| 1. |
- Abdel-Khalik, Jonas, et al.
(author)
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Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
- 2021
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In: The Journal of steroid biochemistry and molecular biology. - : Elsevier BV. - 1879-1220 .- 0960-0760. ; 206
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Journal article (peer-reviewed)abstract
- Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography - mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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| 2. |
- De Bus, Liesbet, et al.
(author)
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Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure : the DIANA study
- 2020
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In: Intensive Care Medicine. - : Springer Science and Business Media LLC. - 0342-4642 .- 1432-1238. ; 46:7, s. 1404-1417
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Journal article (peer-reviewed)abstract
- PURPOSE: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation.METHODS: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure.RESULTS: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60-1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14-1.64).CONCLUSION: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely.
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| 3. |
- Drake, Henrik, et al.
(author)
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Extreme C-13 depletion of carbonates formed during oxidation of biogenic methane in fractured granite
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Precipitation of exceptionally C-13-depleted authigenic carbonate is a result of, and thus a tracer for, sulphate-dependent anaerobic methane oxidation, particularly in marine sediments. Although these carbonates typically are less depleted in C-13 than in the source methane, because of incorporation of C also from other sources, they are far more depleted in C-13 (delta C-13 as light as - 69% V-PDB) than in carbonates formed where no methane is involved. Here we show that oxidation of biogenic methane in carbon-poor deep groundwater in fractured granitoid rocks has resulted in fracture-wall precipitation of the most extremely C-13-depleted carbonates ever reported, delta C-13 down to - 125% V-PDB. A microbial consortium of sulphate reducers and methane oxidizers has been involved, as revealed by biomarker signatures in the carbonates and S-isotope compositions of co-genetic sulphide. Methane formed at shallow depths has been oxidized at several hundred metres depth at the transition to a deep-seated sulphate-rich saline water. This process is so far an unrecognized terrestrial sink of methane.
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| 4. |
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| 5. |
- Nemlander, Elinor, et al.
(author)
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Validation of a diagnostic prediction tool for colorectal cancer : a case–control replication study
- 2023
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In: Family Practice. - : Oxford University Press. - 0263-2136 .- 1460-2229.
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Journal article (peer-reviewed)abstract
- BackgroundEarly detection of colorectal cancer (CRC) is crucial for survival. Primary care, the first point of contact in most cases, needs supportive risk assessment tools. We aimed to replicate the Swedish Colorectal Cancer Risk Assessment Tool (SCCRAT) for non-metastatic CRC in primary care and examine if risk factor patterns depend on sex and age.Methods2,920 adults diagnosed with non-metastatic CRC during the years 2015–2019 after having visited a general practitioner the year before the diagnosis were selected from the Swedish Cancer Register and matched with 11,628 controls, using the same inclusion criteria except for the CRC diagnosis. Diagnostic codes from primary care consultations were collected from a regional health care database. Positive predictive values (PPVs) were estimated for the same 5 symptoms and combinations thereof as in the baseline study.ResultsThe results for patients aged ≥50 years old in the present study were consistent with the results of the SCCRAT study. All symptoms and combinations thereof with a PPV >5% in the present study had a PPV >5% in the baseline study. The combination of bleeding with abdominal pain (PPV 9.9%) and bleeding with change in bowel habit (PPV 7.8%) were the highest observed PPVs in both studies. Similar risk patterns were seen for all ages and when men and women were studied separately.ConclusionThis external validation of the SCCRAT for non-metastatic CRC in primary care replicated the baseline study successfully and identified patients at high risk for CRC.
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| 6. |
- Robertson, Stephanie, et al.
(author)
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Waiting times for cancer patients in Sweden : A nationwide population-based study
- 2017
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In: Scandinavian Journal of Public Health. - : SAGE PUBLICATIONS LTD. - 1403-4948 .- 1651-1905. ; 45:3, s. 230-237
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Journal article (peer-reviewed)abstract
- Aims: The reported long waiting times for cancer patients have mostly been related to prognostic outcome and less to patient-related experience to outcome. We assessed waiting times for patients with cancer of the breast, prostate, colon or rectum in Sweden.Methods: The median time from referral to start of treatment was assessed using data from clinical cancer registers for patients who received curative treatment during 2011, 2012 and 2013.Results: The median overall waiting time in different counties ranged from 7 to 28 days for breast cancer, from 117 to 280 days for prostate cancer, from 27 to 64 days for colon cancer and from 48 to 80 days for rectal cancer. For the entire nation, the median time from referral to start of treatment remained unchanged from 2011 to 2013 for each cancer diagnosis.Conclusions: Large variations were found in waiting times between different counties in Sweden and between different types of cancer. The long waiting times identified in this study emphasize the need to improve national programmes for more rapid diagnosis and treatment.
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| 7. |
- Rossmeisl, Martin, et al.
(author)
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Metabolic effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: Possible role of endocannabinoids
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7
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Journal article (peer-reviewed)abstract
- Background: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. Methodology/Principal Findings: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ~35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. Conclusions/Significance: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT. © 2012 Rossmeisl et al.
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| 8. |
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| 9. |
- Siljeström, Sandra, et al.
(author)
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Detection of organic biomarkers in crude oils using ToF-SIMS
- 2009
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In: Organic Geochemistry. - : Elsevier BV. - 0146-6380 .- 1873-5290. ; 40:1, s. 135-143
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Journal article (peer-reviewed)abstract
- In this study, we show that time of flight-secondary ion mass spectrometry (ToF-SIMS) can be used todetect organic biomarkers, such as hopanes and steranes, in non-fractionated crude oils, without extractionand chemical preparation. Hopanes and steranes may provide valuable information on the history oflife on early Earth, particularly if they are present in fluid inclusions in ancient rocks. Due to the presenceof different generations of inclusions in even very small rock samples, it would be advantageous to find amethod capable of detecting biomarkers in single oil rich fluid inclusions. The capability of ToF-SIMS fordetailed chemical analysis of very small sample amounts makes it a potential technique for such analysis,and in this work this possibility is explored. The presence of hopanes and steranes in four different crudeoils of different ages and stages of biodegradation was investigated using ToF-SIMS and GC–MS. By combininganalyses of biomarker standards, crude oils and chromatographic oil fractions, specific peaks forthe different biomarkers were identified in the ToF-SIMS spectra. The presence of these peaks in the spectrafrom the crude oil samples could be attributed to the biomarkers based on exact mass determinationand by comparison with the spectra from the biomarker containing and biomarker lacking fractions,respectively. In addition, the results show that a significant biomarker signal may be obtained from a 10 µm2 oil sample, demonstrating the potential of ToF-SIMS for analysis of single oil bearing fluid inclusions,which in turn may contribute to a better understanding of the early history of life on Earth.
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| 10. |
- Sjövall, Peter, et al.
(author)
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Detection of organic biomarkers in crude oils using ToF-SIMS
- 2009
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In: Organic Geochemistry. ; 40, s. 135-143
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Journal article (peer-reviewed)abstract
- In this study, we show that time of flight-secondary ion mass spectrometry (ToF-SIMS) can be used to detect organic biomarkers, such as hopanes and steranes, in non-fractionated crude oils, without extraction and chemical preparation. Hopanes and steranes may provide valuable information on the history of life on early Earth, particularly if they are present in fluid inclusions in ancient rocks. Due to the presence of different generations of inclusions in even very small rock samples, it would be advantageous to find a method capable of detecting biomarkers in single oil rich fluid inclusions. The capability of ToF-SIMS for detailed chemical analysis of very small sample amounts makes it a potential technique for such analysis, and in this work this possibility is explored.
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