Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling

Foot and ankle: Core knowledge in orthopaedics

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The Pregnant Patient – Why Do My Feet Hurt?

Although hormonal and anatomical changes that occur during pregnancy have been well documented, how these changes affect foot and ankle function are less understood. Changes during pregnancy in body mass, body-mass distribution, joint laxity, and muscle strength can all contribute to alterations in gait pattern that can lead to pain or injury to the foot and ankle. This review provides an overview of the various foot and ankle anatomic, biomechanic, and kinematic changes that occur during pregnancy. In addition, this article presents the most common causes of foot and ankle symptoms expressed by the pregnant patient population and discuss the management and treatment of each condition

Chronic Disorders of the Peroneal Tendons: Current Concepts Review of the Literature

Chronic disorders of the peroneal tendons are a common cause of posterolateral ankle pain, including tendinopathy, tendon instability, and chronic tendon tears. They are often preceded by ligamentous instability or predisposing anatomic abnormalities such as a shallow fibular groove or a cavovarus foot deformity. Given the substantial disability associated with chronic peroneal tendon disorders, it is important for orthopaedic surgeons to optimize the diagnostic and treatment strategies of these entities based on contemporary studies. This article reviews both classic and recent scientific evidence regarding the diagnosis and treatment of patients with chronic peroneal tendon disorders

Stress Fractures of the Foot and Ankle in Athletes

Stress fractures of the foot and ankle are common injuries in athletes. Management differs considerably based on fracture location and predisposing factors. Repetitive loading of the foot and ankle in athletes should result in physiologic bone remodeling in accordance with Wolff’s law. However, when there is not sufficient time for complete healing to occur before additional loads are incurred, this process can instead lead to stress fracture. Assessment of the athlete’s training regimen and overall bone health is paramount to both the discovery and treatment of these injuries, although diagnosis is often delayed in the setting of normal-appearing initial radiographs. While most stress fractures of the foot or ankle can usually be treated nonoperatively with a period of activity modification, fractures in certain locations are considered “high risk” due to poor intrinsic healing and may warrant more proactive operative management

Health-related quality of life after adverse bleeding events associated with antithrombotic drug therapy – A systematic review

Little is known about the health-related quality of life (HRQOL) following adverse bleeding events associated with antithrombotic drug therapy. This systematic review assesses the HRQOL of patients who suffered a bleeding event related to antithrombotic drug use. A literature search was performed using PubMed, EMBASE, and the Cochrane Library from inception through June 16, 2017. Studies measuring HRQOL after a bleeding event related to antithrombotic drug therapy for primary or secondary prevention of a thromboembolic event were included. Four studies with a total of 13,209 patients met the inclusion criteria, and of them, 3,649 patients developed a bleeding event. Patients who were included received antithrombotic drugs because of acute myocardial infarction or atrial fibrillation. EQ-5D, SF-36, and GHP MOS-13 were used to measure HRQOL. The follow-up time ranged from 6 to 29 months. Patients who suffered a bleeding event reported worse HRQOL compared to those who did not (EQ-5D – average increase on all domains of 0.09, p-values ranging from <0.001 to 0.003; SF-36 – average decrease on all domains of 21.4, p < 0.001; and GHP MOS-13 score – decrease of 11.9 points, p < 0.05) and an increased health concern (13.4-point increase; p < 0.05). In conclusion, adverse bleeding events occurring because of the use of antithrombotic agents are associated with a clinically relevant lower HRQOL and hence deserve more attention as part of the shared decision-making process between patients and providers. These data should be valuable for facilitating more substantive care and risk discussions regarding potential changes in outcome and rehabilitation