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Complications associated with subpectoral biceps tenodesis: Low rates of incidence following surgery
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Andrea Milenkovic Caroline Brandl Vladimir M. Milenkovic Thomas Jendryke Lalida Sirianant Potchanart Wanitchakool Stephanie Zimmermann Charlotte M. Reiff Franziska Horling Heinrich Schrewe Rainer Schreiber Karl Kunzelmann Christian H. Wetzel Bernhard H. F. Weber 《Proceedings of the National Academy of Sciences of the United States of America》2015,112(20):E2630-E2639
In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1−/−) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1−/− mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.Tight regulation of cell volume is fundamental to proper cell function and survival. In general, rapid water influx across cell membranes leads to cell swelling, which in turn activates net efflux of K+ and Cl−, thereby triggering the release of osmotically obligated water from the cell. Essential to this process is the activation of a current primarily carried by chloride ions (Iswell). This current is gated by volume-regulated anion channels (VRACs) returning the cell to a controlled state of homeostatic integrity, a complex mechanism commonly referred to as regulatory volume decrease (RVD) (1, 2). Although VRACs share common features in almost all cell types, it is unclear whether there is one ubiquitous channel or a diversity of chloride channels with slightly differing functional properties. In this context, three families of proteins—the Ca2+- and/or volume-sensitive anoctamins, bestrophins, and the recently discovered LRRC8s—are presently at the center of interest (3–7).Bestrophin 1 (BEST1), a member of the human bestrophin family of four paralogous genes, encodes an integral membrane protein strongly expressed in the human retinal pigment epithelium (RPE) (8). Mutations in BEST1 have been associated with various macular dystrophies most prominently represented by Best disease (BD), a central retinopathy with autosomal dominant inheritance but variable penetrance and expressivity (9, 10). Key features of BD pathology include a striking lipofuscin accumulation in the macular RPE (11) and an abnormal light peak (LP)/dark trough ratio in the electro-oculogram (EOG) reflective of an impaired RPE (12). The abnormalities in the LP were suggested to be compatible with a function of BEST1 as a Ca2+-activated Cl− channel (CaCC) (13, 14).Addressing BEST1 function, several studies have suggested a role of the protein in distinct basic cellular processes such as Ca2+ homeostasis, neurotransmitter release, and cell volume regulation. These studies mostly relied on BEST1 overexpression in HEK293 cells or conducted in vitro experiments with isolated cells from existing Best1-deficient mouse lines. In summarizing these data, BEST1 was shown to be (i) a calcium sensor localized to the endoplasmic reticulum (ER) of mouse RPE (15), (ii) an intracellular Cl− channel activating anoctamin 1 (ANO1) located at the plasma membrane of mouse trachea (5), (iii) a modulator of voltage-gated Ca2+ channels in murine RPE (16), and (iv) a channel for tonic GABA or slow glutamate release in mouse glia cells and astrocytes (17, 18). To date, the functional role of Best1 has not been determined in the mouse testis, the site of highest endogenous Best1 expression in the mouse (19). In addition, using patient-derived hiRPE cells, the role of BEST1 in mediating ER calcium release and/or uptake was shown (20). In contrast, two independent studies in S2R+ cells from Drosophila melanogaster strongly suggested the invertebrate Drosophila Best1 (dBest1) to act as a volume-regulated chloride channel but with biophysical characteristics clearly distinct from a vertebrate VRAC (3, 21). By small interfering RNA (siRNA)-mediated knockdown of BEST1 in HEK293 cells (6) and mouse Best1 (mBest1) gene disruption in murine peritoneal macrophages (22), two studies could not show a functional effect of BEST1 on Iswell, thus questioning this protein as a candidate for mammalian VRAC in these cell types. Instead, two studies identified the LRRC8A gene as an essential component of a VRAC in various cultured cell lines (6, 7). In these latter studies, the authors propose a scenario where LRRC8A and the isoforms LRRC8B to LRRC8E form variable cell type-specific hexamers, explaining the variability of VRAC properties in different cell types.Together, the rather disparate reports on BEST 1 function underscore the need to further clarify its role in mammalian VRACs. To this end, we focused on two tissues with strong endogenous BEST1 protein expression—namely, human RPE (8) and mouse sperm (19). Major insight into BEST1 function was gained from (i) RPE cell culture models established via hiPSC technology from a healthy donor and two macular dystrophy patients with established pathologic mutations in BEST1 and (ii) a mouse strain deficient for Best1, the murine ortholog of the human BEST1 gene. When exposed to hypo-osmotic challenge, both the mutant hiPSC-RPE cells and Best1-deficient mouse spermatozoa exhibited severe phenotypes, suggesting BEST1 as a crucial component of VRAC function in these cell types. In addition, membrane rupture experiments and voltage-clamp recordings in oocytes from Xenopus laevis, coexpressing aquaporin-1 (AQP1) and BEST1 from mouse and human, respectively, demonstrated identical functional properties of the mammalian BEST1 orthologs. 相似文献
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Aminoguanidine inhibits albuminuria, but not the formation of advanced glycation end-products in skin collagen of diabetic rats 总被引:5,自引:0,他引:5
Degenhardt TP Fu MX Voss E Reiff K Neidlein R Strein K Thorpe SR Baynes JW Reiter R 《Diabetes research and clinical practice》1999,43(2):81-89
Aminoguanidine, an inhibitor of advanced glycation reactions in vitro, inhibits the development of diabetic complications in animal models of diabetes, suggesting that it acts by inhibition of advanced glycation reactions in vivo. However, effects of aminoguanidine on the formation of specific advanced glycation end-products (AGEs) in vivo have not been rigorously examined. Therefore, we studied the effects of aminoguanidine on the formation of pentosidine and N(epsilon)-(carboxymethyl)lysine (CML), measured by analytical chemical methods, in collagen of streptozotocin-diabetic Lewis rats at doses which ameliorated urinary albumin excretion, an index of diabetic nephropathy. At 12 weeks, diabetic animals had fivefold higher blood glucose, threefold higher glycated hemoglobin and fivefold higher collagen glycation, compared to metabolically healthy controls; pentosidine and CML in skin collagen were increased by approximately 30 and 150%, respectively. Administration of aminoguanidine, 50 mg/kg by daily intraperitoneal injection, significantly inhibited the development of albuminuria (approximately 60%, P < 0.01) in diabetic rats, without an effect on blood glucose or glycation of hemoglobin or collagen. Surprisingly, aminoguanidine failed to inhibit the increase in pentosidine and CML in diabetic rat skin collagen. Similar results were obtained in an independent experiment in which aminoguanidine was administered in drinking water at a dose of 0.5 g/l. We conclude that the therapeutic benefits of aminoguanidine on albuminuria may not be the result of inhibition of AGE formation. 相似文献
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Lovell DJ Giannini EH Reiff A Jones OY Schneider R Olson JC Stein LD Gedalia A Ilowite NT Wallace CA Lange M Finck BK Burge DJ;Pediatric Rheumatology Collaborative Study Group 《Arthritis and rheumatism》2003,48(1):218-226
OBJECTIVE: To evaluate the long-term efficacy and safety of etanercept in children with juvenile rheumatoid arthritis (JRA) participating in an ongoing multicenter, open-label, extended-treatment trial. All patients had been participants in an initial randomized efficacy and safety trial of etanercept. METHODS: Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice each week. Safety and efficacy evaluations were performed every 3-4 months. The JRA 30% definition of improvement (DOI) was defined as improvement of > or =30% in at least 3 of 6 response variables used to assess disease activity, with no more than 1 variable worsening by more than 30%. RESULTS: At the time of analysis, 48 of the 58 patients (83%) were still enrolled in the study; 43 of them (74%) had completed 2 years of treatment. Of these 43 patients, 81% met the JRA 30% DOI, 79% met the JRA 50% DOI, and 67% met the JRA 70% DOI. Ten children started low-dose methotrexate after year 1. Of the 32 children taking prednisone, the dosage was decreased to <5 mg/day in 26 (81%). Two children had serious infections (varicella with aseptic meningitis in one and complicated sepsis in the other). In general, adverse events were of the types seen in a general pediatric patient population. CONCLUSION: Children with severe, longstanding, methotrexate-resistant polyarticular JRA demonstrated sustained clinical improvement with >2 years of continuous etanercept treatment. Etanercept was generally well-tolerated. There were no increases in the rates of adverse events over time. However, children taking etanercept should be monitored closely for infections. 相似文献
28.
Etanercept treatment in patients with refractory systemic onset juvenile rheumatoid arthritis 总被引:2,自引:0,他引:2
Kimura Y Pinho P Walco G Higgins G Hummell D Szer I Henrickson M Watcher S Reiff A 《The Journal of rheumatology》2005,32(5):935-942
OBJECTIVE:. To assess the efficacy and safety of etanercept in a large cohort of children with refractory systemic onset juvenile rheumatoid arthritis (SOJRA). METHODS: Standardized questionnaires were sent to US pediatric rheumatologists about patients with SOJRA treated with etanercept. Data were collected at baseline and at the last visit on etanercept. Response to treatment was assessed and compared to baseline as the mean percentage reduction in the following: acute phase reactants, prednisone dose, active joint count, and physician global assessment of disease activity. Response was defined as poor if the mean reduction was < 30%, fair if 30% to < 50%, good if 50% to < 70%, and excellent if > 70%. RESULTS: We analyzed data obtained by survey of 82 SOJRA patients treated with etanercept for a mean of 25 months. Poor response to treatment was observed in 45% of the children, fair response in 9%, good in 13%, and excellent in 33%. Baseline steroid therapy could be discontinued in 27/59 (46%) patients. One or more disease flares occurred in 45% of all patients. Twenty-nine patients (35%) discontinued therapy, mostly due to lack of response or flare. There were 32 adverse event reports, most not considered serious, except for 2 cases of macrophage activation syndrome. CONCLUSION: In this cohort of children with SOJRA, 46% had a good or excellent response, and most were able to reduce concomitant corticosteroid doses. The response to etanercept was fair or poor in more than half our study population, and disease flares were common. Due to the unique cytokine profile of SOJRA, tumor necrosis factor blockade may not be the optimal therapeutic approach for children with treatment-resistant SOJRA. 相似文献
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Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis 总被引:5,自引:0,他引:5
Takei S Groh D Bernstein B Shaham B Gallagher K Reiff A 《The Journal of rheumatology》2001,28(7):1677-1680
OBJECTIVE: To evaluate safety and efficacy of high dose etanercept (> 0.8 mg/kg, maximum 25 mg subcutaneously twice weekly) (Enbrel) in children with juvenile rheumatoid arthritis (JRA) and inadequate prior response to standard dose etanercept. METHODS: Retrospective chart review of 8 children (6 girls, 2 boys, mean age 8.4 yrs, range 5-16 yrs). Five children had systemic onset, polyarticular course JRA; 2 had polyarticular onset; and one had pauciarticular onset, polyarticular course JRA. All children had failed at least 3 mo (mean 9 mo) treatment with standard dose etanercept (0.4 mg/kg SC twice a week). All 8 children had increase in the etanercept dose to at least 0.8 mg/kg (mean 1.1 mg/kg, maximum 25 mg SC twice weekly) for a mean of 7 mo (range 3-10 mo). Efficacy of high dose etanercept was evaluated by changes in joint count, laboratory data, and ability to decrease concomitant medication. RESULTS: Improvements in the joint count and laboratory findings (erythrocyte sedimentation rate, hemoglobin and platelet count) were observed in 2 of 8 (25%) children. In these 2, concomitant prednisone was reduced or discontinued. In contrast, no changes in disease activity or laboratory findings were observed in the other 6 children. Overall, high dose etanercept was well tolerated. No laboratory abnormalities were detected and no child withdrew because of adverse events. CONCLUSION: High dose etanercept is safe and well tolerated in children, but efficacy seems limited. In children with unsatisfactory response to standard dose etanercept, an increased dose or treatment prolongation may not offer any additional benefit. 相似文献
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T R Reiff 《Geriatrics》1987,42(6):53-4, 59, 62
Tissue water loss that occurs in aging has important implications for health status and treatment. This article discusses known mechanisms, physiologic examples, and clinical consequences of body-water changes with age, and suggests that careful monitoring of these changes can lead to better guiding of medication and fluid administration to avoid preventable complications. 相似文献