John M. O’Byrne

Pravastatin Reduces Marfan Aortic Dilation

Background— The sequelae of aortic root dilation are the lethal consequences of Marfan syndrome. The root dilation is attributable to an imbalance between deposition of matrix elements and metalloproteinases in the aortic medial layer as a result of excessive transforming growth factor-beta signaling. This study examined the efficacy and mechanism of statins in attenuating aortic root dilation in Marfan syndrome and compared effects to the other main proposed preventative agent, losartan. Methods and Results— Marfan mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G) were treated daily from 6 weeks old with pravastatin 0.5g/L or losartan 0.6 g/L. The end points of aortic root diameter (n=25), aortic thickness, and architecture (n=10), elastin volume (n=5), dp/dtmax (maximal rate of change of pressure) (cardiac catheter; n=20), and ultrastructural analysis with stereology (electron microscopy; n=5) were examined. The aortic root diameters of untreated Marfan mice were significantly increased in comparison to normal mice (0.161±0.001 cm vs 0.252±0.004 cm; P<0.01). Pravastatin (0.22±0.003 cm; P<0.01) and losartan (0.221±0.004 cm; P<0.01) produced a significant reduction in aortic root dilation. Both drugs also preserved elastin volume within the medial layer (pravastatin 0.23±0.02 and losartan 0.29±0.03 vs untreated Marfan 0.19±0.02; P=0.01; normal mice 0.27±0.02). Ultrastructural analysis showed a reduction of rough endoplasmic reticulum in smooth muscle cells with pravastatin (0.022±0.004) and losartan (0.013±0.001) compared to untreated Marfan mice (0.035±0.004; P<0.01). Conclusions— Statins are similar to losartan in attenuating aortic root dilation in a mouse model of Marfan syndrome. They appear to act through reducing the excessive protein manufacture by vascular smooth muscle cells, which occurs in the Marfan aorta. As a drug that is relatively well-tolerated for long-term use, it may be useful clinically.

Effect of Prehabilitation on the Outcome of Anterior Cruciate Ligament Reconstruction

Background: Prehabilitation is defined as preparing an individual to withstand a stressful event through enhancement of functional capacity. Hypothesis: We hypothesized that a preoperative exercise program would enhance postoperative outcomes after anterior cruciate ligament reconstruction (ACLR). Study Design: Randomized controlled clinical trial; Level of evidence, 1. Methods: Twenty volunteers awaiting ACLR were randomly assigned to a control or exercise intervention group. The exercise group completed a 6-week gym- and home-based exercise program. Assessments include single-legged hop test; quadriceps and hamstring peak torque and magnetic resonance imaging cross-sectional area (CSA); Modified Cincinnati Knee Rating System score; and muscle biopsy of the vastus lateralis muscle completed at baseline, preoperatively, and 12 weeks postoperatively. Myosin heavy chain (MHC) isoforms protein and messenger RNA (mRNA) expression were determined with SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) and RT-PCR (real-time polymerase chain reaction), respectively; IGF-1 (insulin-like growth factor 1), MuRF-1 (muscle RING-finger protein-1), and MAFbx (muscle atrophy f-box) mRNA expression were determined with quantitative RT-PCR. Results: Following 6 weeks of exercise intervention, the single-legged hop test results improved significantly in the exercise-injured limb compared with baseline (P = .001). Quadriceps peak torque in the injured limb improved with similar gains in CSA compared with baseline (P = .001). However, this was not significantly increased compared with the control group. Quadriceps and vastus medialis CSA were also larger in the exercise group than in controls (P = .0024 and P = .015, respectively). The modified Cincinnati score was better in the exercise-injured limb compared with baseline. At 12 weeks postoperatively, the rate of decline in the single-legged hop test was reduced in the exercise group compared with controls (P = .001). Similar trends were not seen for quadriceps peak torque and CSA. The vastus medialis CSA had regressed to similar levels as the control group (P = .008). The modified Cincinnati score continued to increase in the exercise group compared with controls (P = .004). The expression of the hypertrophic IGF-1 gene was significantly increased after the exercise intervention (P = .028), with a decrease back to baseline 12 weeks postoperatively (P = .012). Atrophic MuRF-1 gene expression was decreased after intervention compared with baseline (P = .05) but increased again at 12 weeks postoperatively (P = .03). The MAFbx levels did not change significantly in either group and within each time point. On the mRNA level, there was a shift from MHC-IIx isoform to MHC-IIa after exercise, with significant changes compared with control preoperatively (P = .028). Protein testing was able to reproduce this increase for MHC-IIa isoform expression only. Conclusion: The 6-week progressive prehabilitation program for subjects undergoing ACLR led to improved knee function based on the single-legged hop test and self-reported assessment using the modified Cincinnati score. These effects were sustained at 12 weeks postoperatively. This study supports prehabilitation as a consideration for patients awaiting ACLR; however, further studies are warranted.

The benefits and limitations of animal models for translational research in cartilage repair.

Much research is currently ongoing into new therapies for cartilage defect repair with new biomaterials frequently appearing which purport to have significant regenerative capacity. These biomaterials may be classified as medical devices, and as such must undergo rigorous testing before they are implanted in humans. A large part of this testing involves in vitro trials and biomechanical testing. However, in order to bridge the gap between the lab and the clinic, in vivo preclinical trials are required, and usually demanded by regulatory approval bodies. This review examines the in vivo models in current use for cartilage defect repair testing and the relevance of each in the context of generated results and applicability to bringing the device to clinical practice. Some of the preclinical models currently used include murine, leporine, ovine, caprine, porcine, canine, and equine models. Each of these has advantages and disadvantages in terms of animal husbandry, cartilage thickness, joint biomechanics and ethical and licencing issues. This review will examine the strengths and weaknesses of the various animal models currently in use in preclinical studies of cartilage repair.

Pretreatment with ω-3 fatty acid infusion to prevent leukocyte–endothelial injury responses seen in cardiac surgery

OBJECTIVE Inappropriate multiorgan endothelial-leukocyte activation is major causative factor in organ dysfunction after cardiac surgery. We investigated in vitro, mechanism and magnitude of attenuation of the pathogenic response through pretreatment with an omega-3 fatty acid infusion. METHODS Perioperative saphenous endothelial cell monolayers were pretreated and then stimulated with perioperative inflammatory mediators. Endothelial production of interleukin 6, interleukin 8, and adhesion molecules necessary for neutrophil tissue penetration, were examined, together with inflammatory endothelial coagulant responses. Pretreatment effects on isolated blood neutrophil inflammatory responses were similarly noted. Mechanistic insight was obtained through assessment of the temporal response of nuclear factor-kB and its association with heat shock protein 72(HSP72) expression. RESULTS Four-hour pretreatment markedly reduced inflammatory endothelial release of interleukin 8 (2587 +/- 82 pg/mL control vs 208 +/- 3 pg/mL omega-3 pretreated, P < .01) and endothelial expression of intercellular adhesion molecule 1 (196.1 +/- 2.0 vs 71.9 +/- 0.6 mean channel fluorescence, P < .01) in response to endotoxin and tumor necrosis factor a. Neutrophil activation (CD11b and respiratory burst) was maintained, but pretreated neutrophils had shorter survival. Endothelial inflammatory stimulation produced rapid increase in nuclear activity of nuclear factor-kB, which was attenuated by 43% with omega-3 pretreatment (P < .01). This coincided with 3-fold increase (P = .03) in protective HSP72 expression with pretreatment. CONCLUSION Acute pre-treatment with a clinically acceptable omega-3 infusion attenuates perioperative endothelial-neutrophil activation through transcription-level interaction.

High Power, Low Frequency Ultrasound: Meniscal Tissue Interaction and Ablation Characteristics

This study evaluates high power low frequency ultrasound transmitted via a flat vibrating probe tip as an alternative technology for meniscal debridement in the bovine knee. An experimental force controlled testing rig was constructed using a 20 kHz ultrasonic probe suspended vertically from a load cell. Effect of variation in amplitude of distal tip displacement (242-494 μm peak-peak) settings and force (2.5-4.5 N) on tissue removal rate (TRR) and penetration rate (PR) for 52 bovine meniscus samples was analyzed. Temperature elevation in residual meniscus was measured by embedded thermocouples and histologic analysis. As amplitude or force increases, there is a linear increase in TRR (Mean: 0.9 to 11.2 mg/s) and PR (Mean: 0.08 to 0.73 mm/s). Maximum mean temperatures of 84.6°C and 52.3°C were recorded in residual tissue at 2 mm and 4 mm from the ultrasound probe-tissue interface. There is an inverse relationship between both amplitude and force, and temperature elevation, with higher settings resulting in less thermal damage.

Surgical tuition within Irish hospitals: a national survey

IntroductionThe General Medical Council (GMC) of the UK states that doctors have a duty to train and contribute to the education of colleagues, and that those involved in formal clinical teaching should have a teaching qualification.ObjectivesWe sought to evaluate the current levels of engagement of surgical trainees and recently appointed surgical consultants in clinical teaching.MethodsAll trainees who commenced a basic or higher surgical training post during or after 2007 were invited to participate. The electronic questionnaire was administered using the survey tool GetFeedback, collecting information regarding subspecialty, current role, quantity of teaching that respondents engaged in and who they taught and teaching motivations and barriers.ResultsThere were 128 respondents out of 358 invitations to participate (36% response rate). Less than half (39%) of respondents had attended formal courses on clinical education. Over 70% of respondents engaged in clinical teaching for two or more hours each week. A lack of time and resources were noted as barriers to engaging in teaching. We found a low number of those involved in teaching seeking feedback after teaching sessions.ConclusionIn surgery, the apprenticeship model is still the framework for developing the surgeons of the future. In attempting to produce a highly skilled workforce for the future, we rely on those in senior positions to train those coming through; higher surgical trainees are relied on to teach the core surgical trainees and so on. Our study shows a low level of formalisation of this model.

Undergraduate Clinical Teaching in Orthopedic Surgery: A Randomized Control Trial Comparing the Effect of Case-Based Teaching and Bedside Teaching on Musculoskeletal OSCE Performance

INTRODUCTION Musculoskeletal (MSK) complaints are the second most common reason for a hospital outpatient appointment in the US, and account for 19.5% of general practice consultations. Previous studies have shown that passive teaching in medical school does not imbue students with an adequate degree of confidence in MSK evaluation. The aim of this study was to conduct a randomized control trial to compare the effect of the gold standard small group tutorial of bedside teaching against case-based teaching (CBT) in relation to orthopedic surgery in medical students. METHODS All third-year medical students at our institution were invited to participate in a randomized control trial comparing CBT and bedside tutorials in relation to MSK. The primary outcome was student performance in an Objective Structured Clinical Examination (OSCE). Participants were randomized into 2 groups, receiving either a bedside tutorial or a case-based tutorial. Participants were then assigned self-directed learning before undergoing a final OSCE assessment. Student feedback was attained through a poststudy questionnaire. RESULTS Complete data was acquired for 96 study participants (n = 45 CBT; n = 51 bedside tutorial). The results of a linear regression model used to assess differences in the final OSCE scores, adjusting for the baseline OSCE score, gender, age, previous problem-based learning exposure and whether English was their first language or not showed no evidence of a difference between the bedside teaching group and the CBT group (mean difference: 0.34; 95% confidence interval: -3.79 to 4.47; p = 0.872). Almost all (95%) of the study participants felt that CBT was an important component in their learning. CONCLUSION There was no difference in OSCE performance between groups. The introduction of CBT before clinical placement in medical school could accentuate the clinical skills of students before transition into the apprenticeship model of clinical attachment.