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Biomechanical effect of ultraviolet-A-riboflavin cross-linking on simulated human corneal stroma model and its correlation with changes in corneal stromal microstructure.
Li, H, Liu, T, Mu, B, Zhao, X, Xue, C, Shen, M, Jhanji, V, Wang, Y
Experimental eye research. 2020;:108109
Abstract
In this study, we established an experimental human corneal stroma model of simulated cornea tissue composed of thin anterior cornea strips layers obtained from small incision lenticular extraction (SMILE) surgery. We investigated the biomechanical effect of ultraviolet-A- riboflavin cross-linking at different depths of corneal stroma model and correlated it with stromal microstructural changes examined by transmission electron microscopy (TEM). Corneal strips were harvested from fresh human corneal lenticules obtained after SMILE surgery. Experimental models (n = 34) were established by superimposing the corneal lenticule strips until their thickness reached close to 500 μm. Corneal cross-linking (CXL) was performed subsequently using standard or accelerated protocol. Elasticity and viscosity were quantified using stress-strain extensometer. TEM was used to visualize the collagen fiber diameter and interfibrillar spacing. The relative change in Young's modulus (rel. ΔE) decreased nonlinearly with increasing stromal depth both in the standard and accelerated groups. Compared to the sham controls, the rel. ΔE in standard and accelerated CXL groups increased significantly in the anterior 400 μm and 275 μm depth, respectively. Also, the relative change in stress (rel. ΔS) was significantly lower after standard and accelerated CXL compared to sham controls. Depth analysis showed similar results for the elastic effect. TEM images showed a small, non-significant increase in fibril diameter. The interfibrillar spacing decreased significantly after standard and accelerated CXL in the anterior-mid stromal region. We noted that the increase of corneal stiffness correlated with decrease in interfibrillar spacing after CXL. The stiffening effect was depth dependent. The effect of accelerated CXL was less in the deep corneal stromal regions compared to standard CXL.
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Randomized Control Trial on the Effectiveness of Collagen Cross-linking on Bullous Keratopathy.
Choy, BNK, Ng, ALK, Zhu, MM, Liu, CC, Xu, S, Lai, JSM
Cornea. 2020;(11):1341-1347
Abstract
PURPOSE To investigate the long-term effect and safety of collagen cross-linking (CXL) on patients with bullous keratopathy (BK) in a randomized control manner. It is, to our knowledge, the first randomized control study on the effect of CXL on BK. METHODS Subjects were randomized to receive CXL as in the standard protocol for treating keratoconus or a placebo treatment. Subjects were assessed at baseline and up to 12 months after treatment. Primary outcomes were central corneal thickness (CCT) and pain scores. RESULTS Forty-two patients with BK participated in the study treatment, 26 subjects were randomized to the CXL group and 16 subjects to the control group. The reduction of CCT in the CXL group was 37.6 and 63.8 μm at 2 and 4 weeks, respectively, which were significantly higher than that in the control group. However, there was no statistical difference in CCT reduction between the 2 groups at 12 weeks and after. There were no consistent advantages in pain score, corneal clarity, and visual acuity over the controls throughout the 1-year follow-up. However, CXL was associated with more recurrent epithelial defect (12%), and 2 of the 3 subjects with epithelial defect required amniotic membrane transplant. CONCLUSIONS CXL reduced corneal thickness in the patients with BK, at least for the initial period. However, there were no improvement in pain, corneal clarity, and vision that were of more clinical relevance to the patients. Its short-term benefit was unlikely to outweigh its potential risk of recurrent epithelial defect.
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Accelerated Versus Standard Corneal Cross-Linking for Progressive Keratoconus: A Meta-Analysis of Randomized Controlled Trials.
Kobashi, H, Tsubota, K
Cornea. 2020;(2):172-180
Abstract
PURPOSE To compare the clinical results of accelerated corneal collagen cross-linking (ACXL) to standard corneal collagen cross-linking (SCXL) in progressive keratoconus by summarizing randomized controlled trials using a meta-analysis. METHODS Trials meeting the selection criteria were quality appraised, and data were extracted by 2 independent authors. A comprehensive search was performed using the Cochrane methodology to evaluate the clinical outcomes of ACXL and SCXL for treating progressive keratoconus. Estimates were evaluated by weighted mean difference (WMD) and 95% confidence interval (CI) for absolute changes of the outcomes during 12-month observation periods. Postoperative demarcation line depth was also compared. RESULTS We identified 6 randomized controlled trials that met the eligibility criteria for this meta-analysis. SCXL resulted in a significantly better outcome in postoperative changes in best spectacle-corrected visual acuity (WMD = -0.02; 95% CI, -0.03 to -0.01; P < 0.0001); however, the small differences may not be clinically significant. ACXL provided a significantly better improvement of cylindrical refraction after the 1-year follow-up (WMD = 0.15; 95% CI, 0.05-0.26; P = 0.005). Demarcation line depth at 1 month after SCXL was deeper than that after ACXL (WMD = -102.25; 95% CI, -157.16 to -47.35; P = 0.0003). No differences in the changes in maximum keratometry, central corneal thickness, uncorrected visual acuity, spherical equivalent refraction, corneal biomechanical properties, and corneal endothelial cell density were found among both groups. CONCLUSIONS An ACXL shows a comparable efficacy and safety profile at the 1-year follow-up, but it has less impact on improving best spectacle-corrected visual acuity when compared with the Dresden protocol. Overall, both methods similarly stop the disease progression.
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Corneal collagen cross-linking for bacterial infectious keratitis.
Davis, SA, Bovelle, R, Han, G, Kwagyan, J
The Cochrane database of systematic reviews. 2020;(6):CD013001
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Abstract
BACKGROUND Infectious keratitis is an infection of the cornea that can be caused by bacteria, viruses, fungi, protozoa, or parasites. It may be associated with ocular surgery, trauma, contact lens wear, or conditions that cause deficiency or loss of corneal sensation, or suppression of the immune system, such as diabetes, chronic use of topical steroids, or immunomodulatory therapies. Photoactivated chromophore for collagen cross-linking (PACK-CXL) of the cornea is a therapy that has been successful in treating eye conditions such as keratoconus and corneal ectasia. More recently, PACK-CXL has been explored as a treatment option for infectious keratitis. OBJECTIVES To determine the comparative effectiveness and safety of PACK-CXL with standard therapy versus standard therapy alone for the treatment of bacterial keratitis. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2019, Issue 7); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Science Information database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 8 July 2019. SELECTION CRITERIA We included randomized controlled trials (RCTs), quasi-RCTs, and controlled clinical trials (CCTs) of PACK-CXL for bacterial keratitis. We included quasi-RCTs and CCTs as we anticipated that there would not be many RCTs eligible for inclusion. DATA COLLECTION AND ANALYSIS Two review authors working independently selected studies for inclusion in the review, assessed trials for risk of bias, and extracted data. The primary outcome was proportion of participants with complete healing at four to eight weeks. Secondary outcomes included visual acuity, morphology, adverse events, and treatment failure at four to eight weeks. MAIN RESULTS We included three trials (two RCTs and one quasi-RCT) in this review for a total of 59 participants (59 eyes) with bacterial keratitis. Trials were all single-center and were conducted in Egypt, Iran, and Thailand between 2010 and 2014. It is very uncertain whether PACK-CXL with standard antibiotic therapy is more effective than standard antibiotic therapy alone for re-epithelialization and complete healing (risk ratio (RR) 1.53, 95% confidence interval (CI) 0.88 to 2.66; participants = 15). We judged the certainty of the evidence to be very low due to the small sample size and high risk of selection and performance bias. The high risk of selection bias reflects the overall review. Masking of participants was not possible for the surgical arm. No participant had a best-corrected visual acuity of 20/100 or better at eight weeks (very low certainty evidence). There is also no evidence that use of PACK-CXL with standard therapy results in fewer instances of treatment failure than standard therapy alone (RR 0.50, 95% CI 0.05 to 4.98; participants = 32). We judged the certainty of evidence to be low due to the small sample size and high risk of selection bias. There were no adverse events reported at 14 days (low certainty evidence). Data on other outcomes, such as visual acuity and morphological characteristics, could not be compared because of variable time points and specific metrics. AUTHORS' CONCLUSIONS The current evidence on the effectiveness of PACK-CXL for bacterial keratitis is of low certainty and clinically heterogenous in regard to outcomes. There are five ongoing RCTs enrolling 1136 participants that may provide better answers in the next update of this review. Any future research should include subgroup analyses based on etiology. A core outcomes set would benefit healthcare decision-makers in comparing and understanding study data.
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Standard and accelerated corneal cross-linking long-term results: A randomized clinical trial.
Hashemi, H, Mohebbi, M, Asgari, S
European journal of ophthalmology. 2020;(4):650-657
Abstract
PURPOSE To compare long-term results between accelerated and standard corneal cross-linking protocols in the treatment of progressive keratoconus and compare their effectiveness between central (cone in the central 3 mm) and peripheral (cone beyond 3 mm) cases. METHODS In this randomized clinical trial, we compared 31 eyes treated with accelerated corneal cross-linking (18 mW/cm2, 5 min) and 31 eyes treated with standard corneal cross-linking (3 mW/cm2, 30 min), 16 central and 11 peripheral keratoconus in each group. In this report, 4-year changes in vision, refraction, topography, corneal biomechanics, and corneal cell count were evaluated. RESULTS Uncorrected distance visual acuity improvement was better with standard corneal cross-linking (0.19 ± 0.30 logMAR) than accelerated corneal cross-linking (0.08 ± 0.35 logMAR), but the intergroup difference was not statistically significant (p = 0.283). Cylinder and spherical equivalent significantly increased similarly in both groups. Among topographic indices, anterior Kmax-3 mm showed more reduction in standard corneal cross-linking than accelerated corneal cross-linking (1.35 ± 1.39 vs 0.36 ± 1.10 D, p = 0.011). Anterior Kmax-8 mm reduced by 1.50 ± 1.82 and 0.37 ± 1.58 D in the standard corneal cross-linking and accelerated corneal cross-linking groups, respectively (p = 0.029). Compared to 18-month results, none of the indices at 4 years showed any significant intergroup difference (all p > 0.05). In cases with peripheral keratoconus, changes in anterior Kmax-3 mm (+0.03 ± 0.66 vs -1.17 ± 1.15 D, p = 0.012) and anterior Kmax-8 mm (+0.43 ± 1.09 vs -1.57 ± 1.40 D, p = 0.003) were greater with standard corneal cross-linking. In central cases, no significant intergroup difference was observed. CONCLUSION At 4 years after the procedure, standard corneal cross-linking offered better anterior corneal flattening in the center and periphery. These differences concerned cases of peripheral keratoconus, and the two protocols were similarly effective in central cases. Beyond the 18th month, the two protocols appeared to be similarly effective.
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Collagens and elastin genetic variations and their potential role in aging-related diseases and longevity in humans.
Romero-Ortuno, R, Kenny, RA, McManus, R
Experimental gerontology. 2020;:110781
Abstract
Collagens and elastin are 'building blocks' of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; and the association between genetic variation in those and longevity and/or healthy aging in humans. A systematic search was conducted in MEDLINE and other online databases (OMIM, Genetics Home Reference, Orphanet, ClinVar). Results suggest that genetic variants lead to aging phenotypes of known congenital disease, but also to association with common age-related diseases in adults without known congenital disease. This may be due to the variable penetrance and expressivity of many variants. Some collagen variants have been associated with longevity or healthy aging. A limitation is that most studies had <1000 participants and their criterion for statistical significance was p < 0.05. Results highlight the importance of adopting a lifecourse approach to the study of the genomics of aging. Gerontology can help with new methodologies that operationalize biological aging.
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Effect of an Oral Nutrition Supplement Containing Collagen Peptides on Stratum Corneum Hydration and Skin Elasticity in Hospitalized Older Adults: A Multicenter Open-label Randomized Controlled Study.
Nomoto, T, Iizaka, S
Advances in skin & wound care. 2020;(4):186-191
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Abstract
OBJECTIVE The purpose of this randomized open-label study was to investigate the effect of an oral nutrition supplement containing collagen peptides on stratum corneum hydration and skin elasticity. METHODS The study protocol was registered at the UMIN Clinical Trials Registry (UMIN 000027347). Once-a-day oral administration of a nutrition supplement containing collagen peptides (10.0 g) was instituted in 39 inpatients 65 years or older who were assigned to either the intervention or the control group using a block-randomization design. Stratum corneum hydration and skin elasticity were measured at baseline and at 2, 4, 6, and 8 weeks after the start of the intervention. RESULTS Mean stratum corneum hydration was significantly increased from 43.7 at baseline to 51.7 at postintervention week 8 in the intervention group (P = .001). Differences in skin elasticity from baseline were significant at postintervention week 6 (P = .026) and week 8 (P = .049). CONCLUSIONS Oral nutrition supplements containing collagen peptides may reduce skin vulnerability in older adults and thus prevent conditions such as skin tears.
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Zonal regulation of collagen-type proteins and posttranslational modifications in prostatic benign and cancer tissues by imaging mass spectrometry.
Angel, PM, Spruill, L, Jefferson, M, Bethard, JR, Ball, LE, Hughes-Halbert, C, Drake, RR
The Prostate. 2020;(13):1071-1086
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BACKGROUND The emergence of reactive stroma is a hallmark of prostate cancer (PCa) progression and a potential source for prognostic and diagnostic markers of PCa. Collagen is a main component of reactive stroma and changes systematically and quantitatively to reflect the course of PCa, yet has remained undefined due to a lack of tools that can define collagen protein structure. Here we use a novel collagen-targeting proteomics approach to investigate zonal regulation of collagen-type proteins in PCa prostatectomies. METHODS Prostatectomies from nine patients were divided into zones containing 0%, 5%, 20%, 70% to 80% glandular tissue and 0%, 5%, 25%, 70% by mass of PCa tumor following the McNeal model. Tissue sections from zones were graded by a pathologist for Gleason score, percent tumor present, percent prostatic intraepithelial neoplasia and/or inflammation (INF). High-resolution accurate mass collagen targeting proteomics was done on a select subset of tissue sections from patient-matched tumor or nontumor zones. Imaging mass spectrometry was used to investigate collagen-type regulation corresponding to pathologist-defined regions. RESULTS Complex collagen proteomes were detected from all zones. COL17A and COL27A increased in zones of INF compared with zones with tumor present. COL3A1, COL4A5, and COL8A2 consistently increased in zones with tumor content, independent of tumor size. Collagen hydroxylation of proline (HYP) was altered in tumor zones compared with zones with INF and no tumor. COL3A1 and COL5A1 showed significant changes in HYP peptide ratios within tumor compared with zones of INF (2.59 ± 0.29, P value: .015; 3.75 ± 0.96 P value .036, respectively). By imaging mass spectrometry COL3A1 showed defined localization and regulation to tumor pathology. COL1A1 and COL1A2 showed gradient regulation corresponding to PCa pathology across zones. Pathologist-defined tumor regions showed significant increases in COL1A1 HYP modifications compared with COL1A2 HYP modifications. Certain COL1A1 and COL1A2 peptides could discriminate between pathologist-defined tumor and inflammatory regions. CONCLUSIONS Site-specific posttranslational regulation of collagen structure by proline hydroxylation may be involved in reactive stroma associated with PCa progression. Translational and posttranslational regulation of collagen protein structure has potential for new markers to understand PCa progression and outcomes.
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Histological validation of adipogenic differentiation potential of ASC on collagen-based 2D scaffolds.
Gomarasca, M, Savadori, P, Mariano, S, Cipolla, L, Lombardi, G
Histochemistry and cell biology. 2020;(4):449-455
Abstract
Determination of the adipogenic potential and behavior of adipose-derived mesenchymal stem/stromal cells (ASCs) is particularly relevant for their potential clinical application in regenerative medicine, especially when regeneration is supported by biomaterials or scaffolds. Scaffolds need to be able to induce tissue repair and limit undesired adipogenic differentiation. Depending on the scaffold employed, determination of cell behavior may be hindered by material interference with staining, which will limit either cells identification or dye quantification. Collagen is a promising biomaterial in regenerative medicine, however, histological analysis of cells cultured on collagen-based scaffolds is challenging. Here we describe a new histological method based on iron hematoxylin combined with Oil red O (ORO) staining, for the determination of the adipogenic differentiation of ASCs cultivated on a collagen-based 2D scaffold. ASCs were seeded on collagen films or plastic, differentiated into adipocytes for 14 days, and then stained with either ORO or iron hematoxylin and ORO combined. The collagen films avidly absorbed the ORO dye; conventional staining and quantification by dye extraction failed to discriminate between differentiated and undifferentiated cells on the films. On the contrary, the iron hematoxylin-ORO combination provided a quantitative and more reliable determination of adipocytes based on single cell count. This method is particularly recommended for determining the adipogenic differentiation potential of ASCs and other cell types grown on highly absorptive materials that need to be validated for their potential use in bioengineering and regenerative medicine.
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Lactalbumin, Not Collagen, Augments Muscle Protein Synthesis with Aerobic Exercise.
Oikawa, SY, Macinnis, MJ, Tripp, TR, McGlory, C, Baker, SK, Phillips, SM
Medicine and science in sports and exercise. 2020;(6):1394-1403
Abstract
INTRODUCTION Protein ingestion and the ensuing hyperaminoacidemia stimulates skeletal muscle protein synthesis in the postexercise period. This response facilitates muscle remodeling, which is important during intensified training. The aim of this study was to determine whether supplementation with α-lactalbumin (LA), with high leucine and tryptophan contents, would improve responses to short periods of intensified aerobic training compared with supplementation with an isonitrogenous quantity of collagen peptides (CP). METHODS Endurance-trained participants (5 male, 6 female, 24 ± 4 yr, V˙O2 = 53.2 ± 9.1 mL·kg·min, peak power output = 320 ± 48 W; means ± SD) consumed a controlled diet (1.0 g·kg·d protein) and refrained from habitual training for 11 d while taking part in this double-blind randomized, crossover trial. The two intervention phases, which consisted of brief intensified training (4 × 4-min cycling intervals at 70% of peak power output on 3 consecutive days) combined with the ingestion of LA or CP supplements after exercise (20 g) and before sleep (40 g), were separated by 4 d of washout without protein supplementation (i.e., the control phase). In response to each phase, myofibrillar (MyoPS), sarcoplasmic protein synthesis (SarcPS) rates (via H2O ingestion) and parameters of sleep quality were measured. RESULTS LA ingestion increased plasma leucine (P < 0.001) and tryptophan concentrations (P < 0.001) relative to CP. Intensified training increased MyoPS and SarcPS above the washout phase in LA- and CP-supplemented phases (P < 0.01), with increases being 13% ± 5% and 5% ± 7% greater with LA than CP for MyoPS (P < 0.01) and SarcPS, respectively (P < 0.01). CONCLUSIONS Despite an isonitrogenous diet, protein synthesis was enhanced to a greater extent when trained participants consumed LA compared with CP during intensified aerobic training, suggesting that protein quality is an important consideration for endurance-trained athletes aiming to augment adaption to exercise training.