| 1. |
- Borgegard, Tomas, et al.
(author)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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In: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Journal article (peer-reviewed)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 2. |
- Borgegård, Tomas, et al.
(author)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
-
In: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
-
Journal article (peer-reviewed)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 3. |
- Lundkvist, Annika, et al.
(author)
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Motor function after selective dorsal rhizotomy: a 10-year practice-based follow-up study.
- 2012
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In: Developmental Medicine & Child Neurology. - : Wiley. - 0012-1622. ; 54:5, s. 429-435
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Journal article (peer-reviewed)abstract
- Aim The aim of this study was to explore changes in motor function up to 10 years after selective dorsal rhizotomy (SDR). Method The participants comprised 29 children (20 males, nine females) with bilateral spastic diplegia who were consecutively operated on at a median age of 4 years and 3 months and followed until a median age of 15 years. SDR was combined with physiotherapy and regular follow-up visits. The distribution of preoperative Gross Motor Function Classification System (GMFCS) levels was as follows: I, n=1; II, n=7; III, n=8; IV, n=12; and V, n=1. Muscle tone in hip flexors, hip adductors, knee flexors, and plantar flexors was assessed with the modified Ashworth scale, passive range of motion in hip abduction, popliteal angle, maximum knee extension, dorsiflexion of the foot was measured with a goniometer, and gross motor function was assessed using the Gross Motor Function Measure (GMFM-66). The results were compared with preoperative values, taking into account age at the time of SDR. Results After 10 years, muscle tone in hip flexors, hip adductors, knee flexors and plantar flexors was normalized in 19, 24, 13 and 23 participants respectively; mean change in passive range of motion ranged from -2.0° to 8.6°, and the mean increase in GMFM-66 was 10.6. Changes in GMFM-66 were associated with preoperative GMFCS level and GMFM-66 scores. Interpretation Children who underwent SDR and physiotherapy and were regularly followed up by an experienced team showed improved gross motor function for up to 10 years postoperatively.
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| 4. |
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| 5. |
- Lönnbring, Gunilla, et al.
(author)
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En nätverksfälla? Företagande kvinnor i regionalpolitiken
- 2012
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In: Arbetsmarknad & Arbetsliv. - Karlstad : Karlstads universitet. - 1400-9692 .- 2002-343X. ; 18:2, s. 45-58
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Journal article (peer-reviewed)abstract
- Projektet Nya Nätverk handlar om företagande kvinnors organisering. Utifrån institutionell etnografi och en interaktiv forskningsansats analyseras här de mekanismer som marginaliserar kvinnors affärsnätverk i det regionalpolitiska tillväxtarbetet. Organiseringen är på många sätt problematisk. Den blir en nätverksfälla som erbjuder lösningar men inte håller vad den lovar. Trots detta är autonoma nätverk nödvändiga för legitimitet och påverkan men det måste också finnas tydliga mottagande instanser för att krav på jämställd hållbar tillväxt ska omvandlas till praktik.
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| 6. |
- Westbom, Lena, et al.
(author)
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Growth in Children with Cerebral Palsy during five years after Selective Dorsal Rhizotomy: a practice-based study
- 2010
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In: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 10
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Journal article (peer-reviewed)abstract
- Background: Overweight is reported as a side effect of SDR. The aims were to study the development of weight, height and body mass index (BMI) during five years after SDR. Methods: This prospective, longitudinal and practice-based study included all 56 children with CP spastic diplegia undergoing SDR from the start in March 1993 to April 2003 in our hospital. The preoperative Gross Motor Function Classification System (GMFCS) levels were I-II in 17, III in 15, IV-V in 24 children. Median age at SDR was 4.3 years (range 2.4-7.4 years). Weight and height/recumbent length were measured. Swedish growth charts for typically developing children generated weight, height and BMI z-scores for age and gender. Results: The preoperative median z-scores were for height-1.92 and for body mass index (BMI)-0.22. Five years later, the median BMI z-score was increased by + 0.57 (p < 0.05). The occurrence of thinness (BMI < -2 SD) was decreased (n.s.) and obesity (BMI > + 2 SD) increased (p < 0.05). Baseline BMI and age at the start of follow-up influenced the BMI change during the five years (p < 0.001 and p < 0.05 respectively). The individual growth was highly variable, but a tendency towards increasing stunting with age was seen in severe gross motor dysfunction (GMFCS levels IV-V) and the opposite, a slight catch-up of height in children with walking ability (GMFCS levels I-III). Conclusions: These are the first available subtype-and GMFCS-specific longitudinal growth data for children with CP spastic diplegia. Their growth potential according to these data should be regarded as a minimum, as some children were undernourished. It is unknown whether the spasticity reduction through SDR increased the weight gain velocity, or if the relative weight increase was part of the general "obesity epidemic". For some children the weight increase was highly desirable. In others, it resulted in overweight and obesity with risk of negative health effects. Weight and height should be monitored to enable early prevention of weight aberrations also causing problems with mobility, activity and participation.
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