Comparison of endoscopic ultrasound-guided drainage and percutaneous catheter drainage of postoperative fluid collection after pancreaticoduodenectomy.

Backgrounds/Aims: Postoperative fluid collection is a common complication of pancreatic resection without clear management guidelines. This study aimed to compare outcomes of endoscopic ultrasound (EUS)-guided trans-gastric drainage and percutaneous catheter drainage (PCD) in patients who experienced this adverse event after pancreaticoduodenectomy (PD). Methods: Demographic and clinical data and intervention outcomes of 53 patients who underwent drainage procedure (EUS-guided, n = 32; PCD, n = 21) for fluid collection after PD between January 2015 and June 2019 in our tertiary referral center were retrospectively analyzed. Results: Prior to drainage, 83.0% had leukocytosis and 92.5% presented with one or more of the following signs or symptoms: fever (69.8%), abdominal pain (69.8%), and nausea/vomiting (17.0%). Within 8 weeks of drainage, 77.4% showed a diameter decrease of more than 50% (87.5% in EUS vs. 66.7% in PCD, p = 0.09). Post-procedural intravenous antibiotics were used for an average of 8.1 ± 4.3 days and 12.4 ± 7.4 days for EUS group and PCD group, respectively (p = 0.01). The EUS group had a shorter post-procedural hospital stay than the PCD group (9.8 ± 1.1 vs. 15.8 ± 2.2 days, p < 0.01). However, the two groups showed no statistically significant difference in technical or clinical success rate, reintervention rate, or adverse event rate. Conclusions: EUS-guided drainage and PCD are both safe and effective methods for managing fluid collection after PD. However, EUS-guided drainage can shorten hospital stay and duration of intravenous antibiotics use.

Effect of Dexmedetomidine Combined Anesthesia on Motor evoked Potentials During Brain Tumor Surgery.

BACKGROUND: Dexmedetomidine (DEX) is used as an adjunct to total intravenous anesthesia. However, its effect on intraoperative neurophysiologic monitoring (IOM) during brain tumor surgery remains controversial. The aim of this study was to explore the effect of DEX on IOM during brain tumor surgery. METHODS: Seventy-eight consecutive patients (DEX group, n = 40; control group, n = 38), who underwent brain tumor surgery with IOM, were retrospectively reviewed. The outcomes included the predictability, laterality of alterations, and stimulation parameters of transcranial motor evoked potentials (tcMEPs) and somatosensory evoked potentials (SSEPs). RESULTS: The predictability of tcMEPs for postoperative motor outcomes showed a higher false-positive rate in the DEX group than in the control group (27.5% vs. 5.3%, P = 0.047). Bilateral alterations were observed only in the DEX group (31.3%; P = 0.053). Compared with the control group, the DEX group required significantly higher intensity (377.5 ± 48.0 vs. 347.1 ± 30.0 mV; P = 0.001) and repetition rate (6.0 ± 0.2 vs. 5.7 ± 0.5 pulse/train; P = 0.001) of transcranial electric stimulation to evoke adequate tcMEPs. The SSEP results were comparable between both groups. In the DEX group, false-positive tcMEPs changes occurred 222.2 ± 70.5 minutes (range, 95-342 minutes) after the induction of anesthesia. In addition, the patients who were administered DEX under bispectral index monitoring (n = 12) showed a significantly higher false-positive rate than shown by the control group (50.5% vs. 5.3%; P = 0.003). CONCLUSIONS: This study showed that DEX had significant effects on tcMEPs during IOM in brain tumor surgery. Because the high false-positive rate could decrease the accuracy of IOM, outcomes after using DEX should be cautiously interpreted.

SYSTEMATIC REVIEW WITH NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS OF ROTATOR CUFF TEAR TREATMENT.

Objectives: Rotator cuff tear is the leading cause of the decline in quality of life for older adults, but comparative evidence on treatment effectiveness is lacking. This study systematically reviewed the effects of various rotator cuff tear treatments through a Bayesian meta-analysis of the related randomized clinical trials (RCTs).Methods: We searched nine electronic databases for RCTs evaluating rotator cuff tear treatments from their inception through June 2017. A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the National Institute for Health and Care Excellence-Decision Support Unit guidelines (Supplementary Table 1). Outcomes included functional improvement, pain one year after surgical treatment, and tendon structural integrity. The Bayesian network meta-analysis was applied for functional improvement and pain, based on an assumption of consistency and similarity. Tendon integrity was reported descriptively.Results: Fifteen RCTs were selected. Patients undergoing physiotherapy after open surgery showed statistically significant functional improvements compared with those undergoing physiotherapy only (mean differences, 9.1 [credible interval, 0.9-17.4]). Open surgery with physiotherapy was associated with a decrease in pain 1 year after treatment compared with when physiotherapy was combined with arthroscopic rotator cuff surgery, mini open surgery, platelet-rich plasma therapy, or physiotherapy alone (absolute value of mean difference 1.2 to 1.4). The tendon integrity results were inconsistent.Conclusions: Some surgical treatments were associated with significant improvement in function and pain, but evidence regarding their comparative effectiveness is still lacking. A well-designed RCT discussing functional and structural treatment outcomes is needed in future.

Diagnostic Accuracy of Clinical Measures Considering Segmental Tissue Composition and Volume Changes of Breast Cancer-Related Lymphedema.

BACKGROUND: If we use only volumetry for measuring lymphedema, we could underdiagnose lymphedema with characteristics of biomechanical changes without definite volume change, especially in the medial forearm. METHODS AND RESULTS: In total, 158 breast cancer patients participated in this study. Arm volume was measured by water displacement volumetry, and segmental volumes were calculated from circumferences by using the truncated cone method. Subcutaneous ultrasound echogenicities were assessed on the medial side of the upper arm and forearm of both arms and graded by subcutaneous echogenicity grade (SEG) and revised SEG (rSEG). The standards for diagnosing secondary lymphedema were according to the volume change and clinical stage. Sensitivity, specificity, receiver-operating characteristic (ROC) curve, and area under the curve (AUC) were used. Analysis of ROC curves yielded AUCs of 0.875-0.933 (p < 0.001). Volume differences in each segment were significantly different among the grades by SEG. The highest AUC was found for volume difference (AUC = 0.919, 95% confidence interval [CI] = 0.860-0.978) in the upper arm near the elbow; however, in the medial forearm, the highest AUC was found for rSEG (AUC = 0.948, 95% CI = 0.923-0.965 in the proximal forearm; AUC = 0.940, 95% CI = 0.923-0.965 in the distal forearm). CONCLUSIONS: Our findings support the use of SEG by ultrasound in the assessment of lymphedema, especially in the medial region of the forearm. Subcutaneous ultrasound echogenicities may improve the accuracy of diagnosis of lymphedema in the forearm.

One-year outcome of postoperative swallowing impairment in pediatric patients with posterior fossa brain tumor.

Impaired swallowing in children who underwent posterior fossa brain tumor (PFBT) resection disrupts development and quality of life, yet its downstream consequences remain unclear. This study explored the risk factors and functional prognosis of postoperative swallowing impairment in pediatric patients (<19 years old) with PFBT. Among 183 patients with PFBT who underwent surgical resection, 39 patients with postoperative swallowing difficulty were analyzed using the videofluoroscopic swallowing study (VFSS). The association between clinical features, swallowing characteristics, and swallowing impairment was explored during the early postoperative phase and 1-year following surgical resection. Duration of tube feeding was investigated using Kaplan-Meier analysis. Twenty-seven (14.8 %) patients needed tube feeding in the early postoperative phase and 11 (6.01 %) at 1-year after surgical resection. Mean duration of tube feeding was 240.2 days and differed by tumor pathologies (P = 0.001), delayed triggering of pharyngeal swallow (DTP) (P = 0.002) and pharyngeal wall coating (P = 0.033). Tumor pathology was associated significantly with the referral for swallowing evaluation (P < 0.001) and 1-year tube feeding (P = 0.019). Tube feeding at 1-year was significantly associated with the tumor's brainstem involvement (P = 0.039), and swallowing abnormalities at early phase including DTP (P = 0.030) and pharyngeal wall coating (P = 0.004). Our results suggest that tumor pathology, brainstem involvement, and specific swallowing abnormalities at early phase are important risk factors for sustained 1-year swallowing impairment following surgical resection. These results can be applied to determine the plan of evaluation, nutrition, and intervention in clinical practice.

Specific oligopeptides in fermented soybean extract inhibit NF-κB-dependent iNOS and cytokine induction by toll-like receptor ligands.

The ethanol extract of fermented soybean from Glycine max (chungkookjang, CHU) has been claimed to have chemopreventive and cytoprotective effects. In the present study, we examined the inhibitory effect of CHU on inducible nitric oxide synthase (iNOS) and cytokine induction by toll-like receptor (TLR) ligands treatment and attempted to identify the responsible active components. Nitric oxide (NO) content and iNOS levels in the media or RAW264.7 cells were measured using the Griess reagent and real-time polymerase chain reaction assays. CHU treatment inhibited NO production and iNOS induction elicited by lipopolysaccharide (LPS, TLR4L) in a concentration-dependent manner. Tumor necrosis factor-α and interleukin-6 productions were also diminished. Peptidoglycans (TLR2/6L) and CpG-oligodeoxynucleotides (TLR9L) from CHU inhibited iNOS induction, but not poly I:C (TLR3L) or loxoribine (TLF7L). The anti-inflammatory effect resulted from the inhibition of nuclear factor-kappa B (NF-κB) through the inhibition of inhibitory-κB degradation. Of the representative components in CHU, specific oligopeptides (AFPG and GVAWWMY) had the ability to inhibit iNOS induction by LPS, whereas others failed to do so. Daidzein, an isoflavone used for comparative purposes, was active at a relatively higher concentration. In an animal model, oral administration of CHU to rats significantly diminished carrageenan-induced paw edema and iNOS induction. Our results demonstrate that CHU has anti-inflammatory effects against TLR ligands by inhibiting NF-κB activation, which may result from specific oligopeptide components in CHU. Since CHU is orally effective, dietary applications of CHU and/or the identified oligopeptides may be of use in the prevention of inflammatory diseases.

Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury.

The contribution of miRNA to the pathogenesis of acute kidney injury (AKI) is not well understood. Here we evaluated an integrative network of miRNAs and mRNA data to discover a possible master regulator of AKI. Microarray analyses of the kidneys of mice treated with cisplatin were used to extract putative miRNAs that cause renal injury. Of them, miR-122 was mostly downregulated by cisplatin, whereas miR-34a was upregulated. A network integrating dysregulated miRNAs and altered mRNA expression along with target prediction enabled us to identify Foxo3 as a core protein to activate p53. The miR-122 inhibited Foxo3 translation as assessed using an miR mimic, an inhibitor, and a Foxo3 3'-UTR reporter. In a mouse model, Foxo3 levels paralleled the degree of tubular injury. The role of decreased miR-122 in inducing Foxo3 during AKI was strengthened by the ability of the miR-122 mimic or inhibitor to replicate results. Increase in miR-34a also promoted the acetylation of Foxo3 by repressing Sirt1. Consistently, cisplatin facilitated the binding of Foxo3 and p53 for activation, which depended not only on decreased miR-122 but also on increased miR-34a. Other nephrotoxicants had similar effects. Among targets of p53, Phlda3 was robustly induced by cisplatin, causing tubular injury. Consistently, treatment with miR mimics and/or inhibitors, or with Foxo3 and Phlda3 siRNAs, modulated apoptosis. Thus, our results uncovered an miR integrative network regulating toxicant-induced AKI and identified Foxo3 as a bridge molecule to the p53 pathway.

Structural requirements within protoporphyrin IX in the inhibition of heat shock protein 90.

Porphyrins are used for photodynamic therapy for their light-absorbing properties, and some of them were approved for the treatment of certain types of cancers. Porphyrins prevent activation of hypoxia inducible factor-1α (HIF-1α) by inhibiting heat shock protein 90 (HSP90). This study investigated the structural requirements within protoporphyrin IX (PPIX) for the inhibition of HSP90 activity. In HCT116, HT29 and DLD-1 cells, PPIX treatment directly hindered the binding between HSP90 and HIF-1α; PPIX treatment inhibited the chaperone activity of HSP90, accelerating protein degradation of HIF-1α. In addition, PPIX treatment suppressed cancer cell migration, endothelial cell tube formation, and aortic ring sprouting, being consistent with its anti-tumor and anti-angiogenic activities. In silico analysis, molecular docking model indicated that a tetrapyrrole macrocycle and two propionate chains within PPIX are necessary for the binding to the adenosine triphosphate (ATP)-binding pocket of HSP90. The predicted structural requirement was verified by the differential inhibitory effects of PPIX analogs, or the precursor of PPIX, on HIF-1α; compounds lacking either the tetrapyrrole macrocycle or the propionate chains were inactive. Our results show that a tetrapyrrole macrocycle and two attached propionate chains in PPIX coordinately interact with the ATP-binding pocket of HSP90, offering structural information on the inhibitory effect of porphyrins on angiogenesis.

Fyn inhibition by cycloalkane-fused 1,2-dithiole-3-thiones enhances antioxidant capacity and protects mitochondria from oxidative injury.

Fyn kinase has emerged as a regulator of diverse pathological processes. However, therapeutic Fyn inhibitors are not available. This study investigated the potential of a series of cycloalkane-fused dithiolethiones (CDTs) or other congeners to increase antioxidant capacity in association with Fyn inhibition, as well as the molecular basis for this effect. Treatment of HepG2 cells with each agent protected the mitochondria from oxidative injury elicited by arachidonic acid and iron, which increased cell viability; 4,5,6,7-tetrahydrobenzo-1,2-dithiole-3-thione (SNU1A) and 5,6-dihydro-4H-cyclopenta-1,2-dithiole-3-thione (SNU2A) were the most effective, whereas 5-methyl-1,2-dithiole-3-thione (SNU3A) was less active. 5-(Quinolin-2-yl)-1,2-dithiole-3-thione (SNU3E) had a minimal effect. SNU1A treatment decreased mitochondrial superoxide production and enabled cells to restore mitochondrial membrane permeability. Oxidative injury caused by arachidonic acid and iron enhanced Fyn phosphorylation at a tyrosine residue, which was decreased by SNU1A treatment. 2,3-Dihydro-N,N-dimethyl-2-oxo-3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1H-indole-5-sulfonamide (SU6656), a known Fyn inhibitor, had a similar effect. Fyn inhibition contributed to protecting mitochondria from injury through AMP-activated protein kinase (AMPK), as supported by reversal of this effect with Fyn overexpression. Consistently, Fyn overexpression attenuated AMPK activation by SNU1A, which strengthens the inhibitory role of Fyn in AMPK activity. CDTs had antioxidant effects, as shown by increases in GSH contents and inhibition of H(2)O(2) production. They also had the ability to activate nuclear factor E2-related factor 2 (Nrf2), a key antioxidant transcription factor. Fyn overexpression decreased the Nrf2 activation induced by SNU1A. Our results demonstrate that CDTs exert cytoprotective effects by protecting mitochondria and increasing the cellular antioxidant capacity, which may result not only from Fyn inhibition leading to AMPK activation but also from Nrf2 activation.

Hypoxia-inducible factor-1α inhibition by a pyrrolopyrazine metabolite of oltipraz as a consequence of microRNAs 199a-5p and 20a induction.

Oltipraz, a cancer chemopreventive agent, has antitumor and antiangiogenic effects. In animal models and clinical studies, a considerable amount of oltipraz is metabolized to pyrrolopyrazines, including M2, 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine; M3, 7-methyl-8-(methylsulfinyl)-6-(methylthio)pyrrolo[1,2-a]pyrazine and M4, 7-methyl-6,8-bis(methylsulfinyl)pyrrolo[1,2-a]pyrazine. In view of the role of hypoxia-inducible factor-1 (HIF-1) α in tumor growth and angiogenesis, this study investigated whether pyrrolopyrazine metabolites of oltipraz inhibit HIF-1α induction, and if so, what the molecular basis is. M2 treatment inhibited the induction of HIF-1α by a variety of stimuli including insulin, hypoxia, CoCl(2) and hydrogen peroxide in HCT116 cells, whereas M3 or M4 failed to do so. Consistently, M2 prevented HIF-1α target gene induction. Moreover, it inhibited cancer cell invasion and migration. M2 caused no change in the expression of HIF-1α transcript but increased the levels of precursor forms of microRNAs (miRNAs) 199a-5p and 20a, but not those of primary forms, indicating facilitation of the maturation process of the miRNAs by M2. Increased levels of the miRNAs contributed to HIF-1α repression, as shown by the results of experiments using mimics. Consistently, M2 treatment inhibited de novo synthesis of HIF-1α, as supported by decreased incorporation of [(35)S]-methionine into HIF-1α with no changes in its ubiquitination or degradation. 7-Ethyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, a synthetic analog of M2, had a similar inhibitory effect. In conclusion, M2 with pyrrolopyrazine structure and its 7-ethyl congenor have the ability to prevent the induction of HIF-1α, which may result from the inhibition of HIF-1α de novo synthesis, as mediated by the induction of miR-199a-5p and miR-20a.

DA6034 promotes gastric epithelial cell migration and wound-healing through the mTOR pathway.

BACKGROUND AND AIM: 7-Carboxymethyloxy-3',4',5-trimethoxy flavone (DA6034), a synthetic derivative of eupatilin, has a protective effect on gastric mucosa against various ulcerogens, and is currently in the phase III clinical trial in the treatment of peptic ulcer disease. Cell migration and/or growth plays a role in the repair process of gastric ulcer, so this study investigated the effect of DA6034 on the movement and proliferation of gastric epithelial cells and its associated signaling pathway. METHODS: The migration of AGS or SNU484 human gastric epithelial cells was shown by scratch-induced wound healing and transwell assays, and the proliferation of the cells was assessed by FACS and proliferation assays. RESULTS: Treatment of DA6034 promoted the migration of gastric epithelial cells in a concentration-dependent manner. DA6034 treatment facilitated the phosphorylation of mTOR that led to an increase in the activity of S6K1, indicating its ability to activate mTOR and S6K1. Rapamycin aborted the wound-healing effect of DA6034, which supported the role of mTOR activation in the wound-healing process. In addition, DA6034 treatment increased PI3K-dependent Akt phosphorylation, which was necessary for the enhancement of cell migration. DA6034, however, did not stimulate the proliferation of gastric epithelial cells, being consistent with no activation of ERK1/2 by the agent. CONCLUSIONS: DA6034 has the ability to heal scratch wounds, which may result from an increase in gastric epithelial cell migration as mediated by PI3K-Akt-dependent activation of mTOR and S6K1. Our finding may be of help in understanding the molecular basis of the anti-ulcer effect of DA6034.

Hemin, an iron-binding porphyrin, inhibits HIF-1α induction through its binding with heat shock protein 90.

Hypoxia and growth factor stimulation induce hypoxia-inducible factor-1α (HIF-1α), conferring upon cancer cells the ability to adapt to microenvironments and enhance proliferation, angiogenesis and metastasis. Hemin, an iron-binding porphyrin, has been used to treat porphyria attacks, particularly in acute intermittent porphyria. Although the anti-inflammatory and antitumor effects of hemin were reported, no information is available regarding its effect on HIF-1α. Our study investigated whether hemin and other protoporphyrin compounds have the ability to inhibit HIF-1α activity, and if so, what is the molecular basis of inhibition. Hemin treatment prevented CoCl(2) -induced HIF-1α expression. HIF-1α inhibition by hemin resulted from an increase in its facilitated ubiquitination and degradation, as shown by the experimental results using cychloheximide treatment and ubiquitination assays. Consistently, hemin repressed HIF-1α-dependent gene transactivation. Intriguingly, hemin directly impeded the binding between heat shock protein 90 (HSP90) and HIF-1α, which was reversed by the addition of an excess amount of ATP required for HSP90 activity. In addition, hemin decreased the expression of client proteins of HSP90. Thus, the inhibition of HIF-1α activity by hemin might result from its interaction with HSP90. Moreover, treatment of protoporphyrin IX, ZnPP or Co(III)PP, but not Mn(III)PP, inhibited HIF-1α induction, indicating that protoporphyrin ring in association with the nature of binding metal leads to HSP90 inhibition. In an in vivo model, hemin treatment inhibited not only the formation of new vessels but also cancer cell proliferation and migration/invasion, supporting the notion that hemin may be applied to the prevention and/or treatment of angiogenesis and/or cancer metastasis.

Postcardiac injury syndrome after percutaneous coronary intervention.

The post cardiac injury syndrome is characterized by the development of a fever, pleuropericarditis, and parenchymal pulmonary infiltrates in the weeks following trauma to the pericardium or myocardium. According to previous reports, almost all cases develop after major cardiac surgery or a myocardial infarction. Recently, a few reports have described post cardiac injury syndrome as a complication of endovascular procedures such as percutaneous cardiac intervention. Here we describe an unusual case of post cardiac injury syndrome after a percutaneous coronary intervention.

Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1alpha activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect.

Hypoxia-inducible factor-1alpha (HIF-1alpha) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1alpha, and the augmented HIF-1alpha activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1alpha activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1alpha expression through an increase in ubiquitination, thereby accelerating HIF-1alpha degradation and inhibiting HIF-1alpha-dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1alpha activity. CA-S6K1 overexpression reversed HIF-1alpha inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1alpha was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-alpha to restore the ability of insulin to increase HIF-1alpha against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H(2)O(2) production, thereby preventing H(2)O(2)-enhanced HIF-1alpha expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1alpha activity and HIF-1alpha-dependent tumor growth, which may result from a decrease in HIF-1alpha stability through S6K1 inhibition in combination with an H(2)O(2)-scavenging effect.

Therapeutic potential of dithiolethiones for hepatic diseases.

Comprehensive studies support the notion that oltipraz [4-methyl-5-(2-pyrazynyl)-1,2-dithiole-3-thione] and its congeners exert cancer chemopreventive effects by the prevention, inhibition or reversal of carcinogenic processes. Recently, it was found that dithiolethione compounds had the activities to prevent or treat fibrosis, insulin resistance, and mitochondrial protective effects in the liver by a mechanism involving AMP-activated protein kinase (AMPK) and/or 70-kDa ribosomal protein S6 kinase 1 (S6K1). Moreover, chemical regulation of the AMPK-S6K1 pathway was found to affect Liver X receptor (LXR) activity and lipogenesis, leading to the identification of AMPK and S6K1 as targets for treating hepatic steatosis. These biological activities of dithiolethiones may offer a novel approach to pharmaceutical intervention. This review focuses on the interaction between oltipraz and the AMPK-mTOR-S6K1 pathway, which regulates genes that confer hepatocyte protection from intoxication, disrupted energy metabolism, and inflammation. In terms of therapeutic potential, the findings reviewed here demonstrate a new therapeutic potential for dithiolethiones, which function in a unique manner, and offer the possibility of new treatments for hepatic diseases.