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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.

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Analysis and interpretation of the thermal test of gas hydrate dissociation in the JAPEX/JNOC/GSC et al. Mallik 5L-38 gas hydrate production research well Abstract:The objectives of this study were to 1) analyze the data from a field test of thermally induced dissociation of gas hydrate in the JAPEX/JNOC/GSC et al. Mallik 5L-38 gas hydrate production research well; 2) validate and calibrate the numerical model; and 3) determine important parameters describing gas hydrate behaviour and dissociation. The initial conditions and properties of the gas hydrate deposit were determined using supporting geological and geophysical data. Direct measurements provided the necessary boundary conditions. The numerical model was calibrated against the cumulative volumes of produced gas, a process that increased confidence in the model. Two possible scenarios of thermal dissociation, using unadjusted and smoothed data, are proposed to interpret the field test results. The parameters of the dominant physical processes are estimated by inverse modelling (history matching). Their results compare favourably with previously published data. Additionally, estimates of long-term production are made, and an alternative well configuration is proposed to substantially increase gas production.

We cloned and sequenced two new Verotoxin 2 (VT2) variant genes: one from an Escherichia coli strain from a case of bovine diarrhea and the other from an E. coli strain from a patient with diarrhea. The nucleotide and amino acid sequences of these two genes were highly homologous with, but distinct from those of the VT2, VT2vha, VT2vhb, SLT-IIv (VT2vp1) and SLT-Hva (VT2vp2) genes. Their nucleotide sequences were much more closely homologous to that of VT2vh than to that of VT2vp. Search for these two new genes in other Verocytotoxin-producing E. coli strains resulted in the isolation of 2 strains carrying one of the new VT2 variant genes, one strain from Tokyo and the other from Canada. Strains of Verocytotoxin-producing Escherichia coli (VTEC) are associated with human diseases such as diarrhea, hemorrhagic colitis and hemolytic uremic syndrome, dysentery in calves and edema disease of pigs (11). Verotoxins which have been well characterized include VT1 (or Shiga-like toxin I, SLT-I) (3,4, 10,18,19,27), VT2 (or Shiga-like toxin II, SLT-II) (17,24,27,30) and several variants of VT2, such as 13,14,29), VT2vha (8,21), VT2vhb (8,21) and SLT-IIva (6). VT1 is identical (28), or almost identical (3, 4, 10) with Shiga toxin of Shigella dysenteriae type 1 in the nucleotide sequence of its gene and amino acid sequence. VT2 is distinct from VT1 and Shiga toxin and is not neutralized by polyclonal antisera against VT1 and Shiga toxin (24, 27, 30). The overall nucleotide sequence homologies of the VT2 gene with those of the VT1 and Shiga toxin genes are approximately 55-60% (9, 16, 17). The VT2 and SLT-IIv genes have 91% homology in nucleotide sequences (7,29). The nucleotide sequences of the VT2vha and VT2vhb genes are nearly identical, showing 99% overall homology (8). The sequences of the genes of the A and B subunits of VT2vha show 98.6 and 95.5% homology, respectively, with those of the VT2 gene (8). The nucleotide sequence of the SLT-IIva gene is most closely homologous with that of the SLTIIv gene: the nucleotide sequences of the A and B subunits of the SLT-IIva gene have 70.6 and 98% homology, respectively, with those of the SLT-IIv gene (6). To simplify the names of VT2 variants, in this paper, we tentatively named SLTIIv and SLT-IIva as VT2vp1 and VT2vp2, respectively.During studies to develop methods for identification of VTEC strains such as the DNA colony hybridization test with poly-and oligonucleotide probes, bead-enzyme-linked immunosorbent assay (bead-ELISA) and the polymerase chain reaction (PCR) with common primers for various VTs and specific primers for each VT (12) (Yamasaki et al, submitted), we found several VTEC strains that possibly carried new VT2 variants genes. In this paper, we report cloning and sequencing of the genes of two new VT2 variants.

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