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Objectives: This study evaluated whether a xanthine oxidase (XO) inhibitor, oxypurinol, produces clinical benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy.Background: Increased XO activity may contribute to heart failure pathophysiology.Methods: Patients (n = 405) were randomized to oxypurinol (600 mg/day) or placebo. Efficacy at 24 weeks was assessed using a composite end point comprising heart failure morbidity, mortality, and quality of life.Results: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving oxypurinol or placebo. Oxypurinol reduced serum uric acid (SUA) by approximately 2 mg/dl (p < 0.001). In a subgroup analysis, patients with elevated SUA (>9.5 mg/dl, n = 108) responded favorably to oxypurinol (p = 0.02 for interaction term), whereas oxypurinol patients with SUA <9.5 mg/dl exhibited a trend towards worsening. In addition, SUA reduction to oxypurinol correlated with favorable clinical response. Within the entire oxypurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who worsened (-2.3 +/- 2.1 mg/dl vs. -1.0 +/- 1.9 mg/dl, p = 0.0006). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome.Conclusions: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Serum uric acid may serve as a valuable biomarker to target XO inhibition in heart failure. (Oxypurinol Compared With Placebo for Class III-IV NYHA Congestive Heart Failure; NCT00063687). [ABSTRACT FROM AUTHOR]

Neptune-sized planets exhibit a wide range of compositions and densities, depending on factors related to their formation and evolution history, such as the distance from their host stars and atmospheric escape processes. They can vary from relatively low-density planets with thick hydrogen-helium atmospheres 1,2 to higher-density planets with a substantial amount of water or a rocky interior with a thinner atmosphere, such as HD 95338 b (ref.  3 ), TOI-849 b (ref.  4 ) and TOI-2196 b (ref.  5 ). The discovery of exoplanets in the hot-Neptune desert 6 , a region close to the host stars with a deficit of Neptune-sized planets, provides insights into the formation and evolution of planetary systems, including the existence of this region itself. Here we show observations of the transiting planet TOI-1853 b, which has a radius of 3.46 ± 0.08 Earth radii and orbits a dwarf star every 1.24 days. This planet has a mass of 73.2 ± 2.7 Earth masses, almost twice that of any other Neptune-sized planet known so far, and a density of 9.7 ± 0.8 grams per cubic centimetre. These values place TOI-1853 b in the middle of the Neptunian desert and imply that heavy elements dominate its mass. The properties of TOI-1853 b present a puzzle for conventional theories of planetary formation and evolution, and could be the result of several proto-planet collisions or the final state of an initially high-eccentricity planet that migrated closer to its parent star., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Temperate Earth-sized exoplanets around late-M dwarfs offer a rare opportunity to explore under which conditions planets can develop hospitable climate conditions. The small stellar radius amplifies the atmospheric transit signature, making even compact secondary atmospheres dominated by N 2 or CO 2 amenable to characterization with existing instrumentation 1 . Yet, despite large planet search efforts 2 , detection of low-temperature Earth-sized planets around late-M dwarfs has remained rare and the TRAPPIST-1 system, a resonance chain of rocky planets with seemingly identical compositions, has not yet shown any evidence of volatiles in the system 3 . Here we report the discovery of a temperate Earth-sized planet orbiting the cool M6 dwarf LP 791-18. The newly discovered planet, LP 791-18d, has a radius of 1.03 ± 0.04 R ⊕ and an equilibrium temperature of 300-400 K, with the permanent night side plausibly allowing for water condensation. LP 791-18d is part of a coplanar system 4 and provides a so-far unique opportunity to investigate a temperate exo-Earth in a system with a sub-Neptune that retained its gas or volatile envelope. On the basis of observations of transit timing variations, we find a mass of 7.1 ± 0.7 M ⊕ for the sub-Neptune LP 791-18c and a mass of [Formula: see text] for the exo-Earth LP 791-18d. The gravitational interaction with the sub-Neptune prevents the complete circularization of LP 791-18d's orbit, resulting in continued tidal heating of LP 791-18d's interior and probably strong volcanic activity at the surface 5,6 ., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Spectroscopy of transiting exoplanets can be used to investigate their atmospheric properties and habitability. Combining radial velocity (RV) and transit data provides additional information on exoplanet physical properties. We detect a transiting rocky planet with an orbital period of 1.467 days around the nearby red dwarf star Gliese 486. The planet Gliese 486 b is 2.81 Earth masses and 1.31 Earth radii, with uncertainties of 5%, as determined from RV data and photometric light curves. The host star is at a distance of ~8.1 parsecs, has a J -band magnitude of ~7.2, and is observable from both hemispheres of Earth. On the basis of these properties and the planet's short orbital period and high equilibrium temperature, we show that this terrestrial planet is suitable for emission and transit spectroscopy., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrine signals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSC) with progenitor-like features. In co-culture and conditioned medium studies, cMSCs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and preserved cardiac mitochondrial transmembrane potential. Protection was independent of exosomes under the conditions tested. In mice, injecting cMSC-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes > 70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMSCs, and suggesting the cMSC secretome or its components as potential cell-free therapeutic products.

A major determinant of maximal exercise capacity is the delivery of oxygen to exercising muscles. myo-Inositol trispyrophosphate (ITPP) is a recently identified membrane-permeant molecule that causes allosteric regulation of Hb oxygen binding affinity. In normal mice, i.p. administration of ITPP (0.5-3 g/kg) caused a dose-related increase in the oxygen tension at which Hb is 50% saturated (p50), with a maximal increase of 31%. In parallel experiments, ITPP caused a dose-related increase in maximal exercise capacity, with a maximal increase of 57 +/- 13% (P = 0.002). In transgenic mice with severe heart failure caused by cardiac-specific overexpression of G alpha q, i.p. ITPP increased exercise capacity, with a maximal increase of 63 +/- 7% (P = 0.005). Oral administration of ITPP in drinking water increased Hb p50 and maximal exercise capacity (+34 +/- 10%; P < 0.002) in normal and failing mice. Consistent with increased tissue oxygen availability, ITPP decreased hypoxia inducible factor-1alpha mRNA expression in myocardium. It had no effect on myocardial contractility in isolated mouse cardiac myocytes and did not affect arterial blood pressure in vivo in mice. Thus, ITPP decreases the oxygen binding affinity of Hb, increases tissue oxygen delivery, and increases maximal exercise capacity in normal mice and mice with severe heart failure. ITPP is thus an attractive candidate for the therapy of patients with reduced exercise capacity caused by heart failure.

Oxypurinol, the active metabolite of allopurinol and a potent xanthine oxidase inhibitor (XOI), is under evaluation as a novel agent for the treatment of congestive heart failure (HF). Several lines of evidence provide the rationale for the hypothesis that XOIs will improve clinical outcomes in patients with HF. First, XOIs have unique positive inotropic effects, improving myocardial contraction and performance while simultaneously improving myocardial energy metabolism. Second, XOIs ameliorate endothelial dysfunction in humans with HF. Finally, XO activity is upregulated in the heart and vasculature of subjects with HF, which may in turn contribute to oxidative stress and/or increased uric acid levels. Together these findings form the rationale for the Controlled Efficacy and Safety Study of Oxypurinol Added to Standard Therapy in Patients with New York Heart Association (NYHA) class III - IV Congestive Heart Failure (OPT-CHF) trial (Food and Drug Administration IND 65,125), a Phase II - III prospective, randomised, double-blind, placebo-controlled trial, which will include patients with stable symptomatic HF in NYHA class III - IV congestive HF who are deemed clinically stable on a standard and appropriately maximised heart failure therapy regimen. The efficacy end point for OPT-CHF is a composite that incorporates measures of patient outcome and well-being.

Objectives: This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI)., Background: Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA., Methods: One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min., Results: TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23)., Conclusions: Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.

Because of the unsatisfactory options available for safe and effective antithrombotic therapy, recent, intense research and development efforts have focused on direct, or site-directed, thrombin inhibitors. Argatroban is a small-molecule, reversible, direct thrombin inhibitor selective for the catalytic site of the thrombin molecule. Argatroban's molecular properties (small molecule; fast, selective, and reversible inhibition of the thrombin catalytic site; and similar in vitro potency for inhibiting both clot-bound and soluble thrombin) offer the potential for significant antithrombotic efficacy with minimal systemic anticoagulant effects. Its clinical pharmacologic properties offer the potential for minimal risk of bleeding, very rapid achievement of therapeutic antithrombotic efficacy, predictable dose response, and rapid restoration of the hemostatic systems to baseline on termination of intravenous infusion. The intravenous agent Novastan (brand of argatroban) is currently approved for clinical use in Japan for the treatment of peripheral arterial occlusive disease. Novastan is in advanced clinical development in North and South America for several indications, including (1) anticoagulant/antithrombotic therapy in heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia, and thrombosis syndrome (HITTS); and (2) adjunctive therapy to thrombolytic agents in acute myocardial infarction. Results from these trials are projected to be available by early 1997.

Patients with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) frequently have coincident vascular disease. Patients with HITTS who require vascular procedures have often been excluded from vascular intervention because intravascular procedures require heparin. Re-exposure to heparin places these patients at great risk for reactivation of thrombosis related to HIT antibody. We present our initial experience with an alternative anticoagulant to heparin, argatroban in patients with HIT antibody who underwent 14 coronary interventions. All 14 coronary lesions were treated successfully and no patient suffered an HITTS-related or an argatroban-related complication.

High-density, three-dimensional cell cultures are difficult to grow in vitro. The rotating-wall vessel (RWV) described here has cultured BHK-21 cells to a density of 1.1 X 10(7) cells/ml. Cells on microcarriers were observed to grow with enhanced bridging in this batch culture system. The RWV is a horizontally rotated tissue culture vessel with silicon membrane oxygenation. This design results in a low-turbulence, low-shear cell culture environment with abundant oxygenation. The RWV has the potential to culture a wide variety of normal and neoplastic cells.

There have been recent, heightened concerns about the integrity and credibility of industry-sponsored clinical research. While attributable to a variety of factors, the potential consequences are a decrease in the ability of the biomedical research enterprise to produce innovative methods for the diagnosis and treatment of disease, with possible adverse implications for the health and well-being of the public. A specific example of a recent industry-sponsored clinical trial is presented as an approach to attempt to avoid any suggestion of fraud, error, or biased interpretation, in a way in which the integrity of the process will not be called into question and the credibility of the results will be maximized.

In a randomized placebo-controlled double-blind trial of 230 congestive heart failure patients, four treatments were evaluated for efficacy, with exercise tolerance time (ETT) as the primary outcome. Various two-sample tests were applied to the analysis of ETT data. It is shown in this paper that the conventional two-sample tests (t and rank-sum) are insensitive to situations where the effect of the experimental therapy is not consistent across a patient population. Tests recommended by O'Brien are more appropriate for these data. It is also shown that the application of the O'Brien tests led to the identification of sub-groups where the observed effect of the experimental therapy was most pronounced.

We have investigated the steps in the actomyosin ATPase cycle that determine the maximum ATPase rate (Vmax) and the binding between myosin subfragment one (S-1) and actin which occurs when the ATPase activity is close to Vmax. We find that the forward rate constant of the initial ATP hydrolysis (initial Pi burst) is about 5 times faster than the maximum turnover rate of the actin S-1 ATPase. Thus, another step in the cycle must be considerably slower than the forward rate of the initial Pi burst. If this slower step occurs only when S-1 is complexed with actin, as originally predicted by the Lymn-Taylor model, the ATPase activity and the fraction of S-1 bound to actin in the steady state should increase almost in parallel as the actin concentration is increased. As measured by turbidity determined in the stopped-flow apparatus, the fraction of S-1 bound to actin, like the ATPase activity, shows a hyperbolic dependence on actin concentration, approaching 100% asymptotically. However, the actin concentration required so that 50% of the S-1 is bound to actin is about 4 times greater than the actin concentration required for half-maximal ATPase activity. Thus, as previously found at 0 degrees C, at 15 degrees C much of the S-1 is dissociated from actin when the ATPase is close to Vmax, showing that a slow first-order transition which follows the initial Pi burst (the transition from the refractory to the nonrefractory state) must be the slowest step in the ATPase cycle. Stopped-flow studies also reveal that the steady-state turbidity level is reached almost instantaneously after the S-1, actin, and ATP are mixed, regardless of the order of mixing. Thus, the binding between S-1 and actin which is observed in the steady state is due to a rapid equilibrium between S-1--ATP and acto--S-1--ATP which is shifted toward acto-S-1--ATP at high actin concentration. Furthermore, both S-1--ATP and S-1--ADP.Pi (the state occurring immediately after the initial Pi burst) appear to have the same binding constant to actin. Thus, at high actin concentration both S-1--ATP and S-1--ADP.Pi are in rapid equilibrium with their respective actin complexes. Although at very high actin concentration almost complete binding of S-1--ATP and S-1--ADP.Pi to actin occurs, there is no inhibition of the ATPase activity at high actin concentration. This strongly suggests that both the initial Pi burst and the slow rate-limiting transition which follows (the transition from the refractory to the nonrefractory state) occur at about the same rates whether the S-1 is bound to or dissociated from actin. We, therefore, conclude that S-1 does not have to dissociate from actin each time an ATP molecule is hydrolyzed.

In a randomized, double-blind, placebo-controlled, 3-months trial involving 111 congestive heart failure patients, one non-validated and three validated Quality of Life (QL) instruments were administered. Two randomized treatment groups were evaluated, one with 62 patients who continued on standard therapy and the other with 49 patients whose standard therapy was replaced by placebo. The data from Patient's Self-rating Scale (a non-validated instrument) and Spitzer's QL index showed a significant difference between the two treatment groups for an overall effect. There were no significant differences between two treatment groups for Sickness Impact Profile (SIP) and Quality of Well-Being (QWB). For analyzing the multiple components in a QL instrument, the global statistics as suggested by O'Brien were applied to compare the two treatment groups. Univariate statistics complemented the global methods. The general use of global statistics in analyzing QL data is recommended.

Two children presented with mild, chronic diarrheal illnesses. Investigation revealed typical pseudomembranous colitis in both cases, which responded to therapy. While variation in the severity of pseudomembranous colitis is recognized, the subtle, chronic presentation exemplified by these cases has not previously been well described.

Frog sartorius muscle treated with 5.0 mM or greater caffeine exhibits stiffness similar to that obtained from muscle in iodoacetate rigor. The data provide quantitative evidence that suggests that caffeine at irreversible contracture-producing concentrations somehow induces a rigor or rigorlike state in skeletal muscle.