| 61. |
- 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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| 62. |
- 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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| 63. |
- Magnusson, Måns, et al.
(författare)
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Cervical Muscle Afferents Play a Dominant Role over Vestibular Afferents during Bilateral Vibration of Neck Muscles.
- 2006
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Ingår i: Journal of Vestibular Research. - 1878-6464. ; 16:3, s. 127-136
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Tidskriftsartikel (refereegranskat)abstract
- A previous study showed that vibratory stimulation of neck muscles in humans induced short-latency electromyographic (EMG) activation of lower leg muscles, producing postural reactions at the feet. These findings indicated that cervical proprioception contributes to stabilization of stance through rapidly integrated pathways. However, as vibration may excite both proprioceptive and vestibular afferents, and because of the proximity of neck muscles to the vestibular apparatus, neck muscle vibration could also have activated the vestibular system thereby contributing to the effect observed. To investigate any possible contribution of vestibular stimulation, vibratory stimuli were applied bilaterally and separately to the splenius muscles of the neck and the planum mastoideum overlying the vestibular organs. Ten normal subjects, with eyes closed, were exposed to vibratory stimulation of two different amplitudes and frequencies. Responses were assessed by EMG activity recorded from tibialis anterior and gastrocnemius muscles of both legs and by changes in center of pressure as measured by a force platform. Results indicated that vibration induced reproducible EMG and postural responses in the anteroposterior direction, particularly on cessation of vibration. EMG and postural responses were considerably lower and less consistent with mastoid vibration compared with neck muscles vibration. Previous reports suggest that vibratory stimulation could propagate to the vestibular organs and generate a vestibular-induced postural activation. However, our findings indicate that cervical muscles afferents play a dominant role over vestibular afferents when vibration is directed towards the neck muscles.
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| 64. |
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| 65. |
- Magnusson, Måns, et al.
(författare)
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Peripheral vestibular disorders with acute onset of vertigo.
- 2002
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Ingår i: Current Opinion in Neurology. - 1473-6551. ; 15:1, s. 5-10
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Tidskriftsartikel (refereegranskat)abstract
- Disorders of the vestibular nerve and end organs are the most common causes of vertigo. The advances in recognizing different forms of canalolithiasis and cupulolithiasis, which sometimes present with continuous positional nystagmus, have revealed a peripheral vestibular aetiology in which central nervous system lesions were previously suspected. Treatments using repositioning manoeuvres are also successful in cases in which nystagmus does not appear, and when administered by less specialized physicians. In acute vestibulopathy, suspicions of the activation of herpes virus infections as a causative agent are increasing, but no reports on the treatment of such infections are yet available. New treatments are in development for use in Ménière's disease.
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| 66. |
- 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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| 67. |
- Magnusson, Måns, et al.
(författare)
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Preoperative vestibular ablation with gentamicin and vestibular 'prehab' enhance postoperative recovery after surgery for pontine angle tumours - first report
- 2007
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 1651-2251 .- 0001-6489. ; 127:12, s. 1236-1240
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Tidskriftsartikel (refereegranskat)abstract
- Conclusions. Preoperative gentamicin in combination with vestibular 'prehab' offers a possibility to reduce postoperative malaise and speed up recovery and may be used for patients undergoing such surgery when there is remaining vestibular function. Objectives. Removal of pontine angle tumours in a patient with remaining vestibular function causes symptoms of acute vestibular loss. A simultaneous cerebellar lesion can cause a combined vestibule-cerebellar lesion. Patients and methods. Twelve patients with pontine angle tumours but with near normal vestibular function were treated with intratympanic gentamicin in combination with vestibular 'prehab' to achieve preoperative vestibular ablation and compensation. After work-up patients started with a home-based vestibular training programme for 14 days. They then received a total of 1.2 ml of 30 mg/ml buffered gentamicin in four intratympanic installations over 2 days. They continued training and returned 6-16 weeks later. All patients were tested with calorics, vestibular video-impulse testing of all six canals, VEMP, subjective visual vertical and horizontal, posturography and pure tone and speech audiometry. Results. There was a loss of caloric reactions and loss of impulses. In two patients the hearing deteriorated and in one hearing improved. All subjects were vestibulary compensated before surgery and no patient complained of dizziness or vertigo after surgery.
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| 68. |
- Magnusson, Måns, et al.
(författare)
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Vestibular "PREHAB"
- 2009
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1164, s. 257-262
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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 a 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 caused by the tumor or the surgery of the posterior cranial fossa, there may be a risk of a combined vestibulocerebellar 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-learned everyday activities may go without any prominent symptoms. A pretreatment plan was therefore implemented before planned vestibular lesions, that is, "PREHAB." This was first done in subjects undergoing gentamicin treatment for morbus Meniere. Subjects would 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. The approach-which is reported here-was then expanded to patients with pontine-angle tumors requiring surgery, but with remaining vestibular function to ease postoperative symptoms and reduce risk of combined cerebellovestibular lesions. Twelve patients were treated with PREHAB and had gentamicin installations transtympanically. In all cases there was a caloric loss, loss of VOR in head impulse tests, and impaired subjective vertical and horizontal. Spontaneous, positional nystagmus, subjective symptoms, and postural function were normalized before surgery and postoperative recovery was swift. Pretreatment training with vestibular exercises continued during the successive loss of vestibular function during gentamicin treatment, and pre-op gentamicin ablation of vestibular function offers a possibility to reduce malaise and speed up recovery.
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| 69. |
- Malmström, Eva-Maj, et al.
(författare)
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Cervical proprioception is sufficient for head orientation after bilateral vestibular loss.
- 2009
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6327 .- 1439-6319. ; 107, s. 73-81
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to investigate the relative importance of cervical proprioception compared to vestibular input for head movements on trunk. Subjects with bilateral vestibulopathy (n = 11) were compared to healthy controls (n = 15). We studied their ability to move the head accurately to reproduce four specified target positions in the horizontal yaw plane (neutral head position, 10 degrees target, 30 degrees target, and 30 degrees target with oscillating movements applied during target introduction). Repositioning ability was calculated as accuracy (constant error, the mean of signed differences between introduced and reproduced target) and precision (variable error, the standard deviation of differences between introduced and reproduced targets). Subjects with bilateral vestibulopathy did not differ significantly from controls in their ability to reproduce different target positions. When the 30 degrees target position was introduced with oscillating movements, overshoot diminished and accuracy improved in both groups, although only statistically significantly when performed towards the right side. The results suggest that at least in some conditions, accurate head on trunk orientation can be achieved without vestibular information and that cervical somato-sensory input is either up-regulated as a compensatory mechanism after bilateral vestibular loss or is important for such tasks.
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| 70. |
- Malmström, Eva-Maj, et al.
(författare)
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Cervicogenic dizziness - musculoskeletal findings before and after treatment and long-term outcome.
- 2007
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Ingår i: Disability and Rehabilitation. - : Informa UK Limited. - 0963-8288 .- 1464-5165. ; 29:15, s. 1193-1205
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. To explore musculoskeletal findings in patients with cervicogenic dizziness and how these findings relate to pain and dizziness. To study treatment effects and long-term symptom progress. Method. Twenty-two patients ( 20 women, 2 men; mean age 37 years) with suspected cervicogenic dizziness underwent a structured physical examination before and after physiotherapy guided by the musculoskeletal findings. Questionnaires were sent to the patients six months and two years after treatment. Results. Dorsal neck muscle tenderness and tightness was found in a majority of the patients. Zygapophyseal joint tenderness was found at all cervical levels. Cervical range of motion was equal to or larger than expected age and gender matched values. The cervico-thoracic region was often hypomobile. Most patients had postural imbalance. Dynamic stabilization capacity was reduced. Suboccipital muscles tightness correlated with posture imbalance and poor neck stability. The treatment resulted in reduced tenderness in levator scapula, high and middle paraspinal and temporalis muscles and zygapophyseal joints at C4-C7 and increased cervico-thoracic mobility. Reduction of middle paraspinal muscle tenderness correlated with neck pain relief. Postural alignment improved, as did dynamic stabilization in trunk, neck and shoulders. After 6 months, 13 of the 17 patients had still no or less neck pain and 14 had no or less dizziness. After 2 years, 7 patients had no or less neck pain and 11 no or less dizziness. Conclusion. Patients with suspected cervicogenic dizziness have some musculoskeletal findings in common. Treatment based on these findings reduces neck pain as well as dizziness long-term but some patients might need a maintenance strategy.
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