Synthetic studies toward [18F]-fluorination of solid-supported silyl ethers

Molekylær avbildning er definert som visualisering av in vivo biologiske prosesser på molekylært- eller cellulært nivå. Dette krever bruk av prober og kan gi anatomisk samt funksjonell informasjon. Molekylær avbildning inkluderer radiotracer-avbildning/nukleær medisin, magnetisk resonanstomografi (MR), MR spektroskopi, optisk avbildning og ultralyd. De mest sensitive molekylære avbildningsteknikkene er de radionuklide-baserte positron emisjons tomografi (PET) og singel foton emisjons-computertomografi (SPECT), som tilbyr noninvasiv avbildning samt kvantitative bilder som kan benyttes for å undersøke biologiske prosesser, som metabolisme og reseptoruttrykking i vev. Alt fra biomakromolekyler til små molekyler og nanopartikler kan brukes som radiomerkede tracere, avhengig av avbildningsformålet og kinetikken til prosessen som studeres. Vår målsetting i dette arbeidet har vært å utvikle en ny metode for 18F-radiomerking av peptider og andre biologisk relevante molekyler, samt å fremstille peptidbaserte tracere for PET-avbildning. Vi har hatt et ønske om å utvide feltet for 18F-radiofluorering av organosilisium-forbindelser ved å immobilisere forløpere på fast-fase via en O-Si binding som kan kløyves med 18F-. Dette kan potensielt anvendes for produksjon av radiotracere uten behov for HPLC-opprensing for å separere radiomerket produkt fra ureagert startmateriale eller umerket tracer. I dette arbeidet har en rekke ulike silyletere blitt fremstilt for å undersøke FOSi-metoden. Syntese av silaner og klorsilaner med ulike substitusjons-mønstre har lagt grunnlaget for videre stabilitetsstudier og utforskning av fluoreringsbetingelser. Tillagingen av Si-O bindinger var utfordrende for de sterisk hindrede di-tert-butylanalogene, mens for diisopropylanalogene ble det laget silyletere med variert funksjonalitet på den aromatiske ringen (azid, aldehyd, etere). Én silyleteranalog ble immobilisert på fast-fase og fluoreringer av både ikke-immobilisert og immobilisert forløper var vellykket. Utprøving av 18F-fluorering av fast-faseforløperen på PET-senteret ga lovende resultater. Videre studier av reaksjonsbetingelser er nødvendig for å kunne belyse det fulle potensialet til FOSi-metoden. Tre peptidbaserte tracere ble syntetisert, bestående av en Granzyme B bindende peptidsekvens, som kan brukes til å observere aktiveringen av immunsystemet, bundet til ulike kelatorer som koordineres til metalliske radioisotoper. NOTA-GzmB, NODAGA-GzmB og DOTA-GzmB ble laget fra samme peptidaldehyd-sekvens (beta-Ala-Gly-Gly-Ile-Glu-Phe-Asp-H), men med ulik kelator-konjugasjon. De tre forløperne skal radiomerkes med 68Ga, og potensielt 64Cu, og studeres videre av våre samarbeidspartnere i Tromsø.Molecular imaging is defined as the visualization of in vivo biological processes at the molecular or cellular level. It requires the use of imaging probes and can provide anatomic as well as functional information. Molecular imaging includes radiotracer imaging/nuclear medicine, magnetic resonance (MR) imaging, MR spectroscopy, optical imaging and ultrasound. The most sensitive molecular imaging techniques are the radionuclide-based positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging modalities, which offer non-invasive and quantitative images that can be used to investigate biological processes, such as metabolism and receptor expression in tissues. Anything from biomacromolecules to small molecules and nanoparticles can be utilized as radiolabeled tracers, depending on the imaging target and the kinetics of the process under investigation. In this work, we aimed at developing a new method for 18F-radiolabeling of peptides or other biologically relevant molecules, as well as preparing relevant peptide-based tracers for PET imaging. We have expanded the field of radiofluorinated organosilicons, by immobilizing precursors onto a solid support, using an O-Si linker that can be cleaved by 18F- to release the 18F-radiolabeled tracer without the need for HPLC purification to separate the product from unreacted material or unlabeled tracer. A wide variety of silyl ethers have been prepared to investigate the use of this new method for radiotracer production. Synthesis of silanes and chlorosilanes with various substitution patterns has laid the foundation for further hydrolytic stability-studies and exploration of fluorination conditions. Constructing the Si-O bond was challenging for bulky di-tert-butyl-substituted analogues, while for diisopropyl-substituted analogues, silyl ethers with various functionality on the benzene ring (azide, aldehyde, ethers) could readily be prepared. One silyl-ether analogue was immobilized on a solid support, and fluorinations of both non-immobilized and immobilized precursors were successful. The immobilized precursor was also subjected to hot fluorination at the PET center, where we obtained promising results. Further studies of the reaction conditions are required to fully elucidate the potential of the FOSi-method. Three peptide-based tracers constituting a Granzyme B (GzmB) binding peptide sequence (beta-Ala-Gly-Gly-Ile-Glu-Phe-Asp-H), which can be used to monitor activation of the immune system, linked to different chelators that can coordinate to metallic radioisotopes, have been prepared in this work. NOTA GzmB, NODAGA GzmB and DOTA GzmB will be radiolabeled with 68Ga and potentially 64Cu, and further studied by our collaborators in Tromsø.Doktorgradsavhandlin

Skolefritidsordningen: Barns aktivitetstid?

Med bakgrunn i helseargument har flere offentlige utredninger slått fast at barn er for lite fysisk aktive (Helsedepartementet, 2003; Utdannings- og forskningsdepartementet, 2003, 2004), og det er tallfestet anbefalinger angående daglig fysisk aktivitet (Helse- og omsorgsdepartementet, 2004; Statens råd for ernæring og fysisk aktivitet, 2000). Prosjektet som beskrives her, bidrar med forskningsbasert kunnskap om småskolebarns fysiske aktivitet i skolefritidsordningen [SFO]. 20 barn fordelt på fire skolefritidsordninger i Oslo er observert. Informasjon om type aktivitet, intensitet, varighet og frekvens ble innhentet gjennom kontinuerlig registrering for et barn av gangen opp til tre timer av en SFO-dag. I tillegg til observasjonsdata ble hjertefrekvens [HF] registrert. I gjennomsnitt brukte barna 60,9 % av SFO-tiden til fysisk aktivitet, 46,3 % med moderat (HF≥120 ^ HF<160) og høy intensitet (HF≥160). 90 % av barna oppfylte anbefalingene om en times daglig fysisk aktivitet bare gjennom SFO-tiden. SFO-tiden var preget av hyppige vekslinger mellom ulike typer aktivitet og intensitet. Selvinitierte aktiviteter utendørs dominerte, og mange aktivitetstyper var representert. Aktiviteter med ball (spesielt fotball), aktiviteter med redskaper (spesielt hoppetau), gange og klatring skåret høyt, men det var store forskjeller mellom individer og SFOer. Gjennomsnittlig intensitet på aktiviteter i SFO-tiden var på moderat nivå (HF = 123 slag pr. minutt). Guttene i utvalget var i fysisk aktivitet en større andel av SFO-tiden enn jentene, og oppholdt seg i større grad utendørs enn jentene

Care givers work with start-up and adaption with the youngest children in the kindergarden.

Bacheloroppgave i barnehagelærerutdanning, Høgskolen i Innlandet, 2016.Norsk: Denne oppgaven baserer seg på problemstillingen: ”På hvilke måter arbeider personalet med oppstart og tilvenning hos de yngste barna i barnehagen?” Formålet med oppgaven er å få innsikt i hvordan en tilvenningsperiode kan gjennomføres i barnehagen. Teoridelen av denne oppgaven består av teori om tilvenning, tilknytning og voksen–barn-relasjonen. Jeg tar utgangspunkt i John Bowlbys forskning og forståelse av tilknytning. Jeg valgte å gjennomføre et fokusgruppeintervju med en småbarnsavdeling i én barnehage. Svarene jeg får i intervjuet blir i oppgaven knyttet opp mot relevant teori og forskning. Det kommer frem flere viktige funn, både i forhold til tilvenning, de strukturelle rammene, foreldrene, barnet og relasjonsbygging. Kompetente og sensitive voksne som har evne til å lese hvert enkelt barn, og forstår at hvert enkelt barn har individuelle behov kommer frem som viktig.English: This thesis is based on the issue: ”In which ways do caregivers work with start-up and adaption with the youngest children in the kindergarden?” The goal of this thesis is to gain insight of how a period of adaption is implemented in kindergarden. The theoretical part of this thesis consist of theories about adaption, affiliation, and the relationship between children and adults. I base my thesis on John Bowbly’s research and understanding of affiliation. I chose to do a focus group interview with a toddler group of one kindergarden. The answers collected from the interview will be attached to relevant theories and research. There are important findings in relations to adaption, the structual frames, the parents, the children, and relationship building. One of the most important findings, is that kindergardens need competent and sensitive adults with the ability to read each child individually, and who understands the needs of each individual child

Campylobacter spp., Salmonella spp., Verocytotoxic Escherichia coli, and Antibiotic Resistance in Indicator Organisms in Wild Cervids

Faecal samples were collected, as part of the National Health Surveillance Program for Cervids (HOP) in Norway, from wild red deer, roe deer, moose and reindeer during ordinary hunting seasons from 2001 to 2003. Samples from a total of 618 animals were examined for verocytotoxic E. coli (VTEC); 611 animals for Salmonella and 324 animals for Campylobacter. A total of 50 samples were cultivated from each cervid species in order to isolate the indicator bacterial species E. coli and Enterococcus faecalis/E. faecium for antibiotic resistance pattern studies. Salmonella and the potentially human pathogenic verocytotoxic E. coli were not isolated, while Campylobacter jejuni jejuni was found in one roe deer sample only. Antibiotic resistance was found in 13 (7.3%) of the 179 E. coli isolates tested, eight of these being resistant against one type of antibiotic only. The proportion of resistant E. coli isolates was higher in wild reindeer (24%) than in the other cervids (2.2%). E. faecalis or E. faecium were isolated from 19 of the samples, none of these being reindeer. All the strains isolated were resistant against one (84%) or more (16%) antibiotics. A total of 14 E. faecalis-strains were resistant to virginiamycin only. The results indicate that the cervid species studied do not constitute an important infectious reservoir for either the human pathogens or the antibiotic resistant microorganisms included in the study

Risk factors for maternal death in the highlands of rural northern Tanzania: a case-control study

<p>Abstract</p> <p>Background</p> <p>Tanzania has one of the highest maternal mortality ratios in sub-Saharan Africa. Due to the paucity of epidemiological information on maternal deaths, and the high maternal mortality estimates found earlier in the study area, our objective was to assess determinants of maternal deaths in a rural setting in the highlands of northern Tanzania by comparing the women dying of maternal causes with women from the same population who had attended antenatal clinics in the same time period.</p> <p>Methods</p> <p>A case-control study was done in two administrative divisions in Mbulu and Hanang districts in rural Tanzania. Forty-five cases of maternal death were found through a comprehensive community- and health-facility based study in 1995 and 1996, while 135 antenatal attendees from four antenatal clinics in the same population, geographical area, and time-span of 1995–96 served as controls. The cases and controls were compared using multivariate logistic regression analyses. Odds ratios, with 95% confidence intervals, were used as an approximation of relative risk, and were adjusted for place of residence (ward) and age. Further adjustment was done for potentially confounding variables.</p> <p>Results</p> <p>An increased risk of maternal deaths was found for women from 35–49 years versus 15–24 years (OR 4.0; 95%CI 1.5–10.6). Women from ethnic groups other than the two indigenous groups of the area had an increased risk of maternal death (OR 13.6; 95%CI 2.5–75.0). There was an increased risk when women or husbands adhered to traditional beliefs, (OR 2.1; 95%CI 1.0–4.5) and (OR 2.6; 95%CI 1.2–5.7), respectively. Women whose husbands did not have any formal education appeared to have an increased risk (OR 2.2; 95%CI 1.0–5.0).</p> <p>Conclusion</p> <p>Increasing maternal age, ethnic and religious affiliation, and low formal education of the husbands were associated with increased risk of maternal death. Increased attention needs to be given to formal education of both men and women. In addition, education of the male decision-makers should be given high priority in the community, especially in matters concerning pregnancy and delivery preparedness, since their choice greatly affects the survival of the pregnant and delivering women.</p

Screening of Feral Pigeon (Colomba livia), Mallard (Anas platyrhynchos) and Graylag Goose (Anser anser) Populations for Campylobacter spp., Salmonella spp., Avian Influenza Virus and Avian Paramyxovirus

A total of 119 fresh faecal samples were collected from graylag geese migrating northwards in April. Also, cloacal swabs were taken from 100 carcasses of graylag geese shot during the hunting season in August. In addition, samples were taken from 200 feral pigeons and five mallards. The cultivation of bacteria detected Campylobacter jejuni jejuni in six of the pigeons, and in one of the mallards. Salmonella diarizona 14:k:z53 was detected in one graylag goose, while all pigeons and mallards were negative for salmonellae. No avian paramyxovirus was found in any of the samples tested. One mallard, from an Oslo river, was influenza A virus positive, confirmed by RT-PCR and by inoculation of embryonated eggs. The isolate termed A/Duck/Norway/1/03 was found to be of H3N8 type based on sequence analyses of the hemagglutinin and neuraminidase segments, and serological tests. This is the first time an avian influenza virus has been isolated in Norway. The study demonstrates that the wild bird species examined may constitute a reservoir for important bird pathogens and zoonotic agents in Norway

Making stillbirths count, making numbers talk - issues in data collection for stillbirths.

BACKGROUND: Stillbirths need to count. They constitute the majority of the world's perinatal deaths and yet, they are largely invisible. Simply counting stillbirths is only the first step in analysis and prevention. From a public health perspective, there is a need for information on timing and circumstances of death, associated conditions and underlying causes, and availability and quality of care. This information will guide efforts to prevent stillbirths and improve quality of care. DISCUSSION: In this report, we assess how different definitions and limits in registration affect data capture, and we discuss the specific challenges of stillbirth registration, with emphasis on implementation. We identify what data need to be captured, we suggest a dataset to cover core needs in registration and analysis of the different categories of stillbirths with causes and quality indicators, and we illustrate the experience in stillbirth registration from different cultural settings. Finally, we point out gaps that need attention in the International Classification of Diseases and review the qualities of alternative systems that have been tested in low- and middle-income settings. SUMMARY: Obtaining high-quality data will require consistent definitions for stillbirths, systematic population-based registration, better tools for surveys and verbal autopsies, capacity building and training in procedures to identify causes of death, locally adapted quality indicators, improved classification systems, and effective registration and reporting systems

Caesarean Section among Referred and Self-Referred Birthing Women: A Cohort Study from a Tertiary Hospital, Northeastern Tanzania.

The inequity in emergency obstetric care access in Tanzania is unsatisfactory. Despite an existing national obstetric referral system, many birthing women bypass referring facilities and go directly to higher-level care centres. We wanted to compare Caesarean section (CS) rates among women formally referred to a tertiary care centre versus self-referred women, and to assess the effect of referral status on adverse outcomes after CS. We used data from 21,011 deliveries, drawn from the birth registry of a tertiary hospital in northeastern Tanzania, during 2000-07. Referral status was categorized as self-referred if the woman had bypassed or not accessed referral, or formally-referred if referred by a health worker. Because CS indications were insufficiently registered, we applied the Ten-Group Classification System to determine the CS rate by obstetric group and referral status. Associations between referral status and adverse outcomes after CS delivery were analysed using multiple regression models. Outcome measures were CS, maternal death, obstetric haemorrhage ≥ 750 mL, postpartum stay > 9 days, neonatal death, Apgar score < 7 at 5 min and neonatal ward transfer. Referral status contributed substantially to the CS rate, which was 55.0% in formally-referred and 26.9% in self-referred birthing women. In both groups, term nulliparous singleton cephalic pregnancies and women with previous scar(s) constituted two thirds of CS deliveries. Low Apgar score (adjusted OR 1.42, 95% CI 1.09-1.86) and neonatal ward transfer (adjusted OR 1.18, 95% CI 1.04-1.35) were significantly associated with formal referral. Early neonatal death rates after CS were 1.6% in babies of formally-referred versus 1.2% in babies of self-referred birthing women, a non-significant difference after adjusting for confounding factors (adjusted OR 1.37, 95% CI 0.87-2.16). Absolute neonatal death rates were > 2% after CS in breech, multiple gestation and preterm deliveries in both referral groups. Women referred for delivery had higher CS rates and poorer neonatal outcomes, suggesting that the formal referral system successfully identifies high-risk birth, although low volume suggests underutilization. High absolute rates of post-CS adverse outcomes among breech, multiple gestation and preterm deliveries suggest the need to target self-referred birthing women for earlier professional intrapartum care

The combination of deoxynivalenol and zearalenone at permitted feed concentrations causes serious physiological effects in young pigs

This study was to investigate the effects of the combination of deoxynivalenol (DON) and zearalenone (ZON) on pigs. Twenty-four weaning piglets were divided into a control group fed a diet free of mycotoxins and a toxin group fed a diet containing 1 mg/kg DON and 250 µg/kg ZON. The results showed that supplementation of DON and ZON in diets had extensive effects on pigs. More specifically, DON and ZON caused levels of total protein, albumin, and globulin in sera to decrease (p < 0.05) by 14.5%, 6.5% and 11.3%, respectively, and at the same time increased (p < 0.05) the serum enzyme activities of γ-glutamyltransferase, aspartate aminotransferase and alanine aminotransferase by 72.0%, 32.6% and 36.6%, respectively. In addition, DON and ZON decreased (p < 0.05) the level of anti-classical swine fever antibody titers by 14.8%. Real-time PCR showed that DON and ZON caused the mRNA expression levels of IFN-γ, TNF-α, IL-2, to decrease (p < 0.05) by 36.0%, 29.0% and 35.4%, respectively. Histopathological studies demonstrated that DON and ZON caused abnormalities in the liver, spleen, lymph nodes, uterus, and kidney. The concentrations of DON and ZON used in this study are in line with the published critical values permitted by BML. Our study clearly put the standard and adequacy of safety measures for these toxins into question. The authors suggest that with the increasing availability of cellular and molecular technologies, it is time to revisit the safety standards for toxins in feeds so as to make feeds safer, providing consumers with safer products

Induction of apoptotic lesions in liver and lymphoid tissues and modulation of cytokine mRNA expression by acute exposure to deoxynivalenol in piglets

Six 1-month-old piglets were intravenously injected with deoxynivalenol (DON) at the concentration of 1 mg/kg body weight, with three pigs each necropsied at 6 and 24 h post-injection (PI) for investigation of hepatotoxicity and immunotoxicity with special attention to apoptotic changes and cytokine mRNA expression. Histopathological examination of the DON-injected pigs revealed systemic apoptosis of lymphocytes in lymphoid tissues and hepatocytes. Apoptosis of lymphocytes and hepatocytes was confirmed by the TdT-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemical staining against single-stranded DNA and cleaved caspase-3. The number of TUNEL-positive cells in the thymus and Peyer's patches of the ileum was increased at 24 h PI compared to 6 h PI, but the peak was at 6 h PI in the liver. The mRNA expression of interleukin (IL)-1β, IL-6, IL-18, and tumor necrosis factor (TNF)-α in the spleen, thymus and mesenteric lymph nodes were determined by semi-quantitative RT-PCR, and elevated expression of IL-1β mRNA at 6 h PI and a decrease of IL-18 mRNA at 24 h PI were observed in the spleen. IL-1β and IL-6 mRNA expressions increased significantly at 6 h PI in the thymus, but TNF-α decreased at 6 h PI in the mesenteric lymph nodes. These results show the apoptosis of hepatocytes suggesting the hepatotoxic potential of DON, in addition to an immunotoxic effect on the modulation of proinflammatory cytokine genes in lymphoid organs with extensive apoptosis of lymphocytes induced by acute exposure to DON in pigs