bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of combined longitudinal and transverse FRPs for strengthening concrete columns
Authors: Sadeghian Pedram , Fillmore Brandon
Published: September 2019

This paper presents the results of a study on the characterization of combined longitudinal near-surface-mounted (NSM) fiber-reinforced polymer (FRP) bars and transverse FRP wraps for strengthening concrete columns. A total of 21 concrete cylinders were prepared, strengthened, and tested to characterize the performance of the strengthening system. Three arrangements of glass FRP (GFRP) bars were mounted in surface grooves, and unidirectional basalt FRP (BFRP) composite was used to wrap the specimens. It was shown that the wrapping system effectively prevented premature failures of the NSM bars and extended the contribution of the bars from a mean of 17.5% in the NSM specimens to a mean of 27.7% in the specimens strengthened with the combined NSM and transverse FRPs. An analytical model was also presented to predict the load–strain behavior and the effect of combined axial load and bending moment.
Rock and age relationships within the Talkeetna forearc accretionary complex in the Nelchina area, southern Alaska
Authors: Barefoot John , Nadin Elisabeth S. , Newberry Rainer J. , Camacho Alfredo
Published: September 2019

Subduction zone processes are challenging to study because of the rarity of good exposures and the complexity of rock relationships within accretionary prisms. We report the results of field mapping and petrographic, geochemical, and geochronological analyses of the McHugh Complex accretionary prism mélange in south-central Alaska that was recently exposed due to retreat of the Nelchina Glacier. Our new mapping and analyses of the mélange, as well as adjacent Talkeetna arc intrusives, suggests that the previously mapped trace of the Border Ranges fault should shift northward in this location. Detailed petrographic analysis places this mélange exposure with the Potter Creek assemblage of the McHugh Complex. Blocks of pillow lavas within the mélange have both mid-ocean ridge basalt and intra-plate geochemical affinities, attesting to the complex relations of subduction-zone inputs in an alternating erosive–accretionary margin. A new zircon U–Pb age and geochemical analyses of a set of felsic dikes that cross-cut the accretionary sequence provide constraints on the regional tectonic evolution, including near-trench plutonism associated with the migration of a subducting spreading ridge along the southern Alaska margin during the Paleocene–Eocene. The McHugh section and cross-cutting dikes in this location are pervasively hydrothermally altered, which we attribute to elevated temperatures related to ridge subduction. Late-stage motion along the Border Ranges fault system, which is also recorded in the area, may also have contributed to the widespread alteration. Our data indicate that the Talkeetna volcanic arc and associated accretionary prism sediments were in their current configuration by 55 Ma.
Effects of industrial disturbance on abundance and activity of small mammals
Authors: Shonfield J. , Bayne E.M.
Published: September 2019

Anthropogenic disturbance can negatively impact animal populations and alter the behaviour of individuals. Disturbance associated with the energy sector has been increasing in the boreal forest of northern Alberta. Disturbances associated with the oil and gas industry vary in the infrastructure present and sensory stimuli generated. Two common types are compressor stations and roads. It is important to assess population consequences of disturbance on small mammals because they serve as prey, predators, and seed–spore dispersers in the terrestrial ecosystems that they inhabit. To test the effects of disturbance from the energy sector on the abundance and activity of small mammals, we used mark–recapture methods and live-trapped in forested areas with one side adjacent to a clearing with industrial infrastructure present (road or compressor station) or absent (control sites). We found no difference in abundance or activity of deer mice (Peromyscus maniculatus (Wagner, 1845)) and southern red-backed voles (Myodes gapperi (Vigors, 1830)) between sites and did not detect an edge effect on abundance within sites, regardless of the presence of industrial infrastructure. Our results suggest minimal effects of industrial disturbance on the abundance and activity of these species, and the infrastructure and sensory stimuli generated are unlikely to be key drivers of their population dynamics or behaviour.
IMPACT OF FINANCIAL CRISES ON THE DYNAMICS OF CAPITAL STRUCTURE: EVIDENCE FROM KOREAN LISTED COMPANIES
Authors: LYUBOV TSOY , HESHMATI ALMAS
Published: September 2019

This study examines the impact of the 1997 Asian financial crisis and the 2008 Global economic crisis on the capital structures of Korean non-financial listed companies. Using a panel data covering 1,159 Korean listed non-financial firms from 10 industrial sectors over a 31-year period (1985–2015), this study investigates the patterns of firms’ capital structures before and after the crises and identifies their speeds of adjustment toward the optimal leverage. This study finds different effects of the two crises on both capital structures and adjustment speeds. The average debt ratio fell significantly after the 1997 Asian financial crisis. The distance between the optimal and the observed debt ratios shrank after the Asian crisis, while the speed of adjustment increased two-fold. Unlike the Asian financial crisis, the global economic crisis of 2008 had a positive effect on companies’ debt ratios and the speeds of adjustments toward the optimal leverage. Our empirical analysis shows that, on average, the Korean non-financial listed companies decreased their debt ratios over the entire period of observation, with the leverage being the highest before the Asian financial crisis and lowest after the global economic crisis. Our results also show that the debt ratios of Korean chaebols were higher than that of non-chaebols. Moreover, we find that the high level of leverage of Korean firms was associated with tangible assets, income variability, size and age of the firm, non-debt tax shield and uniqueness.
A computational approach to the Frobenius–Schur indicators of finite exceptional groups
Authors: Trefethen Stephen , Vinroot C. Ryan
Published: September 2019

We prove that the finite exceptional groups [Formula: see text], [Formula: see text], and [Formula: see text] have no irreducible complex characters with Frobenius–Schur indicator [Formula: see text], and we list exactly which irreducible characters of these groups are not real-valued. We also give a complete list of complex irreducible characters of the Ree groups [Formula: see text] which are not real-valued, and we show the only character of this group which has Frobenius–Schur indicator [Formula: see text] is the cuspidal unipotent character [Formula: see text] found by Geck.
Pyridoxine and pancreatic acinar cells: transport physiology and effect on gene expression profile
Authors: Srinivasan Padmanabhan , Ramesh Vignesh , Wu Jie , Heskett Christopher , Chu Brian D. , Said Hamid M.
Published: September 2019

Pyridoxine (vitamin B6), an essential micronutrient for normal cell physiology, plays an important role in the function of the exocrine pancreas. Pancreatic acinar cells (PACs) obtain vitamin B6 from circulation, but little is known about the mechanism involved in the uptake process; limited information also exists on the effect of pyridoxine availability on the gene expression profile in these cells. We addressed both these issues in the current investigation using mouse-derived pancreatic acinar 266-6 cells (PAC 266-6) and human primary PACs (hPACs; obtained from organ donors), together with appropriate physiological and molecular (RNA-Seq) approaches. The results showed [3H]pyridoxine uptake to be 1) pH and temperature (but not Na+) dependent, 2) saturable as a function of concentration, 3) cis-inhibited by unlabeled pyridoxine and its close structural analogs, 4) trans-stimulated by unlabeled pyridoxine, 5) regulated by an intracellular Ca2+/calmodulin-mediated pathway, 6) adaptively-regulated by extracellular substrate (pyridoxine) availability, and 7) negatively impacted by exposure to cigarette smoke extract. Vitamin B6 availability was found (by means of RNA-Seq) to significantly (FDR < 0.05) modulate the expression profile of many genes in PAC 266-6 cells (including those that are relevant to pancreatic health and development). These studies demonstrate, for the first time, the involvement of a regulatable and specific carrier-mediated mechanism for pyridoxine uptake by PACs; the results also show that pyridoxine availability exerts profound effects on the gene expression profile in mammalian PACs.
Heat therapy reduces sympathetic activity and improves cardiovascular risk profile in women who are obese with polycystic ovary syndrome
Authors: Ely Brett R. , Francisco Michael A. , Halliwill John R. , Bryan Samantha D. , Comrada Lindan N. , Larson Emily A. , Brunt Vienna E. , Minson Christopher T.
Published: September 2019

Polycystic ovary syndrome (PCOS) affects up to 15% of women and is associated with increased risk of obesity and cardiovascular disease. Repeated passive heat exposure [termed “heat therapy” (HT)] is a lifestyle intervention with the potential to reduce cardiovascular risk in obesity and PCOS. Women with obesity ( n = 18) with PCOS [age 27 ± 4 yr, body mass index (BMI) 41.3 ± 4.7 kg/m2] were matched for age and BMI, then assigned to HT ( n = 9) or time control (CON; n = 9). HT subjects underwent 30 one-hour hot tub sessions over 8–10 wk, whereas CON subjects did not undergo HT. Muscle sympathetic nerve activity (MSNA), blood pressure, cholesterol, C-reactive protein, and markers of vascular function were assessed at the start (Pre) and end (Post) of 8–10 wk. These measures included carotid and femoral artery wall thickness and flow-mediated dilation (FMD), measured both before and after 20 min of ischemia-20 min of reperfusion (I/R) stress. HT subjects exhibited reduced MSNA burst frequency (Pre: 20 ± 8 bursts/min, Post: 13 ± 5 bursts/min, P = 0.012), systolic (Pre: 124 ± 5 mmHg, Post: 114 ± 6 mmHg; P < 0.001) and diastolic blood pressure (Pre: 77 ± 6 mmHg, Post: 68 ± 3 mmHg; P < 0.001), C-reactive protein (Pre: 19.4 ± 13.7 nmol/L, Post: 15.2 ± 12.3 nmol/L; P = 0.018), total cholesterol (Pre: 5.4 ± 1.1 mmol/L, Post: 5.0 ± 0.8 mmol/L; P = 0.028), carotid wall thickness (Pre: 0.054 ± 0.005 cm, Post: 0.044 ± 0.005 cm; P = 0.010), and femoral wall thickness (Pre: 0.056 ± 0.009 cm, Post: 0.042 ± 0.005 cm; P = 0.003). FMD significantly improved in HT subjects over time following I/R (Pre: 5.6 ± 2.5%, Post: 9.5 ± 1.7%; P < 0.001). No parameters changed over time in CON, and BMI did not change in either group. These findings indicate that HT reduces sympathetic nerve activity, provides protection from I/R stress, and substantially improves cardiovascular risk profiles in women who are obese with PCOS.
Loss of hepatic PPARα promotes inflammation and serum hyperlipidemia in diet-induced obesity
Authors: Stec David E. , Gordon Darren M. , Hipp Jennifer A. , Hong Stephen , Mitchell Zachary L. , Franco Natalia R. , Robison J. Walker , Anderson Christopher D. , Stec Donald F. , Hinds Terry D.
Published: September 2019

Agonists for PPARα are used clinically to reduce triglycerides and improve high-density lipoprotein (HDL) cholesterol levels in patients with hyperlipidemia. Whether the mechanism of PPARα activation to lower serum lipids occurs in the liver or other tissues is unknown. To determine the function of hepatic PPARα on lipid profiles in diet-induced obese mice, we placed hepatocyte-specific peroxisome proliferator-activated receptor-α (PPARα) knockout ( PparaHepKO) and wild-type ( Pparafl/fl) mice on high-fat diet (HFD) or normal fat diet (NFD) for 12 wk. There was no significant difference in weight gain, percent body fat mass, or percent body lean mass between the groups of mice in response to HFD or NFD. Interestingly, the PparaHepKO mice on HFD had worsened hepatic inflammation and a significant shift in the proinflammatory M1 macrophage population. These changes were associated with higher hepatic fat mass and decreased hepatic lean mass in the PparαHepKO on HFD but not in NFD as measured by Oil Red O and noninvasive EchoMRI analysis (31.1 ± 2.8 vs. 20.2 ± 1.5, 66.6 ± 2.5 vs. 76.4 ± 1.5%, P < 0.05). We did find that this was related to significantly reduced peroxisomal gene function and lower plasma β-hydroxybutyrate in the PparaHepKO on HFD, indicative of reduced metabolism of fats in the liver. Together, these provoked higher plasma triglyceride and apolipoprotein B100 levels in the PparaHepKO mice compared with Pparafl/fl on HFD. These data indicate that hepatic PPARα functions to control inflammation and liver triglyceride accumulation that prevent hyperlipidemia.
Extracorporeal resuscitation with carbon monoxide improves renal function by targeting inflammatory pathways in cardiac arrest in pigs
Authors: Wollborn Jakob , Schlueter Bjoern , Steiger Christoph , Hermann Cornelius , Wunder Christian , Schmidt Johannes , Diel Patric , Meinel Lorenz , Buerkle Hartmut , Goebel Ulrich , Schick Martin A.
Published: September 2019

Deleterious consequences like acute kidney injury frequently occur upon successful resuscitation from cardiac arrest. Extracorporeal life support is increasingly used to overcome high cardiac arrest mortality. Carbon monoxide (CO) is an endogenous gasotransmitter, capable of reducing renal injury. In our study, we hypothesized that addition of CO to extracorporeal resuscitation hampers severity of renal injury in a porcine model of cardiac arrest. Hypoxic cardiac arrest was induced in pigs. Animals were resuscitated using a conventional [cardiopulmonary resuscitation (CPR)], an extracorporeal (E-CPR), or a CO-assisted extracorporeal (CO-E-CPR) protocol. CO was applied using a membrane-controlled releasing system. Markers of renal injury were measured, and histopathological analyses were carried out. We investigated renal pathways involving inflammation as well as apoptotic cell death. No differences in serum neutrophil gelatinase-associated lipocalin (NGAL) were detected after CO treatment compared with Sham animals (Sham 71 ± 7 and CO-E-CPR 95 ± 6 ng/mL), while NGAL was increased in CPR and E-CPR groups (CPR 135 ± 11 and E-CPR 124 ± 5 ng/mL; P < 0.05). Evidence for histopathological damage was abrogated after CO application. CO increased renal heat shock protein 70 expression and reduced inducible cyclooxygenase 2 (CPR: 60 ± 8; E-CPR 56 ± 8; CO-E-CPR 31 ± 3 µg/mL; P < 0.05). Caspase 3 activity was decreased (CPR 1,469 ± 276; E-CPR 1,670 ± 225; CO-E-CPR 755 ± 83 pg/mL; P < 0.05). Furthermore, we found a reduction in renal inflammatory signaling upon CO treatment. Our data demonstrate improved renal function by extracorporeal CO treatment in a porcine model of cardiac arrest. CO reduced proinflammatory and proapoptotic signaling, characterizing beneficial aspects of a novel treatment option to overcome high mortality.
NanoTouch: intracellular recording using transmembrane conductive nanoparticles
Authors: Saito Mitsuyoshi L.
Published: September 2019

Observations of the electrophysiological properties of cells are important for understanding cellular functions and their underlying mechanisms. Short action potentials in axons are essential to rapidly deliver signals from the neuronal cell body to the terminals, whereas longer action potentials are required for sufficient calcium influx for transmitter release at the synaptic terminals and for cardiomyocyte and smooth muscle contractions. To accurately observe the shape and timing of depolarizations, it is essential to measure changes in the intracellular membrane potential. The ability to record action potentials and intracellular membrane potentials from mammalian cells and neurons was made possible by Ling and Gerard’s discovery in 1949, when they introduced sharp glass electrode with a submicron sized tip. Because of the small tip size, the sharp glass electrode could penetrate the cell membrane with little damage, which was one of the major breakthroughs in cellular electrophysiology and is the basic principle of the intracellular recording technique to date, providing the basis for further innovation of patch-clamp electrophysiology. I report a proof-of-principle demonstration of a novel method for recording intracellular potentials without penetrating the cell membrane using glass electrodes. We discovered that magnetically held transmembrane conductive nanoparticles can function as an intracellular electrode to detect transmembrane membrane potentials similar to those obtained by the conventional patch-clamp recording method.

NEW & NOTEWORTHY To accurately observe the shape of action potentials, it is essential to perform intracellular recordings. I present a method to record intracellular potentials using magnetically held magnetic conductive nanoparticles in the membrane as an electrode. These nanoparticles function similarly to a conventional intracellular microelectrode. This is the first report to apply conductive nanoparticles to detect action potentials in the form of electrical signals.
Long-term facilitation of catecholamine secretion from adrenal chromaffin cells of neonatal rats by chronic intermittent hypoxia
Authors: Makarenko Vladislav V. , Peng Ying-Jie , Khan Shakil A. , Nanduri Jayasri , Fox Aaron P. , Prabhakar Nanduri R.
Published: September 2019

In neonates, catecholamine (CA) secretion from adrenal medullary chromaffin cells (AMC) is an important mechanism for maintaining homeostasis during hypoxia. Nearly 90% of premature infants experience chronic intermittent hypoxia (IH) because of high incidence of apnea of prematurity, which is characterized by periodic stoppage of breathing. The present study examined the effects of repetitive hypoxia, designed to mimic apnea of prematurity, on CA release from AMC of neonatal rats. Neonatal rats were exposed to either control conditions or chronic intermittent hypoxia (IH) from ages postnatal days 0–5 (P0–P5), and CA release from adrenal medullary slices was measured after challenge with repetitive hypoxia (5 episodes of 30-s hypoxia, Po2~35 mmHg). In response to repetitive hypoxia, chronic IH-treated AMC exhibited sustained CA release, and this phenotype was not seen in control AMC. The sustained CA release was associated with long-lasting elevation of intracellular Ca2+concentration ([Ca2+]i), which was due to store-operated Ca2+entry (SOCE). 2-Aminoethoxydiphenyl borate, an inhibitor of SOCE, prevented the long-lasting [Ca2+]ielevation and CA release. Repetitive hypoxia increased H2O2abundance, and polyethylene glycol (PEG)-catalase, a scavenger of H2O2blocked this effect. PEG-catalase also prevented repetitive hypoxia-induced SOCE activation, sustained [Ca2+]ielevation, and CA release. These results demonstrate that repetitive hypoxia induces long-term facilitation of CA release in chronic IH-treated neonatal rat AMC through sustained Ca2+influx mediated by SOCE.

NEW & NOTEWORTHY Apnea of prematurity and the resulting chronic intermittent hypoxia are major clinical problems in neonates born preterm. Catecholamine release from adrenal medullary chromaffin cells maintains homeostasis during hypoxia in neonates. Our results demonstrate that chronic intermittent hypoxia induces a hitherto uncharacterized long-term facilitation of catecholamine secretion from neonatal rat chromaffin cells in response to repetitive hypoxia, simulating hypoxic episodes encountered during apnea of prematurity. The sustained catecholamine secretion might contribute to cardiovascular morbidities in infants with apnea of prematurity.
Human Platelet Lysate Media Supplement Supports Lentiviral Transduction and Expansion of Human T Lymphocytes While Maintaining Memory Phenotype
Authors: Canestrari Emanuele , Steidinger Hayley R. , McSwain Brianna , Charlebois Steven J. , Dann Christina Tenenhaus
Published: September 2019

Immune cell therapy has emerged as a promising approach to treat malignancies that were up until recently only treated on a palliative basis. Chimeric antigen receptor- (CAR-) modified T lymphocytes (T cells) in particular have proven to be very effective for certain hematological malignancies. The production of CAR T cells usually involves viral transduction andex vivoculture of T cells. The aim of this study was to explore the use of human platelet lysate (HPL) compared to two commonly used supplements, human AB serum (ABS) and fetal bovine serum (FBS), for modified T cell production. For studying transduction, activated T cells were transduced with lentivirus to deliver GFP transgenes with three different promoters. Transduction efficiency (percent GFP) was similar among the supplements, and a modest increase in the transgene product (mean fluorescence intensity) was observed when HPL was used as a supplement compared to ABS. To study the effect of supplements on expansion, peripheral blood mononuclear cells (PBMCs) were activated and expanded in the presence of interleukin 2 (IL2) for fourteen days. T cell expansions using HPL and ABS were comparable and slightly less than the expansion obtained with FBS. Interestingly, cells expanded in media supplemented with HPL showed a higher percentage of T cells with a central memory phenotype compared to those expanded in ABS or FBS. Protein profiling revealed that the phenotypic differences may be explained by elevated levels of several cytokines in HPL, including IL7. The results suggest that the use of HPL as a cell culture supplement during the production of modified T cells is a reasonable alternative to ABS. Furthermore, the use of HPL may enhancein vivoperformance of the final product by enriching for central memory T cells that are associated with long-term persistence following adoptive transfer.
An Effective Inverse Procedure for Identifying DEMParameters of Rock‐Like Materials
Authors: Chen Rui , Li Jisheng , Qian Yangqing , Peng Ruitao , Jiang Shengqiang , Hu Congfang , Zhao Ziheng
Published: September 2019

This study aims to identify discrete element model parameters of rock‐like materials. An inverse procedure is developed to determine the discrete element model parameters from experimental measurements. This involves the solution of an inverse problem through minimizing the misfit function which describes the error between numerical computation and experiment by an optimization procedure. In this procedure, the discrete element method is adopted as the numerical calculation method of the forward problem. The orthogonal experimental design is used for parameter sensitivity analysis. Besides, the approximation model with radial basis function is adopted instead of the actual calculation model to reduce the time of forward calculation. The ant‐colony optimization algorithm is employed as the inverse operator. Therefore, the parameters of the discrete element model are optimized by this procedure. The three‐point bending experiment with discrete element simulation is provided to verify the validity and accuracy of the inversion results. The results indicate that it can rapidly obtain the available and reliable model parameters just through a few sets of experimental data. As a result, this inverse procedure can be applied more widely to parameter identification of the discrete element model for brittle materials.
The Atypical Receptor CCRL2 Is Essential for Lung Cancer Immune Surveillance
Authors: Del Prete Annalisa , Sozio Francesca , Schioppa Tiziana , Ponzetta Andrea , Vermi William , Calza Stefano , Bugatti Mattia , Salvi Valentina , Bernardini Giovanni , Benvenuti Federica , Vecchi Annunciata , Bottazzi Barbara , Mantovani Alberto , Sozzani Silvano
Published: September 2019

CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and natural killer (NK) cells. In addition, CCRL2 controls the inflammatory response in different pathologic settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis. Here, we investigated the role of CCRL2 in the regulation of lung cancer–related inflammation. The genetic deletion of Ccrl2 promoted tumor progression in urethane-induced and in KrasG12D/+/p53LoxP lung tumor mouse models. Similarly, a Kras-mutant lung tumor displayed enhanced growth in Ccrl2-deficient mice. This phenotype was associated with a reduced inflammatory infiltrate characterized by the impaired recruitment of several leukocyte populations including NK cells. Bone marrow chimeras showed that CCRL2 expression by the nonhematopoietic cell compartment was responsible for the increased tumor formation observed in Kras-mutant Ccrl2-deficient mice. In human and mouse lungs, CCRL2 was expressed by a fraction of CD31+ endothelial cells, where it could control NK infiltration. Elevated CCRL2 expression in biopsies from human lung adenocarcinoma positively correlated with clinical outcome. These results provide evidence for a crucial role of CCRL2 in shaping an anti–lung tumor immune response.
Diffuse Tract Damage in CADASIL Is Correlated with Global Cognitive Impairment
Authors: Ban Shiyu , Wang Hongzhi , Wang Mengxing , Xu Shuai , Qin Zhaoxia , Su Jingjing , Du Xiaoxia , Liu Jian-Ren
Published: September 2019

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy ­(CADASIL) is the most common familial cerebral small vessel disease caused by notch homolog protein 3 gene mutations and is strongly associated with ischemic stroke and dementia. Patients are characterized by cognitive impairment and widespread white matter (WM) lesions. However, the relationship between WM lesions and cognitive impairment is not very clear. The aim of this study was to investigate WM microstructural abnormalities by diffusion tensor imaging (DTI) and the relationship between WM alterations and cognitive impairment in patients with CADASIL. Methods: In the present study, we evaluated WM degeneration in 18 patients with CADASIL and 18 controls by fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) based on DTI. Results: Compared with healthy controls, patients with CADASIL showed extensive and significant reductions in FA and increased RD, AD, and MD. These alterations were distributed throughout the entire brain (mainly the inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, internal capsule, external capsule, corona radiata, thalamic radiation, and cingulum). Furthermore, these WM microstructural alterations were significantly correlated with cognitive scores and stroke scale scores. Conclusion: Patients with ­CADASIL showed widespread WM abnormalities, and WM microstructural integrity and cognitive impairment were significantly correlated. Our results indicated that damage to WM tracts plays an important role in cognitive impairment in CADASIL.
Lipoblast-Like Morphology in a Uveal Melanoma with Delayed Metastasis to the Liver
Authors: Toyama Aimi , Bell W. Robert , Giubellino Alessio , Li Faqian
Published: September 2019

Uveal melanomas are typically described as having epithelial or spindled cell morphology; however, as is the nature of melanomas, the morphology of the malignant melanocytes can be varied. We describe a unique case of metastatic uveal melanoma with lipoblast-like morphology, identified in the liver during an autopsy of a 75-year-old woman. Apart from a remote history of uveal melanoma in the right eye, there was no other history of cancer, and there were no concerning skin lesions present. The liver exhibited hepatomegaly with diffuse and extensive involvement of malignant tumor cells. Histopathological evaluation of liver sections showed malignant epithelioid and spindle cell proliferation. A distinct, spiculated, tan-white area revealed sheets of malignant cells with small and large vacuoles within the cytoplasm and scalloped nuclei, mimicking lipoblasts and adipocytes. Immunohistochemical stains confirmed these cells to be malignant melanoma cells. Being aware of this morphology in uveal melanomas is important especially when there is metastasis to the liver, so that it is not mistaken for more benign processes such as steatosis.
Acute Kidney Injury and Fluid Resuscitation in Septic Patients: Are We Protecting the Kidney?
Authors: Montomoli Jonathan , Donati Abele , Ince Can
Published: September 2019

Acute kidney injury (AKI) is a common complication in critically ill patients, especially among septic patients. Sepsis and hypovolemia are the 2 most frequent etiologies of AKI in intensive care units and frequently coexist in critically ill patients. Effective fluid resuscitation is crucial for the stabilization of sepsis-induced tissue hypoperfusion or septic shock. However, the lack of a goal-directed therapy targeting kidney oxygenation prevents from optimization of the fluid therapy with regard to improvement of renal oxygen delivery and extraction. Similarly, fluid administration as all therapeutic actions carries adverse effects such as the activation of cytokines, disruption of the capillary glycocalyx, and adverse effects on kidney metabolism and oxygenation. Moreover, a positive fluid balance is associated with an increased risk of AKI and is a negative predictor for recovery of renal function. The role of fluid resuscitation on kidney injury stems from the high renal vulnerability to hypoxemic injury. Indeed, fluids have a poor oxygen solubility and hemodilution decreases blood viscosity both promoting intrarenal shunting and heterogeneity with a decreased capillary density and enhanced intrarenal cortex and medullary hypoxia. The development of physiological biomarkers that are able to detect the early development of AKI specifically aimed at the identification of renal microcirculatory dysfunctions should form a valuable contribution to monitoring therapeutic modalities.
DNA Ploidy Analysis and Cell Block Immunohistochemistry in the Diagnosis of Malignant Effusions
Authors: Puri Megha , Sen Rajeev , Gupta Monika , Kalra Rajnish , Bhargava Shilpi , Puri Karan
Published: September 2019

Background: Effusion cytology is a major diagnostic tool in medicine and has both therapeutic and prognostic implications. One of the dilemmas encountered is the differentiation between atypical cells and reactive mesothelial cells. The use of ancillary tools can reduce this grey zone and help to achieve a definitive diagnosis. Objectives: The main objective of this study was to evaluate the role of flow cytometry (FCM) and cell block with immunohistochemistry (IHC), along with the clinicoradiological investigations, to achieve a final diagnosis in effusion cytology to the maximum extent possible. Method: A prospective study was conducted. Effusion fluids, showing adequate amount and cellularity, were processed for conventional cytology, ploidy analysis by FCM, and cell block analysis, followed by IHC wherever required. Conventional cytological analysis was done by 2 independent pathologists, to look for interobserver variation, if any. The final result was achieved on the basis of integration of the results of the aforementioned studies, cytological details, clinicoradiological information, tissue biopsy findings, and follow-up. Result: A total of 90 samples were analyzed. On cytological examination, observer I categorized 60% samples as benign and 18.8% (n = 17) as malignant versus 58% categorized as benign and 23.3% (n = 21) as malignant by observer II. Observer I reported 19 (21.1%) equivocal cases and observer II reported 16 (17.7%). When both pathologists were considered together, the number of equivocal cases increased to 20. Sensitivity and specificity of FCM were 96.67 and 100%, respectively, and 100% for the cell block. On combining all techniques, the equivocal cases were resolved and a total of 33 cases were reported as malignant. However, 3 cases could still not be categorized and were labeled inconclusive. Conclusion: Conventional cytology combined with cell block IHC and FCM has the potential to minimize the requirement of tissue biopsy for confirmation. If the first sample is used judiciously for all the techniques, this may reduce the requirement for a second sample and possibly also the time required for a definite diagnosis and the initiation of therapy.
Autoimmune Thyroid Diseases in Children and Adolescents with Maturity Onset Diabetes of the Young Type 2
Authors: Calcaterra Valeria , Regalbuto Corrado , Dobbiani Giulia , Montalbano Chiara , Vinci Federica , De Silvestri Annalisa , Albertini Riccardo , Larizza Daniela
Published: September 2019

Background/Aim: The relationship between type 1 diabetes mellitus (T1DM) and autoimmune thyropathies is well known and has been described in the literature. Based on present knowledge, the relationship between thyropathies and other forms of diabetes, such as monogenic diabetes, has not been investigated. The aim of our study was to assess the prevalence of autoimmune thyroid diseases (ATD) in children and adolescents with maturity onset diabetes of the young type 2 (MODY2) in comparison with patients with T1DM and a control group. Patients and Methods: We examined 23 children and adolescents with MODY2 (11 F/12 M; 13.5 ± 5.3 years) and 166 patients with T1DM (80 F/86 M; 14.0 ± 4.7 years). The control group consisted of 62 age-matched healthy subjects (34 F/28 M). ATD diagnosis was based on the finding of one or more positive thyroid autoantibodies and characteristic thyroid ultrasound lacking homogeneity, with a hypogenic or mixed echo pattern. Results: ATD was diagnosed in 15 (10.5%; 9 F/6 M) patients with T1DM, in 4 with MODY2 (17.4%; 4 F), and in 1 (1.6%) control. A significantly higher ATD prevalence was detected in T1DM and MODY2 compared to the control subjects (p = 0.02), without differences between T1DM and MODY2 (p = 0.26). There were no gender differences noted in T1DM (p = 0.42); on the contrary, in MODY2 a higher prevalence was noted in females (p = 0.04). Celiac disease and a positive family history of ATD were not detected in subjects with MODY2. Conclusion: Our study showed an increased prevalence of ATD in patients with MODY2. Therefore, a careful follow-up of all children with MODY2 is recommended in order to assess the presence of thyroid disorders.
Clinical Outcomes and Economic Impact of Starting Hemodialysis with a Catheter after Predialysis Arteriovenous Fistula Creation
Authors: Al-Balas Alian , Shariff Saad , Lee Timmy , Young Carlton , Allon Michael
Published: September 2019

Background: Patients with advanced chronic kidney disease frequently undergo arteriovenous fistula creation prior to reaching end-stage renal disease (ESRD), but some initiate hemodialysis with a central vein catheter, if their fistula is not yet usable. The clinical consequences of the delay in fistula use have not been quantified in such patients. We compared patients with pre-ESRD fistula surgery who initiated dialysis with a catheter versus a fistula in terms of the frequency of post-dialysis vascular access procedures and complications and their economic impact. Methods: We identified 205 patients with predialysis fistula creation from 2006 to 2012 at a large dialysis center who started hemodialysis within the ensuing 2 years. Of these, 91 (44%) initiated dialysis with a catheter and 114 (56%) with a fistula. We compared these 2 groups in terms of their annual frequency of percutaneous vascular access procedures, surgical access procedures, total access procedures, hospitalizations due to catheter-related bacteremia, and overall cost of vascular access management. Results: The 2 groups were similar in demographics, comorbidities, and fistula type. As compared to patients initiating dialysis with a fistula, those initiating with a catheter had a significantly greater annual frequency of percutaneous access procedures (1.29 [1.19–1.40] vs. 0.75 [0.68–0.82]), surgical access procedures (0.69 [0.61–0.76] vs. 0.59 [0.53–0.66]), total access procedures (1.98 [1.86–2.11] vs. 1.34 [1.26–1.44]), and hospitalizations due to catheter-related bacteremia (0.09 [0.07–0.12] vs. 0.02 [0.01–0.03]). Patients initiating dialysis with a catheter incurred a median overall annual cost of access management that was USD 2,669 higher (USD 6,372 [3,121–12,242) vs. USD 3,703 [1,867–6,953], p = 0.0001). Conclusion: Among patients with predialysis fistula creation, those initiating dialysis with a catheter versus a fistula had substantially more frequent percutaneous, surgical, and total vascular access procedures, as well as hospitalizations due to catheter-related bacteremia. The annual cost of access management was substantially higher in those initiating dialysis with a catheter.
An Unlikely Route: Metastatic Ovarian Malignancy within the Duodenum
Authors: Kolli Sindhura , Weissman Simcha , Saleem Saad , Chan Owen T.M. , Ver Maria , Inae Richard , Ona Mel A.
Published: September 2019

The small bowel is an uncommon site for cancer metastasis. Despite this, cases have reported the duodenum as a metastatic site from local organs. However, duodenal involvement from more distant organs, such as the ovaries, has rarely been reported. Herein, we present a case of a 68-year-old female who developed duodenal metastatic disease from a primary ovarian serous adenocarcinoma. The goal of this report is to encourage clinicians to keep a broad differential in patients complaining of abdominal pain, especially in those with a history of primary ovarian malignancy.
Tumor Macroenvironment: An Update
Authors: Al-Zoughbi Wael , Hoefler Gerald
Published: September 2019

Modes of tumor cell interaction include autocrine stimulation, secretion of paracrine growth factors and inhibitors, as well as interaction with the tumor macroenvironment. This evolving concept in tumor pathobiology describes the interaction of a malignant tumor with its host as an extension and addition to its local interaction with tumor cells and surrounding nontransformed cells, the tumor microenvironment. Angiogenesis, which is considered part of the tumor microenvironment, also allows reciprocal interactions between cancer cells and other organs and systems. Well-known examples of tumor endocrine signaling are the paraneoplastic syndromes. In addition, cachexia, a severe complication of tumor growth, results from the systemic reprogramming of the host metabolism as a result of tumor growth and progression. Moreover, recent reports indicate that cancer cells may secrete factors that might play a role in forming premetastatic niches at distant sites. In addition, cancer cells seem to be able to secrete factors influencing and resetting endogenous circadian organizers. The importance of understanding the whole complex interaction of a malignant tumor and its host – the tumor macroenvironment – is of great importance for the better management and treatment of cancer patients.
Associations between Childhood Disadvantage and Adult Body Mass Index Trajectories: A Follow-Up Study among Midlife Finnish Municipal Employees
Authors: Salmela Jatta , Mauramo Elina , Lallukka Tea , Rahkonen Ossi , Kanerva Noora
Published: September 2019

Objective: Childhood disadvantage is associated with a higher risk of adult obesity, but little is known about its associations with body mass index (BMI) trajectories during adulthood. This study aimed first to identify adulthood BMI trajectories, and second to investigate how childhood disadvantage is associated with trajectory group membership. Methods: Data from the Helsinki Health Study, a longitudinal cohort study of initially 40- to 60-year-old employees of the City of Helsinki in Finland, were used. The baseline survey was conducted in 2000–2002, and similar follow-up surveys in 2007, 2012, and 2017. Based on self-reported BMI, participants’ (n =5,266; 83% women) BMI trajectories, including their retrospectively reported BMI at the age of 25 years, were examined. Data on childhood disadvantage, including parental education and 7 types of childhood adversity (their own serious illness; parental divorce, death, mental disorder, or alcohol problems; economic difficulties at home; and peer group bullying) before the age of 16 years, were obtained from the baseline survey. Group-based trajectory modeling was used to identify BMI trajectories, and multinomial logistic regression to analyze the odds for trajectory group membership for the disadvantage variables. Results: Four ascending BMI trajectories in women and men were found: persistent normal weight (trajectory 1; women 35% and men 25%), normal weight to overweight (trajectory 2; women 41% and men 48%), normal weight to class I obesity (trajectory 3; women 19% and men 23%) and overweight to class II obesity (trajectory 4; women 5% and men 4%). Compared to trajectory 1, women with multiple adversities and repetitive peer bullying in childhood had greater odds of belonging to trajectories 3 and 4, whereas men with parental alcohol problems had greater odds of belonging to trajectory 4. For women and men, a low level of parental education was associated with a higher-level BMI trajectory. Conclusions: Low parental education for both genders, multiple adversities and repetitive peer bullying in childhood among women, and parental alcohol problems among men increased the odds of developing obesity during adulthood. Further studies are needed to clarify how gender differences modify the effects of childhood disadvantage on adult BMI trajectories.
Successful Treatment of Severe Aspergillosis with Isavuconazole Therapy after Allogeneic Stem Cell Transplantation
Authors: Oarbeascoa Gillen , Dorado Nieves , Bailén Rebeca , Serrano David , Balsalobre Pascual , Pradillo Virginia , Guinea Jesus , Padilla Belen , Sancho Milagros , Machado Marina , Buño Ismael , Anguita Javier , Diez-Martin Jose Luis , Kwon Mi
Published: September 2019

Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.
The Association of Glomerular Glucocorticoid Receptor Expression with Responsiveness to Corticosteroid Treatment in IgA Nephropathy
Authors: Kee Youn Kyung , Nam Bo Young , Jhee Jong Hyun , Park Jung Tak , Lim Beom Jin , Yoo Tae-Hyun , Kang Shin-Wook , Jeong Hyun Joo , Han Seung Hyeok
Published: September 2019

Background: Corticosteroids can be used to treat IgA nephropathy (IgAN). However, responsiveness to these drugs is highly variable and unpredictable. Corticosteroids act by binding glucocorticoid receptors (GCRs). Therefore, we evaluated the association between GCR expression and responsiveness to corticosteroid treatment in IgAN. Methods: We screened 78 IgAN patients receiving steroid treatment between 2010 and 2016. Of these, 33 patients met study inclusion criteria. Glomerular GCR expression was assessed by real-time polymerase chain reaction. Complete remission (CR) and partial remission (PR) were defined as a spot urine protein-to-creatinine ratio (UPCR) of <0.3 g/g and a ≥50% reduction of proteinuria from baseline along with UPCR of ≥0.3 g/g, respectively. Disease progression was defined as a ≥30% decrease in estimated glomerular filtration rate (eGFR) from baseline. Results: The mean age of study patients was 43.9 ± 11.6 years (25 males and 8 females). All 33 patients responded to steroid treatment; CR and PR occurred in 14 (42.4%) and 18 (54.5%) patients, respectively. One patient did not achieve PR, but proteinuria was decreased after treatment. There were no significant differences in baseline eGFR and proteinuria between CR and non-CR groups. GCR mRNA expression was significantly higher in the CR group compared to that in the non-CR group. Immunohistochemistry confirmed higher GCR expression in the CR group. During a median follow-up of 20.6 months, 1 (7.1%) patient in the CR group had disease progression, as compared to 8 (42.1%) patients in non-CR group (p = 0.03). Conclusion: This study suggests that responsiveness to corticosteroid may differ depending on the degree of glomerular GCR expression in IgAN.
Direct Oral Anticoagulant Plasma Levels for the Management of Acute Ischemic Stroke
Authors: Marsch Armin , Macha Kosmas , Siedler Gabriela , Breuer Lorenz , Strasser Erwin F. , Engelhorn Tobias , Dörfler Arnd , Schwab Stefan , Kallmünzer Bernd
Published: September 2019

Introduction: The management of acute ischemic stroke in patients on direct oral anticoagulants (DOACs) is challenging. However, the substance-specific plasma level could guide treatment decisions on recanalization therapies. We present a plasma-level-based protocol for emergency treatment of stroke patients on oral anticoagulants. Bleeding complications and clinical outcome for patients on DOACs are reported and compared to patients on vitamin K antagonists (VKAs). Methods: In patients with acute ischemic stroke and suspected use of DOACs within 48 h prior to hospital admission, plasma levels were measured using the calibrated Xa-activity (apixaban, edoxaban, rivaroxaban) or the Hemoclot®-assay (dabigatran). Levels <50 ng/mL were supportive for thrombolysis, while high values >100 ng/mL excluded patients from recombinant tissue plasminogen activator use. For patients on VKAs, the cutoff was set at international normalized ratio of 1.7. Endovascular thrombectomy of a large vessel occlusion was performed independently from coagulation testing. Consecutive patients were included in an observational registry. Results: Five hundred and twenty-two patients (261 on VKAs and 261 on DOACs) were included. Thirty patients (11.5%) on VKAs and 24 (9.2%) on DOACs received thrombolysis, followed by mechanical thrombectomy in 10 and 14 patients, respectively. Seventeen patients in each group received thrombectomy only. Symptomatic intracranial hemorrhage associated with thrombolysis occurred in 1 patient on VKA (3.3%) and 1 on DOAC (4.2%; p = 0.872). The turnaround time of specific assays did not show a significant delay in comparison to standard coagulation parameters. Conclusion: DOAC plasma levels could support decisions on emergency treatment of ischemic stroke. Systemic thrombolysis below suggested thresholds appears preliminary feasible and safe without an excess in bleeding complications.