| 1. |
- Karlberg, Tobias, et al.
(författare)
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14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomonas are a common cause of hospital-acquired infections that may be lethal. ADP-ribosyltransferase activities of Pseudomonas exotoxin-S and -T depend on 14-3-3 proteins inside the host cell. By binding in the 14-3-3 phosphopeptide binding groove, an amphipathic C-terminal helix of ExoS and ExoT has been thought to be crucial for their activation. However, crystal structures of the 14-3-3 beta: ExoS and -ExoT complexes presented here reveal an extensive hydrophobic interface that is sufficient for complex formation and toxin activation. We show that C-terminally truncated ExoS ADP-ribosyltransferase domain lacking the amphipathic binding motif is active when co-expressed with 14-3-3. Moreover, swapping the amphipathic C-terminus with a fragment from Vibrio Vis toxin creates a 14-3-3 independent toxin that ADP-ribosylates known ExoS targets. Finally, we show that 14-3-3 stabilizes ExoS against thermal aggregation. Together, this indicates that 14-3-3 proteins activate exotoxin ADP-ribosyltransferase domains by chaperoning their hydrophobic surfaces independently of the amphipathic C-terminal segment.
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| 2. |
- Berling Holm, Katarina
(författare)
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The Chorda Tympani Nerve : Role in Taste Impairment in Middle Ear Disease and after Ear Surgery
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The chorda tympani nerve, also known as the taste nerve, runs uncovered through the middle ear cavity, a localization that exposes the nerve to pathological processes and surgical trauma in the middle ear. People operated on for otosclerosis tend to complain more about postoperative taste disturbances than those operated on for chronic otitis media. It has been suggested that this difference may be explained by gradual deterioration of chorda tympani nerve function caused by chronic otitis media infection and that further impairment caused by surgery is less noticeable in these patients.This thesis aimed to evaluate the function of the chorda tympani nerve, the effects of middle ear disease on taste and complications resulting from ear surgery for chronic otitis media or otosclerosis. This information will help to improve the ear surgeon’s ability to predict the prognosis of iatrogenic taste disturbances in patients with middle ear disease and after ear surgery.Taste was assessed using electrogustometry and the filter paper disc method before and after surgery for chronic otitis media or otosclerosis. Patients also completed questionnaires about symptoms and quality of life. The status of the chorda tympani nerve upon surgical opening of the ear and grading of the trauma to the nerve during the surgery were recorded. The ultrastructure of the chorda tympani nerve from healthy ears and from ears with chronic otitis media was examined. Electrogustometry and the filter paper disc method were evaluated.The results of electrogustometry and the filter paper disc method were highly reproducible, although their correlation was moderate. Patients with chronic otitis media, patients with a more traumatized nerve, female patients and younger patients were more likely to report postoperative taste disturbances. Most of the patients recovered their taste after 1 year. The quality of life study showed only minor changes after surgery. Electron microscopic observations of nerves from ears with chronic otitis media showed signs of structural degeneration, although signs of regeneration, such as sprouting were also observed. This results may explain the recovery of taste postoperatively and indicate that the nerve should be carefully handled during surgery.
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| 3. |
- Ekblad, Torun, et al.
(författare)
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Towards small molecule inhibitors of mono-ADP-ribosyltransferases
- 2015
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 95, s. 546-551
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Tidskriftsartikel (refereegranskat)abstract
- Protein ADP-ribosylation is a post-translational modification involved in DNA repair, protein degradation, transcription regulation, and epigenetic events. Intracellular ADP-ribosylation is catalyzed predominantly by ADP-ribosyltransferases with diphtheria toxin homology (ARTDs). The most prominent member of the ARTD family, poly(ADP-ribose) polymerase-1 (ARTD1/PARP1) has been a target for cancer drug development for decades. Current PARP inhibitors are generally non-selective, and inhibit the mono-ADP-ribosyltransferases with low potency. Here we describe the synthesis of acylated amino benzamides and screening against the mono-ADP-ribosyltransferases ARTD7/PARP15, ARTD8/PARP14, ARTD10/PARP10, and the poly-ADP-ribosyltransferase ARTD1/PARP1. The most potent compound inhibits ARTD10 with sub-micromolar IC50.
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| 4. |
- Gorcenco, Sorina, et al.
(författare)
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Ataxia-pancytopenia syndrome with SAMD9L mutations
- 2017
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Ingår i: Neurology: Genetics. - 2376-7839. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
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| 5. |
- Mochalina, Natalia, et al.
(författare)
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ABC om Yrsel på akuten
- 2015
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Ingår i: Läkartidningen. - 0023-7205. ; 112:9, s. 399-404
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Tidskriftsartikel (refereegranskat)abstract
- The majority of patients who present to the Emergency Department with vertigo suffer from benign conditions. However, a few percent of these patients have life-threatening conditions, such as a cerebellar stroke. The HINTS clinical decision rule (Head-Impulse test, Nystagmus, Test-of-Skew) allows the physician to identify patients with an acute vestibular syndrome of central origin. HINTS is more sensitive than early magnetic resonance imaging. There is no role for computed tomography in the evaluation of patients with isolated acute vestibular syndrome in the Emergency Department. For patients with benign paroxysmal positional vertigo, simple reposition maneuvers are effective for symptom relief.
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| 6. |
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| 7. |
- Sjögren, Julia, et al.
(författare)
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Functional Head Impulse Testing Might Be Useful for Assessing Vestibular Compensation After Unilateral Vestibular Loss
- 2018
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 9:NOV
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Tidskriftsartikel (refereegranskat)abstract
- Background: Loss of the vestibulo-ocular reflex (VOR) affects visual acuity during head movements. Previous studies have shown that compensatory eye-saccades improve visual acuity and that the timing of the saccade is important. Most of the tests involved in testing VOR are made with passive head movement, that do not necessarily reflect the activities of daily living and thus not being proportionate to symptoms and distresses of the patients. Objective: To examine differences between active (self-generated) or passive (imposed by the examiner) head rotations while trying to maintain visual focus on a target. Method: Nine subjects with unilateral total vestibular loss were recruited (4 men and 5 women, mean age 47) and tested with video Head Impulse Test (vHIT) and Head Impulse Testing Device-Functional Test (HITD-FT) during passive and active movements while looking at a target. VOR gain, latencies of covert saccades, frequency of covert saccades and visual acuity were measured and analyzed. Results: Active head-impulses toward the lesioned side resulted in better visual acuity (p = 0.002) compared to conventional passive head-impulses and generated eye-saccades with significantly shorter latencies (p = 0.004). Active movements to the lesioned side generated dynamic visual acuities that were as good as when testing the intact side. Conclusion: Actively generated head impulses resulted in normal dynamic visual acuity, even when performed toward the side of total vestibular loss. This might be attributed to the appearance of short-latency covert saccades. The results show a strong relationship between self-generated movements, latencies of covert saccades and outcome in HITD-FT, i.e., a better dynamic visual function with less retinal slip which is the main function of the VOR. The method of active HITD-FT might be valuable in assessing vestibular compensation and monitoring ongoing vestibular rehabilitation.
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| 8. |
- Sjögren, Julia, et al.
(författare)
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Steroids for Acute Vestibular Neuronitis-the Earlier the Treatment, the Better the Outcome?
- 2019
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Ingår i: Otology & Neurotology. - 1537-4505. ; 40:3, s. 372-374
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To present findings that suggest steroid treatment within 24 hours of onset of vestibular neuronitis results in better restitution of vestibular function than treatment between 25 and 72 hours. PATIENTS: Thirty-three consecutive patients (17 men, 16 women, mean age 57 yr, range 17-85 yr) with acute vestibular neuronitis and treated with steroids within 72 hours after symptom onset. Patients were divided into two groups depending on if they were treated within the first 24 hours or not. INTERVENTIONS: Oral prednisolone 50 mg/d for 5 days with tapering of doses for the next 5 days, or combined with initial intravenous betamethasone 8 mg the first 1 to 2 days if the patient was nauseous. MAIN OUTCOME MEASURES: Proportion of patients with normal caloric test result (canal paresis value < 32%) at follow-up after 3 or 12 months. RESULTS: All 9 patients (100%) treated within 24 hours from onset of vestibular neuronitis had normal caloric test results at follow-up after 3 months, as compared with 14 of 24 (58%) of the patients treated between 25 and 72 hours (p < 0,05, Fisher's exact test). CONCLUSIONS: The timing of steroid treatment of vestibular neuronitis may be of importance for subsequent vestibular restitution, and hence, for both time to recovery and late symptoms according to the literature.
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| 9. |
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| 10. |
- Tjernström, Fredrik, et al.
(författare)
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Hearing and Vestibular Function After Preoperative Intratympanic Gentamicin Therapy for Vestibular Schwanomma as Part of Vestibular Prehab
- 2016
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Ingår i: Ear and Hearing. - 0196-0202. ; 37:6, s. 744-750
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:: To evaluate auditory and vestibular function after presurgical treatment with gentamicin in schwannoma patients. BACKGROUND:: The vestibular PREHAB protocol aims at diminishing the remaining vestibular function before vestibular schwannoma surgery, to ensure less acute symptoms from surgery, and initiate a more efficient vestibular rehabilitation already before surgery. However, the potential cochleotoxicity of gentamicin is a concern, since modern schwannoma surgery strives to preserve hearing. STUDY DESIGN:: Retrospective study. SETTING:: University hospital. PATIENTS:: Seventeen patients diagnosed with vestibular schwannoma between 2004 and 2011, and took part in vestibular PREHAB program. The patients were of age 21 to 66 years (mean 48.8), 9 females and 8 males. INTERVENTION:: Intratympanic gentamicin installations before surgery as part of the vestibular PREHAB. MAIN OUTCOME MEASURES:: Hearing thresholds, word recognition score, caloric response, subjective visual vertical and horizontal, cVEMP, and vestibular impulse tests. RESULTS:: Combined analysis of frequency and hearing threshold showed a significant decrease after gentamicin therapy (p <0.001). Pure-tone average decreased with 7.1 ± 8.5 dB (p = 0.004), and speech recognition with 10%. The treatment resulted in unilateral vestibular deafferentation with no notable reaction to bithermal caloric irrigation (reduction 64%, p <0.001), loss of the vestibulo-ocular response measured by the head-impulse test, and deviation of subjective horizontal/vertical to the side of the lesion (+2.2 degrees, p = 0.010). CONCLUSIONS:: Intratympanic installations of gentamicin, as part of the vestibular PREHAB, result in unilateral vestibular deafferentation, but constitute a definite risk for high-frequency hearing loss. The hearing results are in line with those reported upon when treating Menière’s disease.
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