| 1. |
- Brage, M, et al.
(författare)
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Different cysteine proteinases involved in bone resorption and osteoclast formation.
- 2005
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Ingår i: Calcified tissue international. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 76:6, s. 439-47
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Tidskriftsartikel (refereegranskat)abstract
- Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.
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| 2. |
- Fischer, M Dominik, et al.
(författare)
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Expression profiling reveals metabolic and structural components of extraocular muscles
- 2002
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 9:2, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- The extraocular muscles (EOM) are anatomically and physiologically distinct from other skeletal muscles. EOM are preferentially affected in mitochondrial myopathies, but spared in Duchenne's muscular dystrophy. The anatomical and pathophysiological properties of EOM have been attributed to their unique molecular makeup: an allotype. We used expression profiling to define molecular features of the EOM allotype. We found 346 differentially expressed genes in rat EOM compared with tibialis anterior, based on a twofold difference cutoff. Genes required for efficient, fatigue-resistant, oxidative metabolism were increased in EOM, whereas genes for glycogen metabolism were decreased. EOM also showed increased expression of genes related to structural components of EOM such as vessels, nerves, mitochondria, and neuromuscular junctions. Additionally, genes related to specialized functional roles of EOM such as the embryonic and EOM-specific myosin heavy chains and genes for muscle growth, development, and/or regeneration were increased. The EOM expression profile was validated using biochemical, structural, and molecular methods. Characterization of the EOM expression profile begins to define gene transcription patterns associated with the unique anatomical, metabolic, and pathophysiological properties of EOM.
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| 3. |
- Nyberg, Lars, et al.
(författare)
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Longitudinal evidence for diminished frontal-cortex function in aging
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:52, s. 22682-22686
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Tidskriftsartikel (refereegranskat)abstract
- Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.
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| 4. |
- Salami, Alireza, et al.
(författare)
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Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition
- 2012
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Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier. - 0925-4439 .- 1879-260X. ; 1822:3, s. 408-415
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Tidskriftsartikel (refereegranskat)abstract
- Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n = 287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest. WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
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| 5. |
- Salomé, Nicolas, et al.
(författare)
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Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats
- 2009
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 612:1-3, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 mu g) in a dose-dependent manner with a total blockade at concentraions of 0.4 mu g and 8 mu g for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 mu g). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 mu M)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fast mass in clincal studies.
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| 6. |
- Bixo, Marie, 1957-
(författare)
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Ovarian steroids in rat and human brain : effects of different endocrine states
- 1987
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian steroid hormones are known to produce several different effects in the brain. In addition to their role in gonadotropin release, ovulation and sexual behaviour they also seem to affect mood and emotions, as shown in women with the premenstrual tension syndrome. Some steroids have the ability to affect brain excitability. Estradiol decreases the electroshock threshold while progesterone acts as an anti-convulsant and anaesthetic in both animals and humans. Several earlier studies have shown a specific uptake of several steroids in the animal brain but only a few recent studies have established the presence of steroids in the human brain.In the present studies, the dissections of rat and human brains were carried out macroscopically and areas that are considered to be related to steroid effects were chosen. Steroid concentrations were measured by radioimmunoassay after extraction and separation with celite chromatography. The accuracy and specificity of these methods were estimated.In the animal studies, immature female rats were treated with Pregnant Mare's Serum Gonadotropin (PMSG) to induce simultaneous ovulations. Concentrations of estradiol and progesterone were measured in seven brain areas pre- and postovulatory. The highest concentration of estradiol, pre- and postovulatory, was found in the hypothalamus and differences between the two cycle phases were detected in most brain areas. The preovulatory concentrations of progesterone were low and the highest postovulatory concentration was found in the cerebral cortex.In one study, the rats were injected with pharmacological doses of progesterone to induce "anaesthesia". High uptake of progesterone was found and a regional variation in the formation of 5<*-pregnane-3,20-dione in the brain with the highest ratio in the medulla oblongata.Concentrations of progesterone, 5a-pregnane-3*20-dione, estradiol and testosterone were determined in 17 brain areas of fertile compared to postmenopausal women. All steroids displayed regional differences in brain concentrations. Higher concentrations of estradiol and progesterone were found in the fertile compared to the postmenopausal women.In summary, these studies show that the concentrations of ovarian steroids in the brain are different at different endocrine states in both rats and humans and that there are regional differences in brain steroid distribution.
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| 7. |
- Carlsson, Lena, et al.
(författare)
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Desmin-related myopathies in mice and man
- 2001
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Ingår i: Acta Physiologica Scandinavica. - : Wiley-Blackwell. - 0001-6772 .- 1365-201X. ; 171:3, s. 341-8
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Tidskriftsartikel (refereegranskat)abstract
- Desmin, the main intermediate filament (IF) protein in skeletal and heart muscle cells, is of great importance as a part of the cytoskeleton. The IFs surround and interlink myofibrils, and connect the peripheral myofibrils with the sarcolemma. In myotendinous junctions and neuromuscular junctions of skeletal muscle fibres, desmin is enriched. In the heart, desmin is increased at intercalated discs, the attachment between cardiomyocytes, and it is the main component in Purkinje fibres of the conduction system. Desmin is the first muscle-specific protein to appear during myogenesis. Nevertheless, lack of desmin, as shown from experiments with desmin knockout (K/O) mice, does not influence myogenesis or myofibrillogenesis. However, the desmin knock-out mice postnatally develop a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. In other skeletal muscles the organization of myofibrils is remarkably unaffected. Thus, the main consequence of the lack of desmin is that the muscle fibres become more susceptible to damage. The loss of membrane integrity leads to a dystrophic process, with degeneration and fibrosis. In the heart cardiac failure develops, whereas in affected skeletal muscles regenerative attempts are seen. In humans, accumulations of desmin have been a hallmark for presumptive desmin myopathies. Recent investigations have shown that some families with such a myopathy have a defect in the gene coding for alphaB-crystallin, whereas others have mutations in the desmin gene. Typical features of these patients are cardiac affections and muscle weakness. Thus, mutations in the desmin gene is pathogenic for a distinct type of muscle disorder.
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| 8. |
- Hadrévi, Jenny, 1977-, et al.
(författare)
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Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study
- 2013
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Ingår i: European Journal of Applied Physiology. - : Springer Verlag (Germany). - 1439-6319 .- 1439-6327. ; 113:12, s. 2977-2989
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle. less thanbrgreater than less thanbrgreater thanMicrodialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography-mass spectrometry (GC-MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann-Whitney U test of group difference in individual metabolites was also performed. less thanbrgreater than less thanbrgreater thanA large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle. less thanbrgreater than less thanbrgreater thanThis study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.
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| 9. |
- Elcadi, Guilherme H.
(författare)
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Near infrared spectroscopy for assessing oxygenation and hemodynamics in the upper extremities of healthy subjects and patients with work-related muscle pain
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prevalence of work-related muscle pain (WRMP) is large in the general population in the industrialized world. Despite significant advances over recent years in some research areas, the mechanisms of why WRMP occurs and the pathophysiological mechanisms behind the disorders are still unclear. One suggested explanation is that WRMP is caused initially by a limitation of the local muscle circulation and oxidative metabolism. There is a lack of objective methods to gauge the development and diagnosis of WRMP. Near infrared spectroscopy (NIRS) is a non-invasive technique that allows for determinations of oxygenation and blood flow. The purpose of this thesis was to evaluate NIRS (1) as a method for measuring muscle oxygenation and hemodynamics for the extensor carpi radialis (ECR) and trapezius descendens muscles (TD), and (2) to investigate whether variables measured by NIRS differed between patients diagnosed with WRMP and healthy subjects. Several variables of NIRS were produced and investigated. These included muscle oxygenation (StO2%), changes during contractions (∆StO2%) and StO2% recovery (Rslope), total hemoglobin (HbT) as an indication of blood volume and its changes during contractions (∆HbT). In addition, for the ECR, by applying an upper arm venous occlusion (VO) HbTslope increase as a surrogate of blood flow, and for both VO and arterial occlusion (AO) HHbslope increase (i.e. deoxyhemoglobin slope) as a surrogate of oxygen consumption were variables of interest. A first objective was to determine how StO2% and HbT responded to various contraction forces and how it related to muscle activation measured by electromyography (EMG). For both muscles isometric contractions of 10, 30, 50 and 70% of maximal voluntary contraction (MVC) were maintained for 20 s each by healthy males and females; additionally a 10% MVC contraction was sustained for 5 min. For the different contraction levels, predictable relationships were seen between ∆StO2% and force, and between ∆StO2% and EMG RMS amplitude. The general trend was a decrease in ∆StO2% with increasing force and increasing EMG. Females showed a tendency for a higher oxygen use (i.e., drop in StO2%) for the ECR over force levels than males and a higher RMS% MVC for the TD. For the 10% MVC contraction sustained for 5 min gender specific changes over time for HbT and RMS for the ECR, and for StO2% for the TD muscle were seen. A second objective was to determine the day-to-day reliability of NIRS variables for the ECR and TD muscles at group level (Pooled data) and at gender level (males and females). Measurements were performed on two occasions separated by 4-6 days and intraclass correlation coefficients (ICC) and limits of agreement (LOA) were determined as reliability and reproducibility indicators, respectively. Variables tested were ∆StO2% during submaximal isometric contractions of 10, 30, 50 and 70% MVC and StO2% recovery (Rslope) after contractions and after AO. For the ECR, HbTslope as an indication of blood flow (using VO) and HHbslope as a surrogate of oxygen consumption for both VO and AO were computed. For ∆StO2% for the ECR the highest ICC was at 30% MVC for both the pooled data and at gender level. For the TD ICCs were comparably high for 30, 50, 70 % MVC (for both muscles the ∆StO2% at 10% MVC showed the lowest ICC). Further, females showed a higher ICC than males for contraction levels of 50 and 70% MVC. For both muscles, LOA for ∆StO2% was lowest at 10% and highest at 50 and 70% MVC. For the ECR Rslope ICCs were high for all contraction levels, but was lower for AO; LOA was lowest at 70% MVC. For the TD, Rslope ICCs were also high for all contraction levels and LOA was lowest at 30 % MVC. ICC for HbTslope was the lowest of all variables tested. For HHbslope ICC was higher for AO than for VO, and LOA was lower for AO. A third objective was to determine if there were differences between healthy subjects and patients diagnosed with WRMP in ∆StO2% and ∆HbT responses during varying submaximal contractions (10, 30, 50 and 70% MVC), and StO2% recovery (Rslope) immediately after contractions and AO. Additional variables tested in the ECR at rest were HHbslope to indicate oxygen consumption (using AO) and HbTslope as an indication of blood flow. There were no differences between groups in ∆StO2% and ∆HbT variables during the contractions or Rslope in the recovery after contractions or AO. Furthermore, HbTslope was not different between groups However, oxygen consumption for the ECR and StO2% for the TD at rest were significantly greater for healthy subjects compared to patients. A fourth objective was to determine if there were differences in StO2% and HbT between healthy subjects and WRMP patients during a 12 min sustained contraction of 15 % MVC. In addition, the protocol included a recovery period of 30 min. Prior to contraction, as well as during the recovery period, HbTslope as a surrogate of blood flow was determined for the ECR. Neither the ECR nor the TD exhibited significant differences between groups for StO2% and HbT during the contraction. For the TD patients showed a lower StO2% value at rest and throughout the contraction than healthy subjects. For the ECR HbT during the sustained contraction the general trend was an initial decrease with gradual increase throughout the contraction for both groups. For HbTslope no differences were seen between patients and healthy subjects before the sustained contraction and during the recovery period for both muscles.NIRS is deemed a suitable technique for assessing physiological measurements of the upper extremity, including for day-to-day testing.NIRS was not able to distinguish between the patients with WRMP and controls. A concern in the thesis is the characteristics of the patient group in being equally active in recreational sports, actively working, and similar in muscle strength as controls. Thus, applying NIRS for studying a more severe patient group could yield different results.
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| 10. |
- Elcadi, Guilherme H, 1966-, et al.
(författare)
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No differences in oxygenation in the forearm and shoulder of patients with work-related muscle pain and healthy subjects during a low-load sustained contraction
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A frequently ascribed symptom associated to work-related muscle pain (WRMP) is muscle fatigue. Studies investigating oxygenation and hemodynamics in association to fatigue development in the muscles of patients with WRMP are sparse. Inadequate oxygen consumption and/or inadequate blood supply can influence the ability of the muscles to withstand fatigue. In this study we applied near-infrared spectroscopy (NIRS) and electromyography (EMG) to investigate oxygenation, hemodynamics and muscle activity in the extensor carpi radialis (ECR) and trapezius (TD) muscles of patients with WRMP and healthy controls. Eighteen patients with diffuse neck-shoulder-arm pain and 17 controls (matched in age and sex) were equipped with NIRS and EMG probes. After determination of maximal voluntary contraction (MVC) a sustained contraction of 15% MVC was performed with a cutoff for the maximum time of 12 min. Variables generated were StO2% and HbT from NIRS and RMS%max and MPF from EMG during the contraction. T tests and Mann-Whitney tests were used for analyzes of differences in MVC and endurance times. Full factorial repeated measures analyses of variance (ANOVA) were used to assess differences between patients and controls in NIRS and EMG parameters over time. Results showed no differences in MVC between patients and controls. We found, however, a shorter endurance time for patients compared to controls. There were no significant differences in StO2%, HbT, RMS and MPF responses during contraction between groups for the ECR. For the TD there was a group effect for StO2% with patients showing a lower level at rest and throughout the contraction. For the ECR and TD oxygenation, hemodynamics, RMS and MPF there were no straightforward differences between patients and controls that could explain the differences in endurance time. Therefore, we conclude that the shorter endurance time seen in the present study was not measurable by physiological indicators investigated in this group of patients.
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