| 1. |
- Andersson, C David, et al.
(författare)
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Discovery of Ligands for ADP-Ribosyltransferases via Docking-Based Virtual Screening
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:17, s. 7706-7718
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Tidskriftsartikel (refereegranskat)abstract
- The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyses the transfer of ADP-ribose units onto substrate proteins, using nicotinamide adenine dinucleotide (NAD(+)) as a co-substrate. They have a documented role in chromatin remodelling and DNA repair; and inhibitors of ARTD1 and 2 (PARP1 and 2) are currently in clinical trials for the treatment of cancer. The detailed function of most other ARTDs is still unknown. Using virtual screening we identified small ligands of ARTD7 (PARP15/BAL3) and ARTD8 (PARP14/BAL2). Thermal-shift assays confirmed that 16 compounds, belonging to eight structural classes, bound to ARTD7/ARTD8. Affinity measurements with isothermal titration calorimetry for two isomers of the most promising hit compound confirmed binding in the low micromolar range to ARTD8. Crystal structures showed anchoring of the hits in the nicotinamide pocket. These results form a starting point in the development of chemical tools for the study of the role and function of ARTD7 and ARTD8.
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| 2. |
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| 3. |
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| 4. |
- Karlberg, Mikael, et al.
(författare)
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Treatment of acute vestibular neuronitis with glucocorticoids.
- 2011
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Ingår i: Otology & Neurotology. - 1537-4505. ; 32:7, s. 1140-1143
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: : To report the effects of glucocorticoid treatment of acute vestibular neuronitis on recovery of vestibular function and length of hospital stay. STUDY DESIGN: : Prospective, consecutive case series compared with historic controls. SETTING: : Secondary referral academic hospital. PATIENTS: : Patients with acute vestibular neuronitis. One group treated with glucocorticoids within 3 days after symptom onset (n = 33) and 2 historic untreated control groups (n = 41 and n = 67). INTERVENTIONS: : Oral prednisolone 50 mg/d for 5 days with tapering of doses for the next 5 days, alternatively with intravenous betamethasone 8 mg on the first 1 to 2 days if nauseated. MAIN OUTCOME MEASURES: : Extent of unilateral vestibular paresis (%) in the caloric test at presentation and at 12 months of follow-up. Length of hospital stay (days). RESULTS: : The initial vestibular paresis value did not differ between the treatment group and the control group. At follow-up, the treatment group showed a lower value (22.8% versus 47.2%, p = 0.0003) and greater improvement (53.4% versus 35.6%, p = 0.002). At follow-up, 70% of the treatment group had a normal caloric test result compared to only 34% of the control group. The mean hospital stay of the treatment group was significantly shorter than that of the control group (1.8 versus 3.0 d, p = 0.001). CONCLUSION: : Glucocorticoids administered within 3 days after onset of vestibular neuronitis improves long-time recovery of vestibular function and reduces length of hospital stay
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| 5. |
- Kollén, Lena, 1960-
(författare)
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Dizziness, balance and rehabilitation in vestibular disorders
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dizziness and balance problems are common symptoms at all ages. The aims were; to evaluate rehabilitation, static, dynamic balance and recovery in acute unilateral vestibular loss (AUVL), to evaluate the treatment of benign paroxysmal positional vertigo (BPPV) with assessment of static and dynamic balance and to evaluate the prevalence of dizziness and BPPV in a population of 75-year-olds. Study 1: Twenty-seven patients (51years) with AUVL were included and the recovery was followed regarding vestibular function, dizziness, and sick-leave. The recovery was rapid, with disappearance of spontaneous nystagmus and rapid return to work. Study II: Forty two patents (51 years) with AUVL were included and compared with a reference group. Static and dynamic balance were assessed after six months. Significant instability was found both in static and dynamic balance compared to a reference group. Study III: Seventeen patients (52 years) with severe BPPV (> 3 months) were treated with Semonts´s manouver and/or Brandt-Daroff exercises. The recovery was evaluated by Dix-Hallpike test, subjective dizziness, unsteadiness and balance tests, after 1, 6 and 12 months. Semont´s maneouver resolved dizziness but the long term follow up showed impaired balance. Study IV: A large cohort (675) of elderly was assessed regarding dizziness and BPPV. Side lying test and balance tests were applied. A high prevalence of dizziness (36%) and BPPV (11%) was found. Conclusions: Patients with AUVL and BPPV have despite good symptomatic relief, still impaired static and dynamic balance at long term follow up. BPPV in elderly is common and should be examined since it can be treated.
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| 6. |
- Lindgren, Anders E. G., et al.
(författare)
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Chemical Probes to Study ADP-Ribosylation : Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:23, s. 9556-9568
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Tidskriftsartikel (refereegranskat)abstract
- The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
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| 7. |
- Lindgren, Anders E. G., et al.
(författare)
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PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
- 2013
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 8:8, s. 1698-1703
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Tidskriftsartikel (refereegranskat)abstract
- Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.
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| 8. |
- Magnusson, Måns, et al.
(författare)
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'PREHAB': Vestibular prehabilitation to ameliorate the effect of a sudden vestibular loss.
- 2011
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Ingår i: NeuroRehabilitation. - 1878-6448. ; 29:2, s. 153-156
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Tidskriftsartikel (refereegranskat)abstract
- A sudden unilateral loss or impairment of vestibular function causes vertigo, dizziness and impaired postural function. In most occasions, everyday activities supported or not by vestibular rehabilitation programs will promote compensation and the symptoms subside. As the compensatory process requires sensory input, matching performed motor activity, both motor learning of exercises and matching to sensory input are required. If there is a simultaneous cerebellar lesion found during surgery of the posterior cranial fossa, there may be a risk of a combined vestibulo-cerebellar lesion, with reduced compensatory abilities and with prolonged or sometimes permanent disability. On the other hand, a slow gradual loss of unilateral function occurring as the subject continues well everyday activities may go without any prominent symptoms. We therefore implemented a pre treatment plan before planned vestibular lesions (prehab). This was first done in subject undergoing gentamicin treatment for Meniere's disease (MD). Subjects perform vestibular exercises for 14 days before the first gentamicin installation and then continue doing so until free of symptoms. Most subjects would only experience slight dizziness while losing vestibular function. We then expanded the approach to patients with brainstem tumours requiring surgery but with remaining vestibular function to ease postoperative symptoms and reduce risk of combined cerebello-vestibular lesions. This patient group was given gentamicin installations trans-tympanically before tumour sugary and then underwent prehab. In all cases there was a caloric loss, loss of VOR evident in the head impulse tests, impaired subjective vertical and horizontal, and reduced caloric function induced by the pre-surgery gentamicin treatment. The prehab eliminated spontaneous and positional nystagmus, subjective symptoms, and postural function up before surgery and allowed for rapid postoperative recovery.The concept of 'pre-lesion rehabilitation' where training is introduced before a planned lesion and if possible paralleled with a gradual function loss expands the potential of rehabilitation. Here it was used for vestibular lesions but it is possible that similar approaches may be developed for other situations, which include foreseeable loss of function.
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| 9. |
- Malmström, Eva-Maj, et al.
(författare)
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Experimentally induced deep cervical muscle pain distorts head on trunk orientation.
- 2013
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6327 .- 1439-6319. ; 113:10, s. 2487-2499
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Tidskriftsartikel (refereegranskat)abstract
- We wanted to explore the specific proprioceptive effect of cervical pain on sensorimotor control. Sensorimotor control comprises proprioceptive feedback, central integration and subsequent muscular response. Pain might be one cause of previously reported disturbances in joint kinematics, head on trunk orientation and postural control. However, the causal relationship between the impact of cervical pain on proprioception and thus on sensorimotor control has to be established.
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| 10. |
- Malmström, Eva-Maj, et al.
(författare)
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Influence of prolonged unilateral cervical muscle contraction on head repositioning - Decreased overshoot after a 5-min static muscle contraction task.
- 2010
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Ingår i: Manual Therapy. - : Elsevier BV. - 1356-689X. ; 15, s. 229-234
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Tidskriftsartikel (refereegranskat)abstract
- The ability to reproduce a specified head-on-trunk position can be an indirect test of cervical proprioception. This ability is affected in subjects with neck pain, but it is unclear whether and how much pain or continuous muscle contraction factors contribute to this effect. We studied the influence of a static unilateral neck muscle contraction task (5 min of lateral flexion at 30% of maximal voluntary contraction) on head repositioning ability in 20 subjects (10 women, 10 men; mean age 37 years) with healthy necks. Head repositioning ability was tested in the horizontal plane with 30 degrees target and neutral head position tests; head position was recorded by Zebris((R)), an ultrasound-based motion analyser. Head repositioning ability was analysed for accuracy (mean of signed differences between introduced and reproduced positions) and precision (standard deviation of the differences). Accuracy of head repositioning ability increased significantly after the muscle contraction task, as the normal overshoot was reduced. An average overshoot of 7.1 degrees decreased to 4.6 degrees after the muscle contraction task for the 30 degrees target and from 2.2 degrees to 1.4 degrees for neutral head position. The increased accuracy was most pronounced for movements directed towards the activated side. Hence, prolonged unilateral neck muscle contraction may increase the sensitivity of cervical proprioceptors.
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