<p><b>Pressemelding:</b></p><p>Behandling av type 2 diabetes har trolig best effekt i en tidlig fase av sykdommen. Dette skriver assistentlege Elisabeth Qvigstad (36) fra Grimstad i doktoravhandlingen sin ved Norges teknisk-naturvitenskapelige universitet NTNU. Arbeidet kan bidra til at det utvikles nye medisiner mot diabetes.</p><p>Avhandlingen tar utgangspunkt i type 2 diabetes, som rammer 105-120 000 nordmenn. Tidligere forskning i form av celle- og dyreforsøk har vist at vedvarende høye nivåer av fettsyrer i blodet og langvarig stimulering av insulinfrigjøring kan svekke funksjonen til de insulinproduserende beta-cellene i bukspyttkjertelen. Avhandlingen ville teste om lignende forhold er til stede hos mennesker og om korrigerende tiltak ville bedre insulinfrigjøringen ved type 2 diabetes.</p><p>Nivået av frie fettsyrer hos personer med type 2 diabetes er oftest forhøyet. Langvarig faste hos friske gir også forhøyet fettsyrenivå og kan ses på som en modellsituasjon for type 2 diabetes. Qvigstad fant redusert insulinfrigjøring hos friske forsøkspersoner etter 58 timer faste.</p><p>Fettsyrenivået i blod under testing ble senket ved hjelp av et nikotinsyrederivat hos friske personer og personer med type 2 diabetes. Hos friske påvirket ikke medikamentet insulinfrigjøring eller -følsomhet. Imidlertid virket behandlingen positivt på insulinfrigjøring hos de diabetikerne som hadde best blodsukker-kontroll. Derimot, når type 2 diabetikere reduserte fett i kosten, ga dette ingen utslag på insulinfrigjøringen, men noe nedsatt insulinfølsomhet. Nivået av fettvevshormoner (leptin, adiponectin) ble redusert. Den egne insulinfrigjøringen ble hemmet med medikamentet diazoxid, og insulininjeksjoner ble brukt som erstatning. Insulinfrigjøringen økte uten å endre insulinbehov eller blodsukkerkontroll sammenliknet med placebo. Disse resultatene tyder på at "betacelle-hvile" er gunstig ved type-2 diabetes.</p><p>Qvigstads doktorgradsarbeid bidrar til økt forståelse av betydningen av fettsyrer for insulinfrigjøring og insulinfølsomhet hos friske og ved type 2 diabetes. I tillegg støtter funnene betydningen av "betacelle-hvile», som kan bidra til utvikling av nye medisiner mot diabetes.</p><p>http://www.ntnu.no/doktorgrader/dr.med/02.03/qvigstad.htm</p>

<p>The main purpose of the present work was to evaluate the efforts taken by the Norwegian surgical community in order to promote and enhance the standards of rectal cancer treatment on a national level, in particular:</p><p>- to examine the outcome of rectal cancer surgery following implementation of total mesorectal excision as the standard rectal resection technique</p><p>- to explore the prognostic impact of the circumferential resection margin on local recurrence, distant metastases and overall survival following mesorectal excision</p><p>- to evaluate the oncological outcomes following mesorectal excision of cancer of the lower rectum, particularly the rates of local recurrence and overall survival for patients with tumours in this areas</p><p>- to illustrate the influence of a rectal cancer registry as a quality control instrument on outcome of rectal treatment, and furthermore, to investigate the rates of postoperative mortality, anastomic leakage, local recurrence (LR) and overall survival related to hospital caseload among Norwegian hospitals during implementation of mesorectal excision. </p>

<p>The aim of this thesis is to explore why parents bring their children to homeopaths and to investigate the effect of homeopathic treatment for prevention of upper respiratory tract infections (URTI) in children. The reason for doing studies on this is that there has been a nearly threefold increase in the proportion of children among patients visiting Norwegian homeopaths. This raised the question of why it is so. Furthermore, recurrent respiratory complaints are a main reason why child patients consult homeopaths. This raised the question of the effect of homeopathic treatment in this patient group, because there is very little research on this. The thesis builds on four different studies conducted between August 2002 and June 2004.</p><p>Parents of nine children that recently had been to a homeopath for the first time were interviewed to explore why parents take their children to homeopaths. All parents had been to a medical doctor before consulting the homeopath. It was the experiences with conventional medical treatment that led the parents to look for alternatives. The reasons were that 1) the parents did not want to give the medication prescribed by the doctor, 2) they wanted treatment while waiting for a problem to be assessed, 3) they did not want to continue to use the prescribed medication, 4) they stopped taking conventional medication due to side effects or 5) they were not offered any treatment by the medical doctor. The parents would consult a medical doctor if they felt insecure about the health conditions of the child and would visit a homeopath when they felt that the situation was clarified. There are parents who take their child to homeopaths despite not understanding or having belief in whether ultramolecular homeopathic medicines can have effects.</p><p>One hundred and sixty-one children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of treatment by homeopaths for prevention of URTI in children. The children were randomly allocated to two groups. One group received an appointment immediately with one of five homeopaths who treated the patients as they do in their everyday practice. The other group (control) got such treatment after three months. The occurrence of URTI judged by the parents were significantly lower among those treated immediately by homeopaths (median 8 days in three months) compared to the control group who used self-selected conventional health care (median 13 days) (p=0.006).</p><p>Homeopathic medicines are frequently used for self-treatment (over the counter-OTC). It is not known if the choice of the patient is the same, as a homeopath would have prescribed. A study was therefore conducted to explore if there can be developed indications for homeopathic medicines that facilitate that parents can chose the same medicine as a homeopath would prescribe for children with URTI. Firstly, data from a survey was used to find three medicines Calcarea carb, Pulsatilla and Sulphur that accounted for 60% of all prescription made by Norwegian homeopaths for children with URTI. Simplified constitutional indications for these medicines were developed and tested by comparing the choices of 70 parents with the prescription of eleven homeopaths. The parents were able to choose the same homeopathic medicine as homeopaths prescribed for 55% of the children.</p><p>Two hundred and fifty-nine children who had been diagnosed with an URTI by a medical doctor were recruited to participate in a trial on the effect of one of three self-selected ultramolecular homeopathic medicines for prevention of URTI in children. The indications developed were used. The children was randomly allocated to receive either ultramolecular homeopathic medicine (C-30) or placebo. There was no difference in the occurrence of URTI judged by the parents among getting ultramolecular homeopathic medicine compared to those getting placebo (median 9 days in three months for both groups) (p=0.531).</p> / <p>Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004.</p><p>Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet).</p><p>Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI Hensikten med denne avhandlingen er å undersøke hvorfor foreldre tar sine barn med til homøopat og å undersøke effekten av homøopatisk behandling i forebygging av øvre luftveisinfeksjoner (ØLI) hos barn. Bakgrunnen for de undersøkelsene som er gjort, er at det nesten er en tredobling i andelen barn blant pasienter hos homøopat. Dette utløste spørsmål om hvorfor det er slik. Videre er gjentatte luftveisplager en hovedårsak til at barn oppsøker homøopat. Fordi det er lite forskning på dette temaet ble spørsmålet om effekten av homøopatisk behandling i denne pasientgruppen også utløst. Avhandlingen bygger på fire ulike undersøkelser som er gjennomført mellom august 2002 og juni 2004. Foreldre til ni barn som nylig hadde vært hos homøopat for første gang ble intervjuet for å undersøke hvorfor foreldre tar sine barn med til homøopat. Alle foreldrene hadde vært hos lege før de kontaktet homøopaten, og det var erfaringer med legebehandlingen som fikk foreldrene til å søke alternativer. Årsakene var at foreldrene 1) ikke ønsket å gi den behandlingen lege foreskrev til barnet, 2) ønsket behandling mens barnet ventet på å bli ferdig utredet, 3) ønsket å avslutte bruken av de medisinene legen hadde foreskrevet for barnet, 4) opplevde at barnet fikk bivirkninger av behandlingen legen hadde gitt og 5) ikke ble tilbudt noen behandling hos legen. Foreldre oppsøker først lege når de er usikre eller bekymret for barnets helsetilstand. De oppsøker homøopat for behandling når dette er avklart. Det er foreldre som oppsøker homøopat med sine barn selv om de ikke forstår eller tror på effekten av homøopatiske medisiner (som kan være svært fortynnet).</p><p>Ett hundre og sekstini barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av behandling hos homøopat i forebyggingen av ØLI hos barn. Barna ble tilfeldig fordelt i to grupper. Barna i den ene gruppen fikk time med en gang hos en av fem homøopater som foreskrev homøopatisk behandling på vanlig måte. Den andre gruppen fikk slik behandling etter 3 måneder. Forekomsten av ØLI var signifikant lavere hos de som fikk behandling hos homøopat med én gang (median 8 dager på tre måneder) sammenlignet med den andre gruppen som brukte standard behandling ved behov mens de ventet (median 13 dager) (p=0,006).</p><p>Homøopatisk medisin brukes internasjonalt i stor grad til selvbehandling. Man vet ikke om pasientens eget valg av homøopatisk</p><p>medisin er lik det en homøopat ville foreskrevet. Det ble derfor gjennomført en undersøkelse av om det kan utvikles beskrivelser for indikasjoner for homøopatiske medisiner som gjør at foreldre kan velge samme medisin som en homøopat foreskriver for barn med ØLI. Først ble det funnet fram til tre medisiner, Calcarea carb, Pulsatilla og Sulphur som homøopater i Norge foreskriver til 60% av barn med ØLI. Så ble det utviklet indikasjoner for disse tre medisinene som ble testet ut ved at valgene til 70 foreldre ble sammenlignet med foreskrivingen til 11 homøopater. Foreldrene valgte samme medisin som homøopaten for 55% av barna.</p><p>To hundre og femtien barn som hadde vært til lege på grunn av en øvre luftveisinfeksjon ble rekruttert til å være med på en undersøkelse av effekten av en av tre selvvalgte homøopatiske medisiner i forebyggingen av ØLI hos barn. Indikasjonene som ble utviklet ble brukt. Barna ble tilfeldig fordelt til enten å få homøopatisk medisin eller placebo. Det var ingen signifikant forskjell i forekomsten av ØLI mellom de som fikk homøopatisk medisin sammenlignet med de som fikk placebo (median 9 dager på tre måneder i begge grupper) (p=0,531).</p>

<p>The aims of this dissertation were to investigate alcohol-related seizures in clinical neurological practice. We wanted to assess the extent of this problem, to classify the seizures, and to investigate methods to improve the clinical diagnosis of such seizures. We propose an arbitrary but simple and reproducible way of diagnosing alcohol-related seizures and alcohol withdrawal seizures. Papers I and II relate to seizure classification and the extent of the problem in relation to the level and weekly pattern of alcohol use. Paper III investigates the performance of various biological markers as aids in the diagnosis of alcohol-related seizures. Paper IV explores pitfalls in the result interpretation for two methods for detection of CDT in patients with neurological disorders. Paper V investigates the utility of standard EEG for the identification of alcohol-related seizures. </p><p>Even though the general alcohol consumption in our region is low, every third patient with an epileptic seizure leading to hospitalisation had hazardous alcohol consumption.</p><p>Evidence of focal lesions or focal seizure start was found in a high proportion of alcohol-related seizures. All such seizures were secondarily generalized and thus, we challenge the establishment impression that the vast majority of alcohol-related seizures are primarily generalized. Binge drinking (more than six drinks for men or four drinks for women, in a single drinking occasion) was common, but had little influence on seizure susceptibility or timing of seizures. In contrast to prior knowledge, we found that in some patients there was no time lag from cessation of drinking to the occurrence of a seizure, but falling intake levels prior to withdrawal seizures were demonstrated. This indicates that a state of relative withdrawal while still drinking may be sufficient to induce a seizure. Carbohydrate-deficient transferring (CDT) is the most accurate biomarker for alcohol use and good adjunct to the diagnosis of alcohol-related seizures, but its accuracy does not compete with a good clinical investigation. Generally poor accuracy should be expected for fertile women. Women on enzyme-inducing antiepileptic drugs who drink no or little alcohol seem to be at risk of having false positive CDT. Other variables associated with increased CDT were low body mass index, or having total transferring levels outside normal range. A definitely abnormal EEG suggests epilepsy or symptomatic seizures unrelated to alcohol use. The predictive value of a normal EEG is limited, but the typical post-ictal finding in alcohol-related seizures is nevertheless a normal low-amplitude EEG record. </p><p>The best method for identification of alcohol-related seizures is a clinical work-up based on a thorough medical history. The Alcohol Use Disorders Identification Test (AUDIT) provides a reliable measure of drinking habits. CDT is a good supplement to the clinical diagnosis when there is doubt, if factors associated with false-positive values are appreciated. The diagnostic value of EEG is limited. </p>

<p>The studies in the present thesis sought to define virus and host factors that can influence on the susceptibility to murine retrovirus infection. In addition, we wanted to study possible correlations between events of early infection and subsequent disease progression. For an extensive discussion of the major findings, the reader is referred to papers I-IV. The following section will give a general discussion concerning 1) some methodological aspects; 2) the course of FIS-2 infection; 3) determinants responsible for erythroleukaemia; 4) determinants responsible for immunosuppression; and, 5) does sex matter?</p>

<p>The main purpose of the theses is to explore the significance of anxiety and depression in patterns of pain, fatigue, quality of life. Lifestyle, functional disability, co-morbidity and gender among individuals given the diagnosis of fibromyalgia by their doctor.</p>

<p>Diabetic nephropathy (DN) is associated with morbidity and mortality due to cardiovascular disease and renal failure. This study focused on the impact of glycemic control on the development of DN and the metabolic consequences of DN. The euglycemic hyperinsulinemic clamp technique was used to assess insulin sensitivity and insulin clearance. Two different registries, the Diabetes Incidence Study in Sweden (DISS) and the Swedish Childhood Diabetes Registry, as well as questionnaires and data from medical records were used to study diabetic complications in population-based cohorts.</p><p>Microalbuminuria is an early marker of DN and may also be associated with impaired insulin sensitiv-ity in diabetic and non-diabetic subjects. We studied the relationship between insulin sensitivity and the degree of albuminuria in patients with type 1 diabetes and micro- or macroalbuminuria but normal glomerular filtration rate (GFR). We did not find a direct quantitative association between the degree of albuminuria and insulin resistance, arguing against a cause-effect relationship.</p><p>With progression of DN, a decline in GFR is seen. Patients with severe renal failure have both im-paired insulin sensitivity and insulin clearance. We studied insulin sensitivity and insulin clearance in type 1 diabetes patients with three different degrees of renal involvement (none, only albuminuria, and slightly reduced GFR, ~40-70 ml/min/1.73 m2, respectively). A clear reduction in insulin sensitivity in vivo, but not in insulin clearance, was seen in the group with reduced GFR, and concomitant changes in the levels of PTH, IGF-1, IL-6 and TNF-α were found. In parallel, cellular insulin sensitivity and insulin degradation were examined in vitro, in subcutaneous fat cells but no differences were found between the three groups of patients.</p><p>To study the occurrence of renal involvement in patients with modern diabetes treatment we moni-tored a cohort of young adults from the DISS-registry with onset of diabetes in 1987-88 at age 15-34 years. We found that ~7% of the patients had signs of renal involvement, i.e. incipient nephropathy (5%) and overt nephropathy (2%), after a median follow-up of ~9 years and the strongest risk markers were poor glycemic control (HbA1c) and high blood pressure. Patients with type 2 diabetes were most prone to have renal involvement in this age group.</p><p>Retrospectively, we studied 94 patients diagnosed with type 1 diabetes in 1981-1992 at age 0-14 years at the Umeå University Hospital. Incipient nephropathy and background retinopathy occurred in 18 and 45%, respectively, of the patients, during ~12 years of follow-up. Glycemic control, also during the first five years of diabetes, was a strong risk marker. Young age at onset of diabetes prolonged the time to development of microvascular complications.</p><p>Conclusion: Despite modern diabetes treatment some patients with diabetes develop renal involvement within the first ten years. Inadequate glycemic control, also early in the disease, is a risk marker as well as type 2 diabetes and high blood pressure. In patients with type 1 diabetes and diabetic neph-ropathy a slightly reduced GFR, but not albuminuria, is associated with insulin resistance. Concomi-tant changes in insulin-antagonistic hormones and cytokines may be involved.</p>

<p>Neuroblastoma is a malignant childhood cancer, originating from sympathetic neuroblasts of the peripheral nervous system. Neuroblastoma is a heterogenous group of tumours, while some are highly malignant others can spontaneosly mature into a more benign form or regress. Less than half of the patients survive and this statistics has improved only modestly over the past 20 years. </p><p>SH-SY5Y is a human neuroblastoma cell line established from a highly malignant tumour. The cells have retained a capacity to differentiate <i>in vitro</i> in response to low concentrations of the phorbolester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum or defined growth factors. Differentiated cells are characterised by neurite formation and upregulation of neuronal marker genes. SH-SY5Y are unresponsive to nerve growth factor (NGF), but when transfected to express the NGF-receptor TrkA, they differentiate in response to NGF. Protein kinase C (PKC) is pivotal for the differentiation response to take place.</p><p>We have investigated the role of signaling through the Ras-MAPK pathway in differentiating SH-SY5Y, with respect to neurite formation, expression of neuronal marker genes and growth control. Our results show that differentiation-promoting treatment induced a sustained activation and nuclear accumulation of the MAPK ERK in SH-SY5Y. The nuclear accumulation of ERK was PKC-dependent. However, nuclear accumulation of ERK was not sufficient for a differentiation response to take place in these cells, but ERK activity was needed for the characteristic upregulation of <i>NPY</i> and <i>GAP-43</i> induced by TPA. ERK activity did not induce neurite formation, neither was it necessary for TPA-induced neurite formation. Instead, stimulation of a pathway distinct from MEK/ERK, but downstream of Ras, was needed for morphological differentiation. We could also show that differentiated cells still entered S-phase and that there was no correlation between expression of the CKI p21_cip1 (an ERK target), BrdU-incorporation or neurite formation. </p>

<p>Glioblastoma multiforme is a malignant brain tumor characterized by heterogeneity.Interactions between heterogeneous tumor cells are supposed to affect the behavior of awhole tumor cell population. In this thesis an <i>in vitro</i> model system of clonal glioma celllines originating from one glioblastoma tumor was used, and the behavior of cells incocultures was studied and compared the behavior of cells grown separately. The resultsindicate the presence of two types of interactions. In one, paracrine signals acted via extra-cellular media. This was associated with increased growth of the whole co-culture followedby a selective force driving one clone to dominance. In the other type, the cell clones grewside by side without signs of paracrine signalling, in a balance resulting in an increasedterminal cell density. Further investigations focused on mechanisms of interactions in thiscombination.</p><p>Two cell clones were chosen, a GFAP⁺ and a GFAP^-, for further experiments. Withdifferential display PCR it was possible to investigate their specific gene expressionpatterns. Seventeen cDNA fragments were differentially expressed, among them twocorresponded to known transcription factors, ATF3 and prox-1, one to a cytoskeletal protein,α-tropomyosin. The collection also contained eight ESTs (Expressed Sequence Tags) wherethe corresponding genes are unknown at present. Expression of the isolated sequences werealso analyzed in a panel of 12 different glioma cell lines and the results illustrate thecomplexity of gene expression and of tumor heterogeneity. Genes, the expression levels ofwhich were modulated in co-cultures and/or were cell density dependent, were alsoidentified.</p><p>PDGF B is suggested to play a role in sarcomas. The gene codes for an mRNA transcriptwith long UTRs, parts of which are deleted in the homologous oncogene <i>v-sis</i>. The UTRs ofPDGF B mRNAs in human sarcomas were investigated for deletions similar to <i>v-sis</i> thatmight result in increased protein levels. A new transcript variant was identified, lacking a149 base region in the 3'UTR, but its presence was not associated with increased levels ofprotein. Alterations in the 5'UTR were found more likely to be associated with increasedprotein levels.</p>

<p>Adenovirus infected cells provide a good model system for studying nuclear organization during RNA production and transport. This thesis is focused on the dynamic organization of splicing factors during the late phase of Adenovirus infection in HeLa cells, the nuclear localization of viral RNA, and the pathway used for viral RNA transport to the cytoplasm.</p><p>Splicing factors are relocalized from interchromatin granule clusters to sites of transcription in Adenovirus infected cells at intermediate times of infection. Later, splicing factors and viral RNA accumulate posttranscriptionally in interchromatin granule clusters. The release of the splicing factors from transcription sites was energy dependent or preceded by energy requiring mechanisms. Our data indicated that phosphorylation events inhibited by staurosporine, and 3' cleavage of the transcript are two possible mechanisms involved prior to the release of the RNP complex from transcription sites.</p><p>A viral protein derived from orf6 of early region 4, 34K, is important for the nuclear stability and transport of late viral mRNA derived from the major late transcription unit. A viral mutant lacking this region is defective for posttranscriptional accumulation of viral mRNA in interchromatin granule clusters, and for the accumulation of viral RNA in the cytoplasm. These results suggest that posttranscriptional accumulation of viral RNA in interchromatin granule clusters may contribute to the maturation of the RNP complex or sorting of RNAs and proteins, to prepare the final RNP complex for transport to the cytoplasm.</p><p>A previous model suggested that adenoviral late mRNA is transported to the cytoplasm by utilizing the CRM-1 pathway. This pathway can be blocked by the drug leptomycin B. The data presented in paper IV suggests that this model might not be applicable, since leptomycin B did not inhibit adenoviral late gene expression.</p>