| 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. |
- 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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| 3. |
- 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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| 4. |
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| 5. |
- Sassi, Atfa, et al.
(författare)
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Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels
- 2014
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 133:5, s. 1410-U681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. Objective: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. Methods: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. Results: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p. Glu340del and p. Leu83Ser). A third homozygous mutation (p. Asp502Tyr) and the p. Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. Conclusion: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.
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| 6. |
- Siegbahn, Malin, et al.
(författare)
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Auditory Brainstem Implants (ABIs) : 20 Years of Clinical Experience in Uppsala, Sweden
- 2014
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 134:10, s. 1052-1061
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Tidskriftsartikel (refereegranskat)abstract
- CONCLUSIONS:Even though sound perception may be limited after treatment with an auditory brainstem implant (ABI), it provides benefits and should be selectively offered to patients. Importantly the patients must be motivated, given reasonable expectations of outcome and offered long-term rehabilitation with a considerable 'learn to listen' period with the implant device.OBJECTIVES:To describe the clinical experiences and results of 24 ABI surgeries performed in Uppsala University Hospital between 1993 and 2013.METHODS:Most patients (n = 20) suffered from neurofibromatosis type 2 (NF2); a few patients (n = 4) were paediatric non-NF2 patients. The files were searched for information on the presurgery size of the vestibular schwannoma, whether the patient had undergone gamma knife treatment, the surgical approach, the side effects of the surgery and of the use of the implant, the electrode activation pattern and implant use, and categories of auditory performance (CAP) score.RESULTS:Our results show that many patients greatly benefited from an ABI, and most of the patients used their implants even though the hearing improvements usually consisted of awareness of surrounding sounds and improved lip-reading. No severe side effects were observed from implant stimulation.
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