En sjukdom af högst elakt släckte : Återfallsfebern på Sveaborg och i Karlskrona 1788-1790

Sommaren 1788 drabbades den svenska flottan av en svårartad febersjukdom. Febern, som senare definierats som febris recurrens el. återfallsfeber, hade sitt ursprung i den ryska flottan. Besättningen ombord skeppet Vladislav, krigsbytet från slaget vid Hogland, bar på ett stort antal smittade klädlöss. Efter flottans ankomst till Sveaborg spred sig sjukdomen snabbt bland manskapet, men även bland fästningens garnison. Förhållandena inom militären, både inom lantarmén och framför allt inom flottan, var gynnsamma för epidemiers spridning. De trånga utrymmena, den ensidiga kosten, det undermåliga dricksvattnet, den bristande hygienen: allt gynnade uppkomsten och spridningen av olika epidemier. Manskapets försämrade allmäntillstånd gjorde, att sjukdomarna blev mera förödande än vad de i andra förhållanden skulle ha varit. Bristen på manskap och material under Gustav III:s ryska krig var enormt, bl.a. var bristen på medicinsk personal och -utrustning skriande. Då flottan och armén drabbades av en epidemi av katastrofala dimensioner stod myndigheterna hjälplösa. Epidemin visaqr tydligt hur illa förberett hela kriget var och hur misskött flottans sjukvård var. På Sveaborg var förhållandena fruktansvärda. Halva garnisonen uppges ha avlidit, och det låg travar av lik överallt. Kaserner m.fl. byggnader adapterades till provisoriska lasarett och det rådde brist på allt. De medicinska myndigheterna representerades av den till fästningen skickade andra fältläkaren, som tillsammans med läkarna på fästningen gjorde sitt bästa i enlighet med tidens vårdmetoder. Då den svenska örlogsflottan i november seglat över tilll Karlskrona spred sig epidemin i staden. Sjukdomen grasserade också bland de civila. Då sjukdomens orsak och utbredningssätt var okända, kunde man varken hindra epidemin från att spridas eller genomföra adekvata vårdmetoder. Tvärtom, med de hemförlovade båtsmännen spred sig sjukdomen även till de övriga delarna av riket. Under 1789 var flottan p.g.a. de många sjukdomsfallen närmast operationsoduglig. Under vårvintern och våren 1790 avtog epidemin. Epidemin var ett svårt medicinskt problem. För att utreda situationen i Karlskrona skickade den tillförordnade regeringen, utredningskommissionen och Collegium medicum sina egna representanter till staden. De olika läkarnas sjukdomssyner grundade sig främst på tron om sjukdomars uppkomst genom miasma och förbättrandet av luftkvaliteten sågs som en väsentlig vårdform. I arbetet jämförs de olika myndigheternas och några av de på platsen varande läkarnas syn på sjukdomens art, dess orsaker och ursprung. De flesta härleder sjukdomen till den ryska flottan, och nämner någon form av smitta. Som främsta sjukdomsorsak nämns dock miasma och de rekommenderade vårdformerna representerade den humoralpatologiska synen. Förste amiralitetsläkaren Arvid Faxe representerar dock en annan åsikt, i det att han enbart tror på sjukdomens överföring via smitta. Epidemin var också ett politiskt problem. Epidemin var en lokal angelägenhet ända till dess att flottans operationer hämmades av manskapsbristen, varefter den blev ett ärende på högsta nivå. Kungen ingrep sommaren 1789 genom att grunda en kommision med rätt vidsträckta befogenheter. I Karlskrona verkar de militära myndigheterna och läkarna ha misstrott och skuldsatt varandra för katastrofen, och förhållandet mellan de till staden sända utredarna och militärerna var likaså inflammerat. Genom källorna återspeglas rivalitet, avund och inbördes konkurrens. Personalbristen var svår, och den skyldiga söktes utanför den egna kretsen. Den danskfödde apotekaren med sina påstott otjänliga mediciner blev en ypperlig syndabock. Örlogsflottan beräknas i sjukdomar ha förlorat omkring 10.000 man i döda, huvudsakligen i Karlskrona (civila inberäknade). Armén och Skärgårdsflottan uppges likadeles ha mist omkring 10.000 man, medan antalet i strid stupade armésoldater endast var ca 1500. Sammanlagt antas alltså ca 20.000 människor ha mist livet; både i återfallsfeber, men även i andra, samtidigt grasserande farsoter. I denna siffra är inte de övriga delarna av riket inberäknade. Epidemin i fråga kan alltså på goda grunder anses vara det svenska 1700-talets största medicinska katastrof.

Molecular mechanisms of cancer predisposition in HNPCC/Lynch syndrome

Hereditary non-polyposis colorectal carcinoma (HNPCC; Lynch syndrome) is among the most common hereditary cancers in man and a model of cancers arising through deficient DNA mismatch repair (MMR). It is inherited in a dominant manner with predisposing germline mutations in the MMR genes, mainly MLH1, MSH2, MSH6 and PMS2. Both copies of the MMR gene need to be inactivated for cancer development. Since Lynch syndrome family members are born with one defective copy of one of the MMR genes in their germline, they only need to acquire a so called second hit to inactivate the MMR gene. Hence, they usually develop cancer at an early age. MMR gene inactivation leads to accumulation of mutations particularly in short repeat tracts, known as microsatellites, causing microsatellite instability (MSI). MSI is the hallmark of Lynch syndrome tumors, but is present in approximately 15% of sporadic tumors as well. There are several possible mechanisms of somatic inactivation (i.e. the second hit ) of MMR genes, for instance deletion of the wild-type copy, leading to loss of heterozygosity (LOH), methylation of promoter regions necessary for gene transcription, or mitotic recombination or gene conversion. In the Lynch syndrome tumors carrying germline mutations in the MMR gene, LOH was found to be the most frequent mechanism of somatic inactivation in the present study. We also studied MLH1/MSH2 deletion carriers and found that somatic mutations identical to the ones in the germline occurred frequently in colorectal cancers and were also present in extracolonic Lynch syndrome-associated tumors. Chromosome-specific marker analysis implied that gene conversion, rather than mitotic recombination or deletion of the respective gene locus accounted for wild-type inactivation. Lynch syndrome patients are predisposed to certain types of cancers, the most common ones being colorectal, endometrial and gastric cancer. Gastric cancer and uroepithelial tumors of bladder and ureter were observed to be true Lynch syndrome tumors with MMR deficiency as the driving force of tumorigenesis. Brain tumors and kidney carcinoma, on the other hand, were mostly MSS, implying the possibility of alternative routes of tumor development. These results present possible implications in clinical cancer surveillance. In about one-third of families suspected of Lynch syndrome, mutations in MMR genes are not found, and we therefore looked for alternative mechanisms of predisposition. According to our results, large genomic deletions, mainly in MSH2, and germline epimutations in MLH1, together explain a significant fraction of point mutation-negative families suspected of Lynch syndrome and are associated with characteristic clinical and family features. Our findings have important implications in the diagnosis and management of Lynch syndrome families.

Short- and long-term consequences of food resources on Ural owl Strix uralensis reproduction

Life-history theory states that although natural selection would favour a maximisation of both reproductive output and life-span, such a combination can not be achieved in any living organism. According to life-history theory the reason for the fact that not all traits can be maximised simultaneously is that different traits compete with each other for resources. These relationships between traits that constrain the simultaneous evolution of two or more traits are called trade-offs. Therefore, during different life-stages an individual needs to optimise its allocation of resources to life-history components such as growth, reproduction and survival. Resource limitation acts on these traits and therefore investment in one trait, e.g. reproduction, reduces the resources available for investment in another trait, e.g. residual reproduction or survival. In this thesis I study how food resources during different stages of the breeding event affect reproductive decisions in the Ural owl (Strix uralensis) and the consequences of these decisions on parents and offspring. The Ural owl is a suitable study species for such studies in natural populations since they are long-lived, site-tenacious, and feed on voles. The vole populations in Fennoscandia fluctuate in three- to four-year cycles, which create a variable food environment for the Ural owls to cope with. The thesis gives new insight in reproductive costs and their consequences in natural animal populations with emphasis on underlying physiological mechanisms. I found that supplementary fed Ural owl parents invest supplemented food resources during breeding in own self-maintenance instead of allocating those resources to offspring growth. This investment in own maintenance instead of improving current reproduction had carry-over effects to the following year in terms of increased reproductive output. Therefore, I found evidence that reduced reproductive costs improves future reproductive performance. Furthermore, I found evidence for the underlying mechanism behind this carry-over effect of supplementary food on fecundity. The supplementary-fed parents reduced their feeding investment in the offspring compared to controls, which enabled the fed female parents to invest the surplus resources in parasite resistance. Fed female parents had lower blood parasite loads than control females and this effect lasted until the following year when also reproductive output was increased. Hence, increased investment in parasite resistance when resources are plentiful has the potential to mediate positive carry-over effects on future reproduction. I further found that this carry-over effect was only present when potentials for future reproduction were good. The thesis also provides new knowledge on resource limitation on maternal effects. I found that increased resources prior to egg laying improve the condition and health of Ural owl females and enable them to allocate more resources to reproduction than control females. These additional resources are not allocated to increase the number of offspring, but instead to improve the quality of each offspring. Fed Ural owl females increased the size of their eggs and allocated more health improving immunological components into the eggs. Furthermore, the increased egg size had long-lasting effects on offspring growth, as offspring from larger eggs were heavier at fledging. Limiting resources can have different short- and long-term consequences on reproductive decisions that affect both offspring number and quality. In long-lived organisms, such as the Ural owl, it appears to be beneficial in terms of fitness to invest in long breeding life-span instead of additional investment in current reproduction. In Ural owls, females can influence the phenotypic quality of the offspring by transferring additional resources to the eggs that can have long-lasting effects on growth.

Molecular Alterations in Asbestos-Related Lung Cancer

Background: Asbestos is a well known cancer-causing mineral fibre, which has a synergistic effect on lung cancer risk in combination with tobacco smoking. Several in vitro and in vivo experiments have demonstrated that asbestos can evoke chromosomal damage and cause alterations as well as gene expression changes. Lung tumours, in general, have very complex karyotypes with several recurrently gained and lost chromosomal regions and this has made it difficult to identify specific molecular changes related primarily to asbestos exposure. The main aim of these studies has been to characterize asbestos-related lung cancer at a molecular level. Methods: Samples from asbestos-exposed and non-exposed lung cancer patients were studied using array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) to detect copy number alterations (CNA) as well as microsatellite analysis to detect allelic imbalance (AI). In addition, asbestos-exposed cell lines were studied using gene expression microarrays. Results: Eighteen chromosomal regions showing differential copy number in the lung tumours of asbestos-exposed patients compared to those of non-exposed patients were identified. The most significant differences were detected at 2p21-p16.3, 5q35.3, 9q33.3-q34.11, 9q34.13-q34.3, 11p15.5, 14q11.2 and 19p13.1-p13.3 (p<0.005). The alterations at 2p and 9q were validated and characterized in detail using AI and FISH analysis in a larger study population. Furthermore, in vitro studies were performed to examine the early gene expression changes induced by asbestos in three different lung cell lines. The results revealed specific asbestos-associated gene expression profiles and biological processes as well as chromosomal regions enriched with genes believed to contribute to the common asbestos-related responses in the cell lines. Interestingly, the most significant region enriched with asbestos-response genes was identified at 2p22, close to the previously identified region showing asbestos-related CNA in lung tumours. Additionally, in this thesis, the dysregulated biological processes (Gene Ontology terms) detected in the cell line experiment were compared to dysregulated processes identified in patient samples in a later study (Ruosaari et al., 2008a). Commonly affected processes such as those related to protein ubiquitination, ion transport and surprisingly sensory perception of smell were identified. Conclusions: The identification of specific CNA and dysregulated biological processes shed some light on the underlying genes acting as mediators in asbestos-related lung carcinogenesis. It is postulated that the combination of several asbestos-specific molecular alterations could be used to develop a diagnostic method for the identification of asbestos-related lung cancer.

Cystatin C, a measure of renal function, as prognostic risk marker in acute heart failure : Studies on the cardiorenal syndrome

Acute heart failure (AHF) is a complex syndrome associated with exceptionally high mortality. Still, characteristics and prognostic factors of contemporary AHF patients have been inadequately studied. Kidney function has emerged as a very powerful prognostic risk factor in cardiovascular disease. This is believed to be the consequence of an interaction between the heart and kidneys, also termed the cardiorenal syndrome, the mechanisms of which are not fully understood. Renal insufficiency is common in heart failure and of particular interest for predicting outcome in AHF. Cystatin C (CysC) is a marker of glomerular filtration rate with properties making it a prospective alternative to the currently used measure creatinine for assessment of renal function. The aim of this thesis is to characterize a representative cohort of patients hospitalized for AHF and to identify risk factors for poor outcome in AHF. In particular, the role of CysC as a marker of renal function is evaluated, including examination of the value of CysC as a predictor of mortality in AHF. The FINN-AKVA (Finnish Acute Heart Failure) study is a national prospective multicenter study conducted to investigate the clinical presentation, aetiology and treatment of, as well as concomitant diseases and outcome in, AHF. Patients hospitalized for AHF were enrolled in the FINN-AKVA study, and mortality was followed for 12 months. The mean age of patients with AHF is 75 years and they frequently have both cardiovascular and non-cardiovascular co-morbidities. The mortality after hospitalization for AHF is high, rising to 27% by 12 months. The present study shows that renal dysfunction is very common in AHF. CysC detects impaired renal function in forty percent of patients. Renal function, measured by CysC, is one of the strongest predictors of mortality independently of other prognostic risk markers, such as age, gender, co-morbidities and systolic blood pressure on admission. Moreover, in patients with normal creatinine values, elevated CysC is associated with a marked increase in mortality. Acute kidney injury, defined as an increase in CysC within 48 hours of hospital admission, occurs in a significant proportion of patients and is associated with increased short- and mid-term mortality. The results suggest that CysC can be used for risk stratification in AHF. Markers of inflammation are elevated both in heart failure and in chronic kidney disease, and inflammation is one of the mechanisms thought to mediate heart-kidney interactions in the cardiorenal syndrome. Inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) correlate very differently to markers of cardiac stress and renal function. In particular, TNF-α showed a robust correlation to CysC, but was not associated with levels of NT-proBNP, a marker of hemodynamic cardiac stress. Compared to CysC, the inflammatory markers were not strongly related to mortality in AHF. In conclusion, patients with AHF are elderly with multiple co-morbidities, and renal dysfunction is very common. CysC demonstrates good diagnostic properties both in identifying impaired renal function and acute kidney injury in patients with AHF. CysC, as a measure of renal function, is also a powerful prognostic marker in AHF. CysC shows promise as a marker for assessment of kidney function and risk stratification in patients hospitalized for AHF.

“And now to the rest of the trash…” Representations of begging Roma and an ideal society in two Nordic newspapers

Since begging East European Roma became a common view in the streets of larger Nordic cities, vivid discussions about their presence and activities have been carried out in the mass media. This thesis examines the public debates in Finland and Norway through a discursive analysis and comparison of press content from the two countries. The aim of the study is firstly to identify the prominent discourses which construct certain images of the beggars, as well as the elements and internal logics that these discourses are constructed around. But in addition to scrutinizing representations of the Roma, also an opposite perspective is applied. In accordance with the theoretical concept of ‘othering’, debates about ‘them’ are assumed to simultaneously reveal something significant about ‘us’. The second research question is thus what kind of images of the ideal Finnish and Norwegian societies are reflected in the data, and which societal values are salient in these images. The analysis comprises 79 texts printed in the main Finnish and Norwegian quality newspapers; Helsingin Sanomat and Aftenposten. The data consists of news articles, editorials, columns and letters to the editor from a three-month period in the summer of 2010. The analysis was carried out within the theoretical and methodological framework of critical discourse analysis as outlined by Norman Fairclough. A customized nine-step coding scheme was developed in order to reach the most central dimensions of the texts. Seven main discourses were identified; the Deprivation-solidarity, Human rights, Order, Crime, Space and majority reactions, Authority control, and Authority critique discourse. These were grouped into two competing normative stances on what an ideal society looks like; the exclusionary and the inclusionary stance. While the exclusionary stance places the begging Roma within a frame of crime, illegitimate use of public space and threat to the social order, the other advocates an attitude of solidarity and humanitarian values. The analysis points to a dominance of the former, although it is challenged by the latter. The Roma are “individualized” by quoting and/or presenting them by name in a fair part of the Finnish news articles. In Norway, the opposite is true; there the beggars are dominantly presented as anonymous and passive. Overall, the begging Roma are subjected to a double bind as they are faced with simultaneous expectations of activity and passivity. Theories relating to moral panics and ‘the good enemy’ provide for a deepened understanding of the intensity of the debates. Keywords: East European Roma, begging, media, newspapers, Helsingin Sanomat, Aftenposten, critical discourse analysis, Norman Fairclough, othering, ideal society, moral panics, good enemy, double bind, Finland, Norway

Hypertension, kardiotoxicitet och njursvikt i samband med tyrosinkinashämmaren sunitinib

Nybildning av blodkärl från tidigare existerande kärl, angiogenes, är ett väsentligt skede vid tumörtillväxt. Denna process regleras av bland annat tillväxtfaktorer, var av den vaskulära endoteliala tillväxtfaktorn har en central roll. Hämning av angiogenes kan ske antingen extracellulärt med hjälp av humaniserade monoklonala antikroppar eller intracellulärt med hjälp av småmolekylära hämmaren. Sunitinib är en småmolekylär multikinashämmare och inhiberar flera tyrosinkinasreceptorer som påverkar tumörtillväxten och metastasutvecklingen vid cancer. Sunitinibs främsta indikationer är gastrointestinala stromacellstumörer, metastaserad njurcellscancer och neuroendokrina tumörer i bukspottskörteln. Behandling med tyrosinkinashämmare orsakar biverkningar som hypertension, kardiotoxicitet och njursvikt, vilka antas bero på de hämmande effekterna på mål som inte är väsentliga för anti-cancer-aktiviteten (”off-target” biverkningar). Bland annat AMP-aktiverat proteinkinas (AMPK), ett kinas som upprätthåller metabolisk homeostas i hjärtat, inhiberas av sunitinib och antas framkalla kardiovaskulära biverkningar. För att reducera ”off-target” biverkningar strävar man till att hitta alternativ som minskar de skadliga effekterna utan att den terapeutiska aktiviteten försvagas. Bland annat ett begränsat kaloriintag har uppvisat skyddande effekt på hjärtat via mekanismer sammankopplade till ökad resistens mot oxidativ stress, inflammation och mitokondriell dysfunktion, samt avtagande apoptos och autofagi. Detta sker delvis genom aktivering av enzymet Sirt1. Syftet med den här studien var att undersöka ifall kaloribegränsning skyddar mot kardiovaskulära och renala biverkningar inducerade av sunitinib hos råttor. Dessutom studerades vilka signalkedjor i cellen som medverkar. I studien användes 40 spontant hypertensiva råttor samt 10 normotensiva Wistar-Kyoto råttor. Försöksdjuren delades in i fem grupper beroende på behandling; I WKY kontroll, II SHR kontroll, III SHR + kaloribegränsning 70 %, IV SHR + sunitinib 3 mg/kg och V SHR + sunitinib 3 mg/kg + kaloribegränsning 70 %. Behandlingsperioden var åtta veckor. Blodtrycket mättes varje vecka med svansmanchett, urinutsöndringen undersöktes vecka 4 och vecka 8 med metabolismburar, ultraljudsundersökning av hjärtat utfördes sista veckan och blodkärlens respons till acetylkolin och natriumnitroprussid studerades i samband med avlivning. Proteinerna Sirt1 och AMPK analyserades i hjärtat med Western blotting samt förekomsten av makrofagmarkören ED1 i njurarna med immunhistokemi. Studien visade att sunitinibdosen 3 mg/kg är mycket väl tolererbar hos råttor eftersom sunitinib inte orsakade högre blodtryck, kraftigare hypertrofi eller mer omfattande njurskada jämfört med obehandlade SHR- grupper. Utgående från resultaten kan man också konstatera att kaloribegränsningen har positiva kardiovaskulära effekter.

De "de" : Estudio histórico-comparativo de los usos y la semántica de la preposición "de" en español

El presente estudio supone un intento de describir y analizar el uso de la preposición "de" sobre la base de un corpus diacrónico, con énfasis en las diferentes relaciones semánticas que establece. Partiendo de un total de más de 16.000 casos de "de" hemos establecido 48 categorías de uso, que corresponden a cuatro tipos de construcción sintáctica, a saber, el uso de "de" como complemento de nombres (CN), verbos (CV), adjetivos (CA) y, finalmente, su uso como núcleo de expresiones adverbiales independientes (CI). El estudio consta de tres partes fundamentales. En la parte I, se introduce la Lingüística Cognitiva, que constituye la base teórica esencial del trabajo. Más exactamente, se introducen conceptos como la teoría del prototipo, la teoría de las metáforas conceptuales y la gramática cognitiva, especialmente las ideas de "punto de referencia" y "relación intrínseca" (Langacker 1995, 1999). La parte II incluye el análisis de las 48 categorías. En esta parte se presentan y comentan casi 2.000 ejemplos del uso contextual de "de" extraídos del corpus diacrónico. Los resultados más importantes del análisis pueden resumirse en los siguientes puntos: El uso de "de" sigue siendo esencialmente el mismo en la actualidad que hace 800 años, en el sentido de que todas las 48 categorías se identifican en todas las épocas del corpus. El uso de "de" como complemento nominal va aumentando, al contrario de lo que ocurre con su uso como complemento verbal. En el contexto nominal son especialmente las relaciones posesivas más abstractas las que se hacen más frecuentes, mientras que en el contexto verbal las relaciones que se hacen menos frecuentes son las de separación/alejamiento, causa, agente y partitivo indefinido. Destaca la importancia del siglo XVIII como época de transición entre un primer estado de las cosas y otro posterior, en especial en relación con el carácter cada vez más abstracto de las relaciones posesivas así como con la disminución de las categorías adverbales de causa, agente y partitivo. Pese a la variación en el contexto inmediato de uso, el núcleo semántico de "de" se mantiene inalterado. La parte III toma como punto de partida los resultados del análisis de la parte II, tratando de deslindar el aporte semántico de la preposición "de" a su contexto de uso del valor de la relación en conjunto. Así, recurriendo a la metodología para determinar el significado básico y la metodología para determinar lo que constituyen significados distintos de una preposición (Tyler , Evans 2003a, 2003b), se llega a la hipótesis de que "de" posee cuatro significados básicos, a saber, 'punto de partida', 'tema/asunto', 'parte/todo' y 'posesión'. Esta hipótesis, basada en las metodologías de Tyler y Evans y en los resultados del análisis de corpus, se intenta verificar empíricamente mediante el uso de dos cuestionarios destinados a averiguar hasta qué punto las distinciones semánticas a las que se llega por vía teórica son reconocidas por los hablantes nativos de la lengua (cf. Raukko 2003). El resultado conjunto de los dos acercamientos tanto refuerza como especifica la hipótesis. Los datos que arroja el análisis de los cuestionarios parecen reforzar la idea de que el núcleo semántico de "de" es complejo, constando de los cuatro valores mencionados. Sin embargo, cada uno de estos valores básicos constituye un prototipo local, en torno al cual se construye un complejo de matices semánticos derivados del prototipo. La idea final es que los hablantes son conscientes de los cuatro postulados valores básicos, pero que también distinguen matices más detallados, como son las ideas de 'causa', 'agente', 'instrumento', 'finalidad', 'cualidad', etc. Es decir, "de" constituye un elemento polisémico complejo cuya estructura semántica puede describirse como una semejanza de familia centrada en cuatro valores básicos en torno a los cuales se encuentra una serie de matices más específicos, que también constituyen valores propios de la preposición. Creemos, además, que esta caracterización semántica es válida para todas las épocas de la historia del español, con unas pequeñas modificaciones en el peso relativo de los distintos matices, lo cual está relacionado con la observada variación diacrónica en el uso de "de".