It is suggested that NMES is able to induce pH heterogeneity in the medial gastrocnemius, and that the single Pi peaks represent the different muscle fiber types of the skeletal muscle. Magn Reson Med 77:2097-2106, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Measurements of exercise-induced metabolic changes, such as oxygen consumption, carbon dioxide exhalation or lactate concentration, are important indicators for assessing the current performance level of athletes in training science. With exercise-limiting metabolic processes occurring in loaded muscles, P-MRS represents a particularly powerful modality to identify and analyze corresponding training-induced alterations. Against this background, the current study aimed to analyze metabolic adaptations after an exhaustive exercise in two calf muscles (m. soleus - SOL - and m. gastrocnemius medialis - GM) of sprinters and endurance athletes by using localized dynamic P-MRS. In addition, the respiratory parameters VO and VCO , as well as blood lactate concentrations, were monitored simultaneously to assess the effects of local metabolic adjustments in the loaded muscles on global physiological parameters. Besides noting obvious differences between the SOL and the GM muscles, we were also able to identify distinct physiological strategies in dealing with the exhaustive exercise by recruiting two athlete groups with opposing metabolic profiles. Endurance athletes tended to use the aerobic pathway in the metabolism of glucose, whereas sprinters produced a significantly higher peak concentration of lactate. These global findings go along with locally measured differences, especially in the main performer GM, with sprinters revealing a higher degree of acidification at the end of exercise (pH 6.29 ± 0.20 vs. 6.57 ± 0.21). Endurance athletes were able to partially recover their PCr stores during the exhaustive exercise and seemed to distribute their metabolic activity more consistently over both investigated muscles. In contrast, sprinters mainly stressed Type II muscle fibers, which corresponds more to their training orientation preferring the glycolytic energy supply pathway. In conclusion, we were able to analyze the relation between specific local metabolic processes in loaded muscles and typical global adaptation parameters, conventionally used to monitor the training status of athletes, in two cohorts with different sports orientations.

Simultaneous measurements of pulmonary oxygen consumption (VO ), carbon dioxide exhalation (VCO ) and phosphorus magnetic resonance spectroscopy ( P-MRS) are valuable in physiological studies to evaluate muscle metabolism during specific loads. Therefore, the aim of this study was to adapt a commercially available spirometric device to enable measurements of VO and VCO whilst simultaneously performing P-MRS at 3 T. Volunteers performed intense plantar flexion of their right calf muscle inside the MR scanner against a pneumatic MR-compatible pedal ergometer. The use of a non-magnetic pneumotachograph and extension of the sampling line from 3 m to 5 m to place the spirometric device outside the MR scanner room did not affect adversely the measurements of VO and VCO . Response and delay times increased, on average, by at most 0.05 s and 0.79 s, respectively. Overall, we were able to demonstrate a feasible ventilation response (VO = 1.05 ± 0.31 L/min; VCO = 1.11 ± 0.33 L/min) during the exercise of a single calf muscle, as well as a good correlation between local energy metabolism and muscular acidification (τ and pH; R = 0.73, p < 0.005) and global respiration (τ and VO ; R = 0.55, p = 0.01). This provides improved insights into aerobic and anaerobic energy supply during strong muscular performances.

The antioxidant protection from the increased vitamin E was accompanied by a decreased expression of constitutive and function-dependent platelet adhesion molecules. However, increases in platelet-leukocyte coaggregates and a shortened INR time suggest extrinsic coagulation activation, possibly by induction of a leukocyte tissue factor dependent mechanism. High dose supplements of alpha-tocopherol may override the available redox balance in well controlled type 2 diabetes. However, intrinsic effects of alpha-tocopherol must be discussed.

regulatory reviews faster than the EMA while beginning regulatory review first in each case. Three of the four regulatory decisions in which the FDA was slower were outliers in terms of approval time. Additionally, when looking at the median, the FDA approved these moieties 77 days faster than the EMA while Downing's findings only showed a 44-day differential. This was expected because the analysis included the EC decision takes about 2 months on average. ConClusions: After updating the data, restricting it to a particular subset of diabetes treatments, and altering the EMA regulatory endpoint, Downing et al's findings not only still hold true, but become even more pronounced.

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We thank M. Jubeau and J. Gondin for their interest in our work (1). We are grateful that they have pointed our attention to their recent work on neuromuscular electrical stimulation (NMES) (2), which we unintentionally missed during the preparation of our manuscript (1). Both studies, however, differ on crucial points. In contrast to the nonlocalized volume-selection utilizing coil sensitivity, as used in our study, they applied a chemical shift image sequence with a better defined volume selection at the expense of temporal resolution (43.5 s (2) vs. 5 s (1)), which induces substantial temporal averaging over shifting metabolite peaks. Further differences exist with regard to the investigated muscle and stimulation pattern. Nevertheless, our interpretation that the identified pH compartments correspond to different fiber types was supported by their observation of pH-heterogeneity in spectra of homogeneous muscle regions with outer volume contaminations between 9% to 10%.The main difference to the work of Jubeau et al. and the novelty of our study is that we maximized the NMESinduced pH-heterogeneity by a short and strong stimulation (PCr depletion was completed after the first 50 s (1) vs. 400 s in (2)), which would likewise explain the substantially higher shifts of the acidic pH-component (pH < 6.4) in our study. Thus, spectroscopic series were acquired with the best possible time resolution (5 s) while accepting compromises with regard to signal localization and signal-to-noise ratio (SNR). Under these conditions, we observed a split of Pi into three Pi components in all volunteers, which thus far only was detected for voluntary muscle contractions (3). Because it can be assumed that proton enrichment by glycolytic activity and proton exchange are competitive processes, the lower stimulation intensity in the approach of Jubeau et al. may be responsible for smaller pH differences and for the absence of an additional split. Their presentation of the vastus lateralis spectra during NMES stimulation (middle spectrum in the bottom block Figure 1 in Jubeau et al.(2)) lets us assume that the linewidth of the Pi-1 component is larger than for Pi-2, possibly indicating a superposition of two nonresolved components. Unfortunately, we did not find indications of linewidths in their paper.Due to the imprecisely defined muscular contributors to the spectra in our study, it can be assumed that the high pH component represents a contamination of signal from the soleus, which already was discussed in our paper (1). As illustrated by the changes in T 2 *-w images between pre-and postfatigue (Supporting Figs. S9-S12 in Stutzig et al. (1)), these changes are limited to the medial gastrocnemius muscle, and thus no pH-changes are expected in the soleus and the lateral gastrocnemius, whereas all dynamic series apart from one indicate at least a small acidic shift compared to the resting pH ( Fig. 7 in Stutzig et al. (1)). We assume that individual differences are responsible for the prominent shift of two volunteers showing pH o...