| 1. |
- Westman, Gabriel, et al.
(författare)
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N-Methyl-D-Aspartate Receptor Autoimmunity Affects Cognitive Performance in Herpes Simplex Encephalitis
- 2016
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Ingår i: Clinical Microbiology And Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 22:11, s. 934-940
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate the prevalence and temporal development of N-methyl-D-aspartate receptor (NMDAR) autoantibodies in relation to neurocognitive performance in patients with herpes simplex encephalitis (HSE). Methods: This prospective observational study enrolled a total of 49 HSE patients within a randomized controlled trial of valacyclovir. Cerebrospinal fluid and serum samples were drawn in the initial stage of disease, after 2 to 3 weeks and after 3 months. Anti-NMDAR IgG was detected with HEK293 cells transfected with plasmids encoding the NMDA NR1 type glutamate receptor. A batch of neurocognitive tests, including the Mattis Dementia Rating Scale (MDRS), Glasgow Coma Scale (GCS), Reaction Level Scale (RLS85), Mini-Mental State Examination (MMSE) and National Institutes of Health (NIH) stroke scale, was performed during 24 months' follow-up. Results: Anti-NMDAR IgG was detected in 12 of 49 participants. None were antibody positive in the initial stage of disease. In ten of 12 positive cases, specific antibodies were detectable only after 3 months. Notably, the development of NMDAR autoantibodies was associated with significantly impaired recovery of neurocognitive performance. After 24 months' follow-up, the median increase in MDRS total score was 1.5 vs. 10 points in antibody-positive and -negative participants (p = 0.018). Conclusions: Anti-NMDAR autoimmunity is a common complication to HSE that develops within 3 months after onset of disease. The association to impaired neurocognitive recovery could have therapeutical implications, as central nervous system autoimmunity is potentially responsive to immunotherapy.
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| 2. |
- Aguilar, C., et al.
(författare)
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Automated CT-based segmentation and quantification of total intracranial volume
- 2015
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 25:11, s. 3151-3160
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To develop an algorithm to segment and obtain an estimate of total intracranial volume (tICV) from computed tomography (CT) images. Materials and methods Thirty-six CT examinations from 18 patients were included. Ten patients were examined twice the same day and eight patients twice six months apart (these patients also underwent MRI). The algorithm combines morphological operations, intensity thresholding and mixture modelling. The method was validated against manual delineation and its robustness assessed from repeated imaging examinations. Using automated MRI software, the comparability with MRI was investigated. Volumes were compared based on average relative volume differences and their magnitudes; agreement was shown by a Bland-Altman analysis graph. Results We observed good agreement between our algorithm and manual delineation of a trained radiologist: the Pearson's correlation coefficient was r = 0.94, tICVml[manual] = 1.05 x tICVml[automated] - 33.78 (R-2 = 0.88). Bland-Altman analysis showed a bias of 31 mL and a standard deviation of 30 mL over a range of 1265 to 1526 mL. Conclusions tICV measurements derived from CT using our proposed algorithm have shown to be reliable and consistent compared to manual delineation. However, it appears difficult to directly compare tICV measures between CT and MRI.
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| 3. |
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| 4. |
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| 5. |
- Dubrovinsky, L, et al.
(författare)
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Pressure-induced invar effect in Fe-Ni alloys
- 2001
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Ingår i: PHYSICAL REVIEW LETTERS. - 0031-9007. ; 86:21, s. 4851-4854
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Tidskriftsartikel (refereegranskat)abstract
- We have measured the pressure-volume (P-V) relations for cubic iron-nickel alloys for three different compositions: Fe0.64Ni0.36, Fe0.55Ni0.45, and Fe0.20Ni0.80. It is observed that for a certain pressure range the bulk modulus does not change or can even
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| 6. |
- Ekelund, Marie-Louise, et al.
(författare)
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Dialysis-linked complaints and burdens of illness on patient and spouse as predictors of survival in end-stage renal disease patients with home hemodialysis: a 10-year follow-up study
- 2004
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Ingår i: Stress and Health. - : Wiley. - 1532-3005 .- 1532-2998. ; 20:1, s. 29-34
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Tidskriftsartikel (refereegranskat)abstract
- Participants were 40 persons from a group of 44 end-stage renal disease patients in southern Sweden who in 1985 received home hemodialysis under the auspices of a hospital renal unit, together with their spouses (n = 35). At a 10-year follow-up, 15 of the patients had died and 25 had survived. Univariate log rank tests of the influence of physical and demographic factors, the patient's dialysis-linked complaints and the burdens of the illness indicated the most important predictors of 10-year survival to be the patient's age, severity of the illness, the patient's dialysis-linked complaints (notably that of itching), and the burdens of the patient's disease on the spouse (particularly burdens of a sexual character). Copyright (C) 2004 John Wiley Sons, Ltd.
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| 7. |
- Engblom, David, 1975-, et al.
(författare)
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Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis
- 2003
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 6:11, s. 1137-1138
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Tidskriftsartikel (refereegranskat)abstract
- We studied the febrile response in mice deficient in microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal isomerase expressed in cytokine-sensitive brain endothelial cells. These animals showed no fever and no central prostaglandin (PG) E2 synthesis after peripheral injection of bacterial-wall lipopolysaccharide, but their pyretic capacity in response to centrally administered PGE2 was intact. Our findings identify mPGES-1 as the central switch during immune-induced pyresis and as a target for the treatment of fever and other PGE2-dependent acute phase reactions elicited by the brain.
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| 8. |
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| 9. |
- Ferreira, Daniel, et al.
(författare)
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The interactive effect of demographic and clinical factors on hippocampal volume : A multicohort study on 1958 cognitively normal individuals
- 2017
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 27:6, s. 653-667
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.
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| 10. |
- Gustafsson-Larsson, Susanne, et al.
(författare)
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Bun-baking mums and subverters: The agency of network participants in a Rural Swedish county
- 2007
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Ingår i: Women's Studies. - : Elsevier BV. - 0277-5395 .- 1879-243X. ; 30:1, s. 48-58
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Tidskriftsartikel (refereegranskat)abstract
- During the 1990s rural Swedish women positioned themselves as women and formed networks aimed at addressing various local and most often gender-related problems that limited their quality of life. The aim of this article is to empirically describe and theoretically discuss the idea of agency in the context of women's social practices of networking and to examine how the participants either reproduce or transform the gendered structures that shape them. The empirical data for this article consist primarily of discussions with focus groups and interviews with network participants. Through interpretations, a pattern of gendered power-relations was illuminated, which both influenced and constrained the participants' activities. We have interpreted the participants' networking agency as acts of protest against everything that limits their living conditions. As women develop strategies through networking, their resistance seems to become increasingly significant for the ongoing transformations of the gender order.
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| 11. |
- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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| 12. |
- Kadetoff, Diana, et al.
(författare)
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Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels.
- 2012
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 242:1-2, s. 33-8
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Tidskriftsartikel (refereegranskat)abstract
- Activation of glia cells resulting in intrathecal elevation of cytokines and chemokines has been hypothesized in chronic pain syndromes such as fibromyalgia. To our knowledge, this is the first study assessing intrathecal concentrations of pro-inflammatory substances in fibromyalgia. We report elevated cerebrospinal fluid and serum concentrations of interleukin-8, but not interleukin-1beta, in FM patients. This profile is in accordance with FM symptoms being mediated by sympathetic activity rather than dependent on prostaglandin associated mechanisms and supports the hypothesis of glia cell activation in response to pain mechanisms.
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| 13. |
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| 14. |
- Kasrayan, Alex, et al.
(författare)
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Enhancement by effectors and substrate nucleotides of R1-R2 interactions in Escherichia coli class Ia ribonucleotide reductase.
- 2004
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Ingår i: J Biol Chem. - 0021-9258. ; 279:30, s. 31050-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Ribonucleotide reductases are a family of essential enzymes that catalyze the reduction of ribonucleotides to their corresponding deoxyribonucleotides and provide cells with precursors for DNA synthesis. The different classes of ribonucleotide reductase are distinguished based on quaternary structures and enzyme activation mechanisms, but the components harboring the active site region in each class are evolutionarily related. With a few exceptions, ribonucleotide reductases are allosterically regulated by nucleoside triphosphates (ATP and dNTPs). We have used the surface plasmon resonance technique to study how allosteric effects govern the strength of quaternary interactions in the class Ia ribonucleotide reductase from Escherichia coli, which like all class I enzymes has a tetrameric alpha(2) beta(2) structure. The component alpha(2)called R1 harbors the active site and two types of binding sites for allosteric effector nucleotides, whereas the beta(2) component called R2 harbors the tyrosyl radical necessary for catalysis. Our results show that only the known allosteric effector nucleotides, but not non-interacting nucleotides, promote a specific interaction between R1 and R2. Interestingly, the presence of substrate together with allosteric effector nucleotide strengthens the complex 2-3 times with a similar free energy change as the mutual allosteric effects of substrate and effector nucleotide binding to protein R1 in solution experiments. The dual allosteric effects of dATP as positive allosteric effector at low concentrations and as negative allosteric effector at high concentrations coincided with an almost 100-fold stronger R1-R2 interaction. Based on the experimental setup, we propose that the inhibition of enzyme activity in the E. coli class Ia enzyme occurs in a tight 1:1 complex of R1 and R2. Most intriguingly, we also discovered that thioredoxin, one of the physiological reductants of ribonucleotide reductases, enhances the R1-R2 interaction 4-fold.
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| 15. |
- Kosek, Eva, et al.
(författare)
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Evidence of different mediators of central inflammation in dysfunctional and inflammatory pain--interleukin-8 in fibromyalgia and interleukin-1 β in rheumatoid arthritis.
- 2015
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 280, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM).
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| 16. |
- Lampa, Jon, et al.
(författare)
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Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice.
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:31, s. 12728-33
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Tidskriftsartikel (refereegranskat)abstract
- During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
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| 17. |
- Larsson Birgander, Pernilla, et al.
(författare)
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Nucleotide-dependent formation of catalytically competent dimers from engineered monomeric ribonucleotide reductase protein R1
- 2005
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 280:15, s. 14997-15003
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Tidskriftsartikel (refereegranskat)abstract
- Each catalytic turnover by aerobic ribonucleotide reductase requires the assembly of the two proteins, R1 (α2) and R2 (β2), to produce deoxyribonucleotides for DNA synthesis. The R2 protein forms a tight dimer, whereas the strength of the R1 dimer differs between organisms, being monomeric in mouse R1 and dimeric in Escherichia coli. We have used the known E. coli R1 structure as a framework for design of eight different mutations that affect the helices and proximal loops that comprise the dimer interaction area. Mutations in loop residues did not affect dimerization, whereas mutations in the helices had very drastic effects on the interaction resulting in monomeric proteins with very low or no activity. The monomeric N238A protein formed an interesting exception, because it unexpectedly was able to reduce ribonucleotides with a comparatively high capacity. Gel filtration studies revealed that N238A was able to dimerize when bound by both substrate and effector, a result in accordance with the monomeric R1 protein from mouse. The effects of the N238A mutation, fit well with the notion that E. coli protein R1 has a comparatively small dimer interaction surface in relation to its size, and the results illustrate the stabilization effects of substrates and effectors in the dimerization process. The identification of key residues in the dimerization process and the fact that there is little sequence identity between the interaction areas of the mammalian and the prokaryotic enzymes may be of importance in drug design, similar to the strategy used in treatment of HSV infection.
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| 18. |
- Link, Katarina, et al.
(författare)
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Low individualized growth hormone (GH) dose increased renal and cardiac growth in young adults with childhood onset GH deficiency
- 2001
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Ingår i: Clinical Endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 55:6, s. 741-748
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE In childhood onset GH deficiency (GHD) a reduction in left ventricular mass (LV-mass) and impairment of systolic function as well an impairment in glomerular filtration rate (GFR) has been shown. The aim of the present study was to assess if a low GH dose resulted in an improvement in morphological and functional parameters of these organs. DESIGN AND PATIENTS Eleven patients with childhood onset GHD were investigated before and after 10 months of GH treatment at a dose of 1.5 IU/day (range 1-2), corresponding to 0.02 IU/kg/day or 7 mug/kg/day. The GH dose resulted in a serum IGF-I level in the normal range in all but one patient. MEASUREMENTS Doppler echocardiography of the heart and ultrasound examination of the kidneys was performed. Glomerular filtration rate (GFR) was estimated with iohexol clearance and urinary proteinuria was measured with 24-h urinary samples collected for analyses of albumin, alpha-1-microglobulin, IgG and albumin/creatinine clearance ratio. Body composition was measured by bioelectric impedance analysis. RESULTS L V-mass index increased significantly after GH treatment (P = 0.04), and there was a clear trend for a positive correlation between the increase in serum IGF-I and the increase in LV-mass index, although it did not reach significance (r = 0.57, P = 0.07). GH treatment did not increase cardiac fractional shortening. Kidney length increased significantly (P = 0.02) with an average increase of 1 cm (range -0.5-1.5 cm). No significant changes in median GFR or serum creatinine were recorded. Three patients with subnormal GFR before GH treatment normalized after 10 months of treatment. Urine analysis showed no abnormalities before or after GH treatment. A significant decrease in percentage fat mass was recorded (P = 0.03). CONCLUSION A low individualized GH dose to adults with childhood onset GHD resulted in an increase in LV-mass index and kidney length. Re-establishing GH treatment with a low dose in this patient group can lead to a further somatic maturation of these organs, probably not accomplished previously.
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| 19. |
- Lorant, Camilla, et al.
(författare)
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Risk Factors for Developing BK Virus-Associated Nephropathy : A Single-Center Retrospective Cohort Study of Kidney Transplant Recipients
- 2022
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Ingår i: Annals of Transplantation. - 1425-9524 .- 2329-0358. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND BK virus (BKV) infection after kidney transplantation leads to BKV-associated nephropathy (BKVAN) in up to 10% of recipients, and is associated with an increased risk of allograft dysfunction or loss. The objective of this study was to estimate the incidence of BKVAN and to analyze whether enhanced induction is associated with an increased risk of BKVAN, possibly justifying more intensive surveillance.MATERIAL AND METHODS This was a single-center retrospective cohort study. All patients who underwent kidney transplantation or simultaneous pancreas and kidney transplantation at the Uppsala University Hospital in Sweden between 2005 and 2014 were included, a period when BKV screening was not yet implemented. The effect of enhanced induction, defined as treatment with thymoglobulin, rituximab, and/or eculizumab, often in combination with IVIg and glycosorb, immunoadsorption and/or plasmapheresis/apheresis, was analyzed in a multivariable Cox proportional hazards model together with sex, age, cytomegalovirus mismatch (donor+/recipient-) and rejection treatment as co-predictors. Further, the effects of BKVAN on graft survival was analyzed in a univariable Cox proportional hazards model.RESULTS In total 44 of 928 (4.7%) patients developed a biopsy-verified BKVAN 4.8 (1.5-34.2) months after transplantation. Male sex was identified as a risk factor (HR 2.02, P=0.04) but not enhanced induction. Patients with BKVAN experienced a significantly higher risk of graft loss (HR 4.37, P<0.001).CONCLUSIONS Male sex, but not enhanced induction, was found to be a risk factor for BKVAN development after kidney transplantation. BKVAN is associated with an increased risk of graft loss.
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| 20. |
- Lorant, Camilla, et al.
(författare)
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The risk factors associated with post-transplantation BKPyV nephropathy and BKPyV DNAemia : a prospective study in kidney transplant recipients
- 2024
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 24
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Tidskriftsartikel (refereegranskat)abstract
- Background: BK polyomavirus (BKPyV) infection after kidney transplantation can lead to serious complications such as BKPyV-associated nephropathy (BKPyVAN) and graft loss. The aim of this study was to investigate the incidence of BKPyVAN after implementing a BKPyV screening program, to map the distribution of BKPyV genotypes and subtypes in the Uppsala-orebro region and to identify host and viral risk factors for clinically significant events.Methods This single-center prospective cohort study included kidney transplant patients aged >= 18 years at the Uppsala University Hospital in Sweden between 2016 and 2018. BKPyV DNA was analyzed in plasma and urine every 3 months until 18 months after transplantation. Also genotype and subtype were determined. A logistic regression model was used to analyze selected risk factors including recipient sex and age, AB0 incompatibility and rejection treatment prior to BKPyVAN or high-level BKPyV DNAemia.Results: In total, 205 patients were included. Of these, 151 (73.7%) followed the screening protocol with 6 plasma samples, while184 (89.8%) were sampled at least 5 times. Ten (4.9%) patients developed biopsy confirmed BKPyVAN and 33 (16.1%) patients met criteria for high-level BKPyV DNAemia. Male sex (OR 2.85, p = 0.025) and age (OR 1.03 per year, p = 0.020) were identified as significant risk factors for developing BKPyVAN or high-level BKPyV DNAemia. BKPyVAN was associated with increased viral load at 3 months post transplantation (82,000 vs. < 400 copies/mL; p = 0.0029) and with transient, high-level DNAemia (n = 7 (27%); p < 0.0001). The most common genotypes were subtype Ib2 (n = 50 (65.8%)) and IVc2 (n = 20 (26.3%)).Conclusions: Male sex and increasing age are related to an increased risk of BKPyVAN or high-level BKPyV DNAemia. BKPyVAN is associated with transient, high-level DNAemia but no differences related to viral genotype were detected.
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| 21. |
- Löfberg, Anne-Marie, et al.
(författare)
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Percutaneous transluminal angioplasty of the femoropopliteal arteries in limbs with chronic critical lower limb ischemia
- 2001
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Ingår i: Journal of vascular surgery. - : Elsevier BV. - 0741-5214. ; 34:1, s. 114-121
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of the study was to evaluate the results of percutaneous transluminal angioplasty (PTA) of femoropopliteal arteries in patients with subcritical or critical lower limb ischemia. Materials and Methods: Ninety-two patients underwent 121 PTA procedures, 68 were of the superficial femoral artery (SFA), 13 of the popliteal and 40 of both arteries. Fifty-seven procedures were performed for treatment of occlusions. Eighty-four patients (94 procedures) were monitored with duplex scanning. RESULTS: Technical success rate was 88%. Primary success rates at 12 and 60 months in the whole series were 40% and 27%, respectively. The primary success rate in limbs with SFA occlusion of longer than 5 cm was only 12% after 5 years compared with 32% if the occlusion was CONCLUSION: The results of femoropopliteal PTA performed for treatment of subcritical or critical lower limb ischemia seemed to be inferior to the results of infrainguinal bypass grafting reported in literature. However, because the PTA procedure does not preclude the performance of bypass grafting, it might be an alternative to surgical intervention in limbs with stenotic femoropopliteal lesions. PTA might also be considered in patients with high surgical risk and limited life expectancy, having short occlusive lesions (< 5 cm).
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| 22. |
- Löfberg, Anne-Marie, et al.
(författare)
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The use of below-knee percutaneous transluminal angioplasty in arterial occlusive disease causing chronic critical limb ischemia
- 1996
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Ingår i: Cardiovascular and Interventional Radiology. - 0174-1551 .- 1432-086X. ; 19:5, s. 317-322
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To determine the efficacy, safety and long-term results of crural artery percutaneous transluminal angioplasty (PTA) in limbs with chronic critical limb ischemia (CLI). METHODS: Patients undergoing crural artery PTA due to CLI were followed at regular clinic visits with ankle brachial pressure index (ABPI) measurements. PTA of the crural arteries was attempted either alone (n = 39) or in combination with PTA of the superficial and/or popliteal artery (n = 55) in 86 limbs (82 patients and 94 procedures) presenting with CLI. The ages of patients ranged from 37 to 94 years (mean 72 years). The indications for PTA were rest pain in 10 and ulcer/gangrene in 84 limbs. RESULTS: A technically successful PTA with at least one crural level was achieved in 88% of cases (n = 83). Cumulative primary clinical success rates at 6, 12, 24, and 36 months were 55%, 51%, 36%, and 36%, respectively. Cumulative secondary clinical success and limb salvage rates at 36 months were 44% and 72%, respectively. CONCLUSION: PTA of the crural arteries might be considered the primary choice of treatment in patients with CLI and distal lesions with localized stenosis or segmental short occlusions.
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| 23. |
- Löfvenberg, Christian, 1978-, et al.
(författare)
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Prevalence of severe-to-Profound hearing loss in the adult Swedish population and comparison with cochlear implantation rate
- 2022
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Ingår i: Acta Oto-Laryngologica. - : Taylor & Francis. - 0001-6489 .- 1651-2251. ; 142:5, s. 410-414
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalence of disabling hearing loss is increasing worldwide. However, previous studies on hearing loss prevalence have enrolled small populations or only provided estimates.Aim: To establish the prevalence of severe-to-profound hearing loss (STPHL) in the adult Swedish population and compare it with the cochlear implantation rate in Sweden.Material and methods: We established a database containing over 15 million audiograms obtained from regions covering > 99% of the Swedish population by extracting audiogram data from the computer software application, Auditbase. We used this database to calculate the percentage of adult patients with bilateral hearing levels >= 70 dB. We collected data regarding cochlear implantations in Sweden from the National Board of Welfare and Health.Results: The prevalence of STPHL in the adult Swedish population was 0.28%. There were regional variations in the prevalence and rate of cochlear implantation; however, there was no association between both parameters.Conclusions: This study presents an updated and reliable prevalence figure for STPHL in Sweden.Significance: Patients with STPHL have extensive rehabilitation requirements; accordingly, it is important to determine the accurate prevalence of STPHL to inform the allocation of adequate resources.
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| 24. |
- Nääs, Anja, et al.
(författare)
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Temporal pathway analysis of cerebrospinal fluid proteome in herpes simplex encephalitis
- 2023
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 55:10, s. 694-705
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesWe examined the temporal changes of the CSF proteome in patients with herpes simplex encephalitis (HSE) during the course of the disease, in relation to anti-N-methyl-D-aspartate receptor (NMDAR) serostatus, corticosteroid treatment, brain MRI and neurocognitive performance.MethodsPatients were retrospectively included from a previous prospective trial with a pre-specified CSF sampling protocol. Mass spectrometry data of the CSF proteome were processed using pathway analysis.ResultsWe included 48 patients (110 CSF samples). Samples were grouped based on time of collection relative to hospital admission - T1: & LE; 9 d, T2: 13-28 d, T3: & GE; 68 d. At T1, a strong multi-pathway response was seen including acute phase response, antimicrobial pattern recognition, glycolysis and gluconeogenesis. At T2, most pathways activated at T1 were no longer significantly different from T3. After correction for multiplicity and considering the effect size threshold, 6 proteins were significantly less abundant in anti-NMDAR seropositive patients compared to seronegative: procathepsin H, heparin cofactor 2, complement factor I, protein AMBP, apolipoprotein A1 and polymeric immunoglobulin receptor. No significant differences in individual protein levels were found in relation to corticosteroid treatment, size of brain MRI lesion or neurocognitive performance.ConclusionsWe show a temporal change in the CSF proteome in HSE patients during the course of the disease. This study provides insight into quantitative and qualitative aspects of the dynamic pathophysiology and pathway activation patterns in HSE and prompts for future studies on the role of apolipoprotein A1 in HSE, which has previously been associated with NMDAR encephalitis.
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| 25. |
- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
-
Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 26. |
- Skog, Erik, et al.
(författare)
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An oseltamivir-resistant avian H1N1 influenza A virus can transmit from mallards to chickens similarly to a wild-type strain : implications for the risk of resistance transmission to humans
- 2023
-
Ingår i: Journal of General Virology. - : Microbiology Society. - 0022-1317 .- 1465-2099. ; 104:4
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Tidskriftsartikel (refereegranskat)abstract
- The neuraminidase inhibitor (NAI) oseltamivir is stockpiled globally as part of influenza pandemic preparedness. However, oseltamivir carboxylate (OC) resistance develops in avian influenza virus (AIV) infecting mallards exposed to environmental-like OC concentrations, suggesting that environmental resistance is a real concern. Herein we used an in vivo model to investigate if avian influenza H1N1 with the OC-resistant mutation NA-H274Y (51833/H274Y) as compared to the wild-type (wt) strain (51833 /wt) could transmit from mallards, which would potentially be exposed to environmentally contaminated environments, to and between chickens, thus posing a potential zoonotic risk of antiviral-resistant AIV. Regardless of whether the virus had the OC-resistant mutation or not, chickens became infected both through experimental infection, and following exposure to infected mallards. We found similar infection patterns between 51833/wt and 51833/H274Y such that, one chicken inoculated with 51833/wt and three chickens inoculated with 51833/H274Y were AIV positive in oropharyngeal samples more than 2 days consecutively, indicating true infection, and one contact chicken exposed to infected mallards was AIV positive in faecal samples for 3 consecutive days (51833/wt) and another contact chicken for 4 consecutive days (51833/H274Y). Importantly, all positive samples from chickens infected with 51833/H274Y retained the NA-H274Y mutation. However, none of the virus strains established sustained transmission in chickens, likely due to insufficient adaptation to the chicken host. Our results demonstrate that an OC-resistant avian influenza virus can transmit from mallards and replicate in chickens. NA-H274Y does not constitute a barrier to interspecies transmission per se, as the resistant virus did not show reduced replicative capacity compared to the wild-type counterpart. Thus, responsible use of oseltamivir and surveillance for resistance development is warranted to limit the risk of an OC-resistant pandemic strain.
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| 27. |
- Söllvander, Sofia, et al.
(författare)
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Increased Number of Plasma B Cells Producing Autoantibodies Against A beta(42) Protofibrils in Alzheimer's Disease
- 2015
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 48:1, s. 63-72
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Tidskriftsartikel (refereegranskat)abstract
- The Alzheimer's disease (AD)-related peptide amyloid-beta (A beta) has a propensity to aggregate into various assemblies including toxic soluble A beta protofibrils. Several studies have reported the existence of anti-A beta antibodies in humans. However, it is still debated whether levels of anti-A beta antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma A beta makes it difficult to reliably measure the concentration of circulating anti-A beta antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-A beta antibody production on a cellular level by measuring the amount of anti-A beta antibody producing cells instead of the plasma level of anti-A beta antibodies. To our knowledge, this is the first time the anti-A beta antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding A beta(40) monomers, whereas the number of cells producing antibodies toward A beta(42) protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic A beta protofibrils, which is significantly increased in AD patients.
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| 28. |
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| 29. |
- Torrents, Eduard, et al.
(författare)
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Ribonucleotide reductase modularity : Atypical duplication of the ATP-cone domain in Pseudomonas aeruginosa.
- 2006
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Ingår i: J Biol Chem. - 0021-9258. ; 281:35, s. 25287-96
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The opportunistic pathogen Pseudomonas aeruginosa, which causes serious nosocomial infections, is a gamma-proteobacterium that can live in many different environments. Interestingly P. aeruginosa encodes three ribonucleotide reductases (RNRs) that all differ from other well known RNRs. The RNR enzymes are central for de novo synthesis of deoxyribonucleotides and essential to all living cells. The RNR of this study (class Ia) is a complex of the NrdA protein harboring the active site and the allosteric sites and the NrdB protein harboring a tyrosyl radical necessary to initiate catalysis. P. aeruginosa NrdA contains an atypical duplication of the N-terminal ATP-cone, an allosteric domain that can bind either ATP or dATP and regulates the overall enzyme activity. Here we characterized the wild type NrdA and two truncated NrdA variants with precise N-terminal deletions. The N-terminal ATP-cone (ATP-c1) is allosterically functional, whereas the internal ATP-cone lacks allosteric activity. The P. aeruginosa NrdB is also atypical with an unusually short lived tyrosyl radical, which is efficiently regenerated in presence of oxygen as the iron ions remain tightly bound to the protein. The P. aeruginosa wild type NrdA and NrdB proteins form an extraordinarily tight complex with a suggested alpha4beta4 composition. An alpha2beta2 composition is suggested for the complex of truncated NrdA (lacking ATP-c1) and wild type NrdB. Duplication or triplication of the ATP-cone is found in some other bacterial class Ia RNRs. We suggest that protein modularity built on the common catalytic core of all RNRs plays an important role in class diversification within the RNR family.
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| 30. |
- Velickaite, Vilma
(författare)
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Analysis of regional atrophy on brain imaging compared with cognitive function in the elderly and in patients with dementia – cross-sectional and longitudinal evaluation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During aging, brain changes are not homogeneous throughout the entire brain, but are related to changes in the morphology of neurons, as well as to changes in the tissue density, and are specific to each region of the brain. Dementia is a broad category of brain disorders with a set of symptoms including memory, visual-spatial and language problems. Most types of dementia are slowly progressing, and by the time the person shows signs of the disorder, processes in the brain are already advanced. Dementia reduces not only the person’s ability to perform everyday activities, it also increases mortality rates significantly. Because of the increasing incidence of dementia, possible prevention and treatment of dementia as early as possible are essential.The aim of the PhD project is to compare a quantitative and qualitative image analysis of regional cerebral atrophy with cognitive function in the elderly persons.In paper I, 58 persons participated (84–88 years old) from the ULSAM (Uppsala Longitudinal Study of Adult Men) cohort. They underwent CT of the brain, cognitive testing and LP. This study showed that AD biomarkers seem to be less informative in subjects with an advanced age.In papers II–IV, the cohort included subjects from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study.Paper II showed that at age 75, gender and education are confounders for MTA rating. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later.Paper III showed that automated rating of MTA could be used in clinical practice to support the radiological evaluation. Automated rating of PA and F-GCA should be tested in future studies.In paper IV, we found a mild age-associated decrease in regional brain volumes in this healthy cohort with well-preserved cognitive and executive functions.In conclusion, the included studies in this thesis compare regional atrophy grades in the brain on CT and MRI and clinical data and provide knowledge that may be used in future investigations that aim to detect dementia in its early stages.
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| 31. |
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| 32. |
- Velickaite, Vilma, et al.
(författare)
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Medial temporal lobe atrophy ratings in a large 75-year-old population-based cohort : gender-corrected and education-corrected normative data
- 2018
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Ingår i: European Radiology. - : Springer Science and Business Media LLC. - 0938-7994 .- 1432-1084. ; 28:4, s. 1739-1747
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To find cut-off values for different medial temporal lobe atrophy (MTA) measures (right, left, average, and highest), accounting for gender and education, investigate the association with cognitive performance, and to compare with decline of cognitive function over 5 years in a large population-based cohort.METHODS: Three hundred and ninety 75-year-old individuals were examined with magnetic resonance imaging of the brain and cognitive testing. The Scheltens's scale was used to assess visually MTA scores (0-4) in all subjects. Cognitive tests were repeated in 278 of them after 5 years. Normal MTA cut-off values were calculated based on the 10th percentile.RESULTS: Most 75-year-old individuals had MTA score ≤2. Men had significantly higher MTA scores than women. Scores for left and average MTA were significantly higher in highly educated individuals. Abnormal MTA was associated with worse results in cognitive test and individuals with abnormal right MTA had faster cognitive decline.CONCLUSION: At age 75, gender and education are confounders for MTA grading. A score of ≥2 is abnormal for low-educated women and a score of ≥2.5 is abnormal for men and high-educated women. Subjects with abnormal right MTA, but normal MMSE scores had developed worse MMSE scores 5 years later.KEY POINTS: • Gender and education are confounders for MTA grading. • We suggest cut-off values for 75-year-olds, taking gender and education into account. • Males have higher MTA scores than women. • Higher MTA scores are associated with worse cognitive performance.
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| 33. |
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| 34. |
- Velickaite, Vilma, et al.
(författare)
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Visual rating versus volumetry of regional brain atrophy and longitudinal changes over a 5-year period in an elderly population.
- 2020
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The purpose of our study was to compare visual rating and volumetry of brain atrophy in an elderly population over a 5‐year period and compare findings with cognitive test results.Materials and Methods: Two hundred and one subjects were examined with magnetic resonance imaging (MRI) of the brain. Visual rating and volumetry were performed in all subjects at ages 75 and 80. Cognitive function at both time points was assessed with the Mini‐Mental State Examination (MMSE) and Trail Making Tests A and B (TMT‐A and TMT‐B). Changes in visual rating and volumetry were compared with changes in cognitive test.Results: A correlation was found between visual rating of medial temporal lobe atrophy (MTA) and hippocampal volumetry at both time points (rs = −.42 and rs = −.49, p < .001, respectively). The correlation between visual rating of posterior atrophy (PA); frontal atrophy (F‐GCA) and volumetry of these brain regions was significant only at age 80 (rs = −.16, p = .02 for PA and rpb = .19, p = .006 for F‐GCA). Visual rating showed only a minimal progression of regional atrophy at age 80, whereas volumetry showed 2%–5% decrease in volume depending on brain region. Performance in the MMSE, TMT‐A, and TMT‐B was virtually unchanged between ages 75 and 80.Conclusion: We found a mild age‐associated decrease in regional brain volumes in this healthy cohort with well‐preserved cognitive functions. Visual assessment may not be sufficient for detecting mild progression of brain atrophy due to normal aging, whereas volumetry is more sensitive to capture these subtle changes.
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| 35. |
- Voevodskaya, Olga, et al.
(författare)
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The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer's disease
- 2014
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 6, s. 264-
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Tidskriftsartikel (refereegranskat)abstract
- In neurodegeneration research, normalization of regional volumes by intracranial volume (ICV) is important to estimate the extent of disease-driven atrophy. There is little agreement as to whether raw volumes, volume-to-ICV fractions or regional volumes from which the ICV factor has been regressed out should be used for volumetric brain imaging studies. Using multiple regional cortical and subcortical volumetric measures generated by Freesurfer (51 in total), the main aim of this study was to elucidate the implications of these adjustment approaches. Magnetic resonance imaging (MRI) data were analyzed from two large cohorts, the population-based PIVUS cohort (N = 406, all subjects age 75) and the Alzheimer disease Neuroimaging Initiative (ADNI) cohort (N = 724). Further, we studied whether the chosen ICV normalization approach influenced the relationship between hippocampus and cognition in the three diagnostic groups of the ADNI cohort (Alzheimer's disease, mild cognitive impairment, and healthy individuals). The ability of raw vs. adjusted hippocampal volumes to predict diagnostic status was also assessed. In both cohorts raw volumes correlate positively with ICV, but do not scale directly proportionally with it. The correlation direction is reversed for all volume-to-ICV fractions, except the lateral and third ventricles. Most gray matter fractions are larger in females, while lateral ventricle fractions are greater in males. Residual correction effectively eliminated the correlation between the regional volumes and ICV and removed gender differences. The association between hippocampal volumes and cognition was not altered by ICV normalization. Comparing prediction of diagnostic status using the different approaches, small but significant differences were found. The choice of normalization approach should be carefully considered when designing a volumetric brain imaging study.
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| 36. |
- Wahlund, L. O., et al.
(författare)
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Imaging biomarkers of dementia: recommended visual rating scales with teaching cases
- 2017
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Ingår i: Insights into Imaging. - : Springer Science and Business Media LLC. - 1869-4101. ; 8:1, s. 79-90
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Tidskriftsartikel (refereegranskat)abstract
- The diagnostic work up of dementia may benefit from structured reporting of CT and/or MRI and the use of standardised visual rating scales. We advocate a more widespread use of standardised scales as part of the workflow in clinical and research evaluation of dementia. We propose routine clinical use of rating scales for medial temporal atrophy (MTA), global cortical atrophy (GCA) and white matter hyperintensities (WMH). These scales can be used for evaluation of both CT and MRI and are efficient in routine imaging assessment in dementia, and may improve the accuracy of diagnosis. Our review provides detailed imaging examples of rating increments in each of these scales and a separate teaching file. The radiologist should relate visual ratings to the clinical assessment and other biomarkers to assist the clinician in the diagnostic decision.
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| 37. |
- Wahlund, Lars-Olof, et al.
(författare)
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Strukturell hjärnavbildning kan förbättra diagnostiken vid demens
- 2013
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 110:CEY4
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Tidskriftsartikel (refereegranskat)abstract
- Ökad kunskap om demenssjukdomar leder till att de diagnostiska kriterierna förändras. Diagnostiken kan förbättras med hjälp av hjärnavbildningsfynd.Med datortomografi (DT) och magnetisk resonanstomografi (MRT) kan medial temporallobsatrofi, global cerebral atrofi och förändringar i vit substans visualiseras och kvantifieras.För att ge optimal information om dessa förändringar krävs ett strukturerat radiologiskt DT-/MR-utlåtande. Imaging Cognitive Impairment Network (ICINET) har som huvudmål att föreslå ett standardiserat MRT-protokoll och kliniska utvärderingsverktyg (visuella skattningsskalor för MRT och DT).
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| 38. |
- Westman, Gabriel, et al.
(författare)
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Application of a Multiplex Herpesvirus Immunoassay in Alzheimer’s Disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating or confounding factors is yet to be established. Here, we present an application of a suspension matrix immunoassay (SMIA) allowing multiplex detection of IgG levels related to five human herpesviruses. Furthermore, we analysed peripheral blood mononuclear cells with a subtype specific HHV-6 PCR. The level of HHV-6 antibodies was lower in AD subjects (n=51) than in non-demented controls (ND, n=52), whereas there were no differences in HSV, VZV, CMV or EBV antibody levels between groups. AD and ND subjects presented with comparable DNA levels in PBMC and all positive samples were of subtype B. The SMIA protocol, applied to herpesvirus antigens, could provide an useful addition to the scientific arsenal. Whether HHV-6 is a factor in AD remains a hypothesis for future studies.
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| 39. |
- Westman, Gabriel, 1977-, et al.
(författare)
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Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis.
- 2021
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Ingår i: Clinical Microbiology and Infection. - : Elsevier. - 1198-743X .- 1469-0691. ; 27:8, s. 1131-1136
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE).METHODS: A total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months.RESULTS: Impaired cognitive performance significantly correlated with NFL levels (rho = -0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = -0.6249, p = 0.024) and age (z-score beta = -0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006).DISCUSSION: Our findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE.
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| 40. |
- Westman, Gabriel, 1977-, et al.
(författare)
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Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis
- 2018
-
Ingår i: Journal of Clinical Virology. - : Elsevier BV. - 1386-6532 .- 1873-5967. ; 103, s. 75-80
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Tidskriftsartikel (refereegranskat)abstract
- Background: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N-methyl-o-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance. Objectives: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance. Study design: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV-1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow-up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months. Results: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/ 48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance. Conclusions: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting.
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| 41. |
- Westman, Gabriel, et al.
(författare)
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Decreased HHV-6 IgG in Alzheimer's Disease
- 2017
-
Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Human herpesviruses have previously been implicated in the pathogenesis of Alzheimer's disease (AD) but whether they are causal, facilitating, or confounding factors is yet to be established. A total of 50 AD subjects and 52 non-demented (ND) controls were analyzed in a multiplex assay for IgG reactivity toward herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6). The HHV-6 IgG reactivity was significantly lower in AD subjects compared to ND controls, whereas there were no differences in HSV, VZV, or CMV antibody levels between the groups. Analysis of peripheral blood mononuclear cells with a subtype-specific HHV-6 PCR revealed no signs of reactivation, as AD and ND subjects presented with comparable HHV-6 DNA levels in PBMCs, and all positive samples were of subtype B. Whether HHV-6 is a factor in AD remains to be elucidated in future studies.
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| 42. |
- Westman, Gabriel, et al.
(författare)
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Decreased Proportion of Cytomegalovirus Specific CD8 T-Cells but No Signs of General Immunosenescence in Alzheimer's Disease
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e77921-
-
Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naive T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naive CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.
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| 43. |
- Westman, Gabriel, 1977-
(författare)
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Herpesvirus Infection and Immunity in Neurocognitive Disorders
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Herpesviruses have co-speciated with several vertebrate and invertebrate animals throughout the history of evolution. In the immunocompetent human host, primary infection is usually benign, whereafter the virus is brought into life-long latency. Viral reactivation can however cause severe disease in immunocompromised, and rarely also in immunocompetent, patients. The overall aim of this thesis was to study the immunologic effects of cytomegalovirus (CMV) and herpes simplex type 1 (HSV-1) infection in neurocognitive disorders.CMV is known to promote T-cell differentiation towards a more effector-oriented phenotype, similar to what is seen in the elderly. We have addressed the frequency of CMV-specific CD8+ T-cells in Alzheimer's disease (AD). Furthermore, we have investigated whether AD patients present with a different CMV-specific immune profile, overall CD8 phenotype or inflammatory cytokine response to anti-CD3/CD28 beads, CMV pp65 and amyloid beta. Subjects with AD presented with a lower proportion of CMV-specific CD8+ T-cells compared to non-demented (ND) controls, but no differences in overall CD8 differentiation were seen. Overall, AD subjects presented with a more pro-inflammatory peripheral blood mononuclear cell (PBMC) phenotype. When PBMCs were challenged with CD3/CD28-stimulation, CMV seropositive AD subjects presented with more IFN-γ release than both CMV seronegative AD subjects and CMV seropositive ND controls.For effective screening of humoral herpesvirus immunity, both in research and in clinical practice, efficient immunoassays are needed. We have addressed the methodology of multiplex herpesvirus immunoassays and related bioinformatics and investigated antibody levels in AD patients and ND controls. Subjects with AD presented with lower levels of human herpesvirus 6 (HHV-6) IgG. However, there was no difference in HHV-6 DNA levels in PBMCs between the groups.Herpes simplex encephalitis (HSE) is a devastating disease, where antiviral treatment has greatly decreased mortality but not eliminated the associated long-term neurocognitive morbidity. We have investigated the correlation between N-Methyl-D-Aspartate Receptor (NMDAR) autoimmunity and recovery of neurocognitive functions after HSE. Approximately one quarter of all HSE cases developed NMDAR autoantibodies within 3 months after onset of disease. Antibody development was associated with an impaired neurocognitive recovery during the two year follow-up and could become an important therapy guiding factor in the future.
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| 44. |
- Westman, Gabriel, et al.
(författare)
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Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer's Disease
- 2014
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5, s. e96779-
-
Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-gamma, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-alpha, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid beta (A beta) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-gamma levels after anti-CD3/ CD28 and CMV pp65 but not after Ab stimulation, compared to CMV seropositive ND controls. When analysing IFN-gamma response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.
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| 45. |
- Westman, Kasper, 1990, et al.
(författare)
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Diglyme based electrolytes for sodium-ion batteries
- 2018
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Ingår i: ACS Applied Energy Materials. - : American Chemical Society (ACS). - 2574-0962. ; 1:6, s. 2671-2680
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Tidskriftsartikel (refereegranskat)abstract
- Sodium-ion batteries (SIBs) are currently being considered for large-scale energy storage. Optimization of SIB electrolytes is, however, still largely lacking. Here we exhaustively evaluate NaPF6 in diglyme as an electrolyte of choice, via both physicochemical properties and extensive electrochemical tests including half as well as full cells. Fundamentally, the ionic conductivity is found to be quite comparable to carbonate based electrolytes and to obey the fractional Walden rule with viscosity. We find Na metal to work well as a reference electrode and the electrochemical stability, evaluated potentiostatically for various electrodes and corroborated by DFT calculations, to be satisfactory in the entire voltage range 0-4.4 V. Galvanostatic cycling at C/10 of half and full cells using Na3V2(PO4)(3) (NVP) or Na3V2(PO4)(2)F-3 (NVPF) as cathodes and hard carbon (HC) as anodes indicates rapid capacity fading in cells with HC anodes, possibly originating in a lack of a stable SEI or by trapping of sodium. Aiming to understand this capacity fade further, we conducted a GC/MS analysis to determine electrolyte reduction products and to propose reduction pathways, concluding that oligomer and/or alkoxide formation is possible. Overall, the promising results should warrant further investigations of diglyme based electrolytes for modern SIB development, albeit avoiding HC anodes.
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| 46. |
- Westman, Marie
(författare)
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mPGES-1 and the PGE2 pathway in arthritis
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostaglandins are a group of lipid mediators derived from essential fatty acids that act on cells in close proximity of their synthesis. Prostaglandins are produced in a cell specific manner by a variety of cells in response to physiological or pathological stimulation. Microsomal prostaglandin E synthase 1 (mPGES-1) constitutes an enzyme responsible for the inducible production of prostaglandin E2 (PGE2), a prostaglandin thought to play an important role in the pathogenesis of arthritis. In our studies we have demonstrated a pronounced expression of mPGES-1 and cyclooxygenase1 and -2 (COX-1 and -2), the enzymes upstream of mPGES-1, in synovial tissue from patients with rheumatoid arthritis (RA). mPGES-1 was located in synovial fibroblasts and macrophages, but no expression could be detected in B- or T-lymphocytes. During recent years, RA patients have been successfully treated with therapies depleting tumor necrosis factor (TNF). Despite the ability of TNF to induce the expression of mPGES-1 we could not detect a significant decrease of mPGES- 1 expression in synovial tissue from RA patients that had received therapy with TNF blockade. Another common treatment for RA is local injection of steroids. In synovial tissue biopsies from patients that received intraarticular steroid injection we could demonstrate a significant suppression of mpGES-1, COX-1 and COX-2 protein expression. In contrast, in vitro cultures of synovial fluid leukocytes stimulated with endotoxin, the addition of TNF blockers or steroids resulted in similar significant suppressive effects on the expression of COX-2 and mPGES-1 in monocytes. However, neither therapy with TNF blockade nor steroid treatment resulted in decreased expression of COX-1 in these cultures. Expression of COX isoenzymes has previously been described in both B-lymphocytes and Tlymphocytes. We demonstrated expression of mPGES-1 in stimulated synovial fluid Blymphocytes and peripheral blood B-lymphocytes. In these cells the expression of COX-1 and COX-2 were also induced after in vitro stimulation. However, we could not detect a basal expression of mPGES-1 or COX isoenzymes in unstimulated B-lymphocytes. Neither could expression of mPGES-1 be detected in unstimulated or stimulated T-lymphocytes. Several experimental models of RA exist, enabling a more controlled environment in studying the pathological mechanism underlying arthritis. Using one such model, collagen induced arthritis (CIA), we investigated the expression of mPGES-1 and the COX isoenzymes during the development of arthritis. Already at one week before onset of clinical disease we could demonstrate an increased expression of mPGES-1, this increase being sustained throughout the course of disease. Concomitantly, we could demonstrate increase of both COX-1 and COX-2 expression. All three enzymes were mainly located in fibroblast-like cells, but their expressions were also evident in macrophages and, COX-2 was also expressed in Blymphocytes. The presence of mPGES-1 in synovial tissue during RA and the finding that this enzyme is expressed early on in the disease process of experimental arthritis suggest an important role for mPGES-1-derived PGE2 in the pathogenesis of RA.
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| 47. |
- Widén, Johan, et al.
(författare)
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Diagnosis of external ventricular drainage related infections with real-time 16S PCR and third-generation 16S sequencing
- 2024
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 56:7, s. 521-530
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Investigate the performance of real-time 16S PCR and third-generation 16S sequencing in the diagnosis of external ventricular drain related infections (EVDRI).Methods: Subjects with suspected EVDRI were prospectively included at Uppsala University Hospital. Subjects were included into three groups: subjects with negative CSF culture with and without antibiotic treatment and subjects with positive CSF culture, respectively. CSF was analysed with real-time 16S PCR and third-generation 16S sequencing. Real-time 16S PCR positivity/negativity and number of 16S sequence reads were compared between groups. For culture positive subjects, species identification in third-generation sequencing and routine culture was compared.Results: 84 subjects were included. There were 18, 44 and 22 subjects in the three groups. Real-time PCR was positive in 17 of 22 subjects in the culture positive group and negative in 61 of the 62 subjects in the two culture negative groups. The sensitivity and specificity for real-time 16S PCR compared to culture was estimated to 77% and 98%, respectively. Species identification in 16S sequencing and culture was concordant in 20 of 22 subjects. The number of 16S sequence reads were significantly higher in the culture positive group than in both culture negative groups (p < 0.001). There was no significant difference in number of 16S sequences between the two culture negative groups.Conclusions: Real-time 16S PCR predict culture results with sufficient reliability. Third-generation 16S sequencing could enhance sensitivity and species identification in diagnostics of EVD-related infections. False negative culture results appear to be uncommon in patients with suspected EVDRI.
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| 48. |
- Widén, Johan, et al.
(författare)
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Ventriculostomy-related infections in subarachnoid hemorrhage patients - a retrospective study of incidence, etiology, and antimicrobial therapy
- 2017
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 159:2, s. 317-323
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Tidskriftsartikel (refereegranskat)abstract
- This study was performed to investigate the incidence and etiology of ventriculostomy-related infections (VRIs) in patients with subarachnoid hemorrhage (SAH) and to assess adherence to local clinical guidelines regarding empirical antimicrobial therapy and diagnostic routines. A total of 191 consecutive SAH patients treated in the neuro-intensive care unit of Uppsala University Hospital between 2010 and 2013 were included retrospectively. Information regarding cerebrospinal fluid samples, bacterial cultures, ventriculostomy treatment, patient characteristics, and antibiotic treatment were collected from electronic patient records. Eleven patients developed VRI, resulting in an incidence of 5.8% per patient, 5.4% per ventriculostomy catheter, and 4.1 per 1000 catheter days. Coagulase-negative staphylococci caused nine cases of VRI and Klebsiella pneumoniae and Staphylococcus aureus caused one each. Empirical VRI therapy was initiated on 97 occasions in 81 subjects (42.4%). Out of the 11 patients with VRI, four did not receive empirical antibiotic therapy before the positive culture result. The clinical actions performed after analysis of CSF samples were in line with the action suggested by the local guidelines in 307 out of 592 cases (51.9%). The incidence of VRI in our cohort was comparable to what has previously been reported. Coagulase-negative staphylococci was the most common agent. Our study demonstrates the difficulty in diagnosing VRI in SAH patients. Improved adherence to clinical guidelines could to some extent reduce the use of empirical antibiotic treatment, but better diagnostic methods and routines are needed.
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| 49. |
- Wikberg, Carl, et al.
(författare)
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Comparison Between the Montgomery-Asberg Depression Rating Scale–Self and the Beck Depression Inventory II in Primary Care
- 2015
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Ingår i: The Primary Care Companion for CNS Disorders. - 0160-6689 .- 1555-2101 .- 2155-7772. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The Montgomery-Asberg Depression Rating Scale–Self (MADRS-S) and the Beck Depression Inventory II (BDI-II) are commonly used self-assessment instruments for screening and diagnosis of depression. The BDI-II has 21 items and the MADRS-S has 9 items. These instruments have been tested with psychiatric inpatients but not in outpatient primary care, where most patients with symptoms of depression initially seek treatment. The purpose of this study was to compare these 2 instruments in the primary care setting. Method: Data were collected from 2 primary care randomized controlled trials that were performed from 2010 to 2013 in Sweden: the Primary Care Self-Assessment MADRS-S Study and Primary Care Internet-Based Cognitive Behavioral Therapy Study. There were 146 patients (73 patients each from both trials) who had newly diagnosed mild or moderate depression (per DSM-IV recommendations) and who had assessment with both the MADRS-S and BDI-II at primary care centers. Comparability and reliability of the instruments were estimated by Pearson product moment correlation and Cronbach α. Results: A good correlation was observed between the 2 instruments: 0.66 and 0.62 in the 2 study cohorts. The reliability within the 2 study cohorts was good for both MADRS-S (Cronbach α: 0.76 for both cohorts) and BDI-II items (Cronbach α: 0.88 and 0.85). Conclusions: The 2 instruments showed good comparability and reliability for low, middle, and high total depression scores. The MADRS-S may be used as a rapid, easily administered, and inexpensive tool in primary care and has results comparable to the BDI-II in all domains.
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