Comparison of endoscopic retrograde cholangiopancreatography outcomes between cap-fitted forward and side viewing endoscopes in patients with Billroth II anastomosis.

BACKGROUND: There have been no previous studies that directly compared outcomes between cap-fitted forward-viewing and side viewing endoscopes (SE). This study aimed to compare the technical success rate and occurrence of adverse events between the side viewing and cap-fitted forward-viewing endoscope (CE) groups among patients with Billroth II anatomy who underwent ERCP. METHODS: The medical records of patients with a previous history of subtotal gastrectomy using Billroth II reconstruction who underwent ERCP at Yeungnam University Hospital between January 2004 and December 2020 were reviewed retrospectively. The patients were divided into CE and SE group. Propensity score matching analysis was performed to minimize selection bias. RESULTS: Propensity score matching resulted in 55 matched pairs for further analysis. Patients' characteristics were comparable in the matched cohorts. Final success rate of selective bile duct cannulation was not significantly different between the SE and CE groups (98.2% vs. 94.5%, p = 0.308). The complete CBD stone removal rate in CBD stone and successful biliary drainage rate in malignant biliary obstruction were not significantly different between the two groups. The rate of total ERCP-related adverse events was higher in the CE group than in the SE group, but the difference was not statistically significant (10.9% vs. 7.3%, p = 0.507). Among adverse events, the rate of post-ERCP pancreatitis showed higher tendency in the CE group than in the SE group (10.9% vs. 5.5%, p = 0.297). CONCLUSION: In conclusion, CE seems to be equally effective as SE for ERCP in patients with Billroth II anatomy. However, attention should be paid to development of post ERCP complications, especially pancreatitis, when performed by CE.

Human lncRNA SUGCT-AS1 Regulates the Proinflammatory Response of Macrophage.

Macrophages are the major primary immune cells that mediate the inflammatory response. In this process, long non-coding RNAs (lncRNAs) play an important, yet largely unknown role. Therefore, utilizing several publicly available RNA sequencing datasets, we predicted and selected lncRNAs that are differentially expressed in M1 or M2 macrophages and involved in the inflammatory response. We identified SUGCT-AS1, which is a human macrophage-specific lncRNA whose expression is increased upon M1 macrophage stimulation. Conditioned media of SUGCT-AS1-depleted M1 macrophages induced an inflammatory phenotype of vascular smooth muscle cells, which included increased expression of inflammatory genes (IL1B and IL6), decreased contractile marker proteins (ACTA2 and SM22α), and increased cell migration. Depletion of SUGCT-AS1 promoted the expression and secretion of proinflammatory cytokines, such as TNF, IL1B, and IL6, in M1 macrophages, and transcriptomic analysis showed that SUGCT-AS1 has functions related to inflammatory responses and cytokines. Furthermore, we found that SUGCT-AS1 directly binds to hnRNPU and regulates its nuclear-cytoplasmic translocation. This translocation of hnRNPU altered the proportion of the MALT1 isoforms by regulating the alternative splicing of MALT1, a mediator of NF-κB signaling. Overall, our findings suggest that lncRNAs can be used for future studies on macrophage regulation. Moreover, they establish the SUGCT-AS1/hnRNPU/MALT1 axis, which is a novel inflammatory regulatory mechanism in macrophages.

S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction.

BACKGROUND: Although the clinical importance of heart failure with preserved ejection fraction has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit. Although the clinical characteristics of heart failure with preserved ejection fraction are somewhat heterogeneous, diastolic dysfunction (DD) is one of the most important features. Here we report that neuronal NO synthase (nNOS) induces DD by S-nitrosylation of HDAC2 (histone deacetylase 2). METHODS: Two animal models of DD-SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) and mild transverse aortic constriction mice-as well as human heart samples from patients with left ventricular hypertrophy were used. Genetically modified mice that were either nNOS-ablated or HDAC2 S-nitrosylation-resistant were also challenged. N(ω)-propyl-L-arginine, an nNOS selective inhibitor, and dimethyl fumarate, an NRF2 (nuclear factor erythroid 2-related factor 2) inducer, were used. Molecular events were further checked in human left ventricle specimens. RESULTS: SAUNA or mild transverse aortic constriction stress impaired diastolic function and exercise tolerance without overt systolic failure. Among the posttranslational modifications tested, S-nitrosylation was most dramatically increased in both models. Utilizing heart samples from both mice and humans, we observed increases in nNOS expression and NO production. N(ω)-propyl-L-arginine alleviated the development of DD in vivo. Similarly, nNOS knockout mice were resistant to SAUNA stress. nNOS-induced S-nitrosylation of HDAC2 was relayed by transnitrosylation of GAPDH. HDAC2 S-nitrosylation was confirmed in both DD mouse and human left ventricular hypertrophy. S-nitrosylation of HDAC2 took place at C262 and C274. When DD was induced, HDAC2 S-nitrosylation was detected in wild-type mouse, but not in HDAC2 knock-in mouse heart that expressed HDAC2 C262A/C274A. In addition, HDAC2 C262A/C274A mice maintained normal diastolic function under DD stimuli. Gene delivery with adenovirus-associated virus 9 (AAV9)-NRF2, a putative denitrosylase of HDAC2, or pharmacological intervention by dimethyl fumarate successfully induced HDAC2 denitrosylation and mitigated DD in vivo. CONCLUSIONS: Our observations are the first to demonstrate a new mechanism underlying DD pathophysiology. Our results provide theoretical and experimental evidence to explain the ineffectiveness of conventional NO enhancement trials for improving DD with heart failure symptoms. More important, our results suggest that reduction of NO or denitrosylation of HDAC2 may provide a new therapeutic platform for the treatment of refractory heart failure with preserved ejection fraction.

Natural Course of Early Detected Acute Peripancreatic Fluid Collection in Moderately Severe or Severe Acute Pancreatitis.

Background and Objectives: Acute peripancreatic fluid collection (APFC) is an acute local complication of acute pancreatitis (AP) according to the revised Atlanta classification. Sometimes APFC resolves completely, sometimes it changes into a pseudocyst or walled-off necrosis (WON), so called late complications. The aim of this study is to investigate the natural course of APFC detected on early computed tomography (CT) in moderately severe (MSAP) or severe AP (SAP). Materials and Methods: From October 2014 to September 2015, patients with MSAP or SAP were enrolled if there was APFC within 48 h of onset on imaging studies at six medical centers. The status of fluid collection was followed 4-8 weeks after onset. Initial laboratory findings, CT findings and clinical scoring systems were analyzed. Results: A total of 68 patients were enrolled and APFC was completely resolved in 32 (66.7%) patients in the MSAP group and 9 (34.6%) in the SAP group. Patients with a high bedside index for severity in acute pancreatitis (BISAP) score (≥3 points) were common in the SAP group. C-reactive protein (CRP) after 48 h from admission and BUN level were also high in the SAP group. In multivariate analysis, BISAP score (≥3 points), elevation of CRP after 48 h (≥150 mg/L) and nasojejunal feeding after 48 h were risk factors for the development of late complications. Conclusions: Spontaneous resolution of APFC was more common in MSAP group and APFC can be changed to pseudocyst or WON in patients with elevated BISAP score, CRP level after 48 h, and non-improved abdominal pain.

High Energy Density Heteroatom (O, N and S) Enriched Activated Carbon for Rational Design of Symmetric Supercapacitors.

Carbon-based symmetric supercapacitors (SCs) are known for their high power density and long cyclability, making them an ideal candidate for power sources in new-generation electronic devices. To boost their electrochemical performances, deriving activated carbon doped with heteroatoms such as N, O, and S are highly desirable for increasing the specific capacitance. In this regard, activated carbon (AC) self-doped with heteroatoms is directly derived from bio-waste (lima-bean shell) using different KOH activation processes. The heteroatom-enriched AC synthesized using a pretreated carbon-to-KOH ratio of 1:2 (ONS@AC-2) shows excellent surface morphology with a large surface area of 1508 m2 g-1 . As an SC electrode material, the presence of heteroatoms (N and S) reduces the interfacial charge-transfer resistance and increases the ion-accessible surface area, which inherently provides additional pseudocapacitance. The ONS@AC-2 electrode attains a maximum specific capacitance (Csp ) of 342 F g-1 at a specific current of 1 Ag-1 in 1 m NaClO4 electrolyte at the wide potential window of 1.8 V. Moreover, as symmetric SCs the ONS@AC-2 electrode delivers a maximum specific capacitance (Csc ) of 191 F g-1 with a maximum specific energy of 21.48 Wh kg-1 and high specific power of 14 000 W kg-1 and excellent retention of its initial capacitance (98 %) even after 10000 charge/discharge cycles. In addition, a flexible supercapacitor fabricated utilizing ONS@AC-2 electrodes and a LiCl/polyvinyl alcohol (PVA)-based polymer electrolyte shows a maximum Csc of 119 F g-1 with considerable specific energy and power.

Role of SIRT1 in Modulating Acetylation of the Sarco-Endoplasmic Reticulum Ca2+-ATPase in Heart Failure.

RATIONALE: SERCA2a, sarco-endoplasmic reticulum Ca2+-ATPase, is a critical determinant of cardiac function. Reduced level and activity of SERCA2a are major features of heart failure. Accordingly, intensive efforts have been made to develop efficient modalities for SERCA2a activation. We showed that the activity of SERCA2a is enhanced by post-translational modification with SUMO1 (small ubiquitin-like modifier 1). However, the roles of other post-translational modifications on SERCA2a are still unknown. OBJECTIVE: In this study, we aim to assess the role of lysine acetylation on SERCA2a function and determine whether inhibition of lysine acetylation can improve cardiac function in the setting of heart failure. METHODS AND RESULTS: The acetylation of SERCA2a was significantly increased in failing hearts of humans, mice, and pigs, which is associated with the reduced level of SIRT1 (sirtuin 1), a class III histone deacetylase. Downregulation of SIRT1 increased the SERCA2a acetylation, which in turn led to SERCA2a dysfunction and cardiac defects at baseline. In contrast, pharmacological activation of SIRT1 reduced the SERCA2a acetylation, which was accompanied by recovery of SERCA2a function and cardiac defects in failing hearts. Lysine 492 (K492) was of critical importance for the regulation of SERCA2a activity via acetylation. Acetylation at K492 significantly reduced the SERCA2a activity, presumably through interfering with the binding of ATP to SERCA2a. In failing hearts, acetylation at K492 appeared to be mediated by p300 (histone acetyltransferase p300), a histone acetyltransferase. CONCLUSIONS: These results indicate that acetylation/deacetylation at K492, which is regulated by SIRT1 and p300, is critical for the regulation of SERCA2a activity in hearts. Pharmacological activation of SIRT1 can restore SERCA2a activity through deacetylation at K492. These findings might provide a novel strategy for the treatment of heart failure.

Bifunctional Role of CrkL during Bone Remodeling.

Coupled signaling between bone-forming osteoblasts and bone-resorbing osteoclasts is crucial to the maintenance of bone homeostasis. We previously reported that v-crk avian sarcoma virus CT10 oncogene homolog-like (CrkL), which belongs to the Crk family of adaptors, inhibits bone morphogenetic protein 2 (BMP2)-mediated osteoblast differentiation, while enhancing receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation. In this study, we investigated whether CrkL can also regulate the coupling signals between osteoblasts and osteoclasts, facilitating bone homeostasis. Osteoblastic CrkL strongly decreased RANKL expression through its inhibition of runt-related transcription factor 2 (Runx2) transcription. Reduction in RANKL expression by CrkL in osteoblasts resulted in the inhibition of not only osteoblast-dependent osteoclast differentiation but also osteoclast-dependent osteoblast differentiation, suggesting that CrkL participates in the coupling signals between osteoblasts and osteoclasts via its regulation of RANKL expression. Therefore, CrkL bifunctionally regulates osteoclast differentiation through both a direct and indirect mechanism while it inhibits osteoblast differentiation through its blockade of both BMP2 and RANKL reverse signaling pathways. Collectively, these data suggest that CrkL is involved in bone homeostasis, where it helps to regulate the complex interactions of the osteoblasts, osteoclasts, and their coupling signals.

P300/CBP-Associated Factor Activates Cardiac Fibroblasts by SMAD2 Acetylation.

Various heart diseases cause cardiac remodeling, which in turn leads to ineffective contraction. Although it is an adaptive response to injury, cardiac fibrosis contributes to this remodeling, for which the reactivation of quiescent myofibroblasts is a key feature. In the present study, we investigated the role of the p300/CBP-associated factor (PCAF), a histone acetyltransferase, in the activation of cardiac fibroblasts. An intraperitoneal (i.p.) injection of a high dose (160 mg/kg) of isoproterenol (ISP) induced cardiac fibrosis and reduced the amount of the PCAF in cardiac fibroblasts in the mouse heart. However, the PCAF activity was significantly increased in cardiac fibroblasts, but not in cardiomyocytes, obtained from ISP-administered mice. An in vitro study using human cardiac fibroblast cells recapitulated the in vivo results; an treatment with transforming growth factor-ß1 (TGF-ß1) reduced the PCAF, whereas it activated the PCAF in the fibroblasts. PCAF siRNA attenuated the TGF-ß1-induced increase in and translocation of fibrosis marker proteins. PCAF siRNA blocked TGF-ß1-mediated gel contraction and cell migration. The PCAF directly interacted with and acetylated mothers against decapentaplegic homolog 2 (SMAD2). PCAF siRNA prevented TGF-ß1-induced phosphorylation and the nuclear localization of SMAD2. These results suggest that the increase in PCAF activity during cardiac fibrosis may participate in SMAD2 acetylation and thereby in its activation.

The microRNA miR-134-5p induces calcium deposition by inhibiting histone deacetylase 5 in vascular smooth muscle cells.

Calcium deposition in vascular smooth muscle cells (VSMCs) is a form of ectopic ossification in blood vessels. It can result in rigidity of the vasculature and an increase in cardiac events. Here, we report that the microRNA miR-134-5p potentiates inorganic phosphate (Pi)-induced calcium deposition in VSMCs by inhibiting histone deacetylase 5 (HDAC5). Using miRNA microarray analysis of Pi-treated rat VSMCs, we first selected miR-134-5p for further evaluation. Quantitative RT-PCR confirmed that miR-134-5p was increased in Pi-treated A10 cells, a rat VSMC line. Transfection of miR-134-5p mimic potentiated the Pi-induced increase in calcium contents. miR-134-5p increased the amounts of bone runt-related transcription factor 2 (RUNX2) protein and bone morphogenic protein 2 (BMP2) mRNA in the presence of Pi but decreased the expression of osteoprotegerin (OPG). Bioinformatic analysis showed that the HDAC5 3'untranslated region (3'UTR) was one of the targets of miR-134-5p. The luciferase construct containing the 3'UTR of HDAC5 was down-regulated by miR-134-5p mimic in a dose-dependent manner in VSMCs. Overexpression of HDAC5 mitigated the calcium deposition induced by miR-134-5p. Our results suggest that a Pi-induced increase of miR-134-5p may cause vascular calcification through repression of HDAC5.

The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling.

Atrial structural remodelling including atrial hypertrophy and fibrosis is a key mediator of atrial fibrillation (AF). We previously demonstrated that the matricellular protein CCN5 elicits anti-fibrotic and anti-hypertrophic effects in left ventricles under pressure overload. We here determined the utility of CCN5 in ameliorating adverse atrial remodelling and arrhythmias in a murine model of angiotensin II (AngII) infusion. Advanced atrial structural remodelling was induced by AngII infusion in control mice and mice overexpressing CCN5 either through transgenesis (CCN5 Tg) or AAV9-mediated gene transfer (AAV9-CCN5). The mRNA levels of pro-fibrotic and pro-inflammatory genes were markedly up-regulated by AngII infusion, which was significantly normalized by CCN5 overexpression. In vitro studies in isolated atrial fibroblasts demonstrated a marked reduction in AngII-induced fibroblast trans-differentiation in CCN5-treated atria. Moreover, while AngII increased the expression of phosphorylated CaMKII and ryanodine receptor 2 levels in HL-1 cells, these molecular features of AF were prevented by CCN5. Electrophysiological studies in ex vivo perfused hearts revealed a blunted susceptibility of the AAV9-CCN5-treated hearts to rapid atrial pacing-induced arrhythmias and concomitant reversal in AngII-induced atrial action potential prolongation. These data demonstrate the utility of a gene transfer approach targeting CCN5 for reversal of adverse atrial structural and electrophysiological remodelling.

Risk factors of recurrent pancreatitis after first acute pancreatitis attack: a retrospective cohort study.

Background and aims: Few studies have been conducted in Asia on the recurrence of acute pancreatitis (AP). This study was designed to investigate characteristics of the disease to predict recurrence.Methods: We retrospectively analyzed 617 patients that experienced a first AP attack between January 2009 and December 2014. Based on reviews of clinical and follow-up data, we attempted to identify risk factors of recurrence using Cox regression analysis.Results: During a median follow-up of 3.2 years (range 3-72 months), 100(16.2%) of the 617 study subjects experienced one or more episodes of recurrent acute pancreatitis (RAP). Of these 100 patients, 75(75%) experienced one relapse, 12(12%) two relapses, and 13(13%) three or more relapses. The etiologies of RAP were an alcohol (48%), gallstone (31%), idiopathic (14%), and others (7%). Univariate analysis showed that an age of <60 years, male gender, smoking, an alcohol-associated etiology, and a local complication at index admission were significant risk factors of RAP. Cox regression analysis showed that an age of <60 years (HR = 1.602, 95% CI: 1.029-2.493), male gender (HR = 1.927, 95% CI: 1.127-3.295), and the presence of a local complication (HR = 3.334, 95% CI: 2.211-5.026) were significant risk factors of RAP development.Conclusion: A local complication at index admission was found to be the strongest risk factor of RAP, and a male gender and an age of <60 years were significantly associated with RAP. Special attention and close follow-up should be afforded to patients with a local complication at index admission or male patients <60 years old.

Roles of Histone Acetylation Modifiers and Other Epigenetic Regulators in Vascular Calcification.

Vascular calcification (VC) is characterized by calcium deposition inside arteries and is closely associated with the morbidity and mortality of atherosclerosis, chronic kidney disease, diabetes, and other cardiovascular diseases (CVDs). VC is now widely known to be an active process occurring in vascular smooth muscle cells (VSMCs) involving multiple mechanisms and factors. These mechanisms share features with the process of bone formation, since the phenotype switching from the contractile to the osteochondrogenic phenotype also occurs in VSMCs during VC. In addition, VC can be regulated by epigenetic factors, including DNA methylation, histone modification, and noncoding RNAs. Although VC is commonly observed in patients with chronic kidney disease and CVD, specific drugs for VC have not been developed. Thus, discovering novel therapeutic targets may be necessary. In this review, we summarize the current experimental evidence regarding the role of epigenetic regulators including histone deacetylases and propose the therapeutic implication of these regulators in the treatment of VC.

Role of the PRC2-Six1-miR-25 signaling axis in heart failure.

The reduced expression of cardiac sarco-endoplasmic reticulum Ca2+ ATPase (SERCA2a) is a hallmark of heart failure. We previously showed that miR-25 is a crucial transcriptional regulator of SERCA2a in the heart. However, the precise mechanism of cardiac miR-25 regulation is largely unknown. Literatures suggested that miR-25 is regulated by the transcriptional co-factor, sine oculis homeobox homolog 1 (Six1), which in turn is epigenetically regulated by polycomb repressive complex 2 (PRC 2) in cardiac progenitor cells. Therefore, we aimed to investigate whether Six1 and PRC2 are indeed involved in the regulation of the miR-25 level in the setting of heart failure. Six1 was up-regulated in the failing hearts of humans and mice. Overexpression of Six1 led to adverse cardiac remodeling, whereas knock-down of Six1 attenuated pressure overload-induced cardiac dysfunction. The adverse effects of Six1 were ameliorated by knock-down of miR-25. The epigenetic repression on the Six1 promoter by PRC2 was significantly reduced in failing hearts. Epigenetic repression of Six1 is relieved through a reduction of PRC2 activity in heart failure. Six1 up-regulates miR-25, which is followed by reduction of cardiac SERCA2a expression. Collectively, these data showed that the PRC2-Six1-miR-25 signaling axis is involved in heart failure. Our finding introduces new insight into potential treatments of heart failure.

KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing.

The methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominent in actively transcribed regions of the genome; however, demethylase of H3K79 remains unknown despite intensive research. Here, we show that KDM2B, also known as FBXL10 and a member of the Jumonji C family of proteins known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels increase when KDM2B is depleted, which indicates that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibit displacement of NAD+-dependent deacetylase sirtuin-1 (SIRT1) from chromatin, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1-mediated chromatin silencing.-Kang, J.-Y., Kim, J.-Y., Kim, K.-B., Park, J. W., Cho, H., Hahm, J. Y., Chae, Y.-C., Kim, D., Kook, H., Rhee, S., Ha, N.-C., Seo, S.-B. KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing.

Assessment of air purifier on efficient removal of airborne bacteria, Staphylococcus epidermidis, using single-chamber method.

We evaluated the efficiency of an air purifier using the single-chamber method for the effective removal of airborne Staphylococcus epidermidis, a nosocomial infection-causing bacterium. In this experiment, the bacterial strain S. epidermidis was injected using a nebulizer into the test chamber, which was similar to a consumer living space (60 m3). The microbial sampling was conducted via the air sampler method, and the reduction in S. epidermidis growth was monitored by performing three consecutive tests. Initially, a blank test was conducted to determine the natural decay rate and calibrate the experimental setup. After injecting the bacterial strain from 1240 to 11180 CFU per unit volume (m3), the natural decay rate showed a maximum deviation of 3.1% with a sampling error of 1.1% p at a confidence level of 95%. In addition, the particle size distribution in the test chamber was found to range from 0.3 to 5.0 µm, and a subsequent decrease in large-sized particles was observed with the operation of the air purifier, which is the size similar to that of suspended airborne bacteria. This can be used to assess the performance of the air purifier by calibrating the natural reduction value to the reduced operation value. Thus, the single-chamber technique is a promising approach for analyzing the removal efficacy of airborne bacteria from indoor air.

Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Connexin43 and zonula occludens-1 are targets of Akt in cardiomyocytes that correlate with cardiac contractile dysfunction in Akt deficient hearts.

While deletion of Akt1 results in a smaller heart size and Akt2-/- mice are mildly insulin resistant, Akt1-/-/Akt2-/- mice exhibit perinatal lethality, indicating a large degree of functional overlap between the isoforms of the serine/threonine kinase Akt. The present study aimed to determine the cooperative contribution of Akt1 and Akt2 on the structure and contractile function of adult hearts. To generate an inducible, cardiomyocyte-restricted Akt2 knockout (KO) model, Akt2flox/flox mice were crossed with tamoxifen-inducible MerCreMer transgenic (MCM) mice and germline Akt1-/- mice to generate the following genotypes:Akt1+/+; Akt2flox/flox (WT), Akt2flox/flox; α-MHC-MCM (iAkt2 KO), Akt1-/-, and Akt1-/-; Akt2flox/flox; α-MHC-MCM mice (Akt1-/-/iAkt2 KO). At 28 days after the first tamoxifen injection, Akt1-/-/iAkt2 KO mice developed contractile dysfunction paralleling increased atrial and brain natriuretic peptide (ANP and BNP) levels, and repressed mitochondrial gene expression. Neither cardiac fibrosis nor apoptosis were detected in Akt1-/-/iAkt2 KO hearts. To explore potential molecular mechanisms for contractile dysfunction, we investigated myocardial microstructure before the onset of heart failure. At 3 days after the first tamoxifen injection, Akt1-/-/iAkt2 KO hearts showed decreased expression of connexin43 (Cx43) and connexin-interacting protein zonula occludens-1 (ZO-1). Furthermore, Akt1/2 silencing significantly decreased both Cx43 and ZO-1 expression in cultured neonatal rat cardiomyocytes in concert with reduced beating frequency. Akt1 and Akt2 are required to maintain cardiac contraction. Loss of Akt signaling disrupts gap junction protein, which might precipitate early contractile dysfunction prior to heart failure in the absence of myocardial remodeling, such as hypertrophy, fibrosis, or cell death.

Safety and Efficacy of Endoscopic Retrograde Cholangiopancreatography for Choledocholithiasis in Long-Term Dialysis: A Propensity Score Analysis.

BACKGROUND AND AIM: Previous studies evaluating the safety of endoscopic retrograde cholangiopancreatography (ERCP) in patients with end-stage renal disease (ESRD) undergoing hemodialysis reported an increased risk of post-procedural bleeding. We investigated the safety and efficacy of ERCP for the treatment of choledocholithiasis in patients with ESRD undergoing long-term dialysis. METHODS: A total of 3466 patients who underwent ERCP due to choledocholithiasis between January 2000 and Feb 2018 were reviewed and analyzed retrospectively. Patients were divided into dialysis and non-dialysis group, and propensity score matching was used to minimize selection bias. RESULTS: Patients of dialysis group (n = 39) and non-dialysis group (n = 78) were compared after propensity score matching. Among 39 patients of dialysis group, hemodialysis was used in 28 (71.8%) patients for renal replacement therapy, while 11 (28.2%) patients received peritoneal dialysis. The median duration of dialysis was 8 years (range 1-24 years). Overall success rate of ERCP was not different between two groups. The overall prevalence of post-procedural complications in dialysis group and non-dialysis group was 28.2 and 15.4%, respectively (p = 0.100). Post-procedural bleeding occurred more frequently in dialysis group than non-dialysis group (23.1 vs 5.1%, p = 0.004). All procedure-related bleeding episodes were successfully controlled using endoscopic management. Prevalence of post-ERCP pancreatitis, infection, and perforation were not significantly different between two groups (p > 0.05). CONCLUSIONS: Overall success rate of complete ductal clearance was not different between dialysis and non-dialysis groups. The risk of post-procedural bleeding seems to be increased in patients with ESRD undergoing long-term dialysis.

Lower intra-abdominal pressure has no cardiopulmonary benefits during laparoscopic colorectal surgery: a double-blind, randomized controlled trial.

BACKGROUND: Higher intra-abdominal pressure may impair cardiopulmonary functions during laparoscopic surgery. While 12-15 mmHg is generally recommended as a standard pressure, the benefits of lower intra-abdominal pressure are unclear. We thus studied whether the low intra-abdominal pressure compared with the standard pressure improves cardiopulmonary dynamics during laparoscopic surgery. METHODS: Patients were randomized according to the intra-abdominal pressure and neuromuscular blocking levels during laparoscopic colorectal surgery: low pressure (8 mmHg) with deep-block (post-tetanic count 1-2), standard pressure (12 mmHg) with deep-block, and standard pressure with moderate-block (train-of-four count 1-2) groups. During the laparoscopic procedure, we recorded cardiopulmonary variables including cardiac index, pulmonary compliance, and surgical conditions. We also assessed postoperative pain intensity and recovery time of bowel movement. The primary outcome was the cardiac index 30 min after onset of laparoscopy. RESULTS: Patients were included in the low pressure with deep-block (n = 44), standard pressure with deep-block (n = 44), and standard pressure with moderate-block (n = 43) groups. The mean (SD) of cardiac index 30 min after laparoscopy was 2.7 (0.7), 2.7 (0.9), and 2.6 (1.0) L min-1 m-2 in each group (P = 0.715). The pulmonary compliance was higher but the surgical condition was poorer in the low intra-abdominal pressure than the standard pressure (both P < 0.001). Other variables were comparable between groups. CONCLUSION: We observed few cardiopulmonary benefits but poor surgical conditions in the low intra-abdominal pressure during laparoscopy. Considering cardiopulmonary dynamics and surgical conditions, the standard intra-abdominal pressure may be preferable to the low pressure for laparoscopic surgery.