Extended postoperative thromboprophylaxis after pancreatic resection for pancreatic cancer is associated with decreased risk of venous thromboembolism in the minimally invasive approach.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with increased venous thromboembolism (VTE). We sought to compare rates of bleeding complications and VTE in patients receiving extended postoperative thromboprophylaxis (EPT) to those who did not, and identify risk factors for VTE after pancreatectomy for PDAC. METHODS: This is a retrospective review of pancreatectomies for PDAC. EPT was defined as 28 days of low molecular weight heparin. Multivariable analysis (MVA) was performed to identify independent risk factors of VTE. RESULTS: Of 269 patients included, 142 (52.8%) received EPT. Of those who received EPT, 7 (4.9%) suffered bleeding complications, compared to 6 (4.7%) of those who did not (p = 0.938). There was no significant difference in VTE rate at 90 days (2.8% vs. 2.4%, p = 0.728) or at 1 year (6.3% vs. 7.9%, p = 0.624). On MVA, risk factors for VTE included worse performance status, lower preoperative hematocrit, R1/R2 resection, and minimally invasive (MIS) approach. Among those who received EPT, there was no difference in VTE rate between MIS and open approach. CONCLUSIONS: EPT was not associated with a difference in VTE risk or bleeding complications. MIS approach was associated with a higher risk of VTE; however, this was significantly lower among those who received EPT.

Flow-Based Fmoc-SPPS Preparation and SAR Study of Cathelicidin-PY Reveals Selective Antimicrobial Activity.

Antimicrobial peptides (AMPs) hold promise as novel therapeutics in the fight against multi-drug-resistant pathogens. Cathelicidin-PY (NH2-RKCNFLCKLKEKLRTVITSHIDKVLRPQG-COOH) is a 29-residue disulfide-cyclised antimicrobial peptide secreted as an innate host defence mechanism by the frog Paa yunnanensis (PY) and reported to possess broad-spectrum antibacterial and antifungal properties, exhibiting low cytotoxic and low hemolytic activity. Herein, we detail the total synthesis of cathelicidin-PY using an entirely on-resin synthesis, including assembly of the linear sequence by rapid flow Fmoc-SPPS and iodine-mediated disulfide bridge formation. By optimising a synthetic strategy to prepare cathelicidin-PY, this strategy was subsequently adapted to prepare a bicyclic head-to-tail cyclised derivative of cathelicidin-PY. The structure-activity relationship (SAR) of cathelicidin-PY with respect to the N-terminally positioned disulfide was further probed by preparing an alanine-substituted linear analogue and a series of lactam-bridged peptidomimetics implementing side chain to side chain cyclisation. The analogues were investigated for antimicrobial activity, secondary structure by circular dichroism (CD), and stability in human serum. Surprisingly, the disulfide bridge emerged as non-essential to antimicrobial activity and secondary structure but was amenable to synthetic modification. Furthermore, the synthetic AMP and multiple analogues demonstrated selective activity towards Gram-negative pathogen E. coli in physiologically relevant concentrations of divalent cations.

A Prospective Analysis of the SVS WIfI Classification System to Stratify Immediate and 1-Year Patient Outcomes.

The purpose of this study was to prospectively enroll patients that presented to the emergency department with a lower extremity infection, stratify risk and record outcomes. Risk stratification was performed based on the Society of Vascular Surgery Wound, foot Infection, and Ischemia (WIfI) classification system. This study aimed to establish the efficacy and validity of this classification in predicting patient outcomes during immediate hospitalization and throughout a 1 year follow up. A total of 152 patients were enrolled in the study and of these, 116 met the inclusion criteria and had at least 1 year of follow up for analysis. Each patient was assigned a WIfI score based on wound, ischemia, and foot infection severity according to the classification guidelines. Patient demographics as well as all podiatric and vascular procedures were recorded. The major end points of the study were rates of proximal amputation, time to wound healing, surgical procedures, surgical dehiscence, readmission rates, and mortality. A difference in rates of healing (p = .04), surgical dehiscence (p < .01), and 1 year mortality (p = .01) with increasing WIfI stage as well as across the individual component scores was noted. This analysis further supports the application of the WIfI classification system early during patient care to stratify risk and identify the need for early intervention and a multispecialty team approach to potentially improve outcomes in the severe multicomorbid patient.

Risk factors and outcomes in patients undergoing minimally invasive hepatectomy with unplanned conversion: a contemporary NSQIP analysis.

BACKGROUND: Minimally invasive techniques are growing for hepatectomies. Laparoscopic and robotic liver resections have been shown to differ in conversions. We hypothesize that robotic approach will have decreased conversion to open and complications despite being a newer technique than laparoscopy. METHODS: ACS NSQIP study using the targeted Liver PUF from 2014 to 2020. Patients grouped based on hepatectomy type and approach. Multivariable and propensity scored matching (PSM) was used to analyze the groups. RESULTS: Of 7767 patients who underwent hepatectomy, 6834 were laparoscopic and 933 were robotic. The rate of conversions was significantly lower in robotic vs laparoscopic (7.8% vs 14.7%; p < 0.001). Robotic hepatectomy was associated with decreased conversion for minor (6.2% vs 13.1%; p < 0.001), but not major, right, or left hepatectomy. Operative factors associated with conversion included Pringle (OR = 2.09 [95% CI 1.05-4.19]; p = 0.0369), and a laparoscopic approach (OR = 1.96 [95% CI 1.53-2.52]; p < 0.001). Undergoing conversion was associated with increases in bile leak (13.7% vs 4.9%; p < 0.001), readmission (11.5% vs 6.1%; p < 0.001), mortality (2.1% vs 0.6%; p < 0.001), length of stay (5 days vs 3 days; p < 0.001), and surgical (30.5% vs 10.1%; p < 0.001), wound (4.9% vs 1.5%; p < 0.001) and medical (17.5% vs 6.7%; p < 0.001) complications. CONCLUSION: Minimally invasive hepatectomy with conversion is associated with increased complications, and conversion is increased in the laparoscopic compared to a robotic approach.

Association of the new visceral adiposity index with coronary artery calcification and arterial stiffness in Korean population.

BACKGROUND AND AIMS: The new visceral adiposity index (NVAI) is an indirect marker of visceral adipose tissue recently developed using a Korean population. Here we examined the association of NVAI with coronary artery calcification and arterial stiffness in asymptomatic Korean patients. METHODS AND RESULTS: We analyzed data from 60,938 asymptomatic Korean adults. Odds ratios and 95% confidence intervals (CIs) for coronary artery calcification score (CACS) > 100 and brachial-ankle pulse wave velocity (baPWV) ≥14 m/s were calculated across NVAI tertiles using multiple logistic regression analysis. Receiver operating characteristic (ROC) and area under the curve (AUC) analyses were used to assess the ability of NVAI to predict moderate to high risk of cardiovascular disease. The prevalence of moderate and high risk of cardiovascular disease increased significantly as the NVAI tertile increased. The odds ratio (95% CI) of the highest NVAI tertile for CACS >100 was 5.840 (5.101-6.686) for men and 18.916 (11.232-31.855) for women, after adjusting for confounders. All NVAI AUC values were significantly higher than the AUC values for other visceral adiposity markers. CONCLUSIONS: This study provides the evidence that NVAI is independently and positively associated with coronary calcification and arterial stiffness in asymptomatic Korean adults.

SH3YL1 protein as a novel biomarker for diabetic nephropathy in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy. METHODS AND RESULTS: In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis. CONCLUSION: These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy.

Impact of Depressive Symptomology on Pain and Function during Recovery after Total Joint Arthroplasty.

OBJECTIVES: To determine the effect of preoperative depressive symptoms on patient-reported function and pain following total joint arthroplasty (TJA) after controlling for potential confounding factors; how depressive symptoms changed after TJA; and the impact of postoperative depressive symptoms on recovery. METHODS: A prospective cohort study undertaken in a metropolitan region in Canada enrolled 710 participants; 622 (87%) had complete 6-month data. Participants completed standardized measures preoperatively and at 1, 3, and 6 months postoperatively. The primary outcome was Western Ontario McMaster Osteoarthritis Index (WOMAC) pain and function. Three groups were created: depressive symptoms absent (n = 573, 82%), possible depressive symptoms (n = 58, 8%), and probable depressive symptoms (n = 68, 10%) using the Center for Epidemiologic Scale for Depression score. Risk-adjusted analyses examined the association between WOMAC change and the preoperative Center for Epidemiologic Scale for Depression score. RESULTS: After risk adjustment, preoperative possible and probable depressive symptomology was associated with postoperative WOMAC pain scores that were 7.6 and 11.7 points, respectively, worse and WOMAC function scores that were 8.8 and 14.3 points, respectively, worse than those without preoperative depressive symptoms. Depressive symptoms improved postoperatively; by 6 months post-TJA, only 34 (5%) participants screened as having probable depressive symptoms, whereas only 13(2%) had possible depressive symptoms. Postoperative WOMAC pain and function scores improved, but they were negatively affected by possible and probable depressive symptoms. CONCLUSIONS: Although depressive symptoms improve postoperatively, preoperative depressive symptoms, especially for those with probable depressive symptomology, may negatively affect postoperative pain and functional recovery even after risk adjustment.

Nucleic acid-induced dimerization of HIV-1 Gag protein.

HIV-1 Gag is a highly flexible multidomain protein that forms the protein lattice of the immature HIV-1 virion. In vitro, it reversibly dimerizes, but in the presence of nucleic acids (NAs), it spontaneously assembles into virus-like particles (VLPs). High-resolution structures have revealed intricate details of the interactions of the capsid (CA) domain of Gag and the flanking spacer peptide SP1 that stabilize VLPs, but much less is known about the assembly pathway and the interactions of the highly flexible NA-binding nucleocapsid (NC) domain. Here, using a novel hybrid fluorescence proximity/sedimentation velocity method in combination with calorimetric analyses, we studied initial binding events by monitoring the sizes and conformations of complexes of Gag with very short oligonucleotides. We observed that high-affinity binding of oligonucleotides induces conformational changes in Gag accompanied by the formation of complexes with a 2:1 Gag/NA stoichiometry. This NA-liganded dimerization mode is distinct from the widely studied dimer interface in the CA domain and from protein interactions arising in the SP1 region and may be mediated by protein-protein interactions localized in the NC domain. The formation of the liganded dimer is strongly enthalpically driven, resulting in higher dimerization affinity than the CA-domain dimer. Both detailed energetic and conformational analyses of different Gag constructs revealed modulatory contributions to NA-induced dimerization from both matrix and CA domains. We hypothesize that allosterically controlled self-association represents the first step of VLP assembly and, in concert with scaffolding along the NA, can seed the formation of two-dimensional arrays near the NA.

Recent Progress in the Synthesis of Homogeneous Erythropoietin (EPO) Glycoforms.

Erythropoietin (EPO) has been regarded as a therapeutic glycoprotein for the clinical treatment of anaemia since its approval by the Food and Drug Administration (FDA) in 1989. Commercial production of the 165-residue glycoprotein is by recombinant protein expression using mammalian cell lines that renders a complex mixture of glycoforms that have an identical amino acid sequence but variations in the structures of the pendant glycans. This heterogeneous nature of human recombinant EPO restricts structural and bioactivity studies in medicinal chemistry. Consequently, chemical synthesis provides an elegant approach for the preparation of complex homogeneous glycoproteins from a readily accessible pool of amino acids and sugars. In addition, the combination of chemical and biosynthesis enables robust and large-scale production of homogeneous EPO. The scope of this minireview is to summarise the recent advances in the chemical and semisyntheses of homogeneous EPO glycoforms, highlighting the versatile approaches to the preparation and structural manipulations of the carbohydrate chains incorporated into synthetic EPO glycoproteins.

Accuracy of Resident-Performed Point-of-Care Lung Ultrasound Examinations Versus Chest Radiography in Pneumothorax Follow-up After Tube Thoracostomy in Rwanda.

OBJECTIVES: The aim of this study was to evaluate the accuracy and timeliness of resident-performed point-of-care lung ultrasound (LUS) examinations for the follow-up of pneumothorax (PTX) after tube thoracostomy. METHODS: After brief training, Rwandan surgical residents blinded to chest radiography (CXR) performed and interpreted LUS examinations for PTX in participants undergoing CXR for PTX follow-up. Treating clinicians interpreted CXR for the presence of PTX for therapeutic decisions. Lung ultrasound was later reviewed by ultrasound experts, and CXR was reviewed by a radiologist. We defined expert LUS interpretation as the reference standard. The sensitivity and specificity of resident-performed LUS examinations for diagnosing PTX were calculated. We assessed agreement between trained resident versus expert LUS and clinician versus radiology CXR using the Cohen κ coefficient. We compared the time to results between LUS and CXR. RESULTS: Over an 8-month period, 51 participants were enrolled. Compared to expert LUS interpretation, the sensitivity and specificity (95% confidence intervals) of resident LUS were 100% (85%-100%) and 96% (82%-100%), respectively, whereas the sensitivity and specificity of clinician-interpreted CXR were 48% (27%-69%) and 100% (88%-100%). The agreement between resident and expert LUS was excellent (κ = 0.96), whereas the agreement between clinician and radiologist CXR was only moderate (κ = 0.60). The time to results was significantly longer for CXR than LUS (mean, 1335 versus 396 minutes; P = .0001). CONCLUSIONS: A resident-performed LUS examination was a quicker imaging modality with superior sensitivity compared to clinician-interpreted CXR for PTX follow-up after tube thoracostomy in this Rwandan study. Lung ultrasound can be a valuable imaging tool for PTX follow-up, especially in resource-limited settings.

Oncologic Outcome and Morbidity in the Elderly Rectal Cancer Patients After Preoperative Chemoradiotherapy and Total Mesorectal Excision: A Multi-institutional and Case-matched Control Study.

OBJECTIVE: To determine the toxicity and oncologic outcome of neoadjuvant chemoradiotherapy (CRT) followed by curative total mesorectal excision (TME) in the elderly (≥70 yrs) and younger (<70 yrs) rectal cancer patients. BACKGROUND: Sufficient data for elderly rectal cancer patients who received definitive trimodality have not been accumulated yet. PATIENTS AND METHODS: A total of 1232 rectal cancer patients who received neoadjuvant CRT and TME were enrolled in this study. After propensity-score matching, 310 younger patients and 310 elderly patients were matched with 1:1 manner. Treatment response, toxicity, surgical outcome, recurrence, and survival were assessed and compared between the 2 groups of patients. RESULTS: The median age was 58 years for the younger patient group and 74 years for the elderly group. Pathologic complete response rates were not significantly different between the 2 groups (younger and elderly: 17.1% vs 14.8%, P = 0.443). The 5-year recurrence-free survival (younger and elderly: 67.7% vs 65.5%, P = 0.483) and overall survival (younger and elderly: 82.9% vs. 79.5%, P = 0.271) rates were not significantly different between the 2 groups either. Adjuvant chemotherapy after surgery was less frequently delivered to the elderly than that to younger patients (83.9% vs 69.0%). Grade 3 or higher acute hematologic toxicity was observed more frequently in the elderly than that in the younger group (9.0% vs 16.1%, P = 0.008). Late complication rate was higher in the elderly group compared with that in the younger group without statistical significance (2.6% vs 4.5%, P = 0.193). CONCLUSIONS: Although acute hematologic toxicity was observed more frequently in the elderly patients than that in the younger patients, elderly rectal cancer patients with good performance status who received preoperative CRT and TME showed favorable tumor response and recurrence-free survival similar to younger patients.

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk.

The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands. These two domains are joined together by a stretch of amino acids that is referred to as the "stalk". Studies of other class B GPCRs suggest that the stalk may act as hinge, allowing the ECD to adopt multiple conformations. It is unclear what the role of the stalk is within CLR and whether RAMPs can influence its function. Therefore, this study investigated the role of this region using an alanine scan. Effects of mutations were measured with all three RAMPs through cell surface expression, cAMP production and, in select cases, radioligand binding and total cell expression assays. Most mutants did not affect expression or cAMP signaling. CLR C127A, N140A, F142A, and L144A impaired cell surface expression with all three RAMPs. T125A decreased the potency of all peptides at all receptors. N128A, V135A, and L139A showed ligand-dependent effects. While the stalk appears to play a role in CLR function, the effect of RAMPs on this region seems limited, in contrast to their effects on the structure of CLR in other receptor regions.

Global transcriptome analysis identifies weight regain-induced activation of adaptive immune responses in white adipose tissue of mice.

OBJECTIVE: Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain. DESIGN: We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses. RESULTS: In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co-expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns. CONCLUSIONS: Our global transcriptome analysis identified weight regain-induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss.

Chemically Resistant Perfluoroalkoxy Nanoparticle-Packed Porous Substrates and Their Use in Colorimetric Sensor Arrays.

To create printing substrates for colorimetric sensor arrays, chemically resistant membranes are prepared by coating cellulose filter paper with perfluoroalkoxy (PFA) polymer nanoparticles. A water-based fluorothermoplastic polymer dispersion was diluted with an organic solvent that causes weak aggregation of polymer nanoparticles. The resulting solution improved adhesion between the polymer and the cellulose membrane, providing a more mechanically stable substrate. These PFA polymer-coated substrates demonstrated superior chemical resistance against strong alkalines and had relatively uniform nanoporous structures that substantially improved the printability of a colorimetric sensor array. Finally, colorimetric sensor arrays printed on these substrates were evaluated for the detection of four different toxic industrial chemicals (e.g., ammonia, hydrogen sulfide, nitrogen dioxide, and sulfur dioxide) at or below their permissible exposure limits.

Comparison of pancreatic volume and fat amount linked with glucose homeostasis between healthy Caucasians and Koreans.

AIM: To compare pancreatic volume and fat amount, and their associations with glucose homeostasis, in a Korean and a white population. MATERIALS AND METHODS: In 43 healthy Korean and 43 healthy white people, matched for age (±3 years) and body mass index (BMI; ±1 kg/m2 ), we measured pancreatic volume and fat amount in the pancreas and abdomen using computed tomography. Pancreatic ß-cell function and insulin resistance were estimated according to biochemical characteristics and a 75-g oral glucose tolerance test. Body composition and resting energy expenditure (REE) were examined using bioimpedance and indirect calorimetry, respectively. RESULTS: The mean ±SD age of the participants was 29.9 ± 5.9 years and 30.0 ± 5.2 years, and BMI was 24.0 ±3.7 and 24.1 ±3.2 kg/m2 in the white participants and the Korean participants, respectively. Pancreatic volume in the white participants was greater than that in Korean participants (77.8 ±11.6 vs 68.2 ±12.1 cm3 ; P < .001). Pancreatic fat content in Korean participants was 22.8% higher than in white participants (P = .051). Insulinogenic index, disposition index, muscle mass and REE were significantly lower in Korean participants. Pancreatic volume was positively associated with indices linked to ß-cell function; fat content in the pancreas was negatively associated with such indices, and positively with insulin resistance after adjusting for relevant variables including REE. CONCLUSIONS: A smaller pancreas and higher fat deposition might be crucial determinants of vulnerability to diabetes in Korean people compared with white people with similar BMI and body fat levels.

Best Core Stabilization for Anticipatory Postural Adjustment and Falls in Hemiparetic Stroke.

OBJECTIVES: To compare the effects of conventional core stabilization and dynamic neuromuscular stabilization (DNS) on anticipatory postural adjustment (APA) time, balance performance, and fear of falls in chronic hemiparetic stroke. DESIGN: Two-group randomized controlled trial with pretest-posttest design. SETTING: Hospital rehabilitation center. PARTICIPANTS: Adults with chronic hemiparetic stroke (N=28). INTERVENTIONS: Participants were randomly divided into either conventional core stabilization (n=14) or DNS (n=14) groups. Both groups received a total of 20 sessions of conventional core stabilization or DNS training for 30 minutes per session 5 times a week during the 4-week period. MAIN OUTCOME MEASURES: Electromyography was used to measure the APA time for bilateral external oblique (EO), transverse abdominis (TrA)/internal oblique (IO), and erector spinae (ES) activation during rapid shoulder flexion. Trunk Impairment Scale (TIS), Berg Balance Scale (BBS), and Falls Efficacy Scale (FES) were used to measure trunk movement control, balance performance, and fear of falling. RESULTS: Baseline APA times were delayed and fear of falling was moderately high in both the conventional core stabilization and DNS groups. After the interventions, the APA times for EO, TrA/IO, and ES were shorter in the DNS group than in the conventional core stabilization group (P<.008). The BBS and TIS scores (P<.008) and the FES score (P<.003) were improved compared with baseline in both groups, but FES remained stable through the 2-year follow-up period only in the DNS group (P<.003). CONCLUSIONS: This is the first clinical evidence highlighting the importance of core stabilization exercises for improving APA control, balance, and fear of falls in individuals with hemiparetic stroke.

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: role for omega-3 epoxides.

Soluble epoxide hydrolase (sEH) is an emerging therapeutic target in a number of diseases that have inflammation as a common underlying cause. sEH limits tissue levels of cytochrome P450 (CYP) epoxides derived from omega-6 and omega-3 polyunsaturated fatty acids (PUFA) by converting these antiinflammatory mediators into their less active diols. Here, we explored the metabolic effects of a sEH inhibitor (t-TUCB) in fat-1 mice with transgenic expression of an omega-3 desaturase capable of enriching tissues with endogenous omega-3 PUFA. These mice exhibited increased CYP1A1, CYP2E1, and CYP2U1 expression and abundant levels of the omega-3-derived epoxides 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic (19,20-EDP) in insulin-sensitive tissues, especially liver, as determined by LC-ESI-MS/MS. In obese fat-1 mice, t-TUCB raised hepatic 17,18-EEQ and 19,20-EDP levels and reinforced the omega-3-dependent reduction observed in tissue inflammation and lipid peroxidation. t-TUCB also produced a more intense antisteatotic action in obese fat-1 mice, as revealed by magnetic resonance spectroscopy. Notably, t-TUCB skewed macrophage polarization toward an antiinflammatory M2 phenotype and expanded the interscapular brown adipose tissue volume. Moreover, t-TUCB restored hepatic levels of Atg12-Atg5 and LC3-II conjugates and reduced p62 expression, indicating up-regulation of hepatic autophagy. t-TUCB consistently reduced endoplasmic reticulum stress demonstrated by the attenuation of IRE-1α and eIF2α phosphorylation. These actions were recapitulated in vitro in palmitate-primed hepatocytes and adipocytes incubated with 19,20-EDP or 17,18-EEQ. Relatively similar but less pronounced actions were observed with the omega-6 epoxide, 14,15-EET, and nonoxidized DHA. Together, these findings identify omega-3 epoxides as important regulators of inflammation and autophagy in insulin-sensitive tissues and postulate sEH as a druggable target in metabolic diseases.

Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study).

The aim of this study was to evaluate the effect of gemigliptin vs sitagliptin or glimepiride as initial combination therapy with metformin on glycaemic variability and to assess the correlation between glycaemic variability reduction and the dipeptidyl peptidase-4 (DPP-4) inhibition in patients with type 2 diabetes. This multicentre, randomized, active-controlled, open-label exploratory study included 69 patients with HbA1c > 7.5%. Subjects were randomized to receive gemigliptin 50 mg (n = 24), sitagliptin 100 mg (n = 23) or glimepiride 2 mg (n = 22) for 12 weeks. After 12 weeks, the change in mean amplitude of glycaemic excursion (MAGE) compared with baseline was significantly lower in the DPP-4 inhibitor groups compared with that in patients who received glimepiride. Furthermore, the standard deviation (SD) of glucose was significantly lower in patients who received gemigliptin than that in patients who received sitagliptin or glimepiride. The DPP-4 inhibition was significantly correlated with changes in MAGE and SD of glucose. In conclusion, gemigliptin and sitagliptin were more effective than glimepiride in reducing glycaemic variability as initial combination therapy with metformin in patients with type 2 diabetes, and the DPP-4 inhibition was associated with a reduction in glycaemic variability.

Phenotypic changes of methicillin-resistant Staphylococcus aureus during vancomycin therapy for persistent bacteraemia and related clinical outcome.

Persistent bacteraemia (PB) due to methicillin-resistant Staphylococcus aureus (MRSA) that fails to respond to glycopeptide therapy is a well-documented clinical problem. There are limited data on changes in agr functionality, vancomycin susceptibility and heteroresistance during MRSA PB. Thus, the frequency of these changes and their clinical significance remain unclear. Only patients with MRSA PB (≥7 days) from a prospective cohort of S. aureus bacteraemia were included. We collected isogenic paired strains and compared vancomycin MIC, vancomycin heteroresistance, and agr functionality between initial and final blood isolates. We also assessed the clinical outcome. A total of 49 patients had MRSA PB over 22 months. Bacteraemia persisted for a median of 13 days and most patients (98%) received glycopeptide as initial therapy. Among 49 isogenic pairs, only one pair showed a vancomycin MIC increase ≥2-fold by broth microdilution method, and only seven (14%) by E-test. Significant portions of initial isolates had vancomycin heteroresistance (49%) and agr dysfunction (76%). Development of vancomycin heteroresistance during PB occurred in four (16%) among 25 initial vancomycin-susceptible isolates, and acquisition of agr dysfunction occurred in two (16%) among 12 initial agr-functional isolates. Changes in the opposite direction occasionally occurred. These phenotypic changes during PB were not associated with mortality, whereas agr dysfunction of the initial isolates was significantly associated with mortality. During MRSA PB, phenotypic changes of MRSA isolates occurred occasionally under prolonged vancomycin exposure but were not significantly associated with clinical outcome. In contrast, initial agr dysfunction could be a predictor for mortality in MRSA PB.