No abstract

The heart has an intrinsic ability to increase systolic force in response to a rise in ventricular filling (the Frank–Starling law of the heart). It is widely accepted that the length dependence of myocardial activation underlies the Frank–Starling law of the heart. Recent advances in muscle physiology have enabled the identification of the factors involved in length-dependent activation, viz., titin (connectin)-based interfilament lattice spacing reduction and thin filament “on–off” regulation, with the former triggering length-dependent activation and the latter determining the number of myosin molecules recruited to thin filaments. Patients with a failing heart have demonstrated reduced exercise tolerance at least in part via depression of the Frank–Starling mechanism. Recent studies revealed that various mutations occur in the thin filament regulatory proteins, such as troponin, in the ventricular muscle of failing hearts, which consequently alter the Frank–Starling mechanism. In this article, we review the molecular mechanisms of length-dependent activation, and the influence of troponin mutations on the phenomenon.

Aims To assess efficacy and safety of 26‐week treatment with insulin glargine/lixisenatide fixed‐ratio combination (iGlarLixi) compared with insulin glargine U100 (iGlar) in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs). Materials and Methods This phase 3, multicentre, open‐label, 1:1 randomized, parallel‐group study compared efficacy of iGlarLixi and iGlar in patients with T2DM, HbA1c of ≥7.5% to ≤9.5% and fasting plasma glucose ≤10.0 mmol/L (180 mg/dL). The primary endpoint was change in HbA1c from baseline to week 26. Results Patients were randomized to iGlarLixi (n = 260) or iGlar (n = 261) (mean age 59.7 years, baseline BMI 26.04 kg/m2, and HbA1c 8.04% [64.4 mmol/mol]). HbA1c reduction was significantly greater with iGlarLixi (−1.40% [−15.3 mmol/mol]) than with iGlar (−0.76% [−8.3 mmol/mol]). Significantly more iGlarLixi patients reached HbA1c <7% at week 26 (71.5% vs 38.5%, P < .0001), with significantly lower weight gain (LS mean difference −1.06 kg, P < .0001). Documented symptomatic hypoglycemia (plasma glucose ≤3.9 mmol/L [70 mg/dL]) was recorded in 14.2% of patients with iGlarLixi and 12.3% with iGlar. No severe hypoglycemia was reported in either group. Other than the expected gastrointestinal issues associated with glucagon‐like peptide 1 receptor agonists, we found no major difference in the incidence of TEAEs. Conclusions HbA1c reduction was significantly greater with iGlarLixi than with iGlar; significantly more patients achieved HbA1c <7%, with no additional risk of hypoglycemia and without weight gain. iGlarLixi (1:1) provided an effective treatment option for Japanese patients with T2DM inadequately controlled on OADs. Clinical Trial Number: NCT02752828

Abstract:The thermal-stimulation test conducted on the JAPEX/JNOC/GSC et al. Mallik 5L-38 gas hydrate production research well in March of 2002 was designed to increase the in situ temperature of a portion of a well defined and constrained gas hydrate reservoir above the gas hydrate stability point, while maintaining constant pressure. Data collected, including surface and downhole instrumentation readings and data from advanced logging and seismic programs, were then used to calibrate numerical gas hydrate reservoirsimulation models and determine the kinetic and thermodynamic properties of the in situ gas hydrate.The thermal-stimulation test was successful: bottomhole temperature was increased to greater than 50°C during the test; gas from dissociated gas hydrate was produced, sampled, and flared at surface; and significant amounts of real-time downhole temperature and pressure data, as well as other scientific measurements, were obtained. L'essai de stimulation thermique a été une réussite : on a pu accroître la température au fond du puits à plus de 50°C durant l'essai; on a produit, échantillonné et brûlé à la surface du gaz naturel provenant de la dissociation des hydrates de gaz; et on a généré, entre autres données scientifiques, une quantité considérable de mesures de température et de pression, acquises en temps réel dans le puits.

No abstract