| 1. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 2. |
- Dherbecourt, J. B., et al.
(författare)
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Design and pre-development of an airborne multi-species differential absorption Lidar system for water vapor and HDO isotope, carbon dioxide, and methane observation
- 2021
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE-Intl Soc Optical Eng.
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Konferensbidrag (refereegranskat)abstract
- We report on the current design and preliminary developments of the airborne Lidar Emitter and Multi-species greenhouse gases Observation iNstrument (LEMON), which is aiming at probing H2O and its isotope HDO at 1982 nm, CO2 at 2051 nm, and potentially CH4 at 2290 nm, with the Differential Absorption Lidar method (DIAL). The infrared emitter is based on the combination of two Nested Cavity OPOs (NesCOPOs) with a single optical parametric amplifier (OPA) line for high-energy pulse generation. This configuration is enabled by the use of high-aperture periodically poled KTP crystals (PPKTP), which provide efficient amplification in the spectral range of interest around 2 μm with slight temperature adjustments. The parametric stages are pumped with a Nd:YAG laser providing 200 mJ nanosecond double pulses at 75 Hz. According to parametric conversion simulations supported by current laboratory experiments, output energies in the 40 - 50 mJ range are expected in the extracted signal beam whilst maintaining a good beam quality (M2 < 2). The ruler for all the optical frequencies involved in the system is planned to be provided by a GPS referenced frequency comb with large mode spacing (1 GHz) against which the emitter output pulses can be heterodyned. The frequency precision measurement is expected to be better than 200 kHz for the optical frequencies of interest. The presentation will give an overview of the key elements of design and of preliminary experimental characterizations of sub-systems building blocks.
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| 3. |
- Dherbecourt, J. B., et al.
(författare)
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Lidar Emitter and Multi-species greenhouse gases Observation iNstrument (LEMON) : advances on a multi-species differential absorption Lidar system
- 2022
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Ingår i: 73rd International Astronautical Congress, IAC 2022. - : International Astronautical Federation, IAF.
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Konferensbidrag (refereegranskat)abstract
- In the frame of LEMON project (Lidar Emitter and Multi-species greenhouse gases Observation iNstrument - European Union's Horizon 2020 research and innovation program, GA n°821868), we are developing a multi-species differential absorption Lidar (DIAL). The goal is to benefit from innovative technological developments in terms of optical emitter, spectral reference, to be able to address H2O and its isotope HDO at 1982 nm, CO2 at 2051 nm, and potentially CH4 at 2290 nm, for future ground-based range-resolved DIAL sensing, and with the prospect of future airborne integrated-path DIAL (IPDA). The infrared emitter is based on the combination of two specific, patented, no-seeder Nested Cavity OPOs (NesCOPOs) coupled to a single optical parametric amplifier (OPA) line for high energy pulses generation. Specific developments are also pursued on the frequency reference for the emitter, which is planned to be provided by a GPS referenced frequency comb against which the emitter output pulses can be heterodyned. Besides the instrument design, specific tests experiments have been carried out, covering a wide panel of activities: radiation testing of some critical components to assess the potential of some key components for future space applications, emitter and frequency reference testing, preliminary DIAL tests with laboratory test-beds and comparison with specific in-situ calibration instruments as well as additional innovative techniques evaluation for the emitter. The final instrument design was carried out and the sub-units are now being built.
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| 4. |
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| 5. |
- Yang, W., et al.
(författare)
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Immunogenic neoantigens derived from gene fusions stimulate T cell responses
- 2019
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.
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| 6. |
- Rivas, Manuel A., et al.
(författare)
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A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis
- 2016
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Ingår i: Nature Communications. - London, United Kingdom : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.
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| 7. |
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| 8. |
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| 9. |
- Dalin, Peter A., et al.
(författare)
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Wave influence on polar mesosphere summer echoes above Wasa : experimental and model studies
- 2012
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Ingår i: Annales Geophysicae. - : Copernicus GmbH. - 0992-7689 .- 1432-0576. ; 30:8, s. 1143-1157
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive analysis of the wave activity in the Antarctic summer mesopause is performed using polar mesospheric summer echoes (PMSE) measurements for December 2010–January 2011. The 2-day planetary wave is a statistically significant periodic oscillation in the power spectrum density of PMSE power. The strongest periodic oscillation in the power spectrum belongs to the diurnal solar tide; the semi-diurnal solar tide is found to be a highly significant harmonic oscillation as well. The inertial-gravity waves are extensively studied by means of PMSE power and wind components. The strongest gravity waves are observed at periods of about 1, 1.4, 2.5 and 4 h, with characteristic horizontal wavelengths of 28, 36, 157 and 252 km, respectively. The gravity waves propagate approximately in the west-east direction over Wasa (Antarctica). A detailed comparison between theoretical and experimental volume reflectivity of PMSE, measured at Wasa, is made. It is demonstrated that a new expression for PMSE reflectivity derived by Varney et al. (2011) is able to adequately describe PMSE profiles both in the magnitude and in height variations. The best agreement, within 30%, is achieved when mean values of neutral atmospheric parameters are utilized. The largest contribution to the formation and variability of the PMSE layer is explained by the ice number density and its height gradient, followed by wave-induced perturbations in buoyancy period and the turbulent energy dissipation rate
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| 10. |
- Dalin, P., et al.
(författare)
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Studies of noctilucent clouds from the stratosphere during the SONC balloon-borne experiment in 2021
- 2022
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Ingår i: Journal of Atmospheric and Solar-Terrestrial Physics. - : Elsevier BV. - 1364-6826 .- 1879-1824. ; 240
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Tidskriftsartikel (refereegranskat)abstract
- On the night 16–17 August 2021, a balloon-borne experiment called Stratospheric Observations of Noctilucent Clouds (SONC) was successfully performed. A big scientific balloon, having onboard three automated cameras for studies of noctilucent clouds (NLC), was launched to 32.7 km altitude from Esrange (northern Sweden). All three NLC cameras and electronics were completely operational in the stratosphere for more than 10 h at low temperatures of about −30 °C. Two wide angle cameras registered an extended NLC field of about 1700 km long in the twilight sky sector from the north-west to the north-east of Esrange. NLC were of a moderate brightness and were located at high latitudes between 68° and 71°N. The NLC field was located in a cold area (138–142 K) below the frost point temperature (145–148 K) in the mesopause region that was confirmed by Aura/MLS satellite and Esrange lidar measurements. The balloon-borne NLC measurements were accompanied by ground-based lidar and radar measurements. The latter have registered Polar Mesosphere Summer Echoes (PMSE) in the same volume of the summer mesopause along with NLC observed from the stratosphere that has been performed for the first time above northern Scandinavia. We describe the technique and method of the NLC observation from the stratosphere as well as present the first scientific results of the SONC experiment.
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| 11. |
- Eriksson, D, et al.
(författare)
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Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease
- 2016
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 595-608
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology.METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls.RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10(-15) , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex.CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.
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| 12. |
- Johannisson, Anders, et al.
(författare)
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Colloidal centrifugation with Androcoll-E (TM) prolongs stallion sperm motility, viability and chromatin integrity
- 2009
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Ingår i: Animal Reproduction Science. - : Elsevier Masson. - 0378-4320 .- 1873-2232. ; 116:1-2, s. 119-128
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Forskningsöversikt (refereegranskat)abstract
- The objective was to investigate the changes in stallion sperm quality (sperm motility, viability, membrane integrity and chromatin integrity) occurring during cool storage, and to study the effect of sperm selection by single layer colloidal centrifugation on these parameters of sperm quality. Spermatozoa from 3 stallions (10 ejaculates, 3-4 per stallion) were selected by centrifugation through a single layer of colloid (SLC). The resulting sperm preparations and the control samples (extended but unselected semen samples) were stored at 5 degrees C for 48 h. Assessments of sperm quality, such as sperm motility, viability (SYBR-14/PI staining), membrane stability (Annexin-V/PI staining) and chromatin integrity, were performed on aliquots of the selected sperm preparations and unselected samples on the day of collection (3 h) and after 24 and 48 h of storage. In the SLC-selected sperm samples, sperm motility, sperm viability, proportions of spermatozoa with normal morphology and with intact chromatin were significantly better than in unselected samples (motility: 77 +/- 4% vs. 64 +/- 8% at 3 h; P less than 0.001; viability: 79.5 +/- 9% vs. 64.7 +/- 9%, P less than 0.001: normal morphology 89 +/- 6% vs. 69 9%; chromatin integrity DFI 11.3 +/- 5% vs. 22.1 +/- 10%). Membrane stability, however, was not different in the SLC-selected and unselected samples (74.6 +/- 8% vs. 69.3 +/- 8%). The deterioration seen in sperm quality in the unselected samples was prevented by SLC, so that sperm viability, membrane stability and chromatin integrity were unchanged in the selected samples by 48 h compared to 3 h (Pless than0.001), whereas the unselected samples were significantly worse by 48 h (Pless than0.001). Furthermore, it should be possible to send an aliquot of a normal insemination dose (i.e. unselected spermatozoa) overnight to a reference laboratory for analysis of both plasma membrane and chromatin integrity. In conclusion, centrifugation of stallion spermatozoa through a single layer of colloid is a useful technique for selecting the best spermatozoa from an ejaculate and, moreover, sperm quality is maintained during storage. (C) 2009 Elsevier B.V. All rights reserved.
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| 13. |
- Li, Dalin, et al.
(författare)
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A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition
- 2016
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Ingår i: Gastroenterology. - : Saunders Elsevier. - 0016-5085 .- 1528-0012. ; 151:4, s. 724-732
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).Methods: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.Results: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).Conclusions: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
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| 14. |
- Morrell, Jane M., et al.
(författare)
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Sperm morphology and chromatin integrity in Swedish warmblood stallions and their relationship to pregnancy rates
- 2008
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Ingår i: Acta Veterinaria Scandinavica. - : BioMed Central. - 0044-605X .- 1751-0147. ; 50
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Tidskriftsartikel (refereegranskat)abstract
- Background: Artificial insemination is not as widely used in horses as in other domestic species, such as dairy cattle and pigs, partly because of the wide variation in sperm quality between stallion ejaculates and partly due to decreased fertility following the use of cooled transported spermatozoa. Furthermore, predictive tests for sperm fertilising ability are lacking. The objective of the present study was to assess sperm morphology and chromatin integrity in ejaculates obtained from II warmblood breeding stallions in Sweden, and to evaluate the relationship of these parameters to pregnancy rates to investigate the possibility of using these tests predictively. Methods: Aliquots from fortyone ejaculates, obtained as part of the normal semen collection schedule at the Swedish National Stud, were used for morphological analysis by light microscopy, whereas thirtyseven were used for chromatin analysis (SCSA) by flow cytometry. The outcome of inseminations using these ejaculates was made available later in the same year. Results: Ranges for the different parameters were as follows; normal morphology, 27-79.5%; DNA-fragmentation index (DFI), 4.8-19.0%; standard deviation of DNA fragmentation index (SD_DFI) 41.5-98.9, and mean of DNA fragmentation index (mean_DFI), 267.7-319.5. There was considerable variation among stallions, which was statistically significant for all these parameters except for mean_DFI (P less than 0.001, P less than 0.01, P less than 0.001 and P less than 0.2 respectively). There was a negative relationship between normal morphology and DFI (P less than 0.05), between normal morphology and SD_DFI (P less than 0.001), and between normal morphology and mean_DFI (P less than 0.05). For specific defects, there was a direct relationship between the incidence of pear-shaped sperm heads and DFI (P less than 0.05), and also nuclear pouches and DFI (P less than 0.001), indicating that either morphological analysis or chromatin analysis was able to identify abnormalities in spermiogenesis that could compromise DNA-integrity. A positive relationship was found between normal morphology and pregnancy rate following insemination (r = 0.789; P less than 0.01) and a negative relationship existed between DFI and pregnancy rate (r = -0.63; P less than 0.05). Sperm motility, assessed subjectively, was not related to conception rate. Conclusion: Either or both of the parameters, sperm morphology and sperm chromatin integrity, seem to be useful in predicting the fertilising ability of stallion ejaculates, particularly in determining cases of sub-fertility.
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| 15. |
- Popler, Jonathan, et al.
(författare)
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Autoimmune polyendocrine syndrome type 1 : Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab
- 2012
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Ingår i: Pediatric Pulmonology. - : Wiley. - 8755-6863 .- 1099-0496. ; 47:1, s. 84-87
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECD) is a disorder caused by mutations in the autoimmune regulator (AIRE) gene. In some APS-1 patients, significant pulmonary disease is observed. Autoantibodies directed against the potassium channel regulatory protein (KCNRG), found in epithelial cells of terminal bronchioles, have been suggested as a marker for pulmonary disease in APS-1 patients. We report two patients with APS-1; one with and one without lung disease. Patient 1 had multiple admissions for pneumonia and respiratory insufficiency, required non-invasive ventilation, and had findings of bronchiectasis on thoracic imaging and significant lymphocytic infiltrates of the airways on lung biopsy. To verify the autoimmune cause of pulmonary symptoms APS-1 patients, both were tested in a blinded manner for the presence of autoantibodies to KCNRG in serum. We found that only Patient 1 had autoantibodies present. Additionally, Patient 1 had progressive disease despite treatment with several immunomodulating agents, including corticosteroids, azathioprine, and mycophenolate. Patient 1 had a lung biopsy performed which was consistent with B cell lymphocytic aggregates. Rituximab treatment was initiated with apparent good response. This report illustrates the practical use of KCNRG autoantibodies to identify APS-1 patients with pulmonary risk and the successful use of the monoclonal antibody, Rituximab, to treat pulmonary disease in APS-1 patients.
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| 16. |
- Ström, Lena, et al.
(författare)
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Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility
- 2021
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Ingår i: BMC Veterinary Research. - : BioMed Central (BMC). - 1746-6148. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment.Results Atropine sulfate (1mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 mu g/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9L/h?kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols.Conclusions Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 mu g/kg/24h offers a safe alternative.
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