Coming theses from other universities
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Toxicological studies of di-n-butyl phthalate (DBP) : Impact on the reproductive system and gut microbiota
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-225853
The potential health impact of exposure to anthropogenic chemicals has raised major concerns worldwide. Phthalates are mainly used in the plastic industry and have been associated with adverse effects in humans. Di-n-butyl phthalate (DBP) is one of the dominant phthalates with a ubiquitous presence in the environment. While many studies have examined the endocrine disrupting properties of DBP, with a focus on developmental and reproductive dysfunctions, studies of its effects on the adult reproductive system and gut microbiota are limited. This thesis aimed to determine persistent effects of DBP on the adult male reproductive system, provide a high-throughput screening tool for identifying reproductive toxicants, and characterize the effects of DBP on the gut microbiota.
Paper I investigated if adult DBP exposure can induce persistent effects on the mature reproductive system. Adult male mice were orally exposed to 10 or 100 mg/kg/day for five weeks and testes were collected one week after the last dose. The results demonstrated a significant decrease in testosterone levels in the DBP-exposed groups. Mechanistically, the levels of steroidogenic enzymes, cell-specific markers and oxidative stress were increased. In paper II, elements of the in vivo testicular microenvironment, including functional testosterone production, were modeled using a three-dimensional (3D) heterogenous testicular cell co-culture derived from neonatal mice. Automated high-content imaging of cell-specific markers confirmed the presence of germ cells (DAZL+), Leydig cells (CYP11A1+), and Sertoli cells (SOX9+). DBP exposure decreased testosterone production, as well as levels of the steroidogenic enzyme CYP11A1, and the steroidogenic regulator StAR. Overall, this in vitro 3D model recapitulates the testicular pathways involved in DBP toxicity, making it a relevant tool for assessing reprotoxic effects of chemicals.
Paper III investigated the impact of oral DBP exposure on the gut microbiota and the potential interplay with immune and testicular toxicity using 16S rRNA sequencing. DBP-treated mice showed a distinct microbial composition and numerous differentially abundant amplicon sequence variants. Interestingly, the microbial alterations correlated with an increase in non-classical monocytes observed in DBP-exposed mice. In paper IV, a shotgun metagenomic analysis was conducted to achieve a more comprehensive characterization of the DBP-induced effects on gut microbiota composition and function. The DBP-exposed mice had a higher abundance of Adlercreutzia mucosicola, a bacterium linked with intestinal inflammation. In contrast, the beneficial Akkermansia muciniphila was less abundant in DBP-exposed mice. Functional analysis demonstrated that DBP exposure increased the abundance of genes involved in environmental sensing and antimicrobial resistance.
In conclusion, this doctoral thesis demonstrates the antiandrogenic effects of DBP as well as potential underlying mechanisms of testicular dysfunction in adult mice. In addition, we established a powerful in vitro tool for screening reprotoxic effects. The gut microbiota was also impaired by DBP exposure, which may play a potential role in initiating or exacerbating the DBP-induced toxicity. Overall, this work highlights the potential health impact of the interplay between the two exposome components, chemical exposure and gut microbiota.
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The community hospital model in northern Sweden
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-220351
Background: Rural community hospitals (CHs) are vital in delivering healthcare services in sparsely populated regions such as northern Sweden. In Sweden these facilities act as primary care units, staffed by general practitioners (GPs), nurses, and other healthcare professionals. They provide hospital beds, emergency care, and basic diagnostics. The CH model, with GPs responsible for hospital care has not been studied earlier in Sweden.
Aims: This thesis aimed to examine the role and practices of the Swedish rural CH model within the healthcare system and the local community. Furthermore, to investigate the perspectives of rural doctors in Sweden and New Zealand (NZ) working within their respective hospital models. Specific aims:
To characterise patients admitted to hospitals in Norrbotten and Västerbotten Regions and to compare hospitalisations at rural community hospitals and general hospitals (Study I)
To describe registered care measures carried out in rural community hospitals during episodes of hospital care for patients with heart failure, in comparison with a general hospital (Study II)
To explore rural hospital doctors’ experiences of providing care in rural hospitals in Southern New Zealand (Study III)
To explore rural general practitioners’ experiences of providing care in rural community hospitals in northern Sweden (Study IV)
Methods and results: Four original papers form the basis of this thesis. In study I, hospital register data from Norr- and Västerbotten Regions were analysed, focusing on hospital admissions of patients enrolled at CHs 2010-2014. We compared CH admissions with general hospital admissions, examining factors such as age, sex, and diagnoses. CH patients were older than those in general hospitals (median age 80 vs. 68 years), and women had a higher likelihood of admission to CHs compared to men. Common diagnoses in the elderly, such as heart failure and pneumonia were more likely admitted to CHs than to general hospitals. Study II utilized hospital register data from Region Västerbotten to describe registered care measures carried out in rural CHs during episodes of hospital care for patients with heart failure 2015-2019, in comparison with a general hospital. CHs showed documentations by fewer individual doctors, more frequent nursing documentation, and fewer blood tests compared to general hospitals. Radiology, including echocardiography, was performed in general hospitals only but in a minority of cases. Documentation by physiotherapists, occupational therapists, and dietitians was limited in both hospital models.
Studies III and IV involved interviews with rural hospital (RH) doctors in New Zealand (NZ), and rural GPs in northern Sweden, respectively, to explore the role of their RH/CH. In both countries, doctors emphasised advantages with proximity and holistic, patient-centred care for elderly, multimorbid, and end-of-life patients. Their RHs/CHs were described to play a central role in rural patients' healthcare journeys, utilizing small, multidisciplinary teams and collaborating with general hospitals and municipal caregivers. Reported challenges for doctors in RHs and CHs included limited resources and inexperience in handling life-threatening, rare cases, and ethical dilemmas unique to rural practice. Despite this, RH doctors considered RH patient safety similar or better than that in general hospitals. CH doctors prompted the idea of expanding the CH model to urban areas.
Conclusion: We conclude that CHs admit elderly and multimorbid patients elsewhere common in general hospitals. Care for patients with heart failure at CHs showed more nursing notes, greater doctor continuity, and less biomedical examinations. Our results suggest potential for further development in the multidisciplinary care in both hospital models. Rural generalist doctors in Sweden and NZ emphasise the central role of CHs/RHs, their proximity to patients, and their holistic, generalist approach, and they suggest advantages in the RH/CH care for the elderly compared to general hospitals. In Sweden, the importance of relational continuity was stressed, as rural GPs are familiar with their CH patients from primary care.
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Autoantibodies in healthy blood donors, rheumatic and autoimmune liver diseases
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-200649
Autoimmunity is a common phenomenon where the immune system recognises the body's own tissues. Autoimmunity can lead to disease if tissue damage occurs. Autoimmune diseases affect 5–10% of the global population and in many of these autoantibodies can be detected. The autoantibodies can be detected with several different methods. In this thesis, line immunoassays and fluorescence enzyme immunoassay were used to investigate the presence of autoantibodies in blood donors and various disease groups. Line immunoassays use strips while fluorescence enzyme immunoassay uses wells. The strips and wells are coated with proteins that are allowed to react with serum samples from the patient. In the presence of autoantibodies, either a color change (line immunoassay) or a light reaction (fluorescence enzyme immunoassay) occurs.
Study I and II: With the EuroLine -Autoimmune Liver Diseases- (IgG) line immunoassay, the presence of autoantibodies associated with autoimmune liver diseases was analysed in blood donors, patients with autoimmune liver diseases and patients with SLE. Autoantibodies could be detected in several blood donors. A very rare autoantibody, anti-LC- 1, was more common in blood donors than in patients with autoimmune liver diseases. Despite the presence of the autoantibodies, no association was seen with abnormal liver values in blood donors or patients with SLE. By raising the cut-off, the number of "false positive" results decreased. However, this could not correct the problem with anti-LC-1, which seems to indicate that there is a problem with the LC-1 antigen so that non-specific reactions are detected. The risk of developing autoimmune liver disease was considered to be low in the SLE patients, as none of these patients developed autoimmune liver disease despite several years of follow-up. Most of the positive findings with the EuroLine immunoassay could not be confirmed with other methods, indicating that this method is very sensitive.
Study III: With the EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) line immunoassay, the rare autoantibodies anti-Th/To and anti-NOR90 could be detected as frequently in blood donors as in patients with systemic sclerosis. Most of the other autoantibodies were more common in patients with systemic sclerosis compared to blood donors and other disease groups. Some of these autoantibodies were associated with specific clinical manifestations, including renal involvement in patients with SLE. These findings need to be verified.
Study IV: Autoantibodies that bind the U1-RNP protein (anti-U1-RNP) can be detected in patients with SLE. Patients with anti-U1-RNP can be further analysed for the presence of autoantibodies against the protein RNP 70kDa (anti-RNP70). However, the clinical value of further analysis of anti-RNP70 is uncertain. In this study, fluorescence enzyme immunoassay was used to analyse anti-U1-RNP positive samples for anti-RNP70 to evaluate whether it added anything of clinical value in SLE patients. Presence of anti-U1-RNP was associated with low white blood cell counts and less organ damage. However, analysis of anti-RNP70 in patients with SLE did not add any additional clinical information.
Conclusion: Euroline -Autoimmune Liver Diseases- (IgG) and EuroLine Systemic Sclerosis (Nucleoli) Profile (IgG) are tools that are of value in the diagnosis of autoimmune liver diseases and systemic sclerosis, but the methods have high sensitivity which can lead to false positive results. By raising the cut-off, the risk of this can be reduced. Some rare antibodies were found more frequently in blood donors than in patients with the different disease groups, suggesting potential problems with the antigen source. Subtyping of anti-RNP70 in SLE patients with anti-U1-RNP did not add anything of clinical value.