| 1. |
- Masoudzadeh, Nasrin, et al.
(författare)
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Molecular signatures of anthroponotic cutaneous leishmaniasis in the lesions of patients infected with Leishmania tropica.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Anthroponotic cutaneous leishmaniasis (CL) caused by Leishmania tropica (L. tropica) represents a public health challenge in several resource poor settings. We herein employed a systems analysis approach to study molecular signatures of CL caused by L. tropica in the skin lesions of ulcerative CL (UCL) and non-ulcerative CL (NUCL) patients. Results from RNA-seq analysis determined shared and unique functional transcriptional pathways in the lesions of the UCL and NUCL patients. Several transcriptional pathways involved in inflammatory response were positively enriched in the CL lesions. A multiplexed inflammatory protein analysis showed differential profiles of inflammatory cytokines and chemokines in the UCL and NUCL lesions. Transcriptional pathways for Fcγ receptor dependent phagocytosis were among shared enriched pathways. Using L. tropica specific antibody (Ab)-mediated phagocytosis assays, we could substantiate Ab-dependent cellular phagocytosis (ADCP) and Ab-dependent neutrophil phagocytosis (ADNP) activities in the lesions of the UCL and NUCL patients, which correlated with L. tropica specific IgG Abs. Interestingly, a negative correlation was observed between parasite load and L. tropica specific IgG/ADCP/ADNP in the skin lesions of CL patients. These results enhance our understanding of human skin response to CL caused by L. tropica.
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| 2. |
- McLoon, Linda K, et al.
(författare)
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Wnt and Extraocular Muscle Sparing in Amyotrophic Lateral Sclerosis
- 2014
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Ingår i: Investigative Ophthalmology and Visual Science. - : ARVO, The Association for Reserach in Vision and Ophthalmology. - 0146-0404 .- 1552-5783. ; 55:9, s. 5482-5496
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOMs in ALS.METHODS: EOM and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS patients and the SOD1G93A mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and beta-catenin.RESULTS: All four Wnt isoforms were expressed in most axon profiles in all human EOMs. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression was also seen, except for Wnt7a, where expression was elevated. In the SOD1G93A mouse, all 4 Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to age matched controls. Beta-catenin was activated in a subset of myofibers in EOM and limb muscle in all patients.CONCLUSIONS: The differences in Wnt expression in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for Wnt signaling in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.
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| 3. |
- Fontes Oliveira, Cibely, et al.
(författare)
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Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322.
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Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.
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| 4. |
- Gawlik, Kinga I., et al.
(författare)
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Laminin α1 reduces muscular dystrophy in dy2Jmice
- 2018
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Ingår i: Matrix Biology. - : Elsevier BV. - 0945-053X. ; 70, s. 36-49
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Tidskriftsartikel (refereegranskat)abstract
- Muscular dystrophies, including laminin α2 chain-deficient muscular dystrophy (LAMA2-CMD), are associated with immense personal, social and economic burdens. Thus, effective treatments are urgently needed. LAMA2-CMD is either a severe, early-onset condition with complete laminin α2 chain-deficiency or a milder, late-onset form with partial laminin α2 chain-deficiency. Mouse models dy 3K /dy 3K and dy 2J /dy 2J , respectively, recapitulate these two forms of LAMA2-CMD very well. We have previously demonstrated that laminin α1 chain significantly reduces muscular dystrophy in laminin α2 chain-deficient dy 3K /dy 3K mice. Among all the different pre-clinical approaches that have been evaluated in mice, laminin α1 chain-mediated therapy has been shown to be one of the most effective lines of attack. However, it has remained unclear if laminin α1 chain-mediated treatment is also applicable for partial laminin α2 chain-deficiency. Hence, we have generated dy 2J /dy 2J mice (that express a substantial amount of an N-terminal truncated laminin α2 chain) overexpressing laminin α1 chain in the neuromuscular system. The laminin α1 chain transgene ameliorated the dystrophic phenotype, restored muscle strength and reduced peripheral neuropathy. Thus, these findings provide additional support for the development of laminin α1 chain-based therapy for LAMA2-CMD.
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| 5. |
- Golonka, Witold, et al.
(författare)
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Isolated lumbar extension resistance exercise in limited range of motion for patients with lumbar radiculopathy and disk herniation—clinical outcome and influencing factors
- 2021
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Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- (1) Background: Reconditioning of the paraspinal lumbar extensor muscles by isolated lumbar extension resistance exercises (ILEX) has shown good clinical results for patients with chronic unspecific low back pain. However, the clinical value and safety for patients with specific spine pathologies is unclear. In this study, clinical outcome and influencing factors were retrospectively analyzed for patients with lumbar disk herniation (LDH) and radiculopathy. (2) Methods: 189 consecutive patients (123 men and 66 women; mean age, 36 years) with clinically diagnosed LDH and relative indications for surgery started a 9-week rehabilitation program (2x/week) including ILEX in limited range of motion (ROM) adjusted to patients’ symptoms. Patients diagnosed with advanced levels of spine degeneration were excluded. Pain/radiculopathy (PR), influence on mental health (IOMH), satisfaction rates were measured via Numeric Rating Scales (NRS, 0–10), and overall clinical outcome was stated in % (100% = full recovery). Isometric extension strength was tested before and after the program. (3) Results: 168 patients (88.9%) completed the program. For 162 out of 168 patients (96.4%) there was a significant reduction of clinical symptoms, whereas 6 patients reported no changes in symptoms. Scores (mean) for symptom intensity decreased from 4.2 (±1.5) to 1.9 (±1.5) (p < 0.001), the impact on mental health decreased from 5.9 (±2.3) to 2.4 (±2.0) (p < 0.001). There was a (weak) correlation between lower scores for PR and IOMH before the study and better clinical outcomes; PR also weakly correlated with satisfaction. Other factors such as age, strength increase, level/location and number of LDH did not have a significant impact on the clinical results. (4) Conclusion: The results indicate that ILEX in limited ROM can be an effective treatment for the majority of patients with LDH. For patients with high pain levels, the results are less consistent, and surgery may be considered.
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| 6. |
- Harandi, Vahid M., 1985-
(författare)
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A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis : Differences between extraocular and limb muscles
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.
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| 7. |
- Harandi, Vahid M., et al.
(författare)
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Antioxidants reduce muscular dystrophy in the dy2J/dy2J mouse model of laminin α2 chain-deficient muscular dystrophy
- 2020
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Ingår i: Antioxidants. - : MDPI AG. - 2076-3921. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD. We also analyze the effects of two antioxidant molecules, N-acetyl-L-cysteine (NAC) and vitamin E, on disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. We demonstrate increased ROS levels in LAMA2-CMD mouse and patient skeletal muscle. Furthermore, NAC treatment (150 mg/kg IP for 6 days/week for 3 weeks) led to muscle force loss prevention, reduced central nucleation and decreased the occurrence of apoptosis, inflammation, fibrosis and oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg oral gavage for 6 days/week for 2 weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J skeletal muscle. We suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD.
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| 8. |
- Harandi, Vahid M, et al.
(författare)
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Unchanged neurotrophic factors and their receptors correlate with sparing in extraocular muscles in amyotrophic lateral sclerosis
- 2016
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Ingår i: Investigative Ophthalmology and Visual Science. - Rockville : The association for research in vision and ophthalmology. - 0146-0404 .- 1552-5783. ; 57:15, s. 6831-6842
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the impact of amyotrophic lateral sclerosis (ALS) on the extraocular muscles (EOMs) by examining the distribution of neurotrophic factors (NTFs) and their receptors in EOMs and limb muscles from ALS transgenic mice.Methods: Muscle samples collected from transgenic mice overexpressing human superoxide dismutase type 1 mutations (SOD1G93A, the most widely used mouse model of ALS) at 50 and 150 days as well as age-matched controls were analyzed with immunohistochemistry using antibodies against brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4), glial cell line-derived neurotrophic factor (GDNF), and the neurotrophin receptors p75NTR, tyrosine kinase (Trk) receptor TrkB and TrkC, and GDNF family receptor alpha-1 (GFRα-1).Results: There was an intrinsic difference in NTF expression between EOMs and limb muscles in control mice: EOMs presented significantly lower number of neuromuscular junctions (NMJs) labeled for BDNF and NT-4 at 50 days, and for BDNF and GDNF at 150 days, compared with the control limb muscles of corresponding age. In ALS transgenic mice at 150 days, NTF expression in limb muscles was significantly changed but not in EOMs: the limb muscles presented a significant decline in the number of NMJs labeled for BDNF, NT-4, GDNF, p75NTR, TrkB, and TrkC, which was not observed in EOMs.Conclusions: The significant differences in expression of NTFs on NMJs between EOMs and limb muscles in both control and ALS transgenic mice suggest that NTF may be involved in the pathogenesis of ALS and the resistance of EOMs to the disease.
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| 9. |
- M. Harandi, Vahid, et al.
(författare)
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Effects of N-acetyl-L-cysteine and vitamin E on congenital muscular dystrophy type 1A disease progression in mice
- 2019. - Supplement 1
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966. ; 29, s. 163-164
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Konferensbidrag (refereegranskat)abstract
- Congenital muscular dystrophy with laminin alpha2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without cure. Previously, we have demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models using transcriptome and proteome profiling as well and functional assays (e.g. reduced mitochondrial respiration and a compensatory upregulation of glycolysis). Reactive oxygen species (ROS) form naturally during normal metabolism of oxygen but increase when oxygen homeostasis is not maintained. Here we demonstrate that ROS levels are indeed increased in LAMA-CMD mouse muscle. Next, we investigated the effects of the antioxidant N-acetyl-L-cysteine (NAC) and vitamin E, respectively, in reducing disease progression in the dy2J/dy2J mouse model of LAMA2-CMD. NAC treatment (150 mg/kg, IP six times a week for three weeks) enhanced muscle strength, reduced central nucleation, apoptosis, inflammation and fibrosis and decreased oxidative stress in LAMA2-CMD muscle. In addition, vitamin E (40 mg/kg, oral gavage six times a week for two weeks) improved morphological features and reduced inflammation and ROS levels in dy2J/dy2J muscle. Neither NAC nor vitamin E targets the primary genetic defect and is not expected to completely cure LAMA2-CMD. However, we suggest that NAC and to some extent vitamin E might be potential future supportive treatments for LAMA2-CMD as they improve numerous pathological hallmarks of LAMA2-CMD. Both NAC and vitamin E are already approved for use in humans, which is beneficial from a clinical point of view.
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| 10. |
- Spang, Christoph, et al.
(författare)
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Marked innervation but also signs of nerve degeneration in between the Achilles and plantaris tendons and presence of innervation within the plantaris tendon in midportion Achilles tendinopathy
- 2015
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Ingår i: Journal of Musculoskeletal and Neuronal Interactions - JMNI. - 1108-7161. ; 15:2, s. 197-206
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The plantaris tendon is increasingly recognised as an important factor in midportion Achilles tendinopathy. Its innervation pattern is completely unknown. Methods: Plantaris tendons (n=56) and associated peritendinous tissue from 46 patients with midportion Achilles tendinopathy and where the plantaris tendon was closely related to the Achilles tendon were evaluated. Morphological evaluations and stainings for nerve markers [general (PGP9.5), sensory (CGRP), sympathetic (TH)], glutamate NMDA receptor and Schwann cells (S-100β) were made. Results: A marked innervation, as evidenced by evaluation for PGP9.5 reactions, occurred in the peritendinous tissue located between the plantaris and Achilles tendons. It contained sensory and to some extent sympathetic and NMDAR1-positive axons. There was also an innervation in the zones of connective tissue within the plantaris tendons. Interestingly, some of the nerve fascicles showed a partial lack of axonal reactions. Conclusion: New information on the innervation patterns for the plantaris tendon in situations with midportion Achilles tendinopathy has here been obtained. The peritendinous tissue was found to be markedly innervated and there was also innervation within the plantaris tendon. Furthermore, axonal degeneration is likely to occur. Both features should be further taken into account when considering the relationship between the nervous system and tendinopathy
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