The Effect of Granulocyte-colony Stimulating Factor on Rotator Cuff Healing After Injury and Repair

Background

The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF).

Questions/purposes

We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing?

Methods

After creation of full-thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses.

Results

G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 ± 1.14 [confidence interval {CI}, 5.98–8.81] versus 4.50 ± 0.57 [CI, 3.58–5.41], p = 0.038; 19 days: 8.00 ± 1.00 [CI, 6.75–9.24] versus 5.40 ± 0.89 [CI, 4.28–6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0.999, p = 0.964, p = 1.000, p = 0.988, and p = 0.904, respectively). There was no difference in MRI score between G-CSF and control animals at either 12 days (2.7 ± 1.8 [CI, 1.08–4.24] versus 2.3 ± 1.8 [CI, 0.49–4.17], p = 0.623) or 19 days (2.5 ± 1.4 [CI, 1.05–3.94] versus 2.3 ± 1.5 [CI, 0.75–3.91], p = 0.737). G-CSF-treated animals exhibited significantly lower relative bone volume compared with normal animals in the entire humeral head (24.89 ± 3.80 [CI, 20.17–29.60) versus 32.50 ± 2.38 [CI, 29.99–35.01], p = 0.009) and at the supraspinatus insertion (25.67 ± 5.33 [CI, 19.04–32.29] versus 33.36 ± 1.69 [CI, 31.58–35.14], p = 0.027) at 12 days. Further analysis did not reveal any additional significant relationships with respect to regional bone volume or trabecular thickness between groups and time points (p > 0.05).

Clinical Relevance

Postoperative stem cell mobilization agents may be an effective way to enhance rotator cuff repair. Future studies regarding the kinetics of mobilization, the homing capacity of mobilized cells to injured tissues, and the ability of homing cells to participate in regenerative pathways are necessary.     

Role of the renin-angiotensin system in hepatic ischemia reperfusion injury in rats

It has been shown that the renin-angiotensin system (RAS) plays key roles in the development of fibrosis in numerous organs, including the liver. Other studies have suggested that the RAS also may play roles in diseases of chronic inflammation. However, whether the RAS also can mediate acute inflammation in liver is unclear. The purpose of this study therefore was to determine the effect of the RAS inhibitors captopril and losartan on acute liver damage and inflammation caused by hepatic ischemia and subsequent reperfusion. Accordingly, male rats were subjected to 1 hour of hepatic ischemia (70%) followed by reperfusion; animals were killed 3, 8, or 24 hours after reperfusion. The effect of captopril or losartan (100 or 5 mg/kg intragastrically, respectively) was compared with that of vehicle (saline). The expression of angiotensinogen in liver increased fivefold 3 hours after reperfusion. Indices of liver damage and inflammation (e.g., alanine aminotransferase levels, pathological features, tumor necrosis factor-alpha levels, and intercellular adhesion molecule-1 expression) all were significantly elevated in vehicle-treated animals after hepatic ischemia and subsequent reperfusion. Ischemia and reperfusion also caused an increase in the accumulation of protein adducts of 4-hydroxynonenal, an index of oxidative stress. Captopril or losartan treatment showed profound protective effects under these conditions, significantly blunting the increase in all these parameters caused by ischemia and reperfusion. In conclusion, RAS inhibitors prevent acute liver injury in a model of inflammation caused by ischemia and reperfusion. These data further suggest that the RAS may play a key role in mediating such responses in the liver and suggest a novel role for this system.     

The JT-Area Indicates Dispersion of Repolarization in Dogs with Atrioventricular Block

Heterogeneity in cardiac repolarization (APD) is known to be arrhythmic. In the dog model of chronic complete AV-block and acquired long QT syndrome, an increase in MAPD (defined as left ventricular monophasic action potential duration (MAPD) minus right ventricular MAPD) is often associated with changes in T-wave morphology. The purpose of this study was to correlate known changes in MAPD with the planimetric total area of the T-wave on the surface ECG (_J^T,mV · ms). Methods: The relationship between MAPD and total area of the T-wave (i.e., JT-area) was assessed in four different protocols with different types of dispersion: (1) class III drugs followed by levcromakalim (n = 7), (2) LAD coronary artery occlusion and reperfusion (n = 6), (3) dronedarone i.v., an amiodarone like agent (n = 5) and (4) steady state pacing at cycle lengths of 1000 ms and 500 ms (n = 5). Results: Class III drugs increased MAPD (55 ± 40 ms to 120 ± 50 ms^#, P < 0.05), which was correlated (r = 0.74, P < 0.001) with JT-area (50 ± 40 mV · ms to 95 ± 35 mV · ms^#). Ischemia increased both MAPD (30 ± 25 ms to 90 ± 40 ms^#) and JT-area (60 ± 55 mV · ms to 75 ± 50 mV · ms^#). Both levcromakalim and reperfusion reversed these conditions. Dronedarone had no effect on MAPD or on JT-area while a faster frequency reduced both MAPD and JT-area. Conclusion: Changes in dispersion of ventricular repolarization are reflected by alterations in JT-area. This non-invasive parameter may therefore be used to indicate changes in heterogeneity in ventricular repolarization.     

Short- and Medium-Term Efficacy of a Web-Based Computer-Tailored Nutrition Education Intervention for Adults Including Cognitive and Environmental Feedback: Randomized Controlled Trial

Background

Web-based, computer-tailored nutrition education interventions can be effective in modifying self-reported dietary behaviors. Traditional computer-tailored programs primarily targeted individual cognitions (knowledge, awareness, attitude, self-efficacy). Tailoring on additional variables such as self-regulation processes and environmental-level factors (the home food environment arrangement and perception of availability and prices of healthy food products in supermarkets) may improve efficacy and effect sizes (ES) of Web-based computer-tailored nutrition education interventions.

Objective

This study evaluated the short- and medium-term efficacy and educational differences in efficacy of a cognitive and environmental feedback version of a Web-based computer-tailored nutrition education intervention on self-reported fruit, vegetable, high-energy snack, and saturated fat intake compared to generic nutrition information in the total sample and among participants who did not comply with dietary guidelines (the risk groups).

Methods

A randomized controlled trial was conducted with a basic (tailored intervention targeting individual cognition and self-regulation processes; n=456), plus (basic intervention additionally targeting environmental-level factors; n=459), and control (generic nutrition information; n=434) group. Participants were recruited from the general population and randomly assigned to a study group. Self-reported fruit, vegetable, high-energy snack, and saturated fat intake were assessed at baseline and at 1- (T1) and 4-months (T2) postintervention using online questionnaires. Linear mixed model analyses examined group differences in change over time. Educational differences were examined with group×time×education interaction terms.

Results

In the total sample, the basic (T1: ES=–0.30; T2: ES=–0.18) and plus intervention groups (T1: ES=–0.29; T2: ES=–0.27) had larger decreases in high-energy snack intake than the control group. The basic version resulted in a larger decrease in saturated fat intake than the control intervention (T1: ES=–0.19; T2: ES=–0.17). In the risk groups, the basic version caused larger decreases in fat (T1: ES=–0.28; T2: ES=–0.28) and high-energy snack intake (T1: ES=–0.34; T2: ES=–0.20) than the control intervention. The plus version resulted in a larger increase in fruit (T1: ES=0.25; T2: ES=0.37) and a larger decrease in high-energy snack intake (T1: ES=–0.38; T2: ES=–0.32) than the control intervention. For high-energy snack intake, educational differences were found. Stratified analyses showed that the plus version was most effective for high-educated participants.

Conclusions

Both intervention versions were more effective in improving some of the self-reported dietary behaviors than generic nutrition information, especially in the risk groups, among both higher- and lower-educated participants. For fruit intake, only the plus version was more effective than providing generic nutrition information. Although feasible, incorporating environmental-level information is time-consuming. Therefore, the basic version may be more feasible for further implementation, although inclusion of feedback on the arrangement of the home food environment and on availability and prices may be considered for fruit and, for high-educated people, for high-energy snack intake.

Trial Registration

Netherlands Trial Registry NTR3396; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3396 (Archived by WebCite at http://www.webcitation.org/6VNZbdL6w).