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Background: Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown.Methods: We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE-/- mice.Results: Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species-induced regulation of OGG1 acetylation could be caused by reactive oxygen species-induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22α-OGG1 and SM22α-OGG1K-R mice) and crossed them with ApoE-/- mice. We also studied ApoE-/- mice deficient in OGG1 (OGG1-/-). OGG1-/- mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways.Conclusions: We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function. [ABSTRACT FROM AUTHOR]

Background: Congenital talipes equinovarus, or clubfoot, is a common pediatric orthopaedic condition of unknown origin. In many clubfoot clinical trials, interventions are assigned to a patient, but response to treatment is assessed separately in each foot. Trials commonly report x patients with y feet where y is greater than x (eg, 35 patients with 56 feet). However, common statistical tests assume that each data point is independent. Although data from unilateral cases of clubfoot are independent, it is unknown if each foot of patients with bilateral clubfeet are correlated. Questions/purposes: The purpose of this study was to assess the correlation in the feet of patients with bilateral clubfeet by (1) evaluating the degree of severity between lower limbs of each patient with bilateral clubfeet at baseline; (2) determining if right and left feet of each patient responded to intervention in the same way; (3) determining the proportion of bilateral relapse; and (4) determining the proportion of right and left feet which required the same intervention to correct bilateral relapse. Methods: We performed a chart review of the records of 33 patients with bilateral clubfeet (66 feet). Baseline severity was assessed using the Pirani score. The number of Ponseti serial casts to correct the deformity, the proportion of patients who underwent bilateral Achilles tenotomy, the proportion of bilateral relapse, and the treatment to correct bilateral relapse were examined. Results: The degree of severity between right (Pirani score mean, 5.2; SD, 0.8) and left (Pirani score mean, 5.2; SD, 0.5) feet for each patient at baseline was highly correlated (r = 0.76, p < 0.001). Response to intervention between lower limbs was highly correlated for the number of Ponseti casts required for initial correction (right mean, 5.2, SD, 1.1; left mean, 5.2, SD, 1.3) (r = 0.89, p < 0.001) and the proportion of patients who underwent bilateral Achilles tenotomy (right, 17/18; left, 16/18) (r = 0.94, p < 0.001). In the nine patients who experienced relapse, eight experienced bilateral involvement. In all cases of bilateral relapse, the right and left foot of each patient required the same intervention to correct the relapse. Conclusions: In patients with bilateral clubfeet, baseline severity, response to initial Ponseti treatment, Achilles tenotomy, and relapse outcomes were highly correlated in the right and left feet of each patient. Pooling clinical results of patients who present with bilateral clubfeet is statistically inappropriate, since results in two limbs of the same patient do not represent independent observations. These results support analogous work in other specialties suggesting that patients with bilateral presentations should not be analyzed as independent data points. Level of Evidence: Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: Tibialis anterior tendon transfer surgery forms a part of Ponseti management for children with congenital talipes equinovarus who, after initial correction, present with residual dynamic supination. Although retrospective studies support good outcomes, prospective longitudinal studies in this population are lacking. Questions/purposes: We assessed strength, plantar loading, ROM, foot alignment, function, satisfaction, and quality of life in patients with clubfoot that recurred after Ponseti casting who met indications for tibialis anterior tendon transfer surgery, and compared them with a group of patients with clubfoot treated with casting but whose deformity did not recur (therefore who were not indicated for tibialis anterior tendon transfer surgery). Methods: Twenty children with idiopathic congenital talipes equinovarus indicated for tibialis anterior tendon transfer surgery were recruited. Assessment at baseline (before surgery), and 3, 6, and 12 months (after surgery) included strength (hand-held dynamometry), plantar loading (capacitance transducer matrix platform), ROM (Dimeglio scale), foot alignment (Foot Posture Index), function and satisfaction (disease-specific instrument for clubfoot), and quality of life (Infant Toddler Quality of Life Questionnaire™). Outcomes were compared with those of 12 age-matched children with congenital talipes equinovarus not indicated for tibialis anterior tendon transfer surgery. Followup was 100% in the control group and 95% (19 of 20) in the tibialis anterior transfer group. Results: At baseline, the tibialis anterior tendon transfer group had a significantly worse eversion-to-inversion strength ratio, plantar loading, ROM, foot alignment, and function and satisfaction. At 3 months after surgery, eversion-to-inversion strength, plantar loading, and function and satisfaction were no longer different between groups. Improvements were maintained at 12 months after surgery (eversion-to-inversion strength mean difference, 8% body weight; 95% CI, −26% to 11%; p = 0.412; plantar loading, p > 0.251; function and satisfaction, p = 0.076). ROM remained less and foot alignment more supinated in the tibialis anterior tendon transfer group between baseline and followup (p < 0.001, p < 0.001). Conclusions: Tibialis anterior tendon transfer surgery was an effective procedure, which at 12-month followup restored the balance of eversion-to-inversion strength and resulted in plantar loading and function and satisfaction outcomes similar to those of age-matched children with congenital talipes equinovarus who after Ponseti casting were not indicated for tibialis anterior tendon transfer. Level of Evidence: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

A correction to the article "Bilateral Clubfeet Are Highly Correlated: A Cautionary Tale for Researchers" that was published in the 2014 issue is presented.

This study quantifies the change in passive ankle range of motion following modified Ponseti casting in children with relapsed idiopathic clubfoot. Fifty-three cases (feet) were retrospectively reviewed, with 6-month follow-up data available for 72% of participants. The median improvement in dorsiflexion was 15° (95% confidence interval: 12.5°-17.5°, P≤0.05), with 85% achieving dorsiflexion≥10°. At the 6-month follow-up, dorsiflexion remained significantly improved and 12 feet (32%) presented with subsequent relapse. Nine were referred for further casting and three were recommended for extra-articular surgery. Repeat modified Ponseti management clinically and statistically improves passive ankle dorsiflexion in relapsed idiopathic clubfoot.

Objective: Vascular smooth muscle cell (VSMC) apoptosis occurs at low levels in atherosclerotic plaques and in vessel remodeling; however, the consequences and mediators of these levels are not known. Akt1 protects against VSMC apoptosis largely through inactivating target proteins such as forkhead class O transcription factor 3a (FoxO3a), but Akt1 signaling is reduced and FoxO3a activity is increased in human atherosclerosis. We therefore sought to determine whether inhibition of VSMC apoptosis via Akt1 activation regulates vessel remodeling and atherogenesis and to identify FoxO3a target proteins that mediate VSMC apoptosis., Approach and Results: We generated mice that express an Akt1 protein that can be activated specifically in arterial VSMCs. Akt1 activation did not affect normal arteries, but inhibited VSMC apoptosis and negative remodeling after carotid ligation, indicating that VSMC apoptosis is a major determinant of vessel caliber after changes in flow. Akt1 activation inhibited VSMC apoptosis during atherogenesis and increased relative fibrous cap area in plaques. Microarray studies identified multiple FoxO3a-regulated genes involved in VSMC apoptosis, including apoptotic protease activating factor 1 as a novel target. Apoptotic protease activating factor 1 mediated the proapoptotic activity of FoxO3a, was increased in human atherosclerosis, but reduced by Akt1 activity in vivo., Conclusions: Akt1 is a major regulator of VSMC survival in vivo during vessel remodeling and atherogenesis, mediated in large part through inhibition of FoxO3a and its downstream genes, including apoptotic protease activating factor 1. Our data suggest that even the low-level VSMC apoptosis seen during changes in flow determines vessel wall structure and promotes fibrous cap thinning during atherogenesis., (© 2014 American Heart Association, Inc.)

This study compares the severity of unilateral and bilateral clubfoot, and the correlation between right and left feet of bilateral cases. Sixty-six unilateral and 75 bilateral clubfoot patients were assessed for severity using the Pirani score at an average age of 12.9 days (SD 9 days). In bilateral cases, the severity of right and left feet was highly correlated (r=0.68). The odds of being very severe were 2.6 (95% confidence interval 1.3-5.1) times higher in bilateral cases (P=0.007). Bilateral and unilateral clubfeet present with differing severity. Right and left feet from bilateral cases are highly correlated. Researchers need to address these issues during study design and analysis.

Objective: Caffeine remains one of the most widely consumed drugs in the world. Caffeine has multiple actions, including inhibition of the DNA damage response, and its metabolites, 1-methylxanthine and 1-methyluric acid, are potent antioxidants. Combined, these properties can exert direct effects on cell proliferation, cell death, inflammation, and DNA repair, all important processes that occur in atherosclerosis., Methods and Results: We first examined the effects of caffeine on mouse vascular smooth muscle cells. Caffeine inhibited activation of the DNA damage response regulator ataxia telangiectasia mutated protein and its downstream targets. Caffeine delayed DNA repair, had a concentration-dependent effect on cell proliferation, and protected against apoptosis. In vitro caffeine reduced oxygen consumption and decreased generation of reactive oxygen species. In vivo caffeine reduced DDR activation in vascular and nonvascular tissues, reduced reactive nitrogen species and serum levels of the DNA adduct 8-oxo-guanine, and inhibited atherogenesis in fat-fed ApoE(-/-) mice. Reduction in atherosclerosis was independent of the effects on blood pressure and serum lipids but associated with reduced cell proliferation and ataxia telangiectasia mutated protein activation., Conclusions: The Methyl Xanthine caffeine inhibits the DNA damage response in vitro and in vivo, regulates both cell proliferation and apoptosis after DNA damage, inhibits reactive species, and reduces atherogenesis in ApoE(-/-) mice.