Nutrient regulation of energy metabolism in relation to obesity and type 2 diabetes

Over the past decades many western countries have witnessed an epidemic rise in obesity, insulin resistance and type 2 diabetes. There clearly is a link between increased fat storage and decreased insulin sensitivity leading to type 2 diabetes, but the mechanistic explanations have been difficult to pinpoint biochemically and genetically. In this thesis we have observed that there likely are differences in the way skeletal muscle myotubes, derived from type 2 diabetic or healthy controls metabolize fatty acids and respond towards various lipids. We have observed that T2D myotubes on average have a reduced capacity for mitochondrial fatty acids oxidation as compared to myotubes derived from healthy donors. During periods of high fatty acid load, this difference in oxidative capacity may either result in ectopic storage of intramyocellular triacylglycerols imTAG or an increased level of fatty acid metabolic intermediates that may further interfere with insulin signaling. Preincubation of myotubes with eicosapentaenoic acid (EPA) resulted in enhanced fatty acid uptake and storage of imTAG, but also reduced levels of total intracellular acyl-CoA with improved glucose oxidation and unchanged insulin mediated glucose uptake. Preincubetion with the sulfur modified fatty acid analogue tetradecylthioacetic acid (TTA) improved mitochondrial fatty acid oxidation in both T2D and control myotubes, and may thus help alleviate this metabolic difference in T2D. TTA given as a supplement to rodents fed a high fat diet for 7 weeks resulted in 40% reduced weight gain and similar marked reductions in white adipose tissue mass. TTA has previously been shown to activate all peroxisomal proliferator activated receptors (PPARs), and the reduced weight gain possibly resulted because of hepatic PPARα activation, increasing energy expenditure through some unknown mechanism likely involving ectopic uncoupling protein 3 (ucp3) expression

Giardiasis in Bergen. Outbreak and clinical consequences.

Background Giardia lamblia is a common cause of waterborne disease. It is endemic in many parts of the world, especially where sanitation is poor, but in Europe and North America it is most often encountered in outbreaks following contamination of drinking water. The first registered outbreak of giardiasis affecting a large community in Norway happened in Bergen in the autumn of 2004. The reservoir “Svartediket” was the source, and the water probably held Giardia cysts for several weeks. Giardia can cause acute and chronic gastroenteritis. Several drugs constitute effective treatment, and metronidazole is the main drug available in Norway. Prior to the outbreak in Bergen there were no published studies on long term effects after eradication of the parasite. Aims The aim of the studies in this thesis is to investigate the course of giardiasis and its consequences following a large outbreak in an area where Giardia is not endemic. Methods In the first study, we concentrated on patients from general practice. Patients with clinically defined giardiasis were identified through a search in the medical records at two general practice clinics located in the area receiving water from the contaminated reservoir. Of the 7,100 persons registered, 134 fulfilled the inclusion criteria and 119 consented to take part in the study. Data were retrospectively obtained from the medical records. The patients were then requested to complete a mailed questionnaire and submit stool samples six months after the outbreak. A second questionnaire was sent out one year after the outbreak. The main outcome variable was abdominal symptoms that were not present prior to the acute infection. In the second study, we investigated a historic cohort of 1252 patients with giardiasis verified by detection of Giardia in stool samples submitted as part of regular clinical investigations in Bergen during the outbreak. A 2:1 control group matched by age and gender was recruited from the general population of Bergen. This group was later expanded so that the whole control group consisted of 3594 individuals. All participants received a questionnaire by mail three years after the outbreak. Main outcome variables were irritable bowel syndrome (IBS) according to Rome III criteria and “chronic fatigue” as defined by the Fatigue Questionnaire. Results In the group of patients from general practice the majority was between 20 and 39 years of age (51.4%), and there were more women (69.3%) than men. The diagnosis was supported by a positive test for Giardia lamblia in 55% (66/119) of the patients. Treatment with metronidazole was given to 89 (75%), and after initial treatment 36% (32/89) returned to their doctor because symptoms recurred. A second prescription was given to 28% (25/89), after which 16% (14/89) returned once more. 11% (10/89) received a third treatment with metronidazole. Six months after the outbreak stool samples were positive for Giardia in three of 82 patients. At this point 37% (44/118) reported gastrointestinal symptoms related to their Giardia-infection, and after 12 months this proportion was 19% (19/99). In the cohort of patients with laboratory verified giardiasis the prevalence of IBS three years after the outbreak was 46% (355/770), compared to 14% in the control group. The adjusted relative risk (RR) was 3.4 (95% confidence interval (CI) 2.9 to 3.8). The prevalence of chronic fatigue was 46% (366/794) among the Giardiapatients, and 12% among the controls, giving an adjusted RR of 4.0 (95% CI 3.5 to 4.5). IBS and chronic fatigue were associated, but there was also an increased risk of having IBS only (RR 1.8, 95% CI 1.4 to 2.3) or chronic fatigue only (RR 2.2, 95% CI 1.7 to 2.8). Discussion In the study from general practice we identified patients that would have been missed by a strict laboratory based inclusion criterion, either because stool samples were not submitted or due do misclassification when samples were negative. Several patients did not receive treatment and this could suggest that they did not have giardiasis, but another reason could be that they called at the medical centre before the outbreak was known and recovered spontaneously without treatment. After clearance of the parasite a substantial proportion of the patients had persisting symptoms 6 and 12 months after the outbreak, which shows that potential negative health effects of giardiasis was more extensive than first anticipated. In the cohort of persons with verified giardiasis the infection was associated with a high prevalence of IBS and chronic fatigue three years after the outbreak, and the risk was significantly higher than in the control group. This supports the findings in the group from general practice, and shows the consequences in a larger population and over a longer period of time. The prevalence of IBS in this study and gastrointestinal symptoms in the first one differs, but cannot be easily compared. The sample sizes vary, the case definitions are different and the questionnaires used to define the outcomes are not the same. Put together the two studies illustrate a wider range of the clinical consequences after the outbreak. Conclusions These studies show that a considerable proportion of patients consistently had persisting symptoms after giardiasis from the time of the acute infection and up to three years after. The association between acute giardiasis and later gastrointestinal symptoms and fatigue is strong. This calls for more research on the mechanisms for both giardiasis and medically unexplained physical symptoms like IBS and chronic fatigue

Consultations for gastroenteritis in general practice and out-of-hours services in Norway 2006–15

Background: Most of the patients with gastroenteritis seeking health care services are managed in primary care; yet, little is known about these consultations. Syndromic-based surveillance of gastrointestinal infections is used in several countries, including Norway. Aim: To investigate the extent of, and explore characteristics associated with, consultations for gastroenteritis in primary care and to compare consultations in daytime general practice and out-of-hours (OOH) services in Norway. Design and Setting: Registry-based study using reimbursement claims data from all consultations in general practice and OOH services in Norway over the 10-year period, 2006–15. Methods: The main outcome variable was whether the consultation took place in general practice or OOH services. Possible associations with patient age and sex, time and use of point-of-care C-reactive protein (CRP) testing and sickness certificate issuing were investigated. Results: Gastroenteritis consultations (n = 1 281 048) represented 0.9% of all consultations in primary care (n = 140 199 637), of which 84.4% were conducted in general practice and 15.6% in OOH services. Young children and young adults dominated among the patients. Point-of-care CRP testing was used in 36.1% of the consultations. Sickness certificates were issued in 43.6% of consultations with patients in working age. Age-specific time variations in consultation frequencies peaking in winter months were observed. Conclusions: The proportion of gastroenteritis consultations was higher in the OOH services when compared with daytime general practice. Young children and young adults dominated among the patients. The seasonal variation in consultation frequency is similar to that shown for gastroenteritis caused by norovirus.publishedVersio

Sr and Nd isotope data for arc-related (meta) volcanics (SW Iberia)

In the southern sector of the Ossa-Morena Zone (Iberian Variscan Chain), along its boundaries with the Beja-Acebuches Ophiolite and the South-Portuguese Zone, Upper Palaeozoic igneous mafic and intermediate rocks, both intrusive and extrusive, are widely represented. The so-called Odivelas Unit (Andrade,1983), include (meta-) basalts and (meta-) andesites, which, according with previous studies, display low-K tholeiitic to calc-alkaline signatures and, therefore, are interpreted as remnants of an active margin volcanic arc. Santos et al. (1990) subdivided those volcanics into two groups: in Alfundão-Peroguarda, the tholeiitic nature is dominant; in Odivelas-Penique, the calc-alkaline signature becomes more pronounced. Intercalation of limestone layers provided some age constraints, showing that the subduction-related volcanic activity in the studied area began in the Lower Devonian and continued, at least, through the Middle Devonian (Conde & Andrade, 1974; Machado et al., 2010). In this work, samples previously studied by Santos et al. (1990) and Silva et al. (2011) were analysed for Sm-Nd and Rb-Sr isotopes. Considering that the volcanics were systematically affected by hydrothermal metamorphism, it is expected that the Sr signatures show significant disturbance. In contrast, Nd isotope ratios probably reflect the primary features. Alfundão-Peroguarda samples show a very limited range of positive initial εNd, from +5.1 to +4.3 (assuming 400 Ma), showing no evidence for significant crustal assimilation and, therefore, allowing the attribution of negative Nb and Ta anomalies to arc-related processes On the other hand, 87Sr/86Sr varies from 0.7044 to 0.7060 (for 400Ma). These samples rocks define a horizontal trend on the initial εNd vs. initial 87Sr/86Sr plot, typical of co-genetic rocks that underwent interaction with seawater. On the other hand, Odivelas-Penique volcanics show wide spectra for both initial 87Sr/86Sr (from 0.7038 to 0.7066) and εNd (from +4.6 to -4.1). Significantly, the highest εNd values for this group are within the narrow range defined by Alfundão-Peroguarda tholeiitic basalts, suggesting a common mantle source (or very similar sources) for the most mafic magmas of both sectors. The whole set of Nd isotope ratios supports the distinction previously proposed between the two groups of volcanics. In addition, the variation from positive to negative initial εNd values in the Odivelas-Penique suite shows that its geochemical features were likely influenced by assimilation of continental crustal material

Risk of miscarriage in women with chronic diseases in Norway:A registry linkage study

BACKGROUND: Increased risk of miscarriage has been reported for women with specific chronic health conditions. A broader investigation of chronic diseases and miscarriage risk may uncover patterns across categories of illness. The objective of this study was to study the risk of miscarriage according to various preexisting chronic diseases. METHODS AND FINDINGS: We conducted a registry-based study. Registered pregnancies (n = 593,009) in Norway between 2010 and 2016 were identified through 3 national health registries (birth register, general practitioner data, and patient registries). Six broad categories of illness were identified, comprising 25 chronic diseases defined by diagnostic codes used in general practitioner and patient registries. We required that the diseases were diagnosed before the pregnancy of interest. Miscarriage risk according to underlying chronic diseases was estimated as odds ratios (ORs) using generalized estimating equations adjusting for woman’s age. The mean age of women at the start of pregnancy was 29.7 years (SD 5.6 years). We observed an increased risk of miscarriage among women with cardiometabolic diseases (OR 1.25, 95% CI 1.20 to 1.31; p-value <0.001). Within this category, risks were elevated for all conditions: atherosclerosis (2.22; 1.42 to 3.49; p-value <0.001), hypertensive disorders (1.19; 1.13 to 1.26; p-value <0.001), and type 2 diabetes (1.38; 1.26 to 1.51; p-value <0.001). Among other categories of disease, risks were elevated for hypoparathyroidism (2.58; 1.35 to 4.92; p-value 0.004), Cushing syndrome (1.97; 1.06 to 3.65; p-value 0.03), Crohn’s disease (OR 1.31; 95% CI: 1.18 to 1.45; p-value 0.001), and endometriosis (1.22; 1.15 to 1.29; p-value <0.001). Findings were largely unchanged after mutual adjustment. Limitations of this study include our inability to adjust for measures of socioeconomic position or lifestyle characteristics, in addition to the rareness of some of the conditions providing limited power. CONCLUSIONS: In this registry study, we found that, although risk of miscarriage was largely unaffected by maternal chronic diseases, risk of miscarriage was associated with conditions related to cardiometabolic health. This finding is consistent with emerging evidence linking cardiovascular risk factors to pregnancy complications

Serum-borne factors in cancer patients with advanced cachexia: influence on adipose cells

Background: The clinical syndrome cancer cachexia is recognized by a considerable weight loss being out of proportion to any reduction in energy intake. The underlying mechanisms are not completely known, but the marked weight loss is attributable to depletion of adipose tissue as well as skeletal muscle mass. Enhanced lipolysis in adipocytes, apoptosis of preadipocytes may be important for loss of adipose tissue.Results: Sera from cachectic cancer patients induced apoptosis in cultured human preadipocytes at a higher rate than sera from non-cachectic cancer patients (control group). There was a tendency towards increased mRNA levels of the pro-apoptotic Bcl-2 gene Bax after incubation of preadipocytes with cachectic sera. Moreover, the mRNA levels of anti-apoptotic Bcl-XL and pro-apoptotic Bcl-XS were increased and decreased, respectively, as compared to incubation with control sera. However, lipolysis was not enhanced in cultured human adipocytes after incubation with sera from cachectic cancer patients as compared to non-cachectic cancer patients.Methods: Serum samples from cachectic cancer patients (n=8) and non-cachectic cancer patients (n=6) were collected. Human SGBS (Simpson-Golabi-Behmel syndrome) preadipocytes and differentiated adipocytes were incubated in the presence of serum from cachectic and non-cachectic (control) cancer patients. Induction of apoptosis and necrosis was examined by cell staining with Hoechst 342 (HO342) and propidium iodide (PI), respectively. Expression of pro- and anti-apoptotic Bcl-2 genes was measured by quantitative RT-PCR. Lipolysis was monitored by measuring the release of radiolabeled fatty acids.Conclusion: Our in vitro data suggest that apoptosis of preadipocytes can be increased by serum-borne factors in cancer cachexia. Death or survival of preadipocytes may depend on the balance of pro- and anti-apoptotic mediators. Further studies of patients with cancer cachexia will be needed to reveal if the disease involves loss of adipose tissue due to apoptosis of preadipocytes. We could not show that serum-borne factors associated with cachexia have a major impact on lipolysis in cultured human adipocytes.Adipobiology 2009; 1: 57-66

Clinical features of gastroenteritis during a large waterborne Campylobacter outbreak in Askøy, Norway

Purpose: Outbreaks of Campylobacter infection are common, but studies exploring the clinical features of acute illness in the outbreak setting are scarce in existing literature. The main purpose of the present study was to investigate the clinical features of self-reported acute illness in gastroenteritis cases during a large waterborne Campylobacter outbreak in Askøy municipality, Norway, in 2019. Methods: A web-based self-administered questionnaire, and invitation to participate was sent by the municipality of Askøy as text message to mobile phones using the municipality’s warning system to the inhabitants during the ongoing outbreak. Results. Out of 3624 participants, 749 (20.7%) were defined as cases, of which 177 (23.6%) reported severe gastroenteritis. The most common symptoms were loose stools (90.7%), abdominal pain (89.3%) and diarrhea (88.9%), whereas 63.8% reported fever, 50.2% joint pain and 14.2% bloody stools. Tiredness, a symptom non-specific to gastroenteritis, was the overall most common symptom (91.2%). Conclusion: About one in four of the cases reported symptoms consistent with severe gastroenteritis. We found more joint pain and less bloody stools than reported in published studies of laboratory confirmed campylobacteriosis cases. Tiredness was common in the current study, although rarely described in previous literature of acute illness in the outbreak setting.publishedVersio

Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: A controlled prospective cohort study

Objectives To investigate whether acute infection with Giardia lamblia is associated with fibromyalgia 10 years after infection and whether fibromyalgia is associated with irritable bowel syndrome (IBS) and chronic fatigue (CF) in this setting. Methods A cohort study was established after an outbreak of G. lamblia in Bergen, Norway, 2004. Laboratory-confirmed cases and a matched control group were followed for 10 years. The main outcome was fibromyalgia 10 years after giardiasis, defined by the 2016 revisions of the fibromyalgia diagnostic criteria using the Fibromyalgia Survey Questionnaire (FSQ). Results The prevalence of fibromyalgia was 8.6% (49/572) among Giardia exposed compared to 3.1% (21/673) in controls (p<0.001). Unadjusted odds for having fibromyalgia was higher for Giardia exposed compared to controls (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.72, 4.91), but adjusted for IBS and CF it was not (OR: 1.05, 95% CI: 0.57, 1.95). Among participants without CF the odds for fibromyalgia was 6.27 times higher for participants with IBS than those without (95% CI: 3.31, 11.91) regardless of exposure. Among participants without IBS the odds for fibromyalgia was 4.80 times higher for those with CF than those without (95% CI: 2.75, 8.37). Conclusions We found a higher prevalence of fibromyalgia among Giardia exposed compared to controls 10 years after the acute infection. Fibromyalgia was strongly associated with IBS and CF, and the difference between the exposed and controls can be attributed to the high prevalence of IBS and CF among the Giardia exposed. Notably, this study was not designed to establish causality between Giardia exposure and the outcomes.publishedVersio

Consultations and antibiotic treatment for urinary tract infections in Norwegian primary care 2006–2015, a registry-based study

Background Extensive use of antibiotics and the resulting emergence of antimicrobial resistance is a major health concern globally. In Norway, 82% of antibiotics is prescribed in primary care and one in four prescriptions are issued for the treatment of urinary tract infections (UTI). The aim of this study was to investigate time trends in antibiotic treatment following a consultation for UTI in primary care. Methods For the period 2006–2015 we linked data from the Norwegian Registry for Control and Payment of Health Reimbursements on all patient consultations for cystitis and pyelonephritis in general practice and out-of-hours (OOH) services, and data from the Norwegian Prescription Database on all dispensed prescriptions of antibiotics. Results Altogether 2,426,643 consultations by attendance for UTI took place in the study period, of these 94.5% for cystitis and 5.5% for pyelonephritis. Of all UTI consultations, 79.4% were conducted in general practice and 20.6% in OOH services. From 2006 to 2015, annual numbers of cystitis and pyelonephritis consultations increased by 33.9 and 14.0%, respectively. The proportion of UTI consultations resulting in an antibiotic prescription increased from 36.6 to 65.7% for cystitis, and from 35.3 to 50.7% for pyelonephritis. These observed changes occurred gradually over the years. Cystitis was mainly treated with pivmecillinam (53.9%), followed by trimethoprim (20.8%). For pyelonephritis, pivmecillinam was most frequently used (43.0%), followed by ciprofloxacin (20.5%) and sulfamethoxazole-trimethoprim (16.3%). For cystitis, the use of pivmecillinam increased the most during the study period (from 46.1 to 56.6%), and for pyelonephritis, the use of sulfamethoxazole-trimethoprim (from 11.4 to 25.5%) followed by ciprofloxacin (from 18.2 to 23.1%). Conclusions During the 10-year study period there was a considerable increase in the proportion of UTI consultations resulting in antibiotic treatment. Cystitis was most often treated with pivmecillinam, and this proportion increased during the study period. Treatment of pyelonephritis was characterized by more use of broader-spectrum antibiotics, use of both sulfamethoxazole-trimethoprim and ciprofloxacin increased during the study period. These trends, indicative of enduring changes in consultation and treatment patterns for UTIs, will have implications for future antibiotic stewardship measures and policy.publishedVersio

Antibiotics for gastroenteritis in general practice and out-of-hours services in Norway 2006-15

Background When patients with gastroenteritis (GE) seek health care, they are generally managed in primary care. Little is known about the use of antibiotic treatment in these cases. Objective The aim of this study was to investigate time trends and patient characteristics associated with antibiotic treatment for GE in Norwegian primary care in a 10-year period. Methods We linked data from two nationwide registries, reimbursement claims data from Norwegian primary care (the KUHR database) and The Norwegian Prescription Database, for the period 2006–15. GE consultations were extracted, and courses of systemic antibiotics dispensed within 1 day were included for further analyses. Results Antibiotic treatment was linked to 1.8% (n = 23 663) of the 1 279 867 consultations for GE in Norwegian primary care in the period 2006–15. The proportion of GE consultations with antibiotic treatment increased from 1.4% in 2006 to 2.2% in 2012 and then decreased to 1.8% in 2015. Fluoroquinolones (28.9%) and metronidazole (26.8%) were most frequently used. Whereas the number of fluoroquinolones courses decreased after 2012, the number of metronidazole courses continued to increase until year 2015. The antibiotic treatment proportion of GE consultations was lowest in young children and increased with increasing age. Conclusion Antibiotic treatment is infrequently used in GE consultations in Norwegian primary care. Although there was an overall increase in use during the study period, we observed a reduction in overall use after year 2012. Young children were treated with antibiotics in GE consultations less frequent than older patients.publishedVersio