased bone formation and impaired osteoblast development in Sox4 heterozygous mice

The transcription factor Sox4 is vital for fetal development, as Sox4–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (μCT), histomorphometry and biomechanical testing of Sox4+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2

Countrywide outbreak of Pseudomonas aeruginosa in hospitals caused by premoistened non-sterile washcloths, Norway, 2021-2022

Source at https://www.fhi.no/I november 2021 ble Folkehelseinstituttet varslet om at tre intensivpasienter hadde dødd av blodbaneinfeksjon med bakterien Pseudomonas aeruginosa ved Universitetssykehuset Nord-Norge i Tromsø i løpet av kort tid. De hadde identiske isolater forenlig med et klonalt utbrudd. Helgenomsekvensering viste at det var en ny sekvenstype, ST3875, som ikke har vært påvist i Norge eller andre land. Nye tilfeller uten epidemiologiske sammenhenger, ble etter hvert funnet i flere andre sykehus, noe som indikerte en felles smittekilde. Den 17. januar 2022 var det påvist utbruddstilfeller i tre av fire helseregioner, og det ble 19. januar erkjent som et nasjonalt utbrudd. FHI overtok da koordinering av utbruddsarbeidet, og 20. januar ble det etablert en Sentral utbruddsgruppe med fagpersoner fra alle helseregionene. Den 21. januar var det 23 tilfeller i 9 sykehus i 3 regioner. Kasusdefinisjonen var en person med laboratoriebekreftet P. aeruginosa ST3875 fra oktober 2021 i sykehus i Norge, uavhengig av avdeling. Etter systematiske laboratorieundersøkelser av over 300 produkter påviste Oslo Universitetssykehus 18. mars 2022 utbruddsbakterien i pre-fuktede engangs vaskekluter av merket Oasis BedBath Unperfumed produsert i Lancashire, England. Sykehusene sluttet umiddelbart å bruke produktene. Vaskeklutene er definert som et kosmetisk produkt, og Mattilsynet er tilsynsmyndighet. Mattilsynet avdekket at produsenten og importøren ikke hadde full oversikt over produksjonslinjene og hvilke produkter som var forurenset. Det ble også avdekket at P. aeruginosa var blitt påvist i produkter under den interne kvalitetskontrollen i september 2021, uten at produktene var blitt stanset. Den 14. april tilbakekalte den engelske produsenten Vernacare produktene fra markedet både i Norge og internasjonalt. Per 14. juni 2022 omfattet utbruddet 388 tilfeller i 40 sykehus. Gjennomsnittsalder var 68 år og median alder 70 år (interkvartilområde 59- 79 år). Flertallet (63 %) av tilfellene var menn, og seks sykehus rapporterte Pseudomonas som sterkt medvirkende årsak til død hos totalt 8 tilfeller. Til sammen hadde 15 % av tilfellene ST3875 i blodkultur, 21 % i luftveier, 38 % i urin, 19 % i sår og 7 % i andre prøvematerialer, noe som tydet på flere mulige inngangsporter for bakterien. Antall nye tilfeller falt raskt etter at kilden var identifisert, og bruk av produktet ble stoppet i sykehus

Estrogen/Estrogen Receptor Alpha Signaling in Mouse Posterofrontal Cranial Suture Fusion

BACKGROUND: While premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology. METHODOLOGY/PRINCIPAL FINDINGS: Firstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion. CONCLUSIONS/SIGNIFICANCE: Estrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex

Dokkingsystem for automatisk selvstyrt vogn (AGV)

Masteroppgaven Dokkingsystem for automatisk selvstyrt vogn (AGV) har som mål å utvikle en automatisk selvstyrt vogn (AGV) og å skissere et automatisk dokkingsystem for denne AGV-en. En ny AGV har blitt utviklet med fokus på at konstruksjonen skal være så enkel som mulig og at det skal benyttes lett tilgjengelige komponenter. AGV-en er basert på en rammekonstruksjon laget av aluminiumprofiler. Den drives og styres med differensial drift med to elektriske børstemotorer montert direkte i rammens vanger. Den nye AGV-en laget for bruk i instituttets automatiseringslaboratorium presenteres i oppaven. AGV-ens og dens hovedkomponenter som motorer, gir og motorkontrollere beskrives, og det gis også en kort gjennomgang av hvordan man styrer AGV-ens motorer via motorkontrollerne. En introduksjon av teorien bak angivelse av en mobil robots posisjon og orientering, til sammenkalt positur gis. To modeller for kinematikken for roboter med differensial drift og en modell for banestyring av mobile roboter presenteres. Grunnlaget for å utvikle dokkingløsningen gjøres gjennom en analyse av ulike metoder og sensorer som kan benyttes i dokkingoperasjonen. Virkemåten beskrives enkelt, og styrker og svakheter vurderes opp mot hverandre. Blant sensorene som omhandles er en laserbasert områdesensor, maskinsyn basert på digitale kameraer, infrarøde distansesensorer og ultrasoniske distansesensorer. Ut fra denne analysen blir det bestemt å utvikle en dokkingmetode basert på en type infrarøde sensorer som benytter seg av et trianguleringsprinsipp for å måle avstand. Dette er interessant særlig siden disse sensorene er meget billige. En løsning for å gjennomføre dokkingoperasjonen med disse infrarøde sensorene presenteres.Løsningen baserer seg på bruk av seks infrarøde sensorer, to med et måleområde fra 20 til 150cm og fire med et måleområde fra 4 til 30cm. De to sensorene med langt måleområde monteres i front og brukes for å bestemme AGV-ens positur relativt til dokken før dokkingoperasjonen begynner. De fire sensorene med kort måleområde monteres langs AGVens to sider og benyttes for å finjustere AGV-ens posisjon i forhold til veggene i dokken. For å bekrefte at det infrarøde sensorene holder mål blir de grundig testet både i forhold til signalkvalitet og i forhold til oppløsning. En anbefaling for hvordan sensorene kan brukes på en måte som er tilfredsstillende i forhold til behovet blir presentert med bakgrunn i disse testene

Regular distribution of length heterogeneities within non-transcribed spacer regions of cloned and genomic rDNA of Saccharomyces cerevisiae.

A length difference of about 50 bp in the EcoRI fragment B of the rDNA from two different strains of Saccharomyces cerevisiae has been mapped in detail by sequencing of cloned fragments. This 2.4 kb EcoRI fragment contains the start of the 35S rRNA gene at one end and the 5S rRNA gene in the middle flanked by non-transcribed spacers, NTS1 and NTS2. The difference appeared as short deletions or insertions in five regularly spaced regions within the 1 kb NTS1, 3' to the 5S rRNA gene. The same regions of heterogeneities were displayed when all available sequence data of the NTS1 were compared. Four of the variable regions are located 160-170 bp apart, indicating that they might represent linker sequences between phased nucleosomes. Two variant clones, differing in the length of one subfragment of NTS1, were isolated for each strain. In both cases these represented the major variants among chromosomal NTS1 as revealed by sequencing of genomic fragments

Fysioterapi ved Bekhterev sykdom i Trondheim og omkringliggende kommuner

In this study we investigated the use of physiotherapy services and exercise facilities by patients with Ankylosing Spondylitis in Trondheim and three surrounding counties. Patient satisfaction with regard to the services was also recorded. Associations between patient characteristics and the use of physiotherapy were investigated. The aim was to assess the adequacy of the services and facilities offered and to get knowledge of characteristics associated with the use of physiotherapy services. Totally 220 of 410 patients (57 percent) answered a mailed questionnaire about access to and use of physiotherapy services and exercise facilities including questions regarding disease activity (The Bath Ankylosing Spondylitis Disease Activity Index, BASDAI), physical functioning (The Bath Ankylosing Spondylitis Functional Index, BASFI) and burden of disease (BAS-G). The results indicate that 61 percent of the patients had received physiotherapy treatments during the last year, and those who were most affected with regard to disease activity, physical functioning and burden of disease had received more treatments. Pain had the biggest impact on the amount of physiotherapy services received whereas age, residence-county and gender had no influence. Around one third of the patients used exercise facilities outside the regular health care system, while 60 percent stated that the services corresponded well to their needs. The percentage that was satisfied varied between 87 and 100 with the different services. About one third of the patients desired extended physiotherapy services beyond normal working hours