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RATIONALE, AIMS, AND OBJECTIVES: Patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and diabetes mellitus form a special population due to an increased risk of hyperglycemia from the use of corticosteroids. There is limited data regarding specific outcomes in diabetic patients with AECOPD. METHODS: A retrospective data analysis of adult patients admitted to North Florida Division of the Hospital Corporation of America (HCA Healthcare) with a primary or secondary diagnosis of AECOPD from January 1, 2018, to December 31, 2018. We excluded patients who needed intensive care unit (ICU) care on day 0. Outcomes assessed included length of stay, mortality, and need for ICU transfer after 48 h from admission. Characteristics included age, sex, and race, comorbidities such as diabetes mellitus, chronic kidney disease, acute kidney injury, congestive heart failure, and anemia were analyzed. Comparisons were analyzed via binary and multivariate logistic regression models. RESULTS: A total of 3788 patients admitted for AECOPD were included; amongst them, 1356 patients (~36%) had diabetes mellitus. This subset of patients had higher rates of comorbidities. A significant portion of diabetic patients (72%) received intravenous rather than oral steroids, similar to non-diabetic patients. In addition, diabetic patients were more likely to develop acute kidney injury (14.2% vs 8.0%, p

Funding Acknowledgements Type of funding sources: None. Background Transcatheter aortic valve replacement (TAVR) became standard of care for selected patients with severe aortic stenosis. Computed tomography (CT) and 2D/3D echocardiography (ECHO) are used for aortic annulus sizing. As a result of increasing number of TAVR more imaging specialists participate in pre-procedural TAVR assessment. Purpose The aim of this study was to compare accuracy of ECHO aortic annulus measurements vs CT based parameters for Edward Sapiens TAVR in such environment. Methods Data of 145 consecutive patients with TAVR (Sapiens XT or Sapiens 3S) were analysed retrospectively. One radiologist and six echocardiographers trained in aortic annulus size measurements participated in pre-procedural aortic anulus assessment. Aortic annulus area and area derived diameter were measured/calculated in each patient from 3D ECHO data set acquired from mid-oesophageal view and from CT data set, using multiplanar reconstruction. 2D ECHO aortic annulus size was measured from mid-oesophageal 120º view in early systole. Results 139 (96%) patients had favourable TAVR result (max. mild aortic regurgitation, single valve implanted). 3D ECHO aortic anulus area and area derived diameter were smaller than corresponding CT parameters (464 ± 99 vs 479 ± 88 mm2, p Conclusion 3D ECHO aortic annulus measurements are generally smaller then CT ones. If 3D ECHO based parameters only were used for TAVR (Edward Sapiens) size selection, it would have resulted in underestimation of the valve size in up to 1/3 of the patients. CT aortic annulus size assessment should be preferred method over 3D ECHO in daily practice. Abstract Figure 1 Abstract Table 1

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic 17-28265A. Background The optimal timing of surgical treatment is challenging in asymptomatic patients with severe aortic regurgitation (AR). A significant number of patients undergoing aortic valve surgery as per current guidelines have irreversible left ventricular (LV) myocardial damage with a negative impact on their long-term postoperative outcome. Purpose We aimed to determine the value of magnetic resonance-, advanced echocardiography–derived indices and serum B-natriuretic peptide level (BNP) to identify patients with chronic asymptomatic AR who are at risk of early disease progression. Methods We prospectively enrolled a group of asymptomatic patients with pure chronic severe AR, without an indication for surgical treatment as per the current guidelines, in a multicenter study. Baseline examination consisted of serum BNP level analysis, comprehensive echocardiography including 3D vena contracta area (VCA) and 2D global longitudinal strain (GLS), and a comprehensive MRI including regurgitant fraction (RF) measurement; all imaging data were analyzed in Corelab. Patient follow-up was every 6 months. The primary endpoint was a new guideline-directed indication for surgical treatment. Results In total, 129 patients were enrolled between 2015 and 2019, the endpoint occurred in 43 patients during a median follow-up of 1375 (IQR 1041-1783) days. Baseline clinical data did not differ between patients with the endpoint (surgical group) and stable patients (medical group). Baseline BNP levels were significantly higher in the surgical group (55 vs. 21 ng/L, P = 0.008). MRI-derived LV ejection fraction was not different (61 vs 61 %, P = 0.815) at baseline while both CMR-derived end-systolic and end-diastolic LV volumes were significantly higher in the surgical group (all P 31 ng/L), MRI RF (cut-off value > 34 %), 3D VCA (cut-off value 36 mm2) or 2D GLS (cut-off value < 17 %) showed the highest predictive accuracy (P = 0.002) to predict the primary endpoint. (Figure 1). Conclusion A combination of baseline parameters of AR severity (3D VCA, MRI-derived RF) and myocardial impairment (2D GLS, serum BNP level) present an accurate tool for the identification of patients with chronic asymptomatic AR who are at risk of early disease progression. Abstract Figure 1

Background Studies using population-based data from Ontario previously found South Asian (SA) and East Asian immigrants develop IBD at lower rates than non-immigrants. However, incidence among the Canadian-born children of SA immigrants was comparable to those of non-immigrants, and younger age at arrival to Canada was associated with an increased risk. Aims The primary aim of the study was to determine the incidence of IBD in South Asian and Chinese people compared with the general Ontario population. Methods All incident cases of IBD in children (1994–2015) and adults (1999–2015) were identified from population-based health administrative data in Ontario, Canada using validated algorithms. Ethnicity was assigned by linkage of a validated surname-based database to health administrative data, immigration records, and hospital birth data. We determined standardized incidence of IBD and the adjusted incidence rate ratio (aIRR) in SAs and Chinese comparable to the general population. Based on existing evidence, we adjusted for confounders selected a priori: immigration status, sex, income and rurality. Results Amongst 14,483,769 people in the general population, standardised incidence of IBD per 100,000 person-years (PY) was 24.7 (95%CI 24.4–25.0), compared with 14.6 (95%CI 13.7–15.5) in 982,472 SAs and with 5.4 (95%CI 4.8–5.9) in 764,397 Chinese. The risk of IBD in SAs was lower to the general population prior to adjusting for immigration, IRR 0.82 (95%CI 0.78–0.86), but comparable after adjusting for confounders (aIRR 1.10, 95%CI 1.05–1.16). Only SA adults (18-64y) had a higher risk of IBD (aRR 1.10, 95% CI 1.02–1.18), not children or seniors. Compared to the general population, SAs had a lower risk of Crohn disease (CD), irrespective of age (aIRR 0.66, 95%CI 0.60–0.77), but a higher risk of ulcerative colitis (UC) (aIRR 1.47 (95% CI 1.34–1.61).). SAs were more likely to develop UC than CD (aIRR 1.51, 95%CI 1.38–1.66). The risk of IBD was much lower in Chinese people, irrespective of age (aIRR 0.24, 95%CI 0.20–0.28). This lower risk was similar in CD (aIRR 0.21, 95%CI 0.17–0.26) and UC (aIRR 0.28, 95%CI 0.23–0.25). The SA population had a considerably higher risk of developing IBD compared to the Chinese population (aIRR 4.29, 95%CI 3.62–5.08), and were more likely to develop UC (aIRR 1.36, 95% CI 1.08–1.73). Conclusions Canadian SAs had a similarly high risk of developing IBD compared with the general population after adjusting for immigration status, a finding distinct from the Chinese population. There was an age-response relationship in SAs only. Furthermore, SAs were more likely to develop UC than people of Chinese origin, potentially owing to differences in genetic susceptibility and/or environmental factors. Funding Agencies None

Exosomes are nano‐sized vesicles that are involved in various biological processes including cell differentiation, proliferation, signaling, and intercellular communication. Urinary exosomes were isolated from a cohort of hereditary α‐tryptasemia (HαT) patients and from healthy volunteers. There was a greater number of exosomes isolated from the urine in the HαT group compared to the control volunteers. Here, we investigated the differences in both lipid classes and lipid species within urinary exosomes of the two groups. Lipids were extracted from urinary exosomes and subjected to liquid chromatography mass spectrometry using a targeted approach. Various molecular species of glycerophospholipids, glycerolipids, and sterols were significantly reduced in HαT patients. Out of a possible 1127 lipids, 521 lipid species were detected, and relative quantities were calculated. Sixty‐four lipids were significantly reduced in urinary exosomes of HαT patients compared to controls. All significantly reduced sphingolipids and most of the phospholipids were saturated or mono‐unsaturated lipids. These results suggest exosome secretion is augmented in HαT patients and the lipids within these exosomes may be involved in various biological processes. The unique lipid composition of urinary exosomes from HαT patients will contribute to our understanding of the biochemistry of this disease.

Anomalous left coronary artery arising from the pulmonary artery (ALCAPA) syndrome is a very rare congenital heart disease with an incidence of one in 300,000 and a high rate of mortality early in life if left untreated. Adult-type ALCAPA presents when significant collaterals develop from the right coronary artery (RCA) to the left coronary artery (LCA). Even with the collaterals, chronic sub-endocardial ischemia occurs in most cases, and patients die from sudden cardiac death. Here we present a case of a 38-year-old female who lived an active and healthy life and presented with chest pain and palpitations. Initial electrocardiography (EKG) showed atrial fibrillation with rapid ventricular response. Although initial cardiac enzymes were negative and there were no ischemic EKG changes, troponins became elevated over the course of the hospital stay and the patient underwent a left heart catheterization. Results revealed a dilated RCA extending to the left ventricle and an anomalous left main originating from the pulmonary artery with complete occlusion. The patient received medical management for acute coronary syndrome, including heparin infusion for 48 hours, aspirin, metoprolol, and atorvastatin. She was referred to a tertiary care facility for surgical correction of anomaly of the coronary arteries. The next day, the patient arrived in the emergency department with an acute onset of speech difficulty and left-sided weakness. A brain CT without contrast showed hematoma in the right frontal lobe. The patient underwent surgical evacuation of the hematoma with marked improvement of her weakness. The patient recovered after a successful surgical repair involving translocation of the left main coronary artery to the aorta. It has been reported that ALCAPA should be considered in a young adult with dilated cardiomyopathy and mitral regurgitation (MR). Other common presentations include acute myocardial infarction, angina, and dyspnea on exertion. Sudden cardiac death is not uncommon; however, it tends to decrease with age of diagnosis. Interestingly, our patient was known to have MR with regular follow-up at the cardiology clinic for years. Echocardiogram never showed any abnormalities other than MR. She never received further workup to address the reason of MR, although she has no underlying chronic conditions that can explain it. In relatively young patients with a healthy lifestyle presenting with chest pain, a broader look at etiologies should be considered. We would like to emphasize the importance of looking up for possible coronary artery disease, especially in young individuals.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This study was supported by Ministry of Health of the Czech Republic 17-28265A. Background Indication for surgical treatment in asymptomatic patients with severe aortic regurgitation (AR) is curretly based on 2-dimensional echocardiography derived left ventricle (LV) diameter and ejection fraction. Suboptimal sensitivity of this quideline-directed approach may lead to late intervention in a substantial number of patients. Purpose We aimed to develop a new prognostic stratification scheme based on novel imaging and biochemical markers of heart failure. Methods Consecutive patients with chronic severe AR not indicated for surgery per the current guidelines were enrolled into prospective multi-center study. Baseline examination consisted of B-natriuretic peptide (BNP); comprehensive echocardiography (ECHO) including 3-dimensional (3D) vena contracta area (VCA); comprehensive cardiac magnetic resonance (CMR) including regurgitant volume and fraction measurement, and extracellular volume (ECV); all imaging data were analysed in core lab. The perioperative myocardial biopsy from basal septum was performed in all surgically treated patients for histological myocardial fibrosis quantification by Picrosirius Red staining. Patient follow-up was every 6 months. The endpoint was a disease progression (indication for surgery per the current guidelines). Results In total, 132 patients were enrolled between 2015 and 2019, the endpoint occurred in 39 patients during a median follow-up of 1217 days. Baseline clinical data did not differ between patients with endpoint (surgical group) and stable patients (medical group). Baseline BNP levels were higher in the surgical group (57 vs. 20, P Conclusion Baseline CMR-derived LV volumes, CMR-derived regurgitant fraction, and BNP levels can predict disease progression in asymptomatic patients with chronic severe aortic regurgitation. The novel multi-factorial scoring system might identify candidates of early surgical treatment but this hypothesis will require prospective clinical testing. Abstract Figure. Cardiac magnetic resonance imaging

Background The optimal timing of intervention in patients with chronic aortic regurgitation (AR) is currently based on patient symptoms and echocardiography derived parameters. The sensitivity of this approach is suboptimal and late operation often results in irreversible myocardial damage. Purpose To determine the prognostic value of novel parameters in asymptomatic patients with chronic severe AR in optimal timing of aortic valve surgery. Methods Consecutive patients with chronic severe AR not indicated for surgery per the current guidelines were studied in a prospective design in 5 centers. Baseline examination consisted of B-natriuretic peptide (BNP) measurement, comprehensive echocardiography (ECHO) including 3-dimensional (3D) study with vena contracta area (VCA), and complex magnetic resonance (MRI) including regurgitant volume (RV), regurgitant fraction (RF), global myocardial work efficiency (GWE) and extracellular volume (ECV); all analyzed in core lab. All patients were followed every 6 months and the endpoint was disease progression defined as an indication for surgery. The perioperative myocardial biopsy was performed in all surgically treated patients for histological myocardial fibrosis quantification. Results In total, 129 patients were enrolled between 2015 and 2019, the endpoint occurred in 35 patients during a mean follow-up of 1044 days. Baseline clinical data did not differ between patients with disease progression (surgical group) and stable patients. Baseline BNP levels were higher in the surgical group (63 vs. 20, P Conclusions Standard ECHO parameters cannot reliably predict the need for surgery in asymptomatic aortic regurgitation patients. Baseline BNP levels above 30.4 ng/L predict disease progression. Novel imaging parameters – ECHO-derived 3D VCA and MRI-derived parameters of LV size and AR severity might be useful in optimal timing determination. Imaging markers and myocardial histology Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of the Czech Republic

Posterior reversible encephalopathy syndrome (PRES) is a syndrome presenting with neurological manifestations including headaches, seizures, and notable changes in brain imaging. It is typically associated with an acute increase in blood pressure, metabolic abnormalities, and/or medication effects. PRES is challenging to diagnose due to its variable presentation and low incidence. Herein we describe a compelling case of PRES syndrome secondary to uncontrolled hypertension in the setting of systemic lupus erythematosus (SLE) and lupus nephritis.

Reports of the stimulated release of extracellular vesicles (EVs) are few, and the mechanisms incompletely understood. To our knowledge, the possibility that the activation of any one of the multitudes of G‐protein‐coupled receptors (GPCRs) expressed by a single cell‐type might increase EV release has not been explored. Recently, we identified the expression of cholecystokinin (CCK), gastrin, gastrin/cholecystokinin types A and/or B receptors (CCKAR and/or –BR), and the bitter taste receptor, TAS2R14 in the human and mouse placenta. specifically, trophoblast. These GPCR(s) were also expressed in four different human trophoblast cell lines. The current objective was to employ two of these cell lines—JAR choriocarcinoma cells and HTR‐8/SVneo cells derived from first‐trimester human villous trophoblast—to investigate whether CCK, TAS2R14 agonists, and other GPCR ligands would each augment EV release. EVs were isolated from the cell‐culture medium by filtration and ultracentrifugation. The preparations were enriched in small EVs (, Activation of multiple G protein‐coupled receptors stimulated extracellular vesicle release from a single cell‐type trophoblast‐derived cells. Other cell signaling pathways may underlie receptor‐stimulated extracellular vesicle release besides, or in addition to, calcium.

Metformin is the first-line drug in the treatment of type 2 diabetes mellitus. The aim of this work was to evaluate the efficacy of metformin treatment in reducing blood pressure and investigate the molecular mechanism using a preclinical animal model. Adult male and female diabetic db/db mice with a blood glucose of greater than 300 mg/dl were salt-loaded (8% NaCl) for 10 days to induce hypertension. The mice were subject to metabolic cage studies for 24 hour urine collections in order to measure urinary electrolytes, albumin, and creatinine. Blood pressure was measured weekly by the tail-cuff method to assess the effect of metformin or vehicle given by oral gavage (dose of 60 mg/kg of body weight per day). At the end of the study the mice was euthanized and the left kidney was formalin-fixed and paraffin-embedded for immunohistochemistry while the right kidney was homogenized for Western blotting. Western blotting showed attenuation of total NCC and phospho-NCC in diabetic db/db mice given an oral gavage of metformin (Pearson correlation coefficient: 0.9470 +/- 2.52e-3) compared to vehicle (Pearson correlation coefficient: 0.9800 +/- 2.86e-3). Immunohistochemical analysis showed less co-localization of the actin cytoskeleton protein filamin and phosphorylated NCC in the metformin treated group compared to the control group. Taken together, we show metformin decreases sodium retention and blood pressure by reducing the density of renal NCC at the luminal membrane and the association between NCC and the actin cytoskeleton.

Effective treatment of hypertension (HTN) in patients with diabetes may help to significantly reduce the risk of those patients developing additional complications including vascular disease and diabetic nephropathy. Blockers of the renin-angiotensin system including angiotensin converting enzyme inhibitors and angiotensin receptor blockers are not always effective in treating HTN in diabetic patients. Therefore, the aim of this study was to use an animal model of type 2 diabetes to investigate a novel mechanism of diabetes associated HTN involving exosomal lipids in the upregulation of epithelial sodium channel (ENaC) activity in the kidney. We performed metabolic cages studies using male and female hypertensive (salt-loaded induced) diabetic db/db mice and healthy age-matched wild-type control mice in order to isolate and characterize urinary exosomes from each group by nanoparticle tracking analysis, Western blotting, and transmission electron microscopy. Our mass spectrometry based lipidomic studies identified key lipids that were differentially expressed in the kidney derived exosomes from the hypertensive diabetic mice compared to control mice. Sphingomyelin quantification assays showed total sphingomyelin content was elevated in the exosomes from the hypertensive diabetic mice compared to the control group. Single channel patch clamp studies showed urinary exosomes enriched in sphingomyelins from hypertensive diabetic mice compared to controls increase ENaC activity (at the level of channel density and open probability) in cultured distal tubule renal epithelial cells. Moreover, exogenous application of sphinomyelin-6 to cultured mouse cortical collecting duct (mpkCCD) cells resulted in an increase in amiloride-sensitive transepithelial current. Taken together, our data show various lipids are enriched in exosomes from hypertensive diabetic mice compared to controls and these exosomes positively regulate ENaC activity in distal tubule and collecting duct cells.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that originate from the adrenal medulla and extra-adrenal paraganglia, respectively. Inactivating mutations in succinate dehydrogenase (SDHx) genes leads to succinate accumulation, increased HIF1-α levels, and uncontrollable growth of PPGLs. We hypothesized that small extracellular vesicles (EVs) released from progenitor cells derived from pheochromocytoma (hPheo1) with a shRNA mediated knockdown of SDHB are enriched in succinate metabolites that play a key role in the activation of various tyrosine dependent signaling pathways that are involved in turmorigenesis and proliferation. We isolated EVs from the conditioned media of human wild-type hPheo1 cells and hPheo1 cells with shRNA SDHB knockdown. The EVs from three separate preparations of each group were characterized by nanoparticle tracking analysis, transmission electron microscopy, and Western blotting using antibodies against different types of EV and one non-EV marker. Our results show small EVs from the SDHB knockdown hPheo1 cells increased the activation of phosphotyrosine residues in wild-type cells compared to cells treated with control EVs from the same cell type. Additionally, our data show these EVs increase phospho-STAT3 compared to the control EVs (3843.10 +/- 1138.89 vs. 213.65+/- 40.75; p

Abnormally high epithelial Na+ channel (ENaC) activity in the aldosterone-sensitive distal nephron and collecting duct leads to hypertension. Myelin and lymphocyte (Mal) is a lipid raft-associated protein that has been previously shown to regulate Na+-K-2Cl− cotransporter and aquaporin-2 in the kidney, but it is not known whether it regulates renal ENaC. ENaC activity is positively regulated by the anionic phospholipid phosphate phosphatidylinositol 4,5-bisphosphate (PIP2). Members of the myristoylated alanine-rich C-kinase substrate (MARCKS) family increase PIP2 concentrations at the plasma membrane, whereas hydrolysis of PIP2 by phospholipase C (PLC) reduces PIP2 abundance. Our hypothesis was that Mal protein negatively regulates renal ENaC activity by stabilizing PLC protein expression at the luminal plasma membrane. We investigated the association between Mal, MARCKS-like protein, and ENaC. We showed Mal colocalizes with PLC-β3 in lipid rafts and positively regulates its protein expression, thereby reducing PIP2 availability at the plasma membrane. Kidneys of 129Sv mice injected with MAL shRNA lentivirus resulted in increased ENaC open probability in split-open renal tubules. Overexpression of Mal protein in mouse cortical collecting duct (mpkCCD) cells resulted in an increase in PLC-β3 protein expression at the plasma membrane. siRNA-mediated knockdown of MAL in mpkCCD cells resulted in a decrease in PLC-β3 protein expression and an increase in PIP2 abundance. Moreover, kidneys from salt-loaded mice showed less Mal membrane protein expression compared with non-salt-loaded mice. Taken together, Mal protein may play an essential role in the negative feedback of ENaC gating in principal cells of the collecting duct.

α(1)-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. ERdj3 is an ER luminal DnaJ homologue, which, along with calreticulin, directly interacts with misfolded ZAAT. We hypothesize that depletion of each of these chaperones will change the fate of ZAAT polymers. Our study demonstrates that calreticulin modulation reveals a novel ZAAT degradation mechanism mediated by exosomes. Using human PiZZ hepatocytes and K42, a mouse calreticulin-deficient fibroblast cell line, our results show ERdj3 and calreticulin directly interact with ZAAT in PiZZ hepatocytes. Silencing calreticulin induces calcium independent ZAAT–ERdj3 secretion through the exosome pathway. This co-secretion decreases ZAAT aggregates within the ER of hepatocytes. We demonstrate that calreticulin has an inhibitory effect on exosome-mediated ZAAT–ERdj3 secretion. This is a novel ZAAT degradation process that involves a DnaJ homologue chaperone bound to ZAAT. In this context, calreticulin modulation may eliminate the toxic gain of function associated with aggregation of ZAAT in lung and liver, thus providing a potential new therapeutic approach to the treatment of AATD-related liver disease.

Dege, Necmi/0000-0003-0660-4721 WOS: 000471778600014 New organic compound of (Z) -N'- (2, 4-dinitrobenzylidene) -2- (quinolin-8-yloxy) acetohydrazide (DBQA) was synthesized for the first time and its structural characterization was performed by single crystal X-ray diffraction method. The compound crystallizes in the triclinic system with space group P-1. The spectroscopic characterization was also performed by the applying of FT-IR, UV-Vis, H-1 and C-13 NMR spectroscopies. In order to support experimental results, density functional theory (DFT) calculations have been performed using B3LYP functionnal with 6-311++G(d, p) basis set. All of the obtained theoretical results are in a perfect agreement with the experimental ones. Furthermore, nonlinear optical (NLO) behavior of DBQA has been investigated by determining of electric dipole moment (mu), polarizability (alpha) and hyperpolarizability (beta) using the same basis set. Finally, the molecular electrostatic potential (MEP) surface of DBQA molecule was simulated and discussed. (C) 2019 Elsevier B.V. All rights reserved.

Introduction: Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes mellitus (DM). In general, DKA characterized by blood sugar over 250 mg/dL, anion-gap metabolic acidosis, and increased plasma or urine ketones. Approximately 2–3% of DKA patients can present with normal blood glucose levels (less than 250 mg/dl) which called euglycemic DKA. Some of the etiologies of euglycemic DKA include recent use of insulin, low caloric intake, alcoholism, chronic liver disease, and pregnancy. Very rarely, SGLT2 inhibitor use may be responsible for euglycemic DKA. Case Presentation: Here we present a case of 44 years old female with a past medical history of DM type 2 who presented with acute onset of nausea and vomiting. Initial laboratory findings were remarkable for anion gap metabolic acidosis with a blood glucose level of 201 mg/dl. The patient was on long-acting insulin along with Canagliflozin and Metformin therapy over years and reported being compliant with medications. She was treated with intravenous insulin therapy which resolved acidosis as well as symptoms. The patient was discharged with recommendations of discontinuation of Canagliflozin. Discussion: SGLT2 inhibitors are the novel class of oral antidiabetic drugs which widely used due to their favorable cardiovascular and renal outcomes independent of glycemic control. However, their side effects remain a concern. DKA is a rare but serious side effect of SGLT2 inhibitors with an incidence rate of 9.4% in type 1 DM and less than 0.2% in type 2 DM. Patients typically present with euglycemia or low-grade hyperglycemia which results in a diagnostic challenge for treating physicians. SGLT2 inhibitors increase urinary glucose excretion with a subsequent decrease in circulating insulin and an increase in glucagon, rendering a metabolic shift from glucose to fatty acid utilization. During times of intercurrent illness (decreased oral intake, sepsis) or metabolic stress (surgery), decreased carbohydrate intake coupled with the aforementioned changes will result in decreased insulin secretion and increased counter-regulatory hormones including adrenaline and cortisol, promoting lipolysis, fatty acid oxidation, and ketone production by the liver which ultimately leading to euglycemic DKA. Conclusion: SGLT2 inhibitors induced euglycemic DKA treatment is identical to classic DKA with consideration of the lack of hyperglycemia. Appropriate patient counseling to ensure safe SGLT2 inhibitor therapy is crucial, including appropriate holding parameters during concomitant volume-depleting illnesses and decreased oral intake. Timely diagnosis of euglycemic DKA, and recognitions of other rare but lethal side effects to decrease overall morbidity and mortality.

Introduction: Schmidt’s Syndrome, is a rare endocrine disorder defined by the combined occurrence of Addison disease, autoimmune thyroid disease, and type 1 diabetes mellitus. The rarity of the condition and the presentation of adrenal insufficiency and hypothyroidism often lead to misdiagnosis with life-threatening consequences for the patients. We report a case presenting with adrenal insufficiency and diabetic ketoacidosis who was diagnosed with Schmidt’s Syndrome. Case Description: We describe the case of a 38-year-old male with a past medical history of hypothyroidism, who was admitted for worsening abdominal pain, nausea, vomiting, fevers, and chills. Physical exam revealed underweight male with marked dehydration, diaphoresis, in moderate abdominal pain. Initial vital signs and laboratory panel raised suspicion for adrenal insufficiency and diabetic ketoacidosis. Blood pressure 82/42mmHg, HR of 121, sodium 128mmol/L, potassium 6.8mmol/L, chloride 104mmol/L, bicarbonate 5mmol/L, BUN 20mg/dl, Creatinine 1.5mg/dl, Glucose 402mg/dl, TSH 60, and serum osmolality 319mosm/kg. The electrolyte derangements and vital signs improved after the initiation of the high-dose steroids and insulin. The patient was transitioned to a regimen of hydrocortisone/ fludrocortisone, levothyroxine, and insulin basal/bolus and was discharged in clinically stable conditions to follow up with an endocrinologist. Discussion: The prevalence of Schmidt’s syndrome is 1:20,000 in the general population and a 3:1 ratio of females to males. Autoimmune thyroid disease is present in 70–75%, T1DM in 40–60%, and Addison’s disease in 40–50%. This syndrome can be associated with other non-endocrine autoimmune disorders, such as vitiligo, myasthenia gravis, Sjogren’s syndrome, rheumatoid arthritis, and primary antiphospholipid syndrome. The initial step in diagnosis should be checking serum morning cortisol levels to identify adrenal insufficiency. Autoimmune antibodies play an important role to confirm the diagnosis including 21-hydroxylase, 17-hydroxylase, thyroid peroxidase, glutamic acid decarboxylase, islet cells, anti-tissue transglutaminase antibodies, parietal cell, and anti-intrinsic factor antibodies. Currently, treatment is limited to hormone replacement in patients with organ failure. But it is crucial to replace corticosteroids before starting thyroid replacement in patients with adrenal insufficiency. Conclusion: A high level of diagnostic suspicion is required for the diagnosis of Schmidt’s syndrome when encountering a patient with autoimmune disease. The diagnosis of this syndrome is often delayed, causing adverse events. With this case presentation, we add to the data pool of Schmidt’s syndrome with the ability to significantly improve patients outcomes with early diagnosis and hormone replacement.

Addition of follicular fluid to oocyte maturation medium can affect cumulus cell function, increase competence of the oocytes to be fertilised and develop to the blastocyst stage and protect the oocyte from heat shock. Here, it was tested whether exosomes in follicular fluid are responsible for the effects of follicular fluid on the function of the cumulus–oocyte complex (COC). This was accomplished by culturing COCs during oocyte maturation at 38.5°C (body temperature of the cow) or 41°C (heat shock) with follicular fluid or exosomes derived from follicular fluid and evaluating various aspects of function of the oocyte and the embryo derived from it. Negative effects of heat shock on cleavage and blastocyst development, but not cumulus expansion, were reduced by follicular fluid and exosomes. The results support the idea that exosomes in follicular fluid play important roles during oocyte maturation to enhance oocyte function and protect it from stress.

Enteral nutrition (EN) is a widely used, standard-of-care technique for nutrition support in critically ill and trauma patients. To review the current techniques of gastrointestinal tract access for EN. For this traditional narrative review, we accessed English-language articles and abstracts published from January 1988 through October 2012, using three research engines (MEDLINE, Scopus, and EMBASE) and the following key terms: “enteral nutrition,” “critically ill,” and “gut access.” We excluded outdated abstracts. For our nearly 25-year search period, 44 articles matched all three terms. The most common gut access techniques included nasoenteric tube placement (nasogastric, nasoduodenal, or nasojejunal), as well as a percutaneous endoscopic gastrostomy (PEG). Other open or laparoscopic techniques, such as a jejunostomy or a gastrojejunostomy, were also used. Early EN continues to be preferred whenever feasible. In addition, evidence is mounting that EN during the early phase of critical illness or trauma trophic feeding has an outcome comparable to that of full-strength formulas. Most patients tolerate EN through the stomach, so postpyloric tube feeding is not needed initially. In critically ill and trauma patients, early EN through the stomach should be instituted whenever feasible. Other approaches can be used according to patient needs, available expertise, and institutional guidelines. More research is needed in order to ensure the safe use of surgical tubes in the open abdomen.

Effects of ammonium sulphate [(NH4)(2)SO4] on mitosis, cell cycle and chromosomes in Vicia faba L. seeds exposed to extreme temperatures were investigated using flowcytometric and cytogenetic analysis. Seeds germinated at high and low temperatures showed a significant decrease in mitotic index as compared to those of optimum temperature conditions. Application of 50 and 1000 mu M (NH4)(2)SO4 were successful in alleviating the negative effects of low and high temperature on mitotic activity, respectively. 50 mu M (NH4)(2)SO4 showed the most positive effect on cell cycle at the extreme temperatures. This concentration increased the cell division removing or decreasing the negative effects of temperature stress. Namely, the highest G2/M and S phase percentages under stress conditions were obtained with application of 50 mu M (NH4)(2)SO4. Chromosomal aberrations were not observed in cells of seeds germinated in distilled water and also at any temperatures. However, the frequency of chromosomal aberrations increased significantly by increasing (NH4)(2)SO4 concentration. The highest aberration frequency in all temperature degree tested was found at 1000 mu M (NH4)(2)SO4 concentration.

PURPOSE OF THE STUDY The objective of this study was to establish relative fixation strengths of proximal femoral nail (PFN), dynamic hip screw (DHS), monolateral external fixator (EF), and cannulated screw (CS) in basicervical hip fracture model. MATERIAL AND METHODS The study involved four groups of implanted composite proximal femoral synthetic bones of eight specimens per group; nailing with PFN, DHS, fixation with three cannulated screws, and EF. 70˚ osteotomy was performed to simulate a Pauwels Type 3 basicervical fracture. Minimum preload of 100 N was applied before loading to failure. The constructs were subjected to cyclic loading with 16˚ to midline from 100 N to 1,000 N for 10,000 cycles at 3Hz. Axial loading was applied at 10 mm/min until failure. Failure load, failure mode, and displacement were documented. RESULTS Mean failure load was 2182.5 ± 377.9 N in PFN group, 2008.75 ± 278.4 N in DHS group, 1941.25 ± 171.6 N in EF group, and 1551.6 ± 236.2 N in CS group. Average displacement was 15.6 ± 4.5 mm, 15.5 ± 6.7 mm, 11.7 ± 1.9 mm, and 15 ± 1.7 mm, respectively. No significant difference was noted among groups for fixation strength except CS group. All CS constructs failed during cyclic loading. CONCLUSION Our findings suggest that PFN, DHS and EF achieved higher fixation strengths than CS in basicervical fracture. PFN has higher failure loads and possesses biomechanical benefits for fixation of unstable basicervical fractures compared with DHS and EF. Key words: basicervical fracture, internal fixation, biomechanics.

The optimal treatment for in-stent restenosis (ISR) is a subject of controversy. Recently, FX minirail balloon angioplasty (BA) has emerged as a management tool for ISR. We assessed the hypothesis that the FX minirail BA has advantages over conventional percutaneous transluminal balloon angioplasty (PTCA) in the treatment of ISR. FX minirail BA or PTCA were applied to 116 patients with ISR (145 lesions) at our institution. Using a computer algorithm, an attempt was made to match each lesion in the FX minirail BA group with a corresponding lesion in the PTCA group. The lesion pairs should match with respect to the patients’ age and sex, type of target vessel and stent, reference vessel diameter, and baseline minimal lumen diameter (MLD). Following the matching process, 46 ISR lesion pairs were identified. Baseline patient characteristics were similar among the groups (P = not significant). There was no difference in the in-hospital major adverse cardiac events (MACE) between the groups, whereas MACE at follow-up were significantly lower in the FX minirail BA group than in the PTCA group (19.6% vs 41.3%, P < 0.05). The recurrent ISR rate was significantly lower in the FX minirail BA group than in the PTCA group (19.6% vs 39.1%, P < 0.05). Also, a diffuse pattern of recurrence was more common in lesions treated with PTCA, whereas the focal pattern of recurrence was more common in the FX minirail BA group (22.2% vs 50%, P < 0.05). The MLD at follow-up, the acute gain, and net gain were significantly higher in the group of lesions treated with the FX minirail BA than in the PTCA group. In addition, a significantly higher late loss and loss index at follow-up were observed in the PTCA group compared in the FX minirail BA group. The FX minirail BA has advantages over PTCA in the treatment of patients with ISR, with better immediate and follow-up angiographic outcomes, and a better clinical outcome on follow-up.

Background: Coronary slow flow (CSF) is characterized by delayed opacification of coronary arteries in the absence of epicardial occlusive disease. In this study, we aimed to determine endothelin‐1 (ET‐1), nitric oxide (NO(x)) levels and time domain heart rate variability (HRV) parameters in patients with CSF and relationship among these parameters. Methods: Thirty‐three patients with CSF detected in the coronary angiography (17 females; mean age 55 ± 7) and 19 patients with normal coronary flow (10 females; mean age 54 ± 11) as a control group were enrolled in the study. Patients were divided into two groups according to exercise testing as if positive (group A, n = 8) or negative (group B, n = 25). Results: Plasma ET‐1 levels were higher in the group A patients (28.7 ± 17.4 pg/ml) than that of group B (15.9 ± 10.6 pg/ml) and control group (6.0 ± 5.7 pg/ml); and higher in group B patients than that of control group (P < 0.05). Although groups A and B did not differ according to plasma NO(x) levels (23.4 ± 13.5 μmol/L vs. 32.8 ± 22.7 μmol/L, P > 0.05), NO(x) levels in group A were lower than the control group (23.4 ± 13.5 μmol/L versus 42.5 ± 15.9 μmol/L, P < 0.05). Time domain HRV parameters were decreased in all patient groups. This was more prominent in group A. Additionally, HRV parameters were negatively correlated with ET‐1 and TIMI frame counts. TIMI frame count was also significantly correlated with ET‐1 and NO(x) levels (r = 0.61, P < 0.0001, r =−0.30, P < 0.05). Upon intravascular ultrasonography investigation, the common finding was longitudinally extended massive calcification throughout the epicardial arteries. Mean intimal thickness was 0.50 ± 0.13 mm (group A; 0.58 ± 0.11 mm, group B 0.47 ± 0.12 mm, P = 0.029). Conclusions: The present study demonstrated that in patients with CSF, both increased plasma ET‐1, decreased plasma NO(x) and diffuse atherosclerosis may cause the decrease in HRV by effecting myocardial blood flow.

Hyperprolactinemia is the most common endocrinologic disorder in causing menstrual irregularities. Although the correlation between hyperprolactinemia and menstrual dysfunction is widely known, the etiology of menstrual cycle disorders is not profoundly understood in patients with prolactinoma. We aimed to investigate the correlation between prolactin levels and insulin resistance and hyperandrogenism in patients with prolactinoma.Sixty-four patients with microprolactinoma and 33 healthy women were enrolled. Thirty-six of these patients with prolactinoma (group 1) had an estradiol (E2) level under 30 pg/mL, and 28 (group 2) had an E2 level greater than 30 pg/mL. Blood samples were drawn to measure the levels of the following hormones: Follicle stimulating hormone (FSH), luteinizing hormone (LH), E2, prolactin (PRL), total testosterone (TT), androstenedione (AS) and dehydroepiandrostenedione sulphate (DHEAS). Body Mass Index (BMI of ≥30 kg/m2) was excluded from the study. Insulin resistance (IR) was calculated by the HOMA-IR.BMI was higher in patients with prolactinoma than the control group (P=0.02, P=0.025, respectively). IR and glucose intolerance existence were higher in patients with prolactinoma (P=0.007, P=0.097, respectively) than the healthy women, but these differences did not exist between eugonadic and hypogonadic women with prolactinoma (P=0.020, P=0.032, respectively, Bonferroni correction). TT and AS were higher in eugonadic women with prolactinoma than the control group (P=0.004, P=0.003, Bonferroni correction, respectively).Our study revealed that the relationship between hyperprolactinemia and IR/glucose intolerance is irrespective of gonadal status in women with prolactinoma. Also, the study concluded that hyperandrogenism may be a cause of menstrual dysfunction in eugonadic women with prolactinoma.

We present the case of a male newborn, admitted to our unit 4 hours after delivery with respiratory distress syndrome. Born by normal vaginal delivery at 39 weeks of gestation after an uncomplicated pregnancy, weighing 3,070 g, with Apgar score 9/10, he presented with progressive respiratory distress (grunting, tachypnea, nasal flaring, and intercostal retractions) starting one hour after delivery, with mild hypoxemia that resolved with oxygen therapy. Chest radiograph revealed a large pneumomediastinum (Fig. 1a, b). Infection was excluded, and there was a good clinical response to oxygen therapy, with no need for ventilatory support. Serial chest radiographs showed complete resolution. The infant was discharged home at eight post natal days. Pneumomediastinum occurs in about 2.5 to 1000 births and is usually associated with mechanical ventilation, pneumonia, meconium aspiration, or birth-related trauma [1]. Spontaneous pneumomediastinum such as the one we describe is a rare entity [2, 3].

Organic and inorganic pollutants found in municipal landfill leachate lead to severe problems for the environment when directly discharged to water bodies without treatment. Due to the existence of recalcitrant organics in leachate, advanced oxidation processes (AOP) are mostly applied to biologically treated leachate as a polishing step. In this study, the effectiveness of Fenton process on leachate treatment was examined. The Fenton process was applied to both young (untreated) and biologically treated leachate provided from Şile Kömürcüoda Landfill in Istanbul. It was treated by using up flow anaerobic sludge blanket (UASB) reactor and membrane bio-reactor (MBR) processes respectively prior to AOP application. In addition, the combination of Ultraviolet (UV)/Fenton and Ultrasound (US)/Fenton processes were applied to biologically treated leachate to improve the efficiency of Fenton process. The results suggested that, Fenton process is an efficient oxidation method for the treatment of organic matter and color in leachate. It was able to remove 70 % chemical oxygen demand (COD) from the raw leachate, while for biologically treated leachate the COD removal was over 50 %. On the other hand, color removal was observed to be 90 % and 98% in old and young leachate respectively. It was also seen that the additional treatment techniques used in the study did not improve the treatment efficiency of Fenton process., Katı atık depolama sahası sızıntı suyunda bulunan organik ve inorganik kirleticiler arıtılmadan direk olarak su kaynaklarına deşarj edildiğinde ciddi çevresel sorunlara yol açmaktadır. Biyolojik arıtmadan geçmiş sızıntı suyunda bulunan inatçı organikler için ileri oksidasyon yöntemleri çoğunlukla cilalama evresi olarak uygulanır. Bu çalışmada, Fenton prosesinin katı atık depolama sahası sızıntı suyu üzerindeki etkinliği incelenmiştir. Fenton prosesi İstanbul’daki Şile Kömürcüoda katı atık depolama sahasından temin edilen genç (arıtılmamış) ve biyolojik olarak arıtılmış sızıntı suyuna uygulanmıştır. Sızıntı suyu, ileri oksidasyon uygulaması öncesinde sırasıyla anaerobik yukarı akışlı çamur yatağı ve membran biyo-reaktör prosesleri ile arıtılmıştır. Buna ek olarak biyolojik olarak arıtılmış sızıntı suyuna verimi artırabilmek amacı ile ultraviyole/Fenton ve ultrasound/Fenton kombinasyonları da uygulanmıştır. Çalışmalar sonucunda Fenton prosesinin sızıntı suyunda renk ve organik madde arıtımında etkin bir yöntem olduğu ortaya konmuştur. Ham sızıntı suyunda %70 KOİ giderimi elde edilirken biyolojik olarak arıtılmış sızıntı suyunda bu değer %50’nin üzerindedir. Diğer taraftan renk giderimi ham ve biyolojik olarak arıtılmış sızıntı suyunda sırasıyla %90 ve %98 olarak gözlemlenmiştir. Fenton’a ek olarak uygulanan ultraviyole ışın ve ultrasound yöntemlerinin arıtma veriminde artış yaratmadığı belirlenmiştir.

Bicuspid aortic valve is a disease with autosomal dominant inheritance with small penetration. The population of patients with bicuspid aortic valve is heterogenous. In the absence of dilatation of ascending aorta, valvular lesion or degenerative changes of valve leaflets patients are considered to belong to the low risk population. On the other hand patients with the above mentioned characteristics compose a high risk group. Dilatation of the ascending aorta in patients with bicuspid aortic valve has a progressive feature and continues even after replacement of the aortic valve. With progression of aortic dilatation the risk of aortic dissection and rupture increases. The main reasons for aortic dilatation are changes in quality of aortic wall and possibly mechanical stress of aortic wall during asymmetrical and turbulent flow. The progression of aortic dilatation or aortic valve disease is not essentially influenced by farmacologic treatment. Surgery is the treatment of choice. Physiology and pathophysiology of bicuspid and tricuspid aortic valves, prevalence of bicuspid aortic valve in general population and in the group of patients operated on for aortic valve disease, phenotypes of bicuspid aortic valve and follow-up of asymptomatic patients with normal bicuspid valve are reviewed in this article. Indications for operation of dilated ascending aorta according to american, european and czech guidelines are discussed.

We used a new modulation technique, the wavelength modulated photocurrent spectroscopy, to study the field dependent transition from the miniband to the Wannier-Stark regime in GaAsAlAs-superlattices. In the zero field limit the edges of the joint miniband density of states between electrons and heavy as well as light holes create characteristic features in our modulated spectra. Applying small electric fields bulk-like Franz-Keldysh-Oscillations appear at the lower and upper miniband edges. At large electric fields the well known Wannier-Stark-Levels are observable.

The implantation of an artificial heart valve (a mechanical valve or a xenograft valve) involves the risk of serious and life-threatening complications for the patient, such as hemorrhagic complications, thromboembolic complications, the risk of endocarditis, the risk of premature degeneration of the xenograft valve, etc. Preserving the patient's own aortic valve eliminates or at least significantly reduces the above complications. On the other hand, it brings about the disadvantage of a technically more demanding surgery and the possible risk of reoperation due to failure of the spared aortic valve. The authors present a comprehensive and up-to-date view ofthe issue of aortic valve sparing surgeries and plastic corrections, beginning with the basics of aortic root anatomy and ending with the indications and principles of cardiosurgical techniques, and long-term results.

Early mortality after coronary artery bypass grafting is generally higher in women than in men. This study analyzes the effect of female gender on early mortality of coronary artery bypass grafting particularly for left main coronary artery disease.Study population consisted of 144 consecutive patients (33 women, 111 men) undergoing coronary artery bypass grafting for left main coronary artery disease. Mean follow-up was 25.1 +/- 14.0 months. Data were collected retrospectively and presented as mean +/- standard deviation. Survival analysis was done using Kaplan-Meier actuarial curve method with the log rank univariate test, followed by Cox's proportional rate multivariate model.Overall mortality was 7% in the patient population. Cox regression analysis revealed that the independent predictors of increased total mortality were female gender (HR 8.34, 95% CI 1.79 - 38.76, p=0.007), advanced age (HR 1.12, 95% CI 1.02-1.23, p=0.014), degree of left main coronary artery stenosis (HR 1.068, 95%CI 1.005-1.135, p=0.03), and left ventricular ejection fraction (HR 0.93, 95% CI 0.87-0.99, p=0.03). Female gender was found to be the only independent predictor of increased early mortality (HR 13.18, 95%CI 1.444-120.343, p=0.02). After discharge from the hospital, female gender was no more a predictor of increased mortality.According to these data, we may assume that female gender is related with increased mortality in coronary artery surgery for left main disease in the pre-discharge period however after discharge from hospital, long-term benefit of female survivors of coronary artery bypass grafting operated on for left main coronary artery disease might be as good as in men.

International audience; In SoC designs, limited test access to internal cores, low-cost external tester's lack of accuracy and slow frequencies make application of at-speed tests impractical. Therefore, this paper presents an embedded micro-tester for testing IEEE1500-compliant SoCs. In the proposed approach, the test program is no more executed by the external tester but by the embedded micro-tester. Under the control of the embedded SoC microprocessor, the micro-tester executes the test programs stored outside of the SoC in an external memory. The micro-tester supports stuck-at testing as well as both at-speed testing techniques: launch-on-last-shift (LOLS) and launch-on-capture (LOC). Using the ITC'02 benchmarks, experimental results are presented: test application time, test data volume and area overhead.

Background This study investigated the value of exercise-induced ST-segment elevation in lead aVR with or without concomitant ST-segment elevation in lead V 1 for detection of left main (LM) coronary artery disease in patients with Duke treadmill score ≤−11. Methods One hundred and four patients with Duke treadmill score ≤−11 were retrospectively screened for presence of ST-segment elevation in lead aVR and lead V 1 . Results Twenty-six out of 65 patients with ST-segment elevation in lead aVR and 24 out 38 patients with ST-segment elevation in lead aVR with concomitant ST-segment elevation in lead V 1 were found to have LM disease. Exercise-induced ST-segment elevation in lead aVR had a sensitivity of 92.9% and a specificity of 48.6% and ST-segment elevation in lead aVR accompanied by ST-segment elevation in lead V 1 had a sensitivity of 85.7% and a specificity of 81.6% in predicting LM disease. Conclusions This study shows that the observation of exercise-induced ST-segment elevation in lead aVR is a sensitive, but not a specific, electrocardiographic finding of significant LM coronary artery disease. However, exercise-induced ST-segment elevation in lead aVR accompanied by ST-segment elevation in lead V 1 might be not only a sensitive but also a specific finding of LM stenosis in these patients.