| 1. |
- Forsgren, Sture, et al.
(författare)
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Further proof of the existence of a non-neuronal cholinergic system in the human Achilles tendon : Presence of the AChR alpha 7 receptor in tendon cells and cells in the peritendinous tissue
- 2015
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769 .- 1878-1705. ; 29:1, s. 195-200
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Tidskriftsartikel (refereegranskat)abstract
- Human tendon cells have the capacity for acetylcholine (ACh) production. It is not known if the tendon cells also have the potential for ACh breakdown, nor if they show expression of the nicotinic acetylcholine receptor AChR alpha 7 (alpha 7nAChR). Therefore, tendon tissue specimens from patients with midportion Achilles tendinopathy/tendinosis and from normal midportion Achilles tendons were examined. Reaction for the degradative enzyme acetylcholinesterase (AChE) was found in some tenocytes in only a few tendinopathy tendons, and was never found in those of control tendons. Tenocytes displayed more regularly alpha 7nAChR immunoreactivity. However, there was a marked heterogeneity in the degree of this reaction within and between the specimens. alpha 7nAChR immunoreactivity was especially pronounced for tenocytes showing an oval/widened appearance. There was a tendency that the magnitude of alpha 7nAChR immunoreactivity was higher in tendinopathy tendons as compared to control tendons. A stronger alpha 7nAChR immunoreactivity than seen for tenocytes was observed for the cells in the peritendinous tissue. It is likely that the alpha 7nAChR may be an important part of an auto-and paracrine loop of non-neuronal ACh that is released from the tendon cells. The effects may be related to proliferative and blood vessel regulatory functions as well as features related to collagen deposition. ACh can furthermore be of importance in leading to anti-inflammatory effects in the peritendinous tissue, a tissue nowadays considered to be of great relevance for the tendinopathy process. Overall, the findings show that tendon tissue, a tissue known to be devoid of cholinergic innervation, is a tissue in which there is a marked non-neuronal cholinergic system.
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| 2. |
- Gaida, James E., et al.
(författare)
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A pilot study on biomarkers for tendinopathy : lower levels of serum TNF-alpha and other cytokines in females but not males with Achilles tendinopathy
- 2016
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Ingår i: BMC Sports Science, Medicine and Rehabilitation. - : Springer Science and Business Media LLC. - 2052-1847. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Achilles tendinopathy is a painful musculoskeletal condition that is common among athletes, and which limits training capacity and competitive performance. The lack of biomarkers for tendinopathy limits research into risk factors and also the evaluation of new treatments. Cytokines and growth factors involved in regulating the response of tendon cells to mechanical load have potential as biomarkers for tendinopathy. Methods: This case-control study compared serum concentration of cytokines and growth factors (TNF-alpha, IL-1 beta, bFGF, PDFG-BB, IFN-gamma, VEGF) between individuals with chronic Achilles tendinopathy and controls. These were measured in fasting serum from 22 individuals with chronic Achilles tendinopathy and 10 healthy controls. Results were analysed in relation to gender and physical activity pattern. Results: TNF-alpha concentration was lower in the entire tendinopathy group compared with the entire control group; none of the other cytokines were significantly different. TNF-alpha levels were nevertheless highly correlated with the other cytokines measured, in most of the subgroups. Analysed by gender, TNF-alpha and PDGF-BB concentrations were lower in the female tendinopathy group but not the male tendinopathy group. A trend was seen for lower IL-1 beta in the female tendinopathy group. Physical activity was correlated with TNF-alpha, PDGF-BB and IL-1 beta to varying extents for control subgroups, but not for the female tendinopathy group. No correlations were seen with BMI or duration of symptoms. Conclusions: This pilot study indicates a lower level of TNF-alpha and PDGF-BB, and to some extent IL-1 beta among females, but not males, in the chronic phase of Achilles tendinopathy. It is suggested that future studies on tendinopathy biomarkers analyse male and female data separately. The lack of correlation between cytokine level and physical activity in the female tendinopathy group warrants further study.
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| 3. |
- Gaida, James Edmund, et al.
(författare)
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Apolipoprotein A1 distribution pattern in the human Achilles tendon
- 2018
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - : WILEY. - 0905-7188 .- 1600-0838. ; 28:5, s. 1506-1513
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic factors such as cholesterol appear to play an important role in the development of Achilles tendinopathy. There is, however, no morphologic proof explaining the link between high cholesterol and tendinopathy. As apolipoprotein A1 (Apo-A1) is essential for reverse cholesterol transport, it may be related to cholesterol overload in tendon. Nothing is known about Apo-A1 expression in tendon tissue. We examined the distribution of Apo-A1 protein in biopsies from normal and tendinopathy-affected human Achilles tendons, and APOA1 mRNA production from cultured human hamstring tenocytes. Specific immunoreactions for Apo-A1 were detected. The tenocytes showed specific Apo-A1 immunoreactions. These reactions were usually distinct in the tendinopathy specimens. While the tendinopathy specimens often showed granular/small deposit reactions, the slender tenocytes of control specimens did not show this pattern. The magnitude of Apo-A1 immunoreactivity was especially marked in the tendinopathy specimens, as there is a high number of tenocytes. Reactions were also seen in the walls of blood vessels located within the tendon tissue proper of both the normal and tendinopathy tendons and within the peritendinous/fatty tissue of the tendinopathy tendons. The reactions were predominantly in the form of deposit reactions within the smooth muscle layer of the vessel walls. Cultured hamstring tenocytes produced APOA1 mRNA. We demonstrated the presence of Apo-A1 in human tendon tissue. This suggests there may be a link between Achilles tendinopathy and cholesterol metabolism. We hypothesize that Apo-A1 may be important for tenocyte and blood vessel function within tendons.
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| 4. |
- Gouveia-Figueira, Sandra, et al.
(författare)
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Serum Levels of Oxylipins in Achilles Tendinopathy : An Exploratory Study
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Linoleic acid-derived oxidation products are found in experimental pain models. However, little is known about the levels of such oxylipins in human pain. In consequence, in the present study, we have undertaken a lipidomic profiling of oxylipins in blood serum from patients with Achilles tendinopathy and controls.Methodology/Principal findings: A total of 34 oxylipins were analysed in the serum samples. At a significance level of P<0.00147 (<0.05/34), two linoleic acid-derived oxylipins, 13-hydroxy-10E,12Z-octadecadienoic (13-HODE) and 12(13)-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) were present at significantly higher levels in the Achilles tendinopathy samples. This difference remained significant when the dataset was controlled for age, gender and body-mass index. In contrast, 0/21 of the arachidonic acid- and 0/4 of the dihomo-γ-linolenic acid, eicosapentaenoic acid or docosahenaenoic acid-derived oxylipins were higher in the patient samples at this level of significance. The area under the Receiver-Operator Characteristic (ROC) curve for 12,13-DiHOME was 0.91 (P<0.0001). Levels of four N-acylethanolamines were also analysed and found not to be significantly different between the controls and the patients at the level of P<0.0125 (<0.05/4).Conclusions/Significance: It is concluded from this exploratory study that abnormal levels of linoleic acid-derived oxylipins are seen in blood serum from patients with Achilles tendinopathy. Given the ability of two of these, 9- and 13-HODE to activate transient receptor potential vanilloid 1, it is possible that these changes may contribute to the symptoms seen in Achilles tendinopathy.
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| 5. |
- Renström, Lina, et al.
(författare)
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Bilateral muscle fiber and nerve influences by TNF-alpha in response to unilateral muscle overuse : studies on TNF receptor expressions
- 2017
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Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 18:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background:TNF-alpha is suggested to be involved in muscle damage and muscle inflammation (myositis). In order to evaluate whether TNF-alpha is involved in the myositis that occurs in response to muscle overuse, the aim was to examine the expression patterns of TNF receptors in this condition.Methods:A rabbit muscle overuse model leading to myositis in the soleus muscle was used. The expression patterns of the two TNF receptors Tumor Necrosis Factor Receptor type 1 (TNFR1) and Tumor Necrosis Factor Receptor type 2 (TNFR2) were investigated. In situ hybridization and immunofluorescence were utilized. Immunostainings for desmin, NK-1R and CD31 were made in parallel.Results:Immunoreactions (IR) for TNF receptors were clearly observed in white blood cells, fibroblasts and vessel walls, and most interestingly also in muscle fibers and nerve fascicles in the myositis muscles. There were very restricted reactions for these in the muscles of controls. The upregulation of TNF receptors was for all types of structures seen for both the experimental side and the contralateral nonexperimental side. TNF receptor expressing muscle fibers were present in myositis muscles. They can be related to attempts for reparation/regeneration, as evidenced from results of parallel stainings. Necrotic muscle fibers displayed TNFR1 mRNA and TNFR2 immunoreaction (IR) in the invading white blood cells. In myositis muscles, TNFR1 IR was observed in both axons and Schwann cells while TNFR2 IR was observed in Schwann cells. Such observations were very rarely made for control animals.Conclusions:The findings suggest that there is a pronounced involvement of TNF-alpha in the developing myositis process. Attempts for reparation of the muscle tissue seem to occur via both TNFR1 and TNFR2. As the myositis process also occurs in the nonexperimental side and as TNF receptors are confined to nerve fascicles bilaterally it can be asked whether TNF-alpha is involved in the spreading of the myositis process to the contralateral side via the nervous system. Taken together, the study shows that TNF-alpha is not only associated with the inflammation process but that both the muscular and nervous systems are affected and that this occurs both on experimental and nonexperimental sides.
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| 6. |
- Renström, Lina
(författare)
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The involvement of the TNF-alpha system in skeletal muscle in response to marked overuse
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Painful conditions having the origin within the musculoskeletal system is a common cause for people to seek medical care. Between 20-40% of all visits to the primal care in Sweden are coupled to pain from the musculoskeletal system. Muscle pain and impaired muscle function can be caused by muscles being repetitively overused and/or via heavy load. Skeletal muscle is a dynamic tissue which can undergo changes in order to fulfill what is best for optimal function. However, if the load is too heavy, morphological changes including necrosis, as well as pain can occur. The extension of the skeletal muscle is the tendon. Tendinopathy refers to illness and pain of the tendon. The peritendinous tissue is of importance in the features related to tendon pain. Common tendons/origins being afflicted by tendinopathy/pain are the Achilles tendon and the extensor origin at the elbow region. Tumor necrosis factor alpha (TNF-alpha) is a cytokine that is involved in several biological processes. It is well-known for its involvement in the immune system and is an important target for inflammatory disorders such as rheumatoid arthritis. It is not known to what extent the TNF-alpha system is involved in the process of muscle inflammation and damage due to overuse. Studies were conducted on rabbit and human tissue, tissues that either had undergone an excessive loading activity or tissue that was removed with surgery due to painful conditions. The tissues were evaluated via staining for morphology, in situ hybridization and immunofluorescence. Unilateral experimental overuse of rabbit muscle (soleus muscle) led to morphological changes in the soleus muscle tissue bilaterally. The longer the experiment extended, the more was the tissue affected. This included infiltration of white blood cells in the tissue (myositis) and abnormal muscle fiber appearances. TNF-alpha mRNA was seen in white blood cells, in muscle fibers interpreted to be in a reparative stage and in white blood cells that had infiltrated into necrotic muscle fibers. There was an upregulation in expressions of TNF receptor type 1 (TNFR1) and TNF receptor type 2 (TNFR2) in muscles that were markedly overused, with expressions in white blood cells, fibroblasts, blood vessel walls and muscle fibers. Immunoreactions for the receptors were seen in nerve fascicles of markedly overused muscles but only occasionally in normal muscles. The upregulations were seen for both experimental and contralateral sides. Overall the two receptors showed somewhat different expression patterns. Tendinopathy is associated with an increase in blood flow and infiltration of white blood cells in the tissue adjacent to the tendon. It is called the peritendinous tissue and is also richly innervated. The white blood cells and the blood vessels walls in this tissue were showing immunoreaction for TNFR1 and TNFR2. Two types of nerve fascicles were found in this tissue, one normally appearing when staining for nerve markers and one type with signs of axonal loss. The latter had clearly strong immunoreactions for TNFR1 and TNFR2. The findings suggest that the TNF-alpha system is involved in both myopathies occurring due to overuse and in features in the peritendinous tissue in the tendinopathy situation. TNF-alpha and its receptors seem to be involved in degeneration but also in regeneration and healing of the tissue. The findings also suggest that TNF-alpha has effects on nerves showing axonal loss. The changes in the TNF-alpha system were seen both on the experimental side and contralaterally.
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| 7. |
- Shah, Farhan, et al.
(författare)
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Axon and Schwann Cell Degeneration in Nerves of Upper Airway Relates to Pharyngeal Dysfunction in Snorers and Patients With Sleep Apnea
- 2018
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Ingår i: Chest. - : Elsevier. - 0012-3692 .- 1931-3543. ; 154:5, s. 1091-1098
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The pathophysiologic mechanism of nocturnal obstruction and swallowing dysfunction commonly occurring in patients with sleep apnea is unclear. The goal of this study was to investigate whether nerve injuries in the upper airways of snorers and patients with sleep apnea are associated with pharyngeal dysfunction and severity of sleep apnea.METHODS: Twenty-two patients undergoing palatal surgery due to snoring and sleep apnea were investigated for a swallowing dysfunction by using videoradiography. Twelve healthy nonsnoring subjects were included as control subjects. Tissue samples from the soft palate at the base of the uvula were obtained in all patients and control subjects. Nerves and muscle were analyzed with immunohistochemical and morphologic methods, and the findings were correlated with swallowing function and degree of sleep apnea.RESULTS: In the soft palate of patients, nerve fascicles exhibited a significantly lower density of axons (5.4 vs 17.9 x 10(-3) axons/mu m(2); P = .02), a smaller percentage area occupied by Schwann cells (17.5% vs 45.2%; P = .001) and a larger number of circular shaped Schwann cells lacking central axons (43.0% vs 12.7%; P < 0.001) compared with control subjects. The low density of axons was significantly related to degree of swallowing dysfunction (r = 0.5; P = .03) and apnea-hypopnea index > 5 (P = .03). Regenerating axons were frequently observed in patients compared with control subjects (11.3 +/- 4.2% vs 4.8 +/- 2.4%; P = .02).CONCLUSIONS: Axon degeneration in preterminal nerves of the soft palate is associated with pharyngeal dysfunction in snorers and patients with sleep apnea. The most likely cause for the nerve injuries is traumatic snoring vibrations and tissue stretch, leading to swallowing dysfunction and increased risk for upper airway obstruction during sleep.
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| 8. |
- Shah, Farhan, et al.
(författare)
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Desmin and dystrophin abnormalities in upper airway muscles of snorers and patients with sleep apnea
- 2019
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Ingår i: Respiratory Research. - : BioMed Central. - 1465-993X .- 1465-9921. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of obstruction and swallowing dysfunction in snores and sleep apnea patients remains unclear. Neuropathy and to some extent myopathy have been suggested as contributing causes. Recently we reported an absence and an abnormal isoform of two cytoskeletal proteins, desmin, and dystrophin, in upper airway muscles of healthy humans. These cytoskeletal proteins are considered vital for muscle function. We aimed to investigate for muscle cytoskeletal abnormalities in upper airways and its association with swallowing dysfunction and severity of sleep apnea. Cytoskeletal proteins desmin and dystrophin were morphologically evaluated in the uvula muscle of 22 patients undergoing soft palate surgery due to snoring and sleep apnea and in 10 healthy controls. The muscles were analysed with immunohistochemical methods, and swallowing function was assessed using videoradiography. Desmin displayed a disorganized pattern in 21 +/- 13% of the muscle fibres in patients, while these fibers were not present in controls. Muscle fibres lacking desmin were present in both patients and controls, but the proportion was higher in patients (25 +/- 12% vs. 14 +/- 7%, p = 0.009). The overall desmin abnormalities were significantly more frequent in patients than in controls (46 +/- 18% vs. 14 +/- 7%, p < 0.001). In patients, the C-terminus of the dystrophin molecule was absent in 19 +/- 18% of the desmin-abnormal muscle fibres. Patients with swallowing dysfunction had 55 +/- 10% desmin-abnormal muscle fibres vs. 22 +/- 6% in patients without swallowing dysfunction, p = 0.002. Cytoskeletal abnormalities in soft palate muscles most likely contribute to pharyngeal dysfunction in snorers and sleep apnea patients. Plausible causes for the presence of these abnormalities is traumatic snoring vibrations, tissue stretch or muscle overload.
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| 9. |
- Shah, Farhan, 1975-
(författare)
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Neuromuscular injuries and pharyngeal dysfunction in snorers and sleep apnea patients : a study on pathological changes in the human soft palate and its relationship with swallowing dysfunction
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obstructive sleep apnea (OSA) is a prevalent progressive sleep disorder with serious negative health consequences. Although several risk factors such as obesity can make an individual vulnerable to develop OSA, the pathophysiological mechanism for the collapse of the upper airway is unclear. Moreover, the etiology of the commonly occurring swallowing dysfunction in snorers and sleep apnea patients is not understood. In the light of this, we aimed to investigate whether muscle and nerve changes in upper airway contributes to pharyngeal dysfunction in snorers and sleep apnea patients.Twenty-two patients (1 female, 21 males, mean age 45 years) undergoing soft palate surgery because of snoring and sleep apnea were included in the study. Ten healthy non-snoring males, mean age 38 years, were recruited as controls. Biopsies from the uvula were obtained from both patients and voluntary controls. Control autopsies from both uvula and palatopharyngeus muscles were taken post mortem from 6 previously healthy adult subjects (3 males, 3 females, mean age 52 years) and two male infants (age 4 months and 1.4 years). Overnight sleep registration and videoradiographic examinations of pharyngeal swallowing function were performed in both patients and voluntary controls.Enzyme and immunohistochemistry and morphometric techniques were used to investigate cytoskeletal and membrane proteins desmin and dystrophin and two neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). The nerve fascicles in the soft palate were explored for changes in axon and Schwann cell density and for signs of axon regeneration. All patients were snores, and 14 patients had OSA with a mean apnea-hypopnea index 24, range 5-84. Sixteen of the 22 patients had swallowing dysfunction. None of the 10 voluntary controls had sleep apnea or swallowing dysfunction. In both controls and patients, a subgroup of muscle fibers in the soft palate lacked immunoreaction for desmin and the C-terminus of dystrophin, and these fibers were more common in patients than in controls (p<0.001). Moreover, muscle fibers with disorganized desmin were commonly observed in patients, but not in controls (p<0.001). Thus, overall, desmin abnormalities were significantly more frequent in patients (46 vs. 15%, p<0.001), and some of these fibers showed upregulation of BDNF. In addition, nerve fascicles from the soft palate of patients displayed lower density of axons (p<0.02) and a smaller area occupied by Schwann cells (p=0.001) compared to controls. The axon density within nerve fascicles as well as the cytoskeletal abnormalities in muscles correlated significantly with swallowing dysfunction (rs=0.50 and 0.76, respectively, p≤0.03).To conclude, human soft palate muscles seem to be of a unique allotype. In the soft palate of snorers and sleep apnea patients, cytoskeletal myopathy and neuropathy were frequently observed, and these changes correlate significantly with pharyngeal swallowing dysfunction. The upregulation of BDNF in muscle fibers of patients may relate to a regenerative attempt after injury. Consequently, a disturbed sensorimotor function and muscle weakness may contribute to development and progression of swallowing dysfunction and OSA. Traumatic snoring vibrations and muscle overload are plausible causes of the neuromuscular injuries.
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| 10. |
- Shah, Farhan, et al.
(författare)
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Neurotrophic factor BDNF is upregulated in soft palate muscles of snorers and sleep apnea patients
- 2019
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Ingår i: Laryngoscope Investigative Otolaryngology (LIO). - : Wiley Periodicals, Inc.. - 2378-8038. ; 4:1, s. 174-180
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Neuromuscular injuries are suggested to contribute to upper airway collapse and swallowing dysfunction in patients with sleep apnea. Neurotrophins, a family of proteins involved in survival, development, and function of neurons, are reported to be upregulated in limb muscle fibers in response to overload and nerve damage. We aimed to investigate the expression of two important neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in muscle fibers of uvula from snorers and sleep apnea patients and to compare these findings with pharyngeal function.Methods: Uvula muscle biopsies from 22 patients and 10 controls were analyzed for BDNF, NGF, and cytoskeletal protein desmin using immunohistochemistry. Pharyngeal swallowing function was assessed using videoradiography.Results: BDNF, but not NGF, was significantly upregulated in a subpopulation of muscle fibers in snoring and sleep apnea patients. Two major immunoreaction patterns for BDNF were observed; a fine grainy point like BDNF staining was displayed in muscle fibers of both patients and controls (41 +/- 23 vs. 25 +/- 17%, respectively, P = .06), while an abnormal upregulated intense-dotted or disorganized reaction was mainly observed in patients (8 +/- 8 vs. 2 +/- 2%, P = .02). The latter fibers, which often displayed an abnormal immunoreaction for desmin, were more frequent in patients with than without swallowing dysfunction (10 +/- 8 vs. 3 +/- 3%, P = .05).Conclusion: BDNF is upregulated in the upper airway muscles of snorers and sleep apnea patients, and especially in patients with swallowing dysfunction. Upregulation of BDNF is suggested to be a response to denervation, reinnervation, and repair of injured muscle fibers. Our findings propose that damaged upper airway muscles might heal following treatment for snoring and sleep apnea.
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