| 1. |
- Bestas, Burcu, et al.
(författare)
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Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model
- 2014
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 124:9, s. 4067-4081
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Tidskriftsartikel (refereegranskat)abstract
- X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.
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| 2. |
- Dahlgren, Linnea, et al.
(författare)
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"Att bli bemött med förståelse, det är viktigare än att allt det tekniska är 'wow' liksom". Studenters erfarenheter av att studera med talböcker på Malmö universitet
- 2022
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Problemformulering:Vid Malmö universitet har både bibliotekets tillgänglighetsgrupp och annan personal som arbetar med pedagogiskt stöd märkt en ökning i antalet studenter som söker hjälp i sina studier. Omkring 8% av Malmö universitets studenter använder talbokstjänsten Legimus. För att säkerställa att dessa studenter kan studera på lika villkor som andra är det av stor vikt att undersöka deras erfarenheter och attityder till universitetets stödinsatser. Syftet med studien var att undersöka studenternas erfarenheter av att studera med talböcker och andra stödprogram, samt hur de upplever det stöd som biblioteket erbjuder. Metod:För att undersöka studenternas erfarenheter av att studera med lässtöd genomfördes en fokusgruppsstudie. Studien föregicks av en enkät som hösten 2021 skickades till studenter som haft talboksgenomgång samma termin, där deltagarna tillfrågades om hur de upplevde talboksgenomgången samt om deras attityder till de stödprogram som erbjuds. Deltagare till fokusgrupperna rekryterades via enkäten. En fokusgrupp med fyra studenter genomfördes på plats i biblioteket och en fokusgrupp med tre studenter genomfördes via Zoom under våren 2022. Intervjuerna tog omkring en timme. Två bibliotekarier närvarande vid fokusgrupperna där en fungerade som moderator/samtalsledare och en tog anteckningar. Intervjuerna spelades också in. Materialet från inspelningarna transkriberades sedan till text. Transkriberingen bearbetades därefter genom att teman identifierades, sammanställdes och analyserades.Resultat:Legimus och andra stödverktyg har en stor betydelse i deltagarnas studievardag. Flera uttryckte att de inte hade tagit steget att börja studera om de inte hade känt till att stödet fanns, och att de hade haft det mycket svårare att klara studierna utan stöd. Studenterna uppgav bland annat att stödprogrammen förbättrar deras läshastighet och arbetsminne samt hjälper dem att strukturera sina studier. Lika viktigt som de pedagogiska aspekterna är det emotionella stöd som stödprogrammen medför. Flera av deltagarna berättade att Legimus besparat dem mycket stress och oro. Tillgången till kurslitteraturen i talboksform har en lugnande effekt och hjälper studenterna att komma igång med studierna. Stödprogrammen har också gett deltagarna en större självständighet och självförtroende i studierna. Studenterna är i huvudsak nöjda med bemötandet de fått av lärare och annan personal vid Malmö universitet. Personlig kontakt med representanter från universitetet är av stor vikt och underlättar för studenterna att ta till sig viktig information. En vanlig utmaning för deltagarna är att ständigt behöva påtala fall av bristande tillgänglighet och att “stå upp för sig själv”. Brister i talsyntes togs upp som ett problem, dels upplevs rösterna som tråkiga och monotona, vilket försvårar koncentrationen, dels förhindras förståelsen av felaktigt uttal och betoning. Andra problem är sena tillägg till kurslitteraturen och böcker som enbart finns tillgängliga som talbok utan text. Studenterna efterfrågade också bättre utformade hemsidor med mindre text och mer video samt ökad kunskap om läsnedsättningar bland lärare och annan personal. Studien synliggör den avgörande roll som talböcker och andra stödinsatser spelar för att tillgängliggöra högre studier för studenter med läsnedsättningar och pekar på ett behov av insatser för att ytterligare förbättra stödet. Studien belyser också vikten av gott bemötande och personlig kontakt, där bibliotekarien kan spela en viktig roll i mötet med studenter med läsnedsättningar.
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| 3. |
- Dahlgren, Linnea, et al.
(författare)
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Studenters erfarenheter av att studera med talböcker och stödprogram
- 2022
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Rapport (populärvet., debatt m.m.)abstract
- Vid Malmö universitet uppger både bibliotekets tillgänglighetsgrupp och annan personal som arbetar med pedagogiskt stöd att de har märkt en ökning i antalet studenter som söker hjälp i sina studier.Våren 2022 hade Malmö universitetsbibliotek 1 925 aktiva Legimusanvändare av totalt 24 000 studenter vid lärosätet. Detta innebär att omkring 8% av Malmö universitets studenter använder Legimus, vilket kan jämföras med Lunds universitet, där omkring 3% av studenterna använde Legimus under 2021.Som ett led i att förbättra arbetet med studenter med läsnedsättningar genomförde biblioteket under våren 2022 en kvalitativ fokusgruppsstudie med studenter som använder Legimus och andra stödverktyg, för att undersöka deras erfarenheter av att studera med talböcker och deras attityder till bibliotekets stöd.
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| 4. |
- Geny, Sylvain, et al.
(författare)
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Next-generation bis-locked nucleic acids with stacking linker and 2 '-glycylamino-LNA show enhanced DNA invasion into supercoiled duplexes
- 2016
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:5, s. 2007-2019
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Tidskriftsartikel (refereegranskat)abstract
- Targeting and invading double-stranded DNA with synthetic oligonucleotides under physiological conditions remain a challenge. Bis-locked nucleic acids (bisLNAs) are clamp-forming oligonucleotides able to invade into supercoiled DNA via combined Hoogsteen and Watson-Crick binding. To improve the bisLNA design, we investigated its mechanism of binding. Our results suggest that bisLNAs bind via Hoogsteen-arm first, followed by Watson-Crick arm invasion, initiated at the tail. Based on this proposed hybridization mechanism, we designed next-generation bisLNAs with a novel linker able to stack to adjacent nucleobases, a new strategy previously not applied for any type of clamp-constructs. Although the Hoogsteen-arm limits the invasion, upon incorporation of the stacking linker, bisLNA invasion is significantly more efficient than for non-clamp, or nucleotide-linker containing LNA-constructs. Further improvements were obtained by substituting LNA with 2'-glycylamino-LNA, contributing a positive charge. For regular bisLNAs a 14-nt tail significantly enhances invasion. However, when two stacking linkers were incorporated, tail-less bisLNAs were able to efficiently invade. Finally, successful targeting of plasmids inside bacteria clearly demonstrates that strand invasion can take place in a biologically relevant context.
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| 5. |
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| 6. |
- Henriksson, Malin, et al.
(författare)
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Effects of exercise on symptoms of anxiety in primary care patients: A randomized controlled trial.
- 2022
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Ingår i: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 297, s. 26-34
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Tidskriftsartikel (refereegranskat)abstract
- There is a need for high-quality research regarding exercise interventions for persons with anxiety disorders. We investigate whether a 12-week exercise intervention, with different intensities, could reduce anxiety symptoms in patients with anxiety disorders.286 patients were recruited from primary care in Sweden. Severity of symptoms was self-assessed using the Beck Anxiety Inventory (BAI) and the Montgomery Åsberg Depression Rating Scale (MADRS-S). Participants were randomly assigned to one of two group exercise programs with cardiorespiratory and resistance training and one control/standard treatment non-exercise group, with 1:1:1 allocation.Patients in both exercise groups showed larger improvements in both anxiety and depressive symptoms compared to the control group. No differences in effect sizes were found between the two groups. To study a clinically relevant improvement, BAI and MADRS-S were dichotomized with the mean change in the control group as reference. In adjusted models the odds ratio for improved symptoms of anxiety after low-intensity training was 3.62 (CI 1.34-9.76) and after moderate/high intensity 4.88 (CI 1.66-14.39), for depressive symptoms 4.96 (CI 1.81-13.6) and 4.36 (CI 1.57-12.08) respectively. There was a significant intensity trend for improvement in anxiety symptoms.The use of self-rating measures which bears the risk of an under- or overestimation of symptoms.A 12-week group exercise program proved effective for patients with anxiety syndromes in primary care. These findings strengthen the view of physical exercise as an effective treatment and could be more frequently made available in clinical practice for persons with anxiety issues.
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| 7. |
- Lundin, Karin, et al.
(författare)
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Cochlear implantation in the elderly
- 2013
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Ingår i: Cochlear Implants International. - 1467-0100 .- 1754-7628. ; 14:2, s. 92-97
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To analyse complications and outcome of cochlear implant (CI) treatment in seniors receiving CIs during a 10-year period.METHODS:A total of 28 patients, 79 years or older (mean age 81.6 years), were evaluated and compared with a younger group of 76 patients, 20-60 years old (mean age 48.9 years). A retrospective study of the patients' records was performed. Data on per- and post-operative complications, pre- and post-operative speech perception, estimated cognitive skills, and social situation was extracted. A subjective score was assessed and correlated with post-operative performance.RESULTS: No severe per- or post-operative surgical complications were noted. Speech perception improved significantly after surgery (P < 0.001). The younger age group showed better results post-operatively for monosyllabic words (P < 0.01) compared with the older group with no difference seen for bi-syllabic words. In both the groups, there were no significant differences between patients living with or without social support.DISCUSSION:CI surgery for patients 79 years or older was well tolerated. Patients benefited greatly from the device with improved hearing. CI should not be denied older individuals who are otherwise in good health. Non-use in the elderly was associated with post-operative vertigo and tinnitus, severe disease and limited social support.
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| 8. |
- Lundin, Karin E., et al.
(författare)
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Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report
- 2018
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Ingår i: BMC Pediatrics. - : Springer. - 1471-2431 .- 1471-2431. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 +3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naive CD4(+) and CD8(+) T-cells, increased number of activated effector memory CD8(+) T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient's cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.
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| 9. |
- Lundin, Karin E, et al.
(författare)
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Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene
- 2015
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Ingår i: Clinical Immunology. - : Elsevier. - 1521-6616 .- 1521-7035. ; 161:2, s. 366-372
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Tidskriftsartikel (refereegranskat)abstract
- Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetylglucosamine-l-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.
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| 10. |
- Lundin, Karin, et al.
(författare)
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Experiences and Results from Cochlear Implantation in Patients with Long Duration of Deafness
- 2014
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Ingår i: Audiology & Neurotology Extra. - : S. Karger AG. - 1664-5537. ; 4:2, s. 46-55
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Tidskriftsartikel (refereegranskat)abstract
- Objective:The aim of the present study was to gauge factors that influence the outcome of cochlear implants (CI) in patients who have been deaf for an extended period.Patients and Methods:Twelve adult cases (13 ears) were operated on at the CI unit in Uppsala during the period of 2002-2013. These patients had a deafness duration ranging between 20 and 72 years in the implanted ear and severe to profound hearing loss or deafness in the other ear. Data concerning pre- and postoperative speech perception, deafness duration, hearing/deafness duration in the contralateral ear, age at implantation, intraoperative electrophysiological measurements, cause of deafness, and user status were collected.Results:Eleven of 12 patients (13 ears) benefitted from CI treatment.Conclusion: The overall hearing experience, deafness duration, and age at onset of deafness are important issues to consider prior to CI.
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