Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats

The present study was performed to evaluate the potential role and functional interaction of angiotensin II AT1 and AT2 receptors (AT1R and AT2R) in the regulation of blood pressure and glucose homeostasis in fructose-induced insulin-resistant, hypertensive rats. Male Sprague-Dawley rats on fructose-enriched or regular diets for 4 weeks were subjected to 2-step euglycemic euinsulinemic (EEI) and euglycemic hyperinsulinemic (EHI) clamp studies with [3-3H]glucose infusion. After a 40-minute basal period, selective AT1R and AT2R antagonists, losartan (LOS, 10 mg/kg IV bolus) and PD123319 (PD, 50 microg/kg/min), alone or in combination were separately given to control and fructose-fed groups in the 2 clamp periods. The results showed that during the EEI period, LOS significantly reduced the elevated blood pressure in fructose-fed rats, whereas PD further increased fructose-induced high blood pressure. Coadministration of LOS and PD did not alter the elevated blood pressure in fructose-fed rats. Administration of LOS and/or PD failed to change the blood pressure in control rats. During the EHI period, blockade of both AT1R and AT2R eliminated the insulin-induced blood pressure elevation in control and fructose-fed rats. Hepatic glucose production (HGP) did not alter among groups in the basal and EEI periods. Insulin infusion (EHI period) markedly suppressed HGP in control rats, but this suppressive effect was significantly attenuated in fructose-fed rats. LOS administration further reduced the insulin-induced suppression of HGP in fructose-fed rats. The whole-body glucose uptakes (rates of glucose disappearance, Rd) during the basal and EEI periods were similar among groups. During the EHI period, Rd was markedly increased in all groups and the magnitude of increase was significantly greater in control rats than in fructose-fed rats except those with LOS treatment. LOS treatment also redirected Rd in favor of glycolysis in fructose rats, but not in control rats, during the EEI and EHI periods. The effects of LOS on glycolysis during the 2 clamp periods and on HGP during the EHI period were reversed when PD was concomitantly administered, but PD alone did not alter glucose metabolism throughout the experiment in fructose-fed rats. Administration of LOS and/or PD did not change the glucose metabolism in control rats. Our data suggest that AT2R can counterbalance the AT1R-mediated effects on blood pressure and glucose metabolism in fructose-induced insulin-resistant, hypertensive rats. Furthermore, AT1R- and AT2R-mediated effects on blood pressure are disassociated with their actions on glucose metabolism in this hypertensive model.     

Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.     

Trousseau's syndrome in a patient with advanced stage gastric cancer

Patients with cancer are at high risk for thrombotic events,which are known collectively as Trousseau's syndrome. Herein,we report a 66-year-old male patient who was diagnosed with terminal stage gastric cancer and liver metastasis and who had an initial clinical presentation of upper gastrointestinal bleeding. Acute ischemia of the left lower leg that resulted in gangrenous changes occurred during admission. Subsequent angiography of the left lower limb was then performed. This procedure revealed arterial thrombosis of the left common iliac artery with extension to the external iliac artery,the left common iliac artery,the posterior tibial artery,and the peroneal artery,which were occluded by thrombi. Aspiration of the thrombi demonstrated that these were not tumor thrombi. The interesting aspect of our case was that the disease it presented as arterial thrombotic events,which may correlate with gastric adenocarcinoma. In summary,we suggested that the unexplained thrombotic events might be one of the initial presentations of occult malignancy and that thromboprophylaxis should always be considered.     

Fatiguing exercise initiated later in life reduces incidence of fibrillation and improves sleep quality in Drosophila

As the human body ages, the risk of heart disease and stroke greatly increases. While there is evidence that lifelong exercise is beneficial to the heart’s health, the effects of beginning exercise later in life remain unclear. This study aimed to investigate whether exercise training started later in life is beneficial to cardiac aging in Drosophila. We examined 4-week-old wild-type virgin female flies that were exposed to exercise periods of either 1.5, 2.0, or 2.5 h per day, 5 days a week for 2 weeks. Using M-mode traces to analyze cardiac function by looking at parameters including heart rate, rhythmicity, systolic and diastolic diameter, and interval and fractional shortening, we found that cardiac function declined with age, shown by an increase in the number of fibrillation events and a decrease in fractional shortening. About 2.0 and 2.5 h of exercise per day displayed a reduced incidence of fibrillation events, and only physical exercise lasting 2.5-h period increased fractional shortening and total sleep time in Drosophila. These data suggested that training exercise needs to be performed for longer duration to exert physiological benefits for the aging heart. Additionally, climbing ability to assess the exercise-induced muscle fatigue was also measured. We found that 2.0 and 2.5 h of exercise caused exercise-induced fatigue, and fatiguing exercise is beneficial for cardiac and healthy aging overall. This study provides a basis for further study in humans on the impact of beginning an exercise regimen later in life on cardiac health.     

Implantation of a Tissue-Engineered Tubular Heart Valve in Growing Lambs

Current pediatric heart valve replacement options are suboptimal because they are incapable of somatic growth. Thus, children typically have multiple surgeries to replace outgrown valves. In this study, we present the in vivo function and growth potential of our tissue-engineered pediatric tubular valve. The valves were fabricated by sewing two decellularized engineered tissue tubes together in a prescribed pattern using degradable sutures and subsequently implanted into the main pulmonary artery of growing lambs. Valve function was monitored using periodic ultrasounds after implantation throughout the duration of the study. The valves functioned well up to 8 weeks, 4 weeks beyond the suture strength half-life, after which their insufficiency index worsened. Histology from the explanted valves revealed extensive host cell invasion within the engineered root and commencing from the leaflet surfaces. These cells expressed multiple phenotypes, including endothelial, and deposited elastin and collagen IV. Although the tubes fused together along the degradable suture line as designed, the leaflets shortened compared to their original height. This shortening is hypothesized to result from inadequate fusion at the commissures prior to suture degradation. With appropriate commissure reinforcement, this novel heart valve may provide the somatic growth potential desired for a pediatric valve replacement.     

Neutrophil extracellular traps (NETs) in autoimmune diseases: A comprehensive review

Neutrophil extracellular traps (NETs) are fibrous networks which protrude from the membranes of activated neutrophils. NETs are found in a variety of conditions such as infection, malignancy, atherosclerosis, and autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), psoriasis, and gout. Studies suggest that an imbalance between “NETosis,” which is a process by which NETs are formed, and NET degradation may be associated with autoimmune diseases. Neutrophils, interleukin-8, ANCA and other inflammatory molecules are considered to play a key role in NET formation. Prolonged exposure to NETs-related cascades is associated with autoimmunity and increases the chance of systemic organ damage. In this review, we discuss the roles of various inflammatory molecules in relation to NETs. We also describe the role of NETs in the pathogenesis of autoimmune diseases and discuss the possibility of using targeted therapies directed to NETs and associated molecules to treat autoimmune diseases.     

Left Atrial Function Following Surgical Ablation of Atrial Fibrillation: Prospective Evaluation Using Dual-Source Cardiac Computed Tomography

Purpose

The Maze procedure has shown excellent efficacy in the elimination of atrial fibrillation (AF); however, little is known about the quality of functional recovery in the left atrium (LA) following successful sinus rhythm conversion by the Maze procedure.

Materials and Methods

We prospectively enrolled 12 patients (aged 52.5±10.1 years, 1 female) with valvular AF undergoing mitral valve surgery combined with the Maze procedure. Parameters of LA function in three anatomic compartments [anterior, posterior, and LA appendage (LAA)] were evaluated using electrocardiography-gated dual-source cardiac CT at one month and at six months after surgery. Twelve subjects matched by age, gender, and body surface area served as controls.

Results

At one month after surgery, ejection fraction (EF) and emptying volume (EV) of the LA were 14.9±7.4% and 21.3±9.7 mL, respectively, and they were significantly lower than those of the control group (EF, 47.9±11.2%; EV, 46.0±10.7%; p<0001). These values did not significantly change throughout late periods (p=0.22 and 0.21, respectively). Functional contributions of the anterior, posterior, and appendage compartments (EV of each compartment/overall EV) were 80.4%, -0.9%, and 20.5%, respectively, for those with LAA preservation (n=6); 100.1%, -0.1%, and 0% for those with LAA resection (n=6; p<0.05); and 62.2%, 28.2%, and 9.7% in the control subjects (p<0.001).

Conclusion

Contractile functions of the LA significantly decreased after the Maze procedure. Functional contributions of three compartments of the LA were also altered. The influence of LAA preservation on postoperative LA functions needs to be evaluated through studies of larger populations.     

Idiom Comprehension Deficits in High-Functioning Autism Spectrum Disorder Using a Korean Autism Social Language Task

Purpose

High-functioning autism spectrum disorder (ASD) involves pragmatic impairment of language skills. Among numerous tasks for assessing pragmatic linguistic skills, idioms are important to evaluating high-functioning ASD. Nevertheless, no assessment tool has been developed with specific consideration of Korean culture. Therefore, we designed the Korean Autism Social Language Task (KASLAT) to test idiom comprehension in ASD. The aim of the current study was to introduce this novel psychological tool and evaluate idiom comprehension deficits in high-functioning ASD.

Materials and Methods

The participants included 42 children, ages 6-11 years, who visited our child psychiatric clinic between April 2014 and May 2015. The ASD group comprised 16 children; the attention deficit hyperactivity disorder (ADHD) group consisted of 16 children. An additional 10 normal control children who had not been diagnosed with either disorder participated in this study. Idiom comprehension ability was assessed in these three groups using the KASLAT.

Results

Both ASD and ADHD groups had significantly lower scores on the matched and mismatched tasks, compared to the normal control children (matched tasks mean score: ASD 11.56, ADHD 11.56, normal control 14.30; mismatched tasks mean score: ASD 6.50, ADHD 4.31, normal control 11.30). However, no significant differences were found in scores of KASLAT between the ADHD and ASD groups.

Conclusion

These findings suggest that children with ASD exhibit greater impairment in idiom comprehension, compared to normal control children. The KASLAT may be useful in evaluating idiom comprehension ability.     

Spontaneous transition of 2:1 atrioventricular block to 1:1 atrioventricular conduction during atrioventricular nodal reentrant tachycardia: evidence supporting the intra-Hisian or infra-Hisian area as the site of block

INTRODUCTION: The incidence of spontaneous transition of 2:1 AV block to 1:1 AV conduction during AV nodal reentrant tachycardia has not been well reported. Among previous studies, controversy also existed about the site of the 2:1 AV block during AV nodal reentrant tachycardia. METHODS AND RESULTS: In patients with 2:1 AV block during AV nodal reentrant tachycardia, the incidence of spontaneous transition of 2:1 AV block to 1:1 AV conduction and change of electrophysiologic properties during spontaneous transition were analyzed. Among the 20 patients with 2:1 AV block during AV nodal reentrant tachycardia, a His-bundle potential was absent in blocked beats during 2:1 AV block in 8 patients, and the maximal amplitude of the His-bundle potential in the blocked beats was the same as that in the conducted beats in 4 patients and was significantly smaller than that in the conducted beats in 8 patients (0.49 +/- 0.25 mV vs 0.16 +/- 0.07 mV, P = 0.007). Spontaneous transition of 2:1 AV block to 1:1 AV conduction occurred in 15 (75%) of 20 patients with 2:1 AV block during AV nodal reentrant tachycardia. Spontaneous transition of 2:1 AV block to 1:1 AV conduction was associated with transient right and/or left bundle branch block. The 1:1 AV conduction with transient bundle branch block was associated with significant His-ventricular (HV) interval prolongation (66 +/- 19 ms) compared with 2:1 AV block (44 +/- 6 ms, P < 0.01) and 1:1 AV conduction without bundle branch block (43 +/- 6 ms, P < 0.01). CONCLUSION: The 2:1 AV block during AV nodal reentrant tachycardia is functional; the level of block is demonstrated to be within or below the His bundle in a majority of patients with 2:1 AV block during AV nodal reentrant tachycardia, and a minority are possibly high in the junction between the AV node and His bundle.