Cardiac autonomic and left ventricular mechanics following high intensity interval training: a randomised cross-over controlled study.

Physical inactivity and sedentary behaviour is associated with increased cardiovascular disease risk. Short duration high intensity interval training (HIIT) has been shown to improve important health parameters. The aim of the present study was to assess the combined adaptations of the cardiac autonomic nervous system and myocardial functional and mechanical parameters to HIIT. Forty physically inactive and highly sedentary males completed 2-weeks of HIIT and control period. The HIIT protocol consisted of 3x30-second maximal cycle ergometer sprints against a resistance of 7.5% body weight, interspersed with 2-minutes of active recovery. Total power spectral density (PSD) and associated low-frequency (LF) and high-frequency (HF) power spectral components of heart rate variability were recorded. Conventional and speckle tracking echocardiography recorded left ventricular (LV) structural, functional and mechanical parameters. HIIT produced a significant increase in total ln PSD and ln HF, and significant decrease in LF/HF ratio (all p<0.05) compared to the control period. HIIT produced significant improvements in LV diastolic function, including lateral E’, estimated filling pressure (E/E’ ratio), E deceleration time, and isovolumetric relaxation time (p<0.05 for all). Fractional shortening was the only conventional marker of LV systolic function to significantly improve (p<0.05). In this setting, there were significant improvements in global peak systolic strain rate, early and late diastolic strain rate and early to late diastolic strain rate ratio, as well as apical rotation, apical systolic and diastolic rotation velocity, apical radial and circumferential strain and strain rate, LV torsion and LV systolic and diastolic torsion velocity (all p<0.05). A short-term programme of HIIT was associated with a significant increase in cardiac autonomic modulation, demonstrated by a residual increase in cardiac vagal activity as well as significantly improved cardiac function and mechanics. This study demonstrates that HIIT may be an important stimulus to reduce the health implications associated with physical inactivity and sedentary behaviour

Molecular modelling and synthesis of inhibitors of herpes simplex virus type 1 Uracil-DNA glycosylase

We recently reported the properties of the first selective inhibitors of herpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the virus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromolar range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the structure was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimized model, the activity of several octAU analogues was predicted, and the values compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be active as UDG inhibitors. These compounds will be useful to determine if UDG, like the viral thymidine kinase, is required for reactivation of HSV1 from latency in nerve cells