| 1. |
- McCrae, Cristopher, et al.
(författare)
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INEXAS: A Phase 2 Randomized Trial of On-demand Inhaled Interferon Beta-1a in Severe Asthmatics
- 2021
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 51:2, s. 273-283
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Tidskriftsartikel (refereegranskat)abstract
- Background: Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti-viral cytokine, interferon (IFN)-β, during URTI, could prevent these exacerbations. Objective: To evaluate the efficacy of on-demand inhaled IFN-β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI. Methods: This was a randomized, double-blind, placebo-controlled trial in which patients with severe asthma (GINA 4-5; n=121) reporting URTI symptoms were randomized to 14days of once-daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6-item asthma control questionnaire (ACQ-6) and lung function. Exploratory biomarkers included IFN-response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines. Results: Following a pre-planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ-6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3×109/L) at screening and low serum interleukin-18 relative change at pre-treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN-response markers. Conclusions & Clinical Relevance: Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On-demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI-induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin-18 response are potential subgroups for further investigation of inhaled IFN-β1a. @2020 AstraZeneca. International Journal of Cosmetic Science published by John Wiley & Sons
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| 2. |
- Galili, Nir, et al.
(författare)
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The geologic history of seawater oxygen isotopes from marine iron oxides
- 2019
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 365:6452, s. 469-473
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Tidskriftsartikel (refereegranskat)abstract
- The oxygen isotope composition (delta O-18) of marine sedimentary rocks has increased by 10 to 15 per mil since Archean time. Interpretation of this trend is hindered by the dual control of temperature and fluid delta O-18 on the rocks' isotopic composition. A new delta O-18 record in marine iron oxides covering the past similar to 2000 million years shows a similar secular rise. Iron oxide precipitation experiments reveal a weakly temperature-dependent iron oxide-water oxygen isotope fractionation, suggesting that increasing seawater d(18)O over time was the primary cause of the long-term rise in delta O-18 values of marine precipitates. The O-18 enrichment may have been driven by an increase in terrestrial sediment cover, a change in the proportion of high-and low-temperature crustal alteration, or a combination of these and other factors.
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| 3. |
- Aurell, Erik, et al.
(författare)
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Growth optimal investment and pricing of derivatives
- 2000
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Ingår i: Physica A. - 0378-4371 .- 1873-2119. ; 280:04-mar, s. 505-521
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Tidskriftsartikel (refereegranskat)abstract
- We introduce a criterion how to price derivatives in incomplete markets, based on the theory of growth optimal strategy in repeated multiplicative games. We present reasons why these growth-optimal strategies should be particularly relevant to the problem of pricing derivatives. tinder the assumptions of no trading costs, and no restrictions on lending, we find an appropriate equivalent martingale measure that prices the underlying and the derivative security. We compare our result with other alternative pricing procedures in the literature, and discuss the limits of validity of the lognormal approximation. We also generalize the pricing method to a market with correlated stocks. The expected estimation error of the optimal investment fraction is derived in a closed form, and its validity is checked with a small-scale empirical test.
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| 4. |
- Bendz, H., et al.
(författare)
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Kidney damage in long-term lithium patients : A cross-sectional study of patients with 15 years or more on lithium
- 1994
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Ingår i: Nephrology Dialysis Transplantation. - 0931-0509. ; 9:9, s. 1357-1357
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Tidskriftsartikel (refereegranskat)abstract
- The renal risks associated with long-term lithium treatment are a growing concern. We have therefore studied renal function by means of glomerular filtration rate (GFR) and maximum urinary concentrating capacity (Umax) in 142 of 215 patients with more than 15 years of lithium treatment in nine psychiatric clinics. Data on psychiatric and somatic diseases, hospital admissions, cumulative lithium doses, and other psychotropic treatments were extracted from the medical records. The patients were investigated according to a standardized protocol. GFR was measured as51Cr EDTA clearance and Umax using the DDAVP test. Thirteen patients had had signs of lithium intoxication. GFR was reduced in 21% of the patients and Umax in 44%. Nephrogenic diabetes insipidus was present in 12%. Umax but not GFR was inversely correlated to the cumulative lithium dose. Kidney function was more reduced in patients on lithium combined with psychotropic treatment and/or concomitant treatment for somatic disorders. Thirst was a complaint of 53% of the patients, predominantly those with additional psychotropics. We conclude that kidney damage is common in patients on long-term lithium treatment and that both glomerular and tubular function are affected.
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| 5. |
- Bendz, Hans, et al.
(författare)
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Lithium nephropathy in Sweden
- 2008
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Ingår i: European Psychiatry. - : Cambridge University Press (CUP). - 1778-3585 .- 0924-9338. ; 23:Suppl. 2, s. 288-288
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Konferensbidrag (refereegranskat)
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| 6. |
- Ehrenberg, M., et al.
(författare)
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Systems biology is taking off
- 2003
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 13, s. 2475-2484
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Ehrenberg, M, et al.
(författare)
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The logic of life
- 2003
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Ingår i: GENOME RESEARCH. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 13:11, s. 2375-2376
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Ekeberg, Magnus, et al.
(författare)
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Improved contact prediction in proteins : Using pseudolikelihoods to infer Potts models
- 2013
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Ingår i: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics. - 1539-3755 .- 1550-2376. ; 87:1, s. 012707-
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Tidskriftsartikel (refereegranskat)abstract
- Spatially proximate amino acids in a protein tend to coevolve. A protein's three-dimensional (3D) structure hence leaves an echo of correlations in the evolutionary record. Reverse engineering 3D structures from such correlations is an open problem in structural biology, pursued with increasing vigor as more and more protein sequences continue to fill the data banks. Within this task lies a statistical inference problem, rooted in the following: correlation between two sites in a protein sequence can arise from firsthand interaction but can also be network-propagated via intermediate sites; observed correlation is not enough to guarantee proximity. To separate direct from indirect interactions is an instance of the general problem of inverse statistical mechanics, where the task is to learn model parameters (fields, couplings) from observables (magnetizations, correlations, samples) in large systems. In the context of protein sequences, the approach has been referred to as direct-coupling analysis. Here we show that the pseudolikelihood method, applied to 21-state Potts models describing the statistical properties of families of evolutionarily related proteins, significantly outperforms existing approaches to the direct-coupling analysis, the latter being based on standard mean-field techniques. This improved performance also relies on a modified score for the coupling strength. The results are verified using known crystal structures of specific sequence instances of various protein families. Code implementing the new method can be found at http://plmdca.csc.kth.se/.
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| 9. |
- Fava, Cristiano, et al.
(författare)
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Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:3, s. 413-418
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Tidskriftsartikel (refereegranskat)abstract
- Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.
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| 10. |
- Folestad, A., et al.
(författare)
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IL-17 cytokines in bone healing of diabetic Charcot arthropathy patients: a prospective 2 year follow-up study
- 2015
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Ingår i: Journal of Foot and Ankle Research. - : Springer Science and Business Media LLC. - 1757-1146. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Little is currently known of the pathophysiological mechanisms triggering Charcot arthropathy and regulating its recovery although foot trauma has been proposed as a major initiating factor by activation of proinflammatory cytokines leading to increased osteoclastogenic activity and progressive bone destruction. Several members of the IL-17 family of proinflammatory cytokines have been shown to play a key role in the pathogenesis of inflammatory conditions affecting bone and joints but none has previously been studied in Charcot foot patients. The aim of this study was to investigate the role of IL-17A, IL-17E and IL-17F in patients presenting with Charcot foot. Methods: Twenty-six consecutive Charcot patients were monitored during 2 years by repeated foot radiographs, MRI and circulating levels of IL-17A, IL-17E and IL-17F. Analysis of cytokines was done by ultra-sensitive chemiluminescence technique and data were analyzed by one-way repeated measures ANOVA. Neuropathic diabetic patients (n = 20) and healthy subjects (n = 20) served as controls. Results: Plasma IL-17A and IL-17E in weight-bearing Charcot patients at diagnosis were at the level of diabetic controls, whereas IL-17F was significantly lower than diabetic controls. A significant increase in IL-17A and IL-17E reaching a peak 2-4 months after inclusion and start of offloading treatment in Charcot patients was followed by a gradual decrease to the level of diabetic controls at 2 years postinclusion. In contrast, IL-17F increased gradually from inclusion to a level not significantly different from diabetic controls after 2 years. Conclusions: Charcot patients display a significant elevation of all three IL-17 cytokines during the follow-up period relative values at diagnosis and values in control patients supporting a role in the bone repair and remodeling activity during the recovery phase. The rapid increase of IL-17A and IL-17E shortly after initiating off-loading treatment could suggest this to be a response to immobilization and stabilization of the diseased foot.
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