The ability for muscle to repeatedly generate force is limited by fatigue. The cellular mechanisms behind muscle fatigue are complex and potentially include breakdown at many points along the excitation-contraction pathway. In this paper we construct a mathematical model of the skeletal muscle excitation-contraction pathway based on the cellular biochemical events that link excitation to contraction. The model includes descriptions of membrane voltage, calcium cycling and crossbridge dynamics and was parameterised and validated using the response characteristics of mouse skeletal muscle to a range of electrical stimuli. This model was used to uncover the complexities of skeletal muscle fatigue. We also parameterised our model to describe force kinetics in fast and slow twitch fibre types, which have a number of biochemical and biophysical differences. How these differences interact to generate different force/fatigue responses in fast- and slow- twitch fibres is not well understood and we used our modelling approach to bring new insights to this relationship.

Models of skeletal muscle can be classified as phenomenological or biophysical. Phenomenological models predict the muscle’s response to a specified input based on experimental measurements. Prominent phenomenological models are the Hill-type muscle models, which have been incorporated into rigid-body modeling frameworks, and three-dimensional continuum-mechanical models. Biophysically based models attempt to predict the muscle’s response as emerging from the underlying physiology of the system. In this contribution, the conventional biophysically based modeling methodology is extended to include several structural and functional characteristics of skeletal muscle. The result is a physiologically based, multi-scale skeletal muscle finite element model that is capable of representing detailed, geometrical descriptions of skeletal muscle fibers and their grouping. Together with a well-established model of motor-unit recruitment, the electro-physiological behavior of single muscle fibers within motor units is computed and linked to a continuum-mechanical constitutive law. The bridging between the cellular level and the organ level has been achieved via a multi-scale constitutive law and homogenization. The effect of homogenization has been investigated by varying the number of embedded skeletal muscle fibers and/or motor units and computing the resulting exerted muscle forces while applying the same excitatory input. All simulations were conducted using an anatomically realistic finite element model of the tibialis anterior muscle. Given the fact that the underlying electro-physiological cellular muscle model is capable of modeling metabolic fatigue effects such as potassium accumulation in the T-tubular space and inorganic phosphate build-up, the proposed framework provides a novel simulation-based way to investigate muscle behavior ranging from motor-unit recruitment to force generation and fatigue.

Purpose of review -therapeutic hypothermia reduces death or disability in term and near-term infants with moderate-severe hypoxic-ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite hypothermia, supporting further research into ways to further improve neurologic outcomes. Recent findings -recent clinical and experimental studies have refined our understanding of the key parameters for hypothermic neuroprotection, including timing of initiation, depth, and duration of hypothermia, and subsequent rewarming rate. However, important knowledge gaps remain. There is encouraging clinical evidence from a small phase II trial that combined treatment of hypothermia with recombinant erythropoietin further reduces risk of disability but definitive studies are still needed. Summary -In conclusion, recent studies suggest that current protocols for therapeutic hypothermia are nearoptimal, and that the key to better neurodevelopmental outcomes is earlier diagnosis and initiation of hypothermia after birth. Further research is essential to find and evaluate ways to further improve outcomes after hypoxic-ischemic encephalopathy, including add-on therapies for therapeutic hypothermia and preventing pyrexia during labor and delivery.

Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth.

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The majority of intrapartum decelerations are widely believed to be mediated by the baroreflex secondary to brief umbilical cord occlusions (UCOs) but this remains unproven. r We examined the responses to brief-UCOs in fetal sheep and compared these to a phenylephrine-stimulated baroreflex in a separate cohort. A further cohort was instrumented with near-infrared spectroscopy to measure cerebral oxygenation during UCO. r The first 3-4 s of the brief-UCOs were consistent with a baroreflex, and associated with a minor fall in fetal heart rate (FHR). Thereafter, the remainder of the FHR decelerations were highly consistent with the peripheral chemoreflex. r The baroreflex is not sufficient to produce deep, rapid decelerations characteristic of variable decelerations and it is therefore likely to be a minor contributor to intrapartum decelerations.

Background: Increased circulating levels of tumor necrosis factor (TNF) are associated with greater risk of impaired neurodevelopment after preterm birth. In this study, we tested the hypothesis that systemic TNF inhibition, using the soluble TNF receptor Etanercept, would attenuate neuroinflammation in preterm fetal sheep exposed to lipopolysaccharide (LPS). Methods: Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive saline (control; n = 7), LPS infusion (100 ng/kg i.v. over 24 h then 250 ng/kg/24 h for 96 h plus 1 μg LPS boluses at 48, 72, and 96 h, to induce inflammation; n = 8) or LPS plus two i.v. infusions of Etanercept (2 doses, 5 mg/kg infused over 30 min, 48 h apart) started immediately before LPS-exposure (n = 8). Sheep were killed 10 days after starting infusions, for histology. Results: LPS boluses were associated with increased circulating TNF, interleukin (IL)-6 and IL-10, electroencephalogram (EEG) suppression, hypotension, tachycardia, and increased carotid artery perfusion (P < 0.05 vs. control). In the periventricular and intragyral white matter, LPS exposure increased gliosis, TNFpositive cells, total oligodendrocytes, and cell proliferation (P < 0.05 vs control), but did not affect myelin expression or numbers of neurons in the cortex and subcortical regions. Etanercept delayed the rise in circulating IL-6, prolonged the increase in IL-10 (P < 0.05 vs. LPS), and attenuated EEG suppression, hypotension, and tachycardia after LPS boluses. Histologically, Etanercept normalized LPS-induced gliosis, and increase in TNF-positive cells, proliferation, and total oligodendrocytes. Conclusion: TNF inhibition markedly attenuated white matter gliosis but did not affect mature oligodendrocytes after prolonged systemic inflammation in preterm fetal sheep. Further studies of long-term brain maturation are now needed.

Therapeutic hypothermia is now proven to reduce death or disability in term and near‐term born infants with moderate to severe hypoxic‐ischemic encephalopathy. Nevertheless, many infants still survive with disability, despite treatment with hypothermia. Recent preclinical and clinical studies suggest that current protocols for therapeutic hypothermia are near‐optimal. The obvious strategy, in addition to improving early initiation of therapeutic hypothermia after birth, is to combine hypothermia with other neuroprotective agents. We review evidence that the mechanisms of action of many promising agents overlap with the anti‐excitotoxic, anti‐apoptotic, and anti‐inflammatory mechanisms of hypothermia, leading to a lack of benefit from combination treatment. Moreover, even apparently beneficial combinations have failed to translate in clinical trials. These considerations highlight the need for preclinical studies to test clinically realistic protocols of timing and duration of treatment, before committing to large randomized controlled trials.