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Hoyeraal-Hreidarsson syndrome (HHS) is the most severe form of dyskeratosis congenita (DC) and is caused by mutations in genes involved in telomere maintenance. Here, we identified male siblings from a family with HHS carrying a hemizygous mutation (c.1345C > G, p.R449G), located in the C-terminal nuclear localization signal (NLS) of the DKC1 gene. These patients exhibit progressive cerebellar hypoplasia, recurrent infections, pancytopenia due to bone marrow failure, and short leukocyte telomere lengths. Single-cell RNA sequencing analysis suggested defects in the NLRP3 inflammasome in monocytes and the activation and maturation of NK cells and B cells. In experiments using induced pluripotent stem cells (iPSCs) from patients, DKC1_R449G iPSCs had short telomere lengths due to reduced levels of human telomerase RNA (hTR) and increased cytosolic proportions of DKC1. Treatment with dihydroquinolizinone RG7834 and 3′deoxyanosine cordycepin rescued telomere length in patient-derived iPSCs. Together, our findings not only provide new insights into immunodeficiency in DC patients but also provide treatment options for telomerase insufficiency disorders.

When a large-scale natural disaster happens, the evolved node B (eNB) of the disaster area (DA) may be destroyed, and the core network (CN) may be congested with massive data traffic. A disaster-resilient communication system can help relief workers execute the rescue operation. In this paper, we propose a smart traffic offloading mechanism (STOM) on a vehicular eNB (VeNB) to improve the system throughput and delay of the disaster-resilient communication system with heavy CN congestion. Based on the concept of mobile edge computing, the proposed STOM can redirect the traffic flows of relief workers in the same DA to prevent the local data from entering the CN. Therefore, traffic flows between relief workers in the same DA can be transmitted directly through the VeNB only, and system throughput and transmission delay can be significantly improved. Simulation results show that our proposed STOM can achieve 2277% higher system throughput and significantly improve the delay performance, compared with the disaster-resilient communication system without STOM under the worst-case CN congestion environment.

Dipeptidyl peptidase-4 (DPP4) enzyme inhibition has been reported to increase plasma glucagon-like peptide-1 (GLP-1) level for controlling postprandial glucose concentration. Both DPP4 inhibitors and GLP-1 analog have been approved for antihyperglycemic agents. In addition to the insulinotropic effect, GLP-1 signaling was reported to modulate cardiac function. DPP4 inhibition was shown to improve survival rate after myocardial infarction in mice, but the precise mechanism remains unknown. We aimed to compare the cardiovascular responses of ischemia/reperfusion (I/R) between wild-type and DPP4-deficient rats and investigate the underlying mechanism. Rats were subjected to 45 min of coronary artery occlusion, followed by reperfusion for 2 h. Cardiac function was characterized by analyzing pressure-volume loops. As compared to wild-type rats, after I/R, DPP4-deficient rats had better cardiac performance in association with less infarct size and cardiac injury markers (LDH, ANP, and BNP), which could be attenuated by exendin-(9-39), a GLP-1 receptor antagonist. Exendin-(9-39) could diminish the increased phosphorylation levels of myocardial AKT and GSK-3β as well as the higher expression of GLUT4 in post-infarcted DPP4-deficient rats. However, exendin-(9-39) could not completely abrogate the less infarct size in DPP4-deficient rats as compared with that in wild-type rats, implicating the involvement of GLP-1 receptor-independent pathway. In summary, this study demonstrated that the benefit of cardiac protective action against I/R injury was demonstrated in DPP4-deficient rats, which is mediated through both GLP-1 receptor-dependent and receptor-independent mechanisms.

Thaliporphine was found to ameliorate endotoxin-induced circulatory failure and mortality in rodents. The aims of the present study were to assess whether thaliporphine could improve cardiac function in endotoxemic rats and to investigate the underlying mechanisms. Cardiac function was evaluated by pressure-volume loop analysis in pentobarbital-anesthetized rats 24 h after intravenous injection of lipopolysaccharide (LPS) (4 mg/kg) with or without thaliporphine (1 mg/kg, iv). The intracellular Ca(2+) transients, nitric oxide (NO), and reactive oxygen species (ROS) in enzymatically isolated ventricular cells were measured by fluorescent indicators. Western blotting was used to analyze the change of protein expression in response to LPS with or without thaliporphine in rat ventricle, H9C2 and Raw264.7 cells. Cardiac depression was found to coincide with the decreased intracellular Ca(2+) transients and the increased expression of nitrotyrosine on SERCA2 in rat ventricles after 24-h endotoxemia. Thaliporphine decreased intracellular NO and ROS level in ventricular cells and the nitrosylation of SERCA2, which resulted in recovering the functional properties of intracellular Ca(2+) handling and cardiac contraction. In H9C2 cells, LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) could be attenuated by thaliporphine. In Raw264.7 cells, thaliporphine attenuated LPS-induced TAK-1 phosphorylation and IκBα degradation in association with the inhibition of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α) expression and the production of NO and ROS. In conclusion, thaliporphine ameliorates LPS-induced cardiac depression through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling in both cardiomyocytes and macrophage to prevent cardiac SERCA2 from nitrosylation by peroxynitrite via decreasing iNOS and TNF-α expression.

In Langendorff-perfused adult rat heart with constant pressure at 80 mmHg, we found doxazosin, an alpha(1) adrenoceptor blocker, at 10 muM prolonged PR interval and induced occasional arrhythmia followed by complete inhibition of the sinus rhythm, whereas bunazosin, another alpha(1)-blocker, at same concentration did not. The results of voltage-clamp study showed that, at the concentration of 10 muM, doxazosin inhibited I (Na), I ( (Ca,L) ), I (to), and Iss without changing I (k1) but bunazosin only inhibited I ( (Ca,L) ) about 30%. Doxazosin also caused markedly negative shift of the I (Na) inactivation curve. In current-clamp study, doxazosin prolonged action potential duration in association with the decreased action potential amplitude and upstroke velocity, whereas bunazosin did not. We hypothesize that doxazosin-induced arrhythmia may result from the heterogeneous or different level of I ( (Ca,L) ) blockade of AV nodal tissue. In conclusion, the present study suggests that bunazosin is safer than doxazosin for long-term treatment in view of electrophysiological effect. However, the underlying mechanism of doxazosin induced nodal arrhythmia is still needed to be determined.

Few studies of the concordance between patient self-report and medical record data have examined how concordance varies with patient characteristics, and results of such studies have been mixed. Given discrepancies in the quality of care received across patient cohorts, it is important to understand the degree to which concordance metrics are robust across patient characteristics. We hypothesized that concordance between ambulatory medical record and patient survey data varies by patient demographic characteristics, especially education, income, and race/ethnicity. We present the results of bivariate and multivariate analyses including data from 1,270 patients with at least one of: diabetes, ischemic heart disease, asthma or COPD, or low back pain sampled from 39 West Coast medical organizations. We present total agreement, kappa, and survey sensitivity and specificity, stratified by patient demographic and health status characteristics. We conducted logistic regressions to test the impact of patient demographic characteristics, domain of medical care, and health status on these three measures of concordance. Survey sensitivity varied significantly by race/ethnicity in bivariate analyses, but this effect was erased in multivariate analyses. Our findings do not support the hypothesis that patient education, income, or race/ethnicity have an independent effect on concordance when controlling for other factors. However, concordance varied significantly by patient health status. The medical record and patient self-report do not measure quality comparably across patient cohorts. We recommend continued efforts to improve survey data collection across different patient populations and to improve the quality of clinical data.

Alterations in alpha(1)-adrenoceptor (alpha(1)AR) density and related signal transduction proteins were reported in cardiomyopathic hearts in the failing stage. The electromechanical modification of alpha(1)-adrenergic stimulation in the failing heart is unclear. The present study compares the alpha(1)AR-stimulated electromechanical response in failing ventricles of genetically cardiomyopathic BIO 14.6 hamsters (280-320 days old) with that in age-matched normal Syrian hamsters. The action potential was recorded with a conventional microelectrode technique, and twitch force was measured with a transducer. In the presence of propranolol, phenylephrine increased the contraction and prolonged the action potential duration (APD) to similar values in ventricles of both strains, despite a prolonged basal APD in cardiomyopathic ventricles. The positive inotropism stimulated by phenylephrine was inhibited by staurosporine, and was potentiated by 4 beta-phorbol-12,13-dibutyrate (PDBu) in both strains. The maximum positive inotropic effect of phenylephrine in PDBu-treated ventricles of normal hamsters was significantly greater than that in BIO 14.6 hamsters. The effects of phenylephrine on the ventricular force-frequency relationship and on the mechanical restitution in both normal and BIO 14.6 strain hamsters were examined. The uniform negative force-frequency relationship and the altered mechanical restitution reveal a defect of intracellular Ca(2+) handling in cardiomyopathic BIO 14.6 hamsters. alpha(1)-Adrenergic modulation cannot convert the defective properties in the model of the failing heart. Nevertheless, phenylephrine decreased post-rest potentiation in short rest periods, and enhanced post-rest decay after longer resting periods. The results indicate that alpha(1)-adrenergic action enhances a gradual loss of Ca(2+) from the sarcoplasmic reticulum, although its action in prolonging the APD can indirectly increase the influx of Ca(2+).

We investigated the electrophysiological effect and antiarrhythmic potential of cinnamophilin (Cinn), a thromboxane A(2) antagonist isolated from Cinnamomum philippinense, on rat cardiac tissues. Action potential and ionic currents in single rat ventricular cells were examined by current clamp or voltage clamp in a whole-cell configuration. In 9 episodes of ischemia-reperfusion arrhythmia, 10 microM Cinn converted 6 of them to normal sinus rhythm. Cinn suppressed the maximal rate of rise of the action potential upstroke (V(max)) and prolonged the action potential duration at 50% repolarization (APD(50)). Voltage clamp study showed that the suppression of V(max) by Cinn was associated with an inhibition of sodium inward current (I(Na), IC(50) = 10.0 +/- 0.4 microM). At 30 microM, V(1/2) for the steady-state inactivation curve of I(Na) was shifted from -84.1 +/- 0.2 to -93.0 +/- 0.5 mV. Cinn also reduced calcium inward current (I(Ca)) dose-dependently with an IC(50) value of 9.5 +/- 0.3 microM. Cinn (10 microM) reduced the I(Ca) with a negative shift of V(1/2) for the steady-state inactivation curve of I(Ca) from -32.2 +/- 0.3 to -50.7 +/- 0.4 mV. The prolongation of APD(50) was associated with an inhibition of the integral of potassium outward current with IC(50) values between 4.8 and 7.1 microM. At 10 microM, Cinn reduced I(Na) without a negative shift of its voltage-dependent steady-state inactivation curves. The inhibition of transient outward current (I(to)) by Cinn (3-30 microM) was associated with an acceleration of its time constant of inactivation and negative shift of its potential-dependent steady-state inactivation curves. The equilibrium dissociation constant (K(d)) of Cinn to inhibit open state I(to) channels, as calculated from the time constant of developing block, was 18.3 microM. The time constant of recovery of I(to) from inactivation state was unaffected by Cinn. The rate constant for the relief from the depolarization-dependent block of I(to) was calculated to be 23. 9 ms. As compared with its effect on I(to), Cinn exerted about half the potency to block I(Na) and I(Ca). These results indicate that the inhibition of I(Na), I(Ca) and I(to) may contribute to the antiarrhythmic activity of Cinn against ischemia-reperfusion arrhythmia.

Background Glucose intolerance and cardiovascular complications are major symptoms in patients with diabetes. Many therapies have proven beneficial in treating diabetes in animals by protecting the cardiovascular system and increasing glucose utilization. In this study, we evaluated the effects of caffeic acid phenethyl amide (CAPA) on glucose homeostasis and vascular function in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Diabetes (blood glucose levels > 350 mg/dL), was induced in Wistar rats by a single intravenous injection of 60 mg/kg STZ. Hypoglycemic effects were then assessed in normal and type 1 diabetic rats. In addition, coronary blood flow in Langendorff-perfused hearts was evaluated in the presence or absence of nitric oxide synthase (NOS) inhibitor. The thoracic aorta was used to measure vascular response to phenylephrine. Finally, the effect of chronic treatment of CAPA and insulin on coronary artery flow and vascular response to phenylephrine were analyzed in diabetic rats. Results Oral administration of 0.1 mg/kg CAPA decreased plasma glucose in normal (32.9 ± 2.3% decrease, P < 0.05) and diabetic rats (11.8 ± 5.5% decrease, P < 0.05). In normal and diabetic rat hearts, 1–10 μM CAPA increased coronary flow rate, and this increase was abolished by 10 μM NOS inhibitor. In the thoracic aorta, the concentration/response curve of phenylephrine was right-shifted by administration of 100 μM CAPA. Coronary flow rate was reduced to 7.2 ± 0.2 mL/min at 8 weeks after STZ-induction. However, 4 weeks of treatment with CAPA (3 mg/kg, intraperitoneal, twice daily) started at 4 weeks after STZ induction increased flow rate to 11.2 ± 0.5 mL/min (P < 0.05). In addition, the contractile response induced by 1 μM phenylephrine increased from 6.8 ± 0.6 mN to 11.4 ± 0.4 mN (P < 0.05) and 14.9 ± 1.4 mN (P < 0.05) by insulin (1 IU/kg, intraperitoneal) or CAPA treatment, respectively. Conclusions CAPA induced hypoglycemic activity, increased coronary blood flow and vascular response to phenylephrine in type 1 diabetic rats. The increase in coronary blood flow may result from endothelial NOS activation. However, the detailed cellular mechanisms need to be further evaluated.

Oxidative stress and nitrosative stress are both suggested to be involved in cardiac ischemia-reperfusion (I/R) injury. Using time-lapse confocal microscopy of cardiomyocytes and high-affinity O(2)(-•) and Zn(2+) probes, this study is the first to show that I/R, reactive oxygen species (ROS), and reactive nitrogen species (RNS) all cause a marked increase in the [O(2)(-•)](i), resulting in cytosolic and mitochondrial Zn(2+) release. Exposure to a cell-penetrating, high-affinity Zn(2+)(i) chelator, TPEN, largely abolished the Zn(2+)(i) release and markedly protected myocytes from I/R-, ROS-, RNS-, or Zn(2+)/K(+) (Zn(2+)(i) supplementation)-induced myocyte apoptosis for at least 24 h after TPEN removal. Flavonoids and U0126 (a MEK1/2 inhibitor) largely inhibited the myocyte apoptosis and the TPEN-sensitive I/R- or Zn(2+)(i) supplement-induced persistent extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, dephosphorylation of p-Ser9 on glycogen synthase kinase 3β (GSK-3β), and the translocation into and accumulation of p-Tyr216 GSK-3β and p53 in, the nucleus. Silencing of GSK-3β or p53 expression was cardioprotective, indicating that activation of the ERK-GSK-3β-p53 signaling pathway is involved in Zn(2+)-sensitive myocyte death. Moreover, the ERK-dependent Noxa-myeloid cell leukemia-1 (Mcl-1) pathway is also involved, as silencing of Noxa expression was cardioprotective and U0126 abolished both the increase in Noxa expression and in Mcl-1 degradation. Thus, acute upstream Zn(2+)(i) chelation at the start of reperfusion and the use of natural products, that is, flavonoids, may be beneficial in the treatment of cardiac I/R injury.