Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition

BackgroundRecent studies suggest that statins can protect the vasculature in a manner that is independent of their lipid-lowering activity through inhibition of the small guanosine triphosphate-binding protein, Rho, and Rho-associated kinase. Little information is available on the inhibitory effect of statins on vein graft intimal hyperplasia, the main cause of late graft failure after bypass grafting. We therefore examined the effects of a hydrophilic statin on vein graft intimal hyperplasia in vivo and Rho-kinase activity in vitro.MethodsIn the first experiment, rabbits were randomized to a control group (n = 7) that was fed regular rabbit chow or to a pravastatin group (n = 7) that was fed regular rabbit chow supplemented with 10 mg/kg pravastatin sodium. The branches of the jugular vein were ligated and an approximately 3-cm segment of the jugular vein was taken for an autologous reversed-vein graft. The carotid artery was cut and replaced with the harvested autologous jugular vein. At 2 and 4 weeks after the operation, vein grafts in both groups were harvested, and intimal hyperplasia of the vein grafts was assessed. In the second experiment, human umbilical vein endothelial cells and vascular smooth muscle cells were cultured and then treated with 1 μmol/L and 30 μmol/L pravastatin for 24 hours and harvested. Immunoblotting was performed on the resulting precipitates. Quantitative evaluation of phosphorylated myosin binding subunit and endothelial nitric oxide synthase was performed by densitometric analysis.ResultsWe demonstrated that oral administration of the hydrophilic statin pravastatin to normocholesterolemic rabbits inhibited intimal hyperplasia of carotid interposition-reversed jugular vein grafts 4 weeks after implantation (pravastatin group, 39.5 ± 3.5 μm vs control group, 64.0 ± 7.1 μm; n = 7; P < .05) and suppressed cell proliferation and apoptosis in the neointima 2 weeks after implantation. In addition, we found that pravastatin inhibited Rho-kinase activity and accelerated endothelial nitric oxide synthase expression in human umbilical vein endothelial cells but did not inhibit Rho-kinase activity in vascular smooth muscle cells.ConclusionsThese novel findings clearly demonstrate that a hydrophilic statin can suppress intimal hyperplasia of the vein graft in vivo and also show endothelial cell-tropic inhibition of Rho-kinase in vitro. Furthermore, these results strongly support the clinical use of hydrophilic statins to prevent intimal hyperplasia of the vein graft after bypass grafting.Clinical RelevanceLate graft failure caused by neointimal hyperplasia limits the efficacy of vein grafting. Various treatments were examined to reduce neointimal hyperplasia, but a standard clinical treatment has not yet been established. We report here the inhibitory effect of pravastatin on the development of vein graft intimal hyperplasia. In addition, we demonstrate that pravastatin showed endothelial cell-tropic benefits through both the inhibition of Rho-kinase activity and acceleration of eNOS expression in vitro. Because the clinical benefits and safety of pravastatin have been established to a certain extent through long-term clinical usage, pravastatin may soon become standard treatment after vein bypass grafting

Running marathons in high school: A 5-year review of injury in a structured training program

Objective: The aim in this study was to quantify the number, nature, and severity of injuries sustained by male and female high school students who took part in a running training program that culminated in the completion of a half or full marathon. Design: This study is a retrospective clinical audit. Methods: Injury reports from high school students (grades 9 – 12) who participated in a half or full marathon 30-week progressive training program comprising four training days per week (three running days and one cross-training day) were reviewed. The number of runners completing a marathon, together with the number, nature, severity of injuries, and treatment types, as reported to the program physiotherapist, were the main outcome measures. Results: Program completion was 96% (n = 448/469). Of all participants, 186 (39.6 %) were injured, with 14 withdrawing from the program due to injury. For those who completed a marathon, 172 (38 %) reported 205 musculoskeletal injuries (age of injured runners: 16.3 ± 1.1 years; 88 girls (51.2 %) and 84 boys (48.8 %)). More than half (n = 113, 55.1 %) of the reported injuries were soft tissue injuries. Most injuries were localized to the lower leg (n = 88, 42.9 %) and were of a minor nature (n = 181, 90 %), requiring only 1–2 treatments. Conclusions: There was a low number of relatively minor injuries for high school participants taking part in a graduated and supervised marathon training program. The injury definition was conservative (i.e., any attendance to physiotherapist) and the relative severity of injuries was minor (i.e., requiring 1 – 2 treatment sessions). Overall, these results do not support a need to restrict high school students from taking part in marathon running, though continued emphasis on graduated program development and close supervision of young participants is recommended

Prevention, treatment, and rehabilitation of anterior cruciate ligament injuries in children

As more children and adolescents participate in competitive organized sports, there has been an increase in the reported incidence of anterior cruciate ligament (ACL) injuries in these age groups. ACL injuries in skeletally immature athletes present a challenge, as reconstruction must preserve the physis of the distal femur and of the proximal tibia to avoid growth disturbances. Historically, a skeletally immature athlete with an ACL injury was treated with a brace and activity modification until skeletal maturity, with ACL reconstruction being performed at that time in the “non-copers” who experienced instability. More recently, evidence has shown that delayed reconstruction may lead to increased damage to the meniscus and articular cartilage. As a result, early reconstruction is favored to protect the meniscus and allow continued physical activity. While adolescents at or those near skeletal maturity may be treated with standard reconstruction techniques, they may result in growth disturbances in younger athletes with significant growth remaining. In response to the growing need for ACL reconstruction techniques in skeletally immature individuals, physeal-sparing and physeal-respecting reconstruction techniques have been developed. In addition to the advancements in surgical technique, ACL injury prevention has also gained attention. This growing interest in ACL prevention is in part related to the high risk of ACL re-tear, either of the ACL graft or of the contralateral ACL, in children and adolescents. Recent reports indicate that well-designed neuromuscular training programs may reduce the risk of primary and subsequent ACL injuries

Pulmonary alveolar proteinosis after lung transplantation: Two case reports and literature review

Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management

Pulmonary Enteric Adenocarcinoma Harboring a BRAF G469V Mutation

Pulmonary enteric adenocarcinoma (PEAC) is a rare subtype of lung cancer that should be differentiated from colorectal cancer metastasis. Little is known about its genetic background. An 84-year-old male with adenocarcinoma of the lung underwent left upper lobectomy. The histology of the surgical specimen was suggestive of PEAC. Gastrointestinal and colorectal fiberscopy revealed no evidence of colorectal cancer. Next-generation sequencing of the tumor identified a G469V substitution in serine/threonine-protein kinase B-raf (BRAF). Based on the higher prevalence of the G469 substitution in BRAF-mutant lung adenocarcinoma than in BRAFmutant colorectal cancer, the tumor likely originated from the lung. Identification of mutational genotype may be of some help in distinguishing PEAC from the lung metastasis of colorectal cancer

Bony Morphology of Femoroacetabular Impingement in Young Female Dancers and Single-Sport Athletes

Background: Femoroacetabular impingement (FAI) is a painful and limiting condition of the hip that is often seen in young athletes. Previous studies have reported a higher prevalence of this disorder in male athletes, but data on the structural morphology of adolescent and young adult female athletes, specifically those involved in dance, are lacking. Purpose: (1) To investigate the radiographic morphology of FAI deformities in adolescent and young adult female single-sport dance and nondance athletes and (2) to examine the differences in the radiographic findings between these 2 groups. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A retrospective chart review of 56 female single-sport athletes 10 to 21 years of age with a diagnosis of FAI within a single-sports medicine division of a pediatric academic medical center was performed. Acetabular index (AI), lateral center-edge angle (LCEA), crossover sign, and ischial spine sign were measured bilaterally on anteroposterior radiographs; alpha angle (AA) was measured on lateral films, and anterior center-edge angle (ACEA) was measured on false-profile films. Independent t tests and Mann-Whitney U tests were used to compare mean angle measurements between dance and nondance athletes. Dichotomized categorical variables and crossover and ischial spine signs were analyzed between dance and nondance athletes by applying a chi-square test. Statistical significance was set as P < .05 a priori. Results: Significant differences in angle measurements were noted. AA was significantly lower in the dancers compared with the nondance athlete group (49.5° ± 6.0° vs 53.9° ± 7.3°, P = .001). The LCEA and ACEA of dance athletes were significantly greater compared with nondance athletes (33.8° ± 6.7° vs 30.9° ± 5.8° [P = .016] and 36.0° ± 8.1° vs 32.3° ± 7.0° [P = .035], respectively). No significant difference in AI was seen between the 2 cohorts (5.0° ± 4.0° for dancers vs 5.9° ± 3.4° for nondancers, P = .195). Conclusion: Significant differences existed in the radiographic bony morphology of young female single-sport dance athletes compared with nondance athletes with FAI. In dance athletes, symptoms were seen in the setting of normal bony morphology

Spacetime-Filling Branes in Ten and Nine Dimensions

Type-IIB supergravity in ten dimensions admits two consistent $Z_2$ truncations. After the insertion of D9-branes, one of them leads to the low-energy action of type-I string theory, and it can be performed in two different ways, in correspondence with the fact that there are two different consistent ten-dimensional type-I string theories, namely the SO(32) superstring and the $USp(32)$ model, in which supersymmetry is broken on the D9-branes. We derive here the same results for Type-IIA theory compactified on a circle in the presence of D8-branes. We also analyze the $\kappa$-symmetric action for a brane charged with respect to the S-dual of the RR 10-form of type-IIB, and we find that the tension of such an object has to scale like $g_S^{-2}$ in the string frame. We give an argument to explain why this result is in disagreement with the one obtained using Weyl rescaling of the brane action, and we argue that this brane can only be consistently introduced if the other $Z_2$ truncation of type-IIB is performed. Moreover, we find that one can include a 10-form in type-IIA supersymmetry algebra, and also in this case the corresponding $\kappa$-symmetric brane has a tension scaling like $g_S^{-2}$ in the string frame.Comment: 29 pages, LaTeX file. Refs. added, typos corrected. A comment in the conclusions added. To appear on NP

Exact Description of D-branes via Tachyon Condensation

We examine the fluctuations around a Dp-brane solution in an unstable D-brane system using boundary states and also boundary string field theory. We show that the fluctuations correctly reproduce the fields on the Dp-brane. Plugging these into the action of the unstable D-brane system, we recover not only the tension and RR charge, but also full effective action of the Dp-brane exactly. Our method works for general unstable D-brane systems and provides a simple proof of D-brane descent/ascent relations under the tachyon condensation. In the lowest dimensional unstable D-brane system, called K-matrix theory, D-branes are described in terms of operator algebra. We show the equivalence of the geometric and algebraic descriptions of a D-brane world-volume manifold using the equivalence between path integral and operator formulation of the boundary quantum mechanics. As a corollary, the Atiyah-Singer index theorem is naturally obtained by looking at the coupling to RR-fields. We also generalize the argument to type I string theory.Comment: 63 pages, LaTeX, no figures, v2: references adde

Open-string models with broken supersymmetry

I review the salient features of three classes of open-string models with broken supersymmetry. These suffice to exhibit, in relatively simple settings, the two phenomena of ``brane supersymmetry'' and ``brane supersymmetry breaking''. In the first class of models, to lowest order supersymmetry is broken both in the closed and in the open sectors. In the second class of models, to lowest order supersymmetry is broken in the closed sector, but is {\it exact} in the open sector, at least for the low-lying modes, and often for entire towers of string excitations. Finally, in the third class of models, to lowest order supersymmetry is {\it exact} in the closed (bulk) sector, but is broken in the open sector. Brane supersymmetry breaking provides a natural solution to some old difficulties met in the construction of open-string vacua.Comment: 18 pages, LATEX. Minor corrections. Contributed also to Como 2001 "Statistical Field Theory", Les Houches 2001 "Gravity, gauge theories and strings", Johns Hopkins Workshop 200