In summary, this thesis presents the localisation and identification of genetic variants of which some are disease associated and some considered to be neutral. Knowledge of the basic mechanisms behind human disorders is important both from a biological and medical point of view. The thesis is based on four papers of which the first two clarify the genetic basis of autosomal dominant aplasia of lacrimal and salivary glands (ALSG). ALSG is a rare disorder with high penetrance and variable expressivity characterized by dry mouth and eyes. In paper I, we located the ALSG gene to a 22 centiMorgan region on chromosome 5 through a genome-wide linkage scan with microsatellite markers in two families. Mutations were found in the gene encoding fibroblast growth factor 10 (FGF10) situated in the linked chromosome 5 region. Mice having only one copy of the FGF10 gene (Fgf10+/- mice) have a phenotype similar to ALSG, providing an animal model for the disorder. In paper II, we describe two additional patients with ALSG and missense mutations in FGF10, providing further genotype-phenotype correlations. The aim of paper III was to identify a gene involved in autosomal recessive severe congenital neutropenia (SCN), also referred to as Kostmann syndrome. The disease is characterized by a very low absolute neutrophil count and recurrent bacterial infections. Affected individuals from the family with SCN originally described by Dr Kostmann were genotyped with whole-genome SNP arrays. Autozygosity mapping identified a shared haplotype spanning 1.2 Mb on chromosome 1q22. This region contained 37 known genes, of which several were associated with myelopoiesis. Our finding contributed to the identification of the gene mutated in Kostmann syndrome. In paper IV a cytogenetic inversion on chromosome 10 was mapped and characterized. Sequence- and haplotype analysis of carriers from four non-related Swedish families revealed identical inversion breakpoints and established that the rearrangement was identical by descent. A retrospective study of karyotypes together with screening of large sample sets established that the inversion is a rare and inherited chromosome variant with a broad geographical distribution in Sweden. No consistent phenotype was found associated with the inversion. Genetic research increases the understanding of our genomes and makes it possible to discover variants contributing to disease. Identification of such genetic variants further enables studies of gene function and pathogenesis. The finding of the disease associated variants in this thesis will eventually contribute to improved diagnosis, prognosis, risk assessment and a future treatment of patients.

A longitudinal study of 43 families referred to a Clinical Genetic Service was undertaken to ascertain the needs and expectations of the service, from the client's perspective. Previous studies have mainly focussed on changes in knowledge or reproductive patterns as outcomes for genetic counselling. Clients were interviewed before contact with the genetic service, after the consultation, and six months later. At each interview, psychological questionnaires to assess Need for Cognitive Closure (Webster & Kruglanski, 1994), anxiety (Spielberger et aI, 1970) and the impact of the genetic condition on the family (Horowitz et aI, 1979) were used. Statistical analyses of these tools revealed that the Need for Closure is a stable entity, and that genetic counselling does not significantly influence anxiety in the client. A grounded theory approach was used to analyse the data, and the theory presented includes the client's need for certainty, the client's prior lay knowledge, and assimilation of scientific information into the family knowledge base. Clients had little prior knowledge of genetics, but had constructed lay explanations for the inheritance of the condition in their family. Scientific information was tested against the family history for validity, and where there was apparent conflict, the scientific explanation was sometimes rejected. Results of this study indicate that the majority of families are not seeking information for reproductive decision-making, but as a; means of obtaining certainty, via a diagnosis, a prognosis, or a test result. Clients defined the most important outcomes as alterations in their psychological ability to deal with the situation in their family. In this cohort, certainty was seen as helpful in enabling the client to cope, and failure to obtain certainty influenced the outcome adversely. Implications for clinical practice include the need to address the client's need for certainty, to explore the family's lay explanations as part of the genetic counselling process, and to relate explanations directly to the family experience.

No description available.

Lower motor neuron diseases (LMNDs) include a large spectrum of clinically and genetically heterogeneous disorders, characterized by progressive anterior horn cell degeneration. The aims of this thesis were on the one hand to refine the phenotypic description and the clinical classification of hereditary LMNDs, and on the other hand to improve our knowledge of the genetic bases of these disorders. This work was performed in collaboration with the Centre of Human Genetics of the Necker-Enfants-Malades Hospital in Paris. We focused our researches on autosomal recessive variants of LMNDs. First, we selected patients with Spinal Muscular Atrophy with Respiratory Distress (SMARD or d-HMN VI). This severe variant of autosomal recessive LMND is characterized by neurogenic muscular atrophy associated with early life-threatening respiratory failure due to diaphragmatic dysfunction. SMARD type 1 has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We reported the identification of 9 novel IGHMBP2 mutations in five SMARD1 patients, Seven of them occurred at highly conserved residues of the putative DNA helicase domain, suggesting that this particular domain plays a major role in the SMARD1 disease causing mechanism (Hum Mutat. 2004; 23(5):525-6). Then, we collected families and sporadic patients affected by chronic distal spinal muscular atrophy (d-HMN III/IV), an autosomal recessive variant of LMND characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of chronic dSMA gene had been mapped to a 10.3 cM interval on chromosome 11q13. By linkage analysis in 12 European chronic dSMA families, we reduced the genetic interval to a 2.6cM region on chromosome 11q13.3 and showed partial linkage disequilibrium between 3 rare alleles and the mutant chromosome in European patients, suggesting that most chronic dSMA chromosomes are derived from a single ancestor (Eur J Hum Genet. 2004;12(6):483-8). Additional experiments are now in progress at Necker-Enfants-Malades Hospital, in order to identify the disease-causing gene. At last, we described the clinical features of a novel variant of autosomal recessive LMND, characterized by childhood onset, generalized muscle involvement, and severe outcome. Studying a large inbred African family, we mapped the disease gene to a 3.9-cM interval on chromosome 1p36 (Neurology.2006;67(1):120-4). We identified a homozygous missense mutation of the PLEKHG5 gene and performed in vitro experiments to clarify the pathogenic function of this mutation. In transiently transfected HEK293 and MCF10A cell lines, we found that wild-type PLEKHG5 activated the NFkB signaling pathway and that both the stability and the intracellular location of mutant PLEKHG5 protein were altered, severely impairing the NFkB transduction pathway. Moreover, we observed aggregates in transiently transfected NSC34 murine motor neurons overexpressing the mutant PLEKHG5 protein. In conclusion, we showed that both loss of PLEKHG5 function and aggregate formation might contribute to neurotoxicity in this novel form of LMND (Am J Hum Genet. 2007;81(1):67-76). Further experiments should now be planned, in particular to understand the role of aggregates in neurodegeneration, and to precise the links between the PLEKHG5 gene and the other LMNDs-causing genes. In conclusion, we hope that this work, contributing to a better understanding of the molecular mechanisms involved in motor neuron degeneration, will open the way to new therapeutic strategies. / Les amyotrophies spinales (SMA) se caractérisent par une dégénérescence des motoneurones des cornes antérieures de la moelle épinière ou des noyaux du tronc cérébral. Elles comprennent de nombreuses entités, très hétérogènes tant sur le plan clinique que sur le plan génétique. Cette thèse vise à préciser les caractéristiques phénotypiques et génétiques des différentes formes d’amyotrophie spinale, en particulier celles des variants de transmission autosomique récessive. En premier lieu, nous avons sélectionné une cohorte de patients dont le tableau clinique était compatible avec la variante SMARD d’amyotrophie spinale (pour Spinal Muscular Atrophy with Respiratory Distress). Il s’agit d’une forme très sévère d’amyotrophie spinale autosomique récessive, qui associe une faiblesse musculaire à prédominance distale et une détresse respiratoire précoce secondaire à une paralysie diaphragmatique. Nous avons décrit 9 nouvelles mutations au sein du gène IGHMBP2 (pour immunoglobulin µ-binding protein 2) chez 5 patients atteints et confirmé ainsi le rôle pathogène de ce gène. Sept des 9 mutations décrites concernent des acides aminés conservés dans les espèces et localisés dans le domaine hélicase. Ce domaine pourrait donc jouer un rôle essentiel dans la physiopathologie de la maladie (Hum Mutat. 2004; 23(5):525-6). Deuxièmement, nous avons rassemblé des patients atteints d’amyotrophie spinale chronique distale (d-HMN III/IV), de transmission autosomique récessive. Cette affection se définit par une amyotrophie et une faiblesse musculaire progressive qui prédomine au niveau des pieds et des mains. Grâce à des analyses de liaison réalisées dans 12 familles européennes, nous avons restreint la localisation génétique sur le chromosome 11 (en 11q13.3) à un intervalle de 2.6 cM. Nous avons également mis en évidence un déséquilibre de liaison entre 3 allèles rares et le locus génétique, ce qui suggère un phénomène d’effet fondateur dans la population caucasienne (Eur J Hum Genet. 2004;12(6):483-8). Des études complémentaires sont actuellement en cours à l’Hôpital Necker-Enfants-malades à Paris pour identifier le gène responsable de cette forme chronique d’amyotrophie spinale distale. Troisièment, nous avons décrit un nouveau variant d’amyotrophie spinale de transmission autosomique récessive. L’amyotrophie et la faiblesse musculaire débutent vers l’âge de 3 ans et concernent rapidement l’ensemble de la musculature. Le pronostic est sévère, avec perte de la marche durant l’enfance et altération de l’autonomie respiratoire à l’adolescence. L’étude d’une grande famille Malienne consanguine nous a permis de localiser le gène responsable de la maladie dans un intervalle de 3.9 cM sur le chromosome 1, en 1p36 (Neurology. 2006;67(1):120-4). Nous avons ensuite mis en évidence une mutation faux-sens à l’état homozygote dans le gène PLEKHG5 chez les patients atteints et avons prouvé le caractère pathogène de cette mutation grâce à une série d’études fonctionnelles. Nous avons montré que la protéine PLEKHG5 sauvage a une distribution cytoplasmique homogène dans des cellules rénales (HEK293) et mammaires (MCF10A) humaines transfectées et qu’elle y active la voie de signalisation NF-kappaB. La protéine PLEKHG5 mutée est quant à elle instable, ce qui entraîne une perte de sa fonction activatrice sur NF-kappaB. De plus, grâce à des études de transfection transitoire de motoneurones murins (cellules NSC34), nous avons montré que la protéine PLEKHG5 mutée entraîne la formation d’importants agrégats cytoplasmiques. Dans cette nouvelle forme d’amyotrophie spinale, la perte de la fonction activatrice de la voie de signalisation NF-kappaB et la formation d’agrégats pourraient toutes deux contribuer à la neurotoxicité de la protéine PLEKHG5 mutée et conduire ainsi à la dégénérescence des motoneurones (Am J Hum Genet. 2007;81(1):67-76). En conclusion, nous espérons que ces résultats, qui contribuent à améliorer la connaissance des mécanismes physiopathologiques responsables de la dégénérescence des motoneurones, ouvriront à l’avenir la voie vers de nouvelles perspectives thérapeutiques.

Genome wide association studies (GWAS) and their subsequent meta-analysis have identified a large number of susceptibility variants for Type 2 diabetes (T2D) risk. However, the familial aggregation seen in this disease is not yet fully explained. The sibling relative risk (λ_s) due to all known variants is ~1.104 which is well below the epidemiological estimates of λ_s of ~3.0. There has therefore been great interest in the potential role of variants that would have been largely invisible to the initial wave of GWAS and linkage approaches. Low frequency (minor allele frequency 1-5%), incompletely penetrant (odds ratio 2-4) variants (LFIP), are one such group of potential susceptibility variants. The overall objective of this project (designed and implemented in 2007-2010) was to evaluate the contribution of LFIP variants to the inherited susceptibility to T2D. I tested the specific hypothesis that genes already-implicated in diabetes pathogenesis (due to an established role in monogenic or multifactorial disease) also harbour LFIP variants, and that those variants may contribute appreciably to the prediction of disease risk. Mutations in exons only encoding isoform-A of HNF1A have been demonstrated to lead to a later age of diagnosis of HNF1A-MODY. This region was therefore felt to be auspicious for harbouring LFIP variants impacting on T2D risk. I have demonstrated that such variants impacting on T2D risk are unlikely to be present in this region by use of Sanger sequencing in a sample enriched for young onset, familial T2D. The role in T2D risk of candidate LFIP variants across 5 genes (HNF1A, HNF4A, PDX1, KCNJ15 and LARS2), was evaluated by large scale association studies. For one variant, T130I of HNF4A, a modest association (p=5x10^-4) with T2D was seen in UK samples and the strength of association was marginally improved by incorporation of all previous studies of this variant in T2D in a meta-analysis (p=2.1x10^-5). This study demonstrated the difficulties encountered in confirming the association of low frequency variants to complex diseases, especially for those with modest effect sizes. At the time of project design and inception “next-generation” sequencing platforms were in their infancy and the study design I planned (that of pooled, targeted sequencing) had not been widely applied. It was therefore necessary to design and optimise protocols for sample preparation for sequencing on this platform. I used the Genome Analyzer II platform to sequence ten genes previously implicated in T2D or monogenic diabetes pathogenesis in pooled DNA samples. This approach yielded in excess of 2900 variants, a large portion being novel. As part of this project I have highlighted heuristics that can be used in the follow-up of potential susceptibility variants discovered using high throughput sequencing. I have also established protocols and pathways for sample preparation that can be utilised across several next generation sequencing platforms for future studies in the host institution and beyond.

Pathogenic gain-of-function mutations associated with increased paternal age, albeit harmful to embryonic development, are paradoxically enriched in the normal testis. Evidence from previous studies indicates that these so-called paternal age-effect mutations confer a proliferative advantage to the spermatogonia in which they arise, leading to clonal expansion within the normal testis over time. Recently, spermatocytic seminoma (SS; a rare testicular germ cell tumour that occurs mainly in older men) has emerged as a key link between the processes of somatic and germline mutation (Goriely et al, Nat Genet. 41:1247-52, 2009), suggesting that the proposed clonal expansion events can in some cases lead to testicular tumourigenesis. In this thesis, I have used immunohistochemistry to seek evidence for putative clones of cells in the normal adult testis. To address this, a screening approach was developed using markers chosen from analysis of normal testicular tissues and SS. The ontogeny of OCT2 and SSX expression in human testis, from embryonic development to adulthood, identified distinct subpopulations of spermatogonia at different maturation stages. Together, these data reveal the potential of OCT2 as a novel marker of A_dark spermatogonia (human reserve spermatogonial stem cells). In parallel with these observations, two distinct types of SS characterised by differential OCT2 and SSX immunoexpression were identified, providing new evidence for heterogeneity of this tumour. This work provided the backdrop to the detailed immunohistochemical study of normal adult testis by characterising in serial sections the expression of five spermatogonial markers, MAGEA4, SSX, FGFR3, OCT2 and SAGE1, and a proliferation marker, Ki67. Independent sections were screened with predetermined criteria set to identify unusual positively-stained cellular clusters within the seminiferous tubules. Several antigenic combinations previously described in SS were observed in a subset of these clones, suggesting differing genetic origins and a possible link with early events of testicular tumourigenesis. The size (minimum number of cells) of each clonal event was estimated and its correlation with the staining pattern of the molecular markers was investigated. In summary, the data presented in this thesis convincingly identify for the first time the previously hypothesised clonal events in the testis using immunohistochemical markers. My research will pave the way for future work involving genetic analysis of microdissected cells from these putative clones, aimed at identifying the underlying mutational events thought to be present.

<p>Myelomatose (benmargskreft) er en blodsyk dom som rammer ca 200 nordmenn årlig. Sykdommen kan ikke kureres og karakteriseres av symptomer som benmargssvikt og infeksjonstendenns, men kanskje først og fremst av sykelig nedbrytning av skjelettet. Pasientene rammes i høy utstrekning av benbrudd, hvirvelsammenfall og skjelettsmerter. Mekanismene for bennedbrytning og vekstkontroll står sentralt i avhandlingsarbeidet som består av fem artikler om cytokiners rolle i myelomatose. Cytokiner er signalsubstanser som benyttes i celle-celle-kommunikasjon. Det er sannsynligvis ubalanse av cytokiner som forårsaker den sykelige nedbrytningen av bensubstansen. </p><p>Det første delarbeidet omhandler funnet av hepatocyttvekstfaktor (HGF) som er uttrykt hos nesten alle pasienter med myelomatose Dette påvises med forskjellige teknikker og det benyttes bl a en separasjonsmetode for myelomceller basert på Ugelstadkuler som ble utviklet ved IKM i 1993. Videre påvises forhøyede nivåer av HGF i serum fra pasienter. Et interessant funn er at HGF reseptor også er uttrykt i pasientprøver, hvilket kan tale for at myelomceller kan ha en selvstimulerende (autokrin) funksjon.</p><p>I det andre delarbeidet vises en dyremodell for myelomatose i immundefekte mus. Et hovedpoeng er at det lar seg gjøre å få vekst av myelomceller i musebenmarg med påvisbare tegn til patologisk bennedbrytning på røntgen og ved histologisk undersøkelse. Musene har forhøyede nivåer av HGF i serum. Benlesjonene ble karakterisert ved hjelp av histomorfometri. Denne undersøkelse viste 99% reduksjon av de bendannende cellene (osteoblaster) og 33% reduksjon av bennedbrytende celler (osteklaster).</p><p>I tredje delarbeidet viser man at HGF induserer interleukin (IL)-11-produksjon i osteoblaster. IL-11 er en kjent påskynder av benresorpsjon og osteoklastaktivator. Et interessant fenomen er at HGF ser ut til å være bundet til heparansulfat på cellemembranen og at slikt membranbundet HGF virker bedre enn løselig HGF. Effekten av HGF potensieres av cytokinene TGF-beta og IL-1. En styrke ved arbeidet er at såvel ferskisolerte pasientceller som cellelinjer viser identiske mønstre. Arbeidet angir en mulig måte som HGF kan befremme bennedbrytning.</p><p>I fjerde delarbeid vises at cytokinet IL-15 forhindrer programmert celledød (apoptose) i myelomcellelinjen OH-2. Det var fra før kjent at myelomceller relativt hyppig lar seg stimulere av cytokinet IL-6, som fortsatt er den mest anerkjente myelomvekstfaktoren. IL-15 var tilnærmet like potent antiapoptotisk som IL-6, og befremmet også kortvarig proliferasjon. IL-15s effekt kunne potensieres av TNF-alfa </p><p>I femte delarbeid påvises at cytokinet benmorfogent protein (BMP)-4 hemmer vekst av myelomceller. BMP-4 befremmer bendannelse. Effekten av BMP-4 kom fram i IL-6-stimulerte cellelinjer og pasientprøver. Effekten skyldtes såvel induksjon av apoptose som stopp i cellesyklus G1-fase. Dette er et mulig viktig funn siden man kan tenke seg at pasienter med myelomatose kunne behandles med BMP-4 eller lignende substanser. På slik måte ville såvel skjelettnedbrytningen som myelomcellevekst kunne påvirkes gunstig. </p><p>Arbeidet bidrar til forståelse av molekylære mekanismer for bendestruksjon og myelomcellevekst og ble veiledet av profesor dr. med. Anders Waage. Henrik Hjorth-Hansen har vært stipendiat i Den norske kreftforening, og undersøkelsen ble dessuten støttet av Kreftfondet ved RiT og Blix’ legat. </p>

<p>Seasonal variations of mood, behavior and physiology have been of increasing interest. At least two different seasonal rhythms seem to exist: Descriptions of Seasonal Affective Disorder (SAD) with increased weight, increased sleep and fatigue during winter have attracted attention in academic psychiatry and in the general public the last two decades. In addition to such a difference in mood, weight and sleep between summer and winter, many studies describe a spring and fall increase in frequency of suicides and of admissions to hospital for mood disorders. In searching for a possible etiology for these seasonal changes, the main focus has been on variations in length of day. </p><p>The objective of this thesis was to study the existence and pattern of seasonal variation in some forms of behavior and of psychiatric illness among children and adults in Norway. Possible statistical connections between seasonal variations of behavior and changes in length of day and the influences of latitude, sex and age were also studied.</p><p>The monthly numbers of incidents in different groups were studied: All suicides in Norway 1969-96 (N=14.503), admissions to hospital for depression and mania in some hospitals 1992-96 (N=4.341), all violent episodes recorded by the police in Norway 1991-97 (N=82.537), all patient-staff incidents in a psychiatric department 1990-97 (N=502), all telephone calls to the Red Cross help-line for children and adolescents in Norway 1996-98 (N=691.787calls, 220.602 conversations) and in Trondheim, Norway 1991-97 (N=80.983 calls, 22.698 conversations) were included in the thesis. The monthly frequencies of these incidents were compared to an expected equal daily frequency of incidents through the year. Changes with increasing age and increasing latitude were examined. Correlations between the monthly frequencies of incidents and the length of day, with maximum impact at midsummer, and correlations between the monthly frequencies of incidents and the speed of change in length of day, with maximum impact at the equinoxes, were also studied. </p><p>In this thesis, an increased activity in April-June and in October-November is described for all the groups that were studied. In summer and winter there is less activity than in the rest of the year. Among children calling the help-line, a steady diminishing seasonal variation in number of calls with increasing age from 7 to 17 years of age and an increasing seasonal variation in number of calls with increasing latitude were found. Also the seasonal variation of violence increases with increasing latitude in Norway. Among men there is a correlation between the monthly number of suicides and the monthly number of admissions for mania and a correlation between the monthly number of suicides and the monthly number of admissions for depression. Among women there is a diminishing seasonal variation of admissions for depressions with increasing age. The monthly frequency of violence in Norway and the monthly frequency of calls to the Red Cross help-Line for children and adolescents correlated with a delay of 1-2 months with the monthly change in length of day with maximum impact at the equinoxes. </p><p>The results in the thesis correspond with earlier studies describing an increase in the frequency of suicides and an increase in admissions for depressions in spring and fall. A corresponding rhythm for other forms of human behavior is described in the present thesis, indicating that the seasonal rhythm of psychiatric illness reflects a seasonal rhythm of behavior in greater parts of the population. The seasonal variation in behavior seems to increase with increasing latitude, to be more dramatic in the northern than in the southern parts of Norway. In this thesis results supporting a hypothesis of human behavior being influenced by changes in length of day are given. Changes in length of day may induce changes in sleep and other disturbances in the daily rhythm that could change mood and other emotional qualities in vulnerable individuals. The demands on our capability to adapt to changes in length of day are largest at the equinoxes. </p> / <p><b>Årstidsvariasjon av sinnstemning og adferd.</b></p><p>Det er økende interesse for årstidsvariasjon av adferd og av forekomsten av psykiske lidelser. Det synes å foreligge minst to ulike årstidsrytmer i befolkningen; Størst oppmerksomhet har oppdagelsen av vinterdepresjon karakterisert ved tristhet, tretthet, økt vekt og forlenget søvn vakt. I tillegg til en slik forskjell i humør, vekt og søvn mellom sommer og vinter, er det en rekke beskrivelser av overhyppighet av selvmord og av innleggelser i sykehus for depresjoner vår og høst. Årsakene til disse to ulike årstidsrytmene er ikke kjent, men man har antatt at variasjon i dagslengde gjennom året spiller en rolle.</p><p>Hensikten med denne avhandlingen har vært å undersøke om det er årstidsvariasjon i forekomsten av ulike former for adferd og av psykiske lidelser hos barn og voksne i Norge. Videre er eventuelle statistiske sammenhenger mellom adferd og dagslengde gjennom året undersøkt. Til sist er forskjeller i årstidsrytme knyttet til breddegrad, alder og kjønn undersøkt.</p><p>Antallet hendelser pr måned i ulike grupper ble studert; Alle selvmord i Norge 1969-96 (N=14.503), innleggelser for depresjon og mani i en del sykehus 1992-96 (N=4.341), alle registrerte voldsepisoder i Norge 1991-97 (N= 82.537), personalskader i et psykiatrisk sykehus 1991-97 (N=502), alle telefoner til Røde Kors Kontakttelefon for barn og unge i Norge 1996–98 (N=691.787 oppringninger, 220.602 samtaler) og i Trondheim 1991-97 (N=80.983 oppringninger, 22.698 samtaler) ble inkludert i arbeidet. Hyppigheten av alle disse hendelsene i hver måned ble sammenlignet med en forventet lik fordeling av hendelsene året igjennom. Endringer med økende alder og med økende breddegrad ble undersøkt. Videre ble det gjort sammenligninger med dagslengde som er lengst ved sommersolverv og kortest ved vintersolverv, og sammenligninger med endringer av dagslengde som er hurtig ved vår og høstjamndøgn og sakte ved solvervene.</p><p>I alle disse materialene er det en økt aktivitet april – juni og oktober – november, videre er det stille perioder om vinteren og om sommeren. Blant barn som ringer kontakttelefonen er det gradvis avtagende årstidsvariasjon av henvendelser med økende alder fra 7 til 17 år og økende årstidsvariasjon i antallet henvendelser jo lenger nord man kommer i Norge. Også årstidsvariasjonen av vold i Norge endrer seg jo lengre nord man kommer i landet. </p><p>Blant menn er der en korrelasjon mellom det månedlige antallet av selvmord og av innleggelser for mani og mellom antallet selvmord og innleggelser for depresjon. Blant kvinner er det en avtagende årstidsvariasjon av innleggelser for depresjon med økende alder. </p><p>Den månedlige endring av dagslengde som er raskest ved jamndøgnene korrelerer med en viss forsinkelse med forekomsten av vold i Norge og med antallet oppringninger til Barn og Unges kontakttelefon.</p><p>Funnene i avhandlingen er i samsvar med tidligere beskrivelser av en markert økning av suicid og av innleggelser for depresjoner om våren og til dels om høsten. I avhandlingen er en tilsvarende rytme funnet for annen adferd. Dette tyder på at årstidsrytmen av psykiatrisk sykelighet avspeiler en årstidsrytme av adferd i store deler av befolkningen. Videre ser det ut til at forskjellene i adferd gjennom året blir mer markerte jo lengre nord man kommer i landet. I avhandlingen er det funn som støtter en hypotese om at endringer i dagslengde påvirker mennesket, det er mulig at dette skjer gjennom endret søvn og andre forstyrrelser i døgnrytmen. Vår døgnrytme er utsatt for størst krav til å tilpasse seg hurtige endringer i lysforhold rundt jamndøgnene. </p>

No description available.

<p>The purpose of the study was to:</p><p>• Study the effect of vascular gas bubbles on the brain and lung</p><p>• Study changes in the endothelial function caused by gas bubbles</p><p>• Study the preventive effects of monoclonal anti-C5a antibody on functional changes caused by gas bubbles</p><p>It is important to reveal any changes in the function of the endothelium caused by gas bubbles, as the endothelium probably plays an important role in the development of decompression sickness (DCS). Furthermore, we followed up previous studies using monoclonal anti-C5a antibody trying to prevent damages caused by gas bubbles. In order to prevent damages causes by gas bubbles and maybe prevent DCS, the mechanisms behind have to be revealed. This thesis is part of an ongoing project that for several years has tried to bring to light the “secrets” of DCS. </p>