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81.
82.
Therapeutics for Duchenne muscular dystrophy: current approaches and future directions 总被引:10,自引:0,他引:10
Bogdanovich S Perkins KJ Krag TO Khurana TS 《Journal of molecular medicine (Berlin, Germany)》2004,82(2):102-115
Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular disorder. The devastating nature of DMD has led to an intense effort toward finding a cure for this disease, dating back to the time when Duchenne first initiated clinical trials using faradic stimulation for DMD patients. Unfortunately despite the passage of some 150 years the disease remains incurable, and its medical management is largely supportive. However, the discovery of the DMD gene about 20 years ago has allowed a change in the focus of therapeutic strategy dramatically toward delivery of the missing gene/protein. Indeed, some degree of success has been achieved in preclinical animal studies using such strategies, and gene therapy trials are currently underway in humans. Pharmacological approaches for DMD are also being developed since they can circumvent some of the technical problems associated with gene and cell based therapy. This review explores developments in therapeutic approaches for DMD.Abbreviations
BMD
Becker muscular dystrophy
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DAPC
Dystrophin-associated protein complex
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DMD
Duchenne muscular dystrophy
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DRP
Dystrophin-related protein
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IGF
Insulin-like growth factor
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mdx
Dystrophin-deficient mouse
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NMJ
Neuromuscular junction
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TGF
Transforming growth factor
S. Bogdanovich, K.J. Perkins contributed equally to this work 相似文献
83.
The cancer-testis gene,NY-ESO-1, is expressed in normal fetal and adult testes and in spermatocytic seminomas and testicular carcinoma in situ 总被引:2,自引:0,他引:2
Satie AP Rajpert-De Meyts E Spagnoli GC Henno S Olivo L Jacobsen GK Rioux-Leclercq N Jégou B Samson M 《Laboratory investigation; a journal of technical methods and pathology》2002,82(6):775-780
Cancer/testis genes are potential targets for therapeutic genetic and immunologic approaches, and are highly expressed in a large variety of human cancers. However, they are not expressed in normal tissues, with the exception of the testis. The NY-ESO-1 gene is the most recently identified member of the cancer/testis family and its product is one of the most immunogenic tumor antigens. We used immunohistochemistry to investigate the expression of NY-ESO-1 in healthy human prenatal and adult testes and in 59 human testicular tumors of different subtypes. We found that NY-ESO-1 was expressed from 18 weeks until birth in human fetal testes. In the adult testis, NY-ESO-1 was strongly expressed in spermatogonia and in primary spermatocytes, but not in post-meiotic cells or in testicular somatic cells. NY-ESO-1 was not expressed in the Sertoli cells, Leydig cells, classical seminomas, or nonseminomatous germ cells in the 59 testicular tumors. In contrast, NY-ESO-1 was expressed both in carcinomas in situ, which are the earliest stage of testicular tumors (7 of 15 cases), and in spermatocytic seminomas, which are believed to be derived from spermatogonia or primary spermatocytes (8 of 16 cases). We conclude that NY-ESO-1 is a marker that can be used to follow the early progression of testicular tumorigenesis when the tumors present a similar pattern of expression to the cells from which they originated, although the later tumors cease to express NY-ESO-1. 相似文献
84.
Remote Ischemic Conditioning on Recipients of Deceased Renal Transplants Does Not Improve Early Graft Function: A Multicenter Randomized,Controlled Clinical Trial
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N. V. Krogstrup U. Møldrup S. P. Krag B. M. Bibby H. Birn B. Jespersen 《American journal of transplantation》2017,17(4):1042-1049
Delayed graft function is a frequent complication following deceased donor renal transplantation, and is closely related to ischemia–reperfusion injury. Experimental and clinical studies have shown protection by remote ischemic conditioning (RIC). We hypothesized that recipient RIC before kidney graft reperfusion reduces the time to graft recovery. This multicenter, blinded, randomized, controlled clinical trial included 225 adult recipients of renal transplants from deceased donors at four transplantation centers in Denmark, Sweden, and the Netherlands. Participants were randomized 1:1 to RIC or sham‐RIC. RIC consisted of 4 × 5‐min thigh occlusion by an inflatable tourniquet each followed by 5‐min deflation, performed during surgery prior to graft reperfusion. The tourniquet remained deflated for sham‐RIC. The primary endpoint was the estimated time to a 50% decrease in baseline plasma creatinine (tCr50) calculated from plasma creatinine measurements 30 days posttransplant or 30 days after the last, posttransplant dialysis. No significant differences were observed between RIC and sham‐RIC‐treated patients in the primary outcome median tCr50 (122 h [95% confidence interval [CI] 98–151] vs. 112 h [95% CI 91–139], p = 0.58), or the number of patients receiving dialysis in the first posttransplant week (33% vs. 35%, p = 0.71). Recipient RIC does not reduce the time to graft recovery in kidney transplantation from deceased donors. ClinicalTrials.gov: NCT01395719. 相似文献
85.
Collagen XII myopathy with rectus femoris atrophy and collagen XII retention in fibroblasts
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Nanna Witting PhD MD Thomas Krag PhD Ulla Werlauff PhD PT Morten Duno ErCL PhD Sofie Thuroe Oestergaard BSc Julia Rebecka Dahlqvist MD John Vissing MD 《Muscle & nerve》2018,57(6):1026-1030
Introduction: Mutation in the collagen XII gene (COL12A1) was recently reported to induce Bethlem myopathy. We describe a family affected by collagen XII‐related myopathy in 3 generations. Methods: Systematic interview, clinical examination, skin biopsies, and MRI of muscle were used. Results: The phenotype was characterized by neonatal hypotonia, contractures, and delayed motor development followed by resolution of contractures and a motor performance limited by reduced endurance. DNA analyses revealed a novel donor splice‐site mutation in COL12A1 (c.8100 + 2T>C), which segregated with clinical affection and abnormal collagen XII retention in fibroblasts. MRI disclosed a selective wasting of the rectus femoris muscle. Discussion: COL12A1 mutations should be considered in patients with a mild Bethlem phenotype who present with selective wasting of the rectus femoris, absence of the outside‐in phenomenon on MRI, and abnormal collagen XII retention in fibroblasts. Muscle Nerve 57 : 1026–1030, 2018 相似文献
86.
Anne Wilkens Knudsen Aleksander Krag Inge Nordgaard-Lassen Erik Frandsen Flemming Tofteng Christian Mortensen 《Scandinavian journal of gastroenterology》2016,51(5):601-609
Objective Patients with decompensated cirrhosis often suffer from malnutrition. To enable appropriate nutritional supplementation a correct estimation of resting energy expenditure (REE) is needed. It is, however, unclear whether the volume of ascites should be included or not in the calculations of the REE. Material and methods In 19 patients with cirrhosis and ascites, measurements of REE by indirect calorimetry were performed before paracentesis, after paracentesis, and four weeks after paracentesis. Moreover, handgrip strength (HGS), dual X-ray absorptiometry (DXA), and biochemistry were assessed. Results Calculated and measured REE differed more than 10% in 63% of the patients at baseline. By including the weight of ascites in the calculation of REE, the REE was overestimated by 283 (?602–1381)?kJ/day (p?=?0.69). By subtracting the weight of ascites in the calculation of REE, it was underestimated by??379 (?1915???219) kJ/day, (p??=?0.06). Patients in whom measured REE decreased after paracentesis had higher middle arterial pressure (MAP) (p?=?0.02) and p-sodium (p?=?0.02) at baseline. Low HGS (M:?<30 kg; W?20 kg) was evident in 68% of the patients. T-scores revealed osteopenia and osteoporosis in 58% and 16%, respectively. Reduced vitamin D levels (<50 nmol/l) were found in 68%. Conclusions The presence of ascites seems to increase REE, why we suggest that when REE is calculated, the weight of ascites should be included. Indirect calorimetry is, however, preferable for REE estimation. More than two-third of patients with ascites suffer from muscle weakness and/or osteopenia. 相似文献
87.
Marilla C. Pender‐Cudlip Karen J. Krag David Martini Jeanne Yu Anthony Guidi Sandy S. Skinner Yu Zhang Xiying Qu Chengwei He Yi Xu Steven Y. Qian Jing X. Kang 《Cancer science》2013,104(6):760-764
Omega‐6 (n‐6) arachidonic acid (AA) and its pro‐inflammatory metabolites, including prostaglandin E2 (PGE2), are known to promote tumorigenesis. Delta‐6 desaturase (D6D) is the rate‐limiting enzyme for converting n‐6 linoleic acid (LA) to AA. Our objective was to determine if AA synthesis, specifically D6D activity, and PGE2 levels are increased in cancerous breast tissue, and whether these variables differ between estrogen receptor positive (ER+) and negative (ER?) breast cancers. Gas chromatography was performed on surgical breast tissue samples collected from 69 women with breast cancer. Fifty‐four had ER+ breast cancer, and 15 had ER? breast cancer. Liquid chromatography‐mass spectrometry was used to determine PGE2 levels. Lipid analysis revealed higher levels of LA metabolites (C18:3 n‐6, C20:3 n‐6, and AA) in cancerous tissue than in adjacent noncancerous tissue (P < 0.01). The ratio of LA metabolites to LA, a measure of D6D activity, was increased in cancerous tissue, suggesting greater conversion of LA to AA (P < 0.001), and was higher in ER? than in ER+ patients, indicating genotype‐related trends. Similarly, PGE2 levels were increased in cancerous tissue, particularly in ER? patients. The results showed that the endogenous AA synthetic pathway, D6D activity, and PGE2 levels are increased in breast tumors, particularly those of the ER? genotype. These findings suggest that the AA synthetic pathway and the D6D enzyme in particular may be involved in the pathogenesis of breast cancer. The development of drugs and nutritional interventions to alter this pathway may provide new strategies for breast cancer prevention and treatment. 相似文献
88.
89.
Spinal motion usually is recorded from subjective observation of the fully flexed trunk using a goniometer or the distance from the fingertips to the floor. To quantify functional improvement in the low-back pain patient, the repeatability of four clinical techniques was studied: the common fingertip-to-floor distance; the modified Schober; the two-inclinometer method, and a photometric technique. Ten normal subjects (five men, five women), ages 24 to 34 years old, were examined in full flexion, full extension, and the erect position, both standing and sitting. Repeatability was poor for the fingertip-to-floor method in all postures and for the two-inclinometer method in full flexion. Although other methods for various postures had good repeatability, the modified Schober method of determining lumbar spinal motion was the most repeatable and is recommended for a routine, noninvasive, clinical evaluation of lumbar spinal motion. 相似文献
90.
In 40 aphakic eyes undergoing secondary IOL implantation, the axial length was calculated optically as well as measured by ultrasound, and the two methods of axial length determination were compared to evaluate the accuracy in the calculation of secondary IOL power. The mean refractive prediction error (+/- SD) was 0.18 diopters (+/- 0.96) and -0.37 diopters (+/- 0.83) using the optical and the biometric method, respectively. The difference in mean value was significant, whereas the variation around the mean value was not found to be significantly different between the two methods. A calculated axial length may offer a valuable alternative to biometry in the aphakic eye, increasing the accuracy of secondary IOL power calculation. 相似文献