bluuebunny/crossref_metadata_2025 huggingface dataset:
At high altitude in the Netherlands: secondary erythrocytosis due to HB-Malmö
Authors: Santbergen Bart , van der Heul Cees
Published: March 2014

We describe two patients, a father and a son, presenting with erythrocytosis. Evaluation showed no pulmonal or cardial disorders. Owing to an elevated erythropoietin level after phlebotomy, a physiological secondary polycythaemia was suspected. A haemoglobin electrophoresis showed that our patients have a haemoglobinopathy with high affinity for oxygen, called Hb-Malmö (exon 3: c.294 C>G p.His98Gln). Hb-Malmö is a congenital disorder located on a gene at chromosome 11, in the B-chain on codon 97, decoding the α-subunit and β-subunit of the haemoglobin. Through a mutation (CAC→CAG), histidine is replaced by glutamine. The mutation causes a disorder in the connection between the α1-subunit and β2-subunit of the haemoglobin structure. These connections are important sites for binding oxygen. Mutated haemoglobin has a preference for an oxygenated status, which implicates that there is an increased binding and decreased release of oxygen. To compensate, there will be an erythrocytosis to transport sufficient oxygen to the peripheral tissues.
‘Timely’ diagnosis of dementia: what does it mean? A narrative analysis of GPs’ accounts
Authors: Dhedhi Saadia Aziz , Swinglehurst Deborah , Russell Jill
Published: March 2014

Objective

To explore general practitioners’ (GP) perspectives on the meaning of ‘timeliness’ in dementia diagnosis.

Design

Narrative interview study.

Setting

UK academic department of primary care.

Participants

Seven practising GPs with experience of conveying a diagnosis of dementia.

Methods

GPs’ narrative commentaries of encounters with patients with suspected dementia were audio-recorded and transcribed resulting in 51 pages of text (26 757words). A detailed narrative analysis of doctors’ accounts was conducted.

Results

Diagnosis of dementia is a complex medical and social practice. Clinicians attend to multiple competing priorities while providing individually tailored patient care, against a background of shifting political and institutional concerns. Interviewees drew on a range of explanations about the nature of generalism to legitimise their claims about whether and how they made a diagnosis, constructing their accounts of what constituted ‘timeliness’. Three interlinked analytical themes were identified: (1) diagnosis as a collective, cumulative, contingent process; (2) taking care to ensure that diagnosis—if reached at all—isopportune; (3) diagnosis of dementia as constitutive or consequential, but also a diagnosis whose consequences are unpredictable.

Conclusions

Timeliness in the diagnosis of dementia involves balancing a range of judgements and is not experienced in terms of simple chronological notions of time. Reluctance or failure to make a diagnosis on a particular occasion does not necessarily point to GPs’ lack of awareness of current policies, or to a set of training needs, but commonly reflects this range of nuanced balancing judgements, often negotiated with patients and their families with detailed attention to a particular context. In the case of dementia, the taken-for-granted benefits of early diagnosis cannot be assumed, but need to be ‘worked through’ on an individual case-by-case basis. GPs tend to value ‘rightness’ of time over concerns about ‘early’ diagnosis.
Huperzimine, a novel Lycopodium alkaloid from Huperzia serrata
Authors: Yu Chao-Mei , Calhoun Larry A. , Konder Ricarda M. , Grant Andrew S.
Published: March 2014

The structure of huperzimine, a novel Lycopodium alkaloid isolated from Huperzia serrata, was deduced from its spectroscopic properties and confirmed using GIAO DFT chemical shift calculations.
Supersymmetry breaking and the cosmological constant
Authors: Banks Tom
Published: March 2014

I review three attempts to explain the small value of the cosmological constant, and their connection to supersymmetry breaking. They are The String Landscape, Supersymmetric Large Extra Dimensions (SLED), and the Holographic Space–time Formalism invented by Fischler and myself.
Magnetic entropy calculation for a second-order ferromagnetic phase transition
Authors: Zhang Lei , Fan Jiyu , Zhang Yuheng
Published: March 2014

In this paper, we present a new calculation method of magnetic entropy in an arbitrary second-order ferromagnetic phase transition system. Based on the Arrott–Noakes relation (H/M)1/γ = (T-TC)/TC+(M/M1)1/β, the Gibbs energy can be rewritten as a new form where the critical exponents are naturally included. Correspondingly, the magnetic entropy (SM) is presented as: [Formula: see text]. Thus, the magnetic entropy change (ΔSM) can be deduced as [Formula: see text] which is consistent exactly with the previous report [V. Franco et al., Appl. Phys. Lett.89 (2006) 222512]. In addition, the conventional calculation method of magnetic entropy can be treated as a particular form of this calculation method. Furthermore, the obtained magnetic entropy change from experimental measurement are consistent with the theoretical value deduced from the present method.
HUMAN DETECTION IN SURVEILLANCE VIDEO
Authors: CHEN LIANG-HUA , WANG LI-YUN , SU CHIH-WEN
Published: March 2014

In this paper, we propose an integrated approach for human detection in surveillance video. In our approach, the moving object is extracted by background subtraction; and the background model is updated by the first-order recurrence filter. Then, two complementary features are extracted for moving object classification. They are contour-based description: Fourier descriptor and region-based description: histogram of oriented gradient. As the binary classifier (support vector machine) is able to provide the posterior probability, we effectively integrate two types of features to achieve better performance. Experimental results show that the proposed approach is effective and outperforms some existing technique.
Walks along braids and the colored Jones polynomial
Authors: Armond Cody W.
Published: March 2014

Using the Huynh and Lê quantum determinant description of the colored Jones polynomial, we construct a new combinatorial description of the colored Jones polynomial in terms of walks along a braid. We then use this description to show that for a knot which is the closure of a positive braid, the first N coefficients of the N th colored Jones polynomial are trivial.
A family of higher-order isoperimetric inequalities
Authors: Qiu Guohuan
Published: March 2014

In this paper, we prove sharp inequalities between the volume and the integral of the kth mean curvature for (k + 1)-convex domains in the Euclidean space for all k. We generalize the recent results of Chang and Wang [Some higher order isoperimetric inequalities via the method of optimal transport, preprint (2013); arXiv:1305.3004], where they prove the case k = 1, 2. The idea is the same as [S.-Y. A. Chang and Y. Wang, Some higher order isoperimetric inequalities via the method of optimal transport, preprint (2013); arXiv:1305.3004], but calculations are involved.
On a 2D stochastic Euler equation of transport type: Existence and geometric formulation
Authors: Cruzeiro Ana Bela , Torrecilla Iván
Published: March 2014

We prove weak existence of Euler equation (or Navier–Stokes equation) perturbed by a multiplicative noise on bounded domains of ℝ2 with Dirichlet boundary conditions and with periodic boundary conditions. Solutions are H1 regular. The equations are of transport type.
Semi-irreducible Zariski spaces of modules
Authors: Nikseresht A. , Azizi A.
Published: March 2014

In this paper, we state conditions under which, the family of semi-irreducible submodules of a module determine a Zariski space of that module and study the properties of this space. Also we characterize semi-irreducible submodules of finitely generated modules over Dedekind domains. Moreover, assuming that M and M′ are finitely generated modules over a Dedekind domain having isomorphic semi-irreducible Zariski spaces, we find some common properties of M and M′. In particular, we show that in this case the torsion-free components of M and M′ have the same rank and the torsion submodules of [Formula: see text] and [Formula: see text] are isomorphic, where N and N′ are the intersection of all semi-irreducible submodules of M and M′, respectively.
Early identification of acute hypoxia based on brain NADH fluorescence and cerebral blood flow
Authors: Shi Hua , Sun Nannan , Mayevsky Avraham , Zhang Zhihong , Luo Qingming
Published: March 2014

Hypoxia is closely related to many diseases and often leads to death. Early detection and identification of the hypoxia causes may help to promptly determine the right rescue plan and reduce the mortality. We proposed a new multiparametric monitoring method employing mitochondrial reduced nicotinamide adenine dinucleotide (NADH) fluorescence, regional reflectance, regional cerebral blood flow (CBF), electrocardiography (ECG), and respiration under six kinds of acute hypoxia in four categories to investigate a correlation between the parameter variances and the hypoxia causes. The variation patterns of the parameters were discussed, and the combination of NADH and CBF may contribute to the identification of the causes of hypoxia.
The discovery and appraisal of Glenlivet: a West of Shetlands success story
Authors: Horseman Catherine , Ross Alwyn , Cannon Steve
Published: March 2014

The Glenlivet gas field was discovered in 2009 with well 214/30a-2, drilled to test a seismically defined stratigraphic and faulted closure at intra-Tertiary level. A sequence of gas-bearing Vaila Formation sands was penetrated comprising high-density turbidite flows with excellent reservoir properties. The discovery was immediately appraised by two sidetracks that tested the updip and downdip extent of the accumulation: the downdip location penetrated the water leg of the field. A comprehensive programme of data acquisition was carried out on all three penetrations, leading to a series of post-well studies designed to fully appraise the field. Based on post-drilling seismic interpretation and extensive analysis of the well data, a revised depositional model was formulated that allowed the construction of a robust 3D static model used in development planning.
U–Pb detrital zircon ages of Upper Jurassic continental successions: implications for the provenance and absolute age of the Jurassic–Cretaceous boundary in the Neuquén Basin
Authors: Naipauer Maximiliano , Tunik Maisa , Marques Juliana C. , Rojas Vera Emilio A. , Vujovich Graciela I. , Pimentel Marcio M. , Ramos Victor A.
Published: March 2014

New U–Pb detrital zircon ages are presented for the Tordillo Formation. The ages indicate that the most important source region of sediment supply was the Jurassic Andean arc (peaks at
c.
144, 153 and 178 Ma), although two secondary sources were defined at
c.
218 and 275 Ma. Temporal variation in the provenance indicates that at the beginning of the sedimentation, Carboniferous to Lower Jurassic magmatic rocks and Lower Palaeozoic metamorphic rocks were the most important sources. Towards the top, the data suggest that the Andean arc becomes the main source region. The comparison between provenance patterns of the Tordillo Formation and of the Avilé Member (Agrio Formation) showed some differences. In the former, the arc region played a considerable role as a source region, but this is not identified in the latter. The results permit a statistically robust estimation of the maximum deposition age for the Tordillo Formation at
c.
144 Ma. This younger age represents a discrepancy of at least 7 Ma from the absolute age of the Kimmeridgian and Tithonian boundary (from the chronostratigraphic timescale accepted by the International Commission of Stratigraphy, IUGS), and has strong implications for the absolute age of the Jurassic–Cretaceous boundary.

Supplementary material:

Sample coordinates, values of the sandstone compositional framework and U–Pb (LAM-MC-ICP-MS) age measurements of zircons grains are available at
http://www.geolsoc.org.uk/SUP18718
Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics
Authors: Hahn Wendy S. , Kuzmicic Jovan , Burrill Joel S. , Donoghue Margaret A. , Foncea Rocio , Jensen Michael D. , Lavandero Sergio , Arriaga Edgar A. , Bernlohr David A.
Published: March 2014

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNFα, IL-6, and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ΔΨm, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on ΔΨm and varied effects on ATP turnover, proton leak, or basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1α and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology.
Neural circuitry underlying the central hypertensive action of nesfatin-1: melanocortins, corticotropin-releasing hormone, and oxytocin
Authors: Yosten Gina L. C. , Samson Willis K.
Published: March 2014

Nesfatin-1 is produced in the periphery and in the brain where it has been demonstrated to regulate appetite, stress hormone secretion, and cardiovascular function. The anorexigenic action of central nesfatin-1 requires recruitment of neurons producing the melanocortins and centrally projecting oxytocin (OT) and corticotropin-releasing hormone (CRH) neurons. We previously have shown that two components of this pathway, the central melanocortin and oxytocin systems, contribute to the hypertensive action of nesfatin-1 as well. We hypothesized that the cardiovascular effect of nesfatin-1 also was dependent on activation of neurons expressing CRH receptors, and that the order of activation of the melanocortin-CRH-oxytocin circuit was preserved for both the anorexigenic and hypertensive actions of the peptide. Pretreatment of male rats with the CRH-2 receptor antagonist astressin2B abrogated nesfatin-1-induced increases in mean arterial pressure (MAP). Furthermore, the hypertensive action of CRH was blocked by pretreatment with an oxytocin receptor antagonist ornithine vasotocin (OVT), indicating that the hypertensive effect of nesfatin-1 may require activation of oxytocinergic (OTergic) neurons in addition to recruitment of CRH neurons. Interestingly, we found that the hypertensive effect of α-melanocyte stimulating hormone (α-MSH) itself was not blocked by either astressin2B or OVT. These data suggest that while α-MSH-producing neurons are part of a core melanocortin-CRH-oxytocin circuit regulating food intake, and a subpopulation of melanocortin neurons activated by nesfatin-1 do mediate the hypertensive action of the peptide, α-MSH can signal independently from this circuit to increase MAP.
Physiological temperatures drive glutamate release onto trigeminal superficial dorsal horn neurons
Authors: Largent-Milnes Tally M. , Hegarty Deborah M. , Aicher Sue A. , Andresen Michael C.
Published: March 2014

Trigeminal sensory afferent fibers terminating in nucleus caudalis (Vc) relay sensory information from craniofacial regions to the brain and are known to express transient receptor potential (TRP) ion channels. TRP channels are activated by H+, thermal, and chemical stimuli. The present study investigated the relationships among the spontaneous release of glutamate, temperature, and TRPV1 localization at synapses in the Vc. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from Vc neurons ( n = 151) in horizontal brain-stem slices obtained from Sprague-Dawley rats. Neurons had basal sEPSC rates that fell into two distinct frequency categories: High (≥10 Hz) or Low (<10 Hz) at 35°C. Of all recorded neurons, those with High basal release rates (67%) at near-physiological temperatures greatly reduced their sEPSC rate when cooled to 30°C without amplitude changes. Such responses persisted during blockade of action potentials indicating that the High rate of glutamate release arises from presynaptic thermal mechanisms. Neurons with Low basal frequencies (33%) showed minor thermal changes in sEPSC rate that were abolished after addition of TTX, suggesting these responses were indirect and required local circuits. Activation of TRPV1 with capsaicin (100 nM) increased miniature EPSC (mEPSC) frequency in 70% of neurons, but half of these neurons had Low basal mEPSC rates and no temperature sensitivity. Our evidence indicates that normal temperatures (35–37°C) drive spontaneous excitatory synaptic activity within superficial Vc by a mechanism independent of presynaptic action potentials. Thus thermally sensitive inputs on superficial Vc neurons may tonically activate these neurons without afferent stimulation.
Hepatic Iron Overload and Hepatocellular Carcinoma
Authors: Kew Michael C.
Published: March 2014

In recent years it has become increasingly evident that excess body iron may be complicated by the supervention of hepatocellular carcinoma (HCC). Hereditary hemochromatosis (HH) was the first condition in which hepatic iron overload was shown to predispose to the development of HCC. The inherited predisposition to excessive absorption of dietary iron in HH is almost always the result of homozygosity of the C282Y mutation of the HFE gene, which causes inappropriately low secretion of hepcidin. HCC develops in 8-10% of patients with HH and is responsible for approximately 45% of deaths in the HCC patients. Cirrhosis is almost always present when HCC is diagnosed. Dietary iron overload is a condition which occurs in rural-dwelling Black Africans in southern Africa as a result of the consumption, over time, of large volumes of alcohol home-brewed in iron containers and having, as a consequence, a high iron content. Iron loading of the liver results and may be complicated by malignant transformation of the liver (relative risk of approximately 10.0). Accompanying cirrhosis does occur but is less common than that in HH. The development of HCC as a consequence of increased dietary iron, and the fact that it may develop in the absence of cirrhosis, has been confirmed in an animal model. Drinking water with a high iron content might contribute to the high incidence of HCC in parts of Taiwan. The metabolic syndrome [obesity, insulin resistance type 2 (or diabetes mellitus type 2), non-alcoholic fatty liver or non-alcoholic steatohepatitis] has in recent years become a major public health problem in some resource-rich countries. A link between excess body iron and insulin resistance or the metabolic syndrome has become apparent. The metabolic syndrome may be complicated by the supervention of HCC, and recent evidence suggests that increased body iron may contribute to this complication.
Esophageal Epithelial Resistance
Authors: Günther Claudia , Neumann Helmut , Vieth Michael
Published: March 2014

Besides its important role of digestion and absorption, esophageal tissue has an essential role as a major barrier against intraluminal pathogens like hostile microorganisms and toxins. This barrier function is achieved via various mechanical, chemical, and immunological mechanisms which are typically altered in inflammatory diseases, thereby causing subsequent damage of the mucosa. In this review we will focus on the main structural and functional barriers of host defense within the esophageal mucosa, including the epithelial layer, membrane-bound and secretory mucins, and different types of defensins. In addition, we will discuss the relevance of biofilm on esophageal tissue and will illustrate the importance of different regulators of intestinal permeability like zonulin and desmosomal components.
Immunopathogenesis of Eosinophilic Esophagitis
Authors: Simon Hans-Uwe , Straumann Alex
Published: March 2014

Background: Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus associated with dysphagia in adults and refractory reflux syndromes in children. Methods: Immunological and genetic approaches have been used to better understand the pathophysiology of the underlying inflammation. Results and Conclusions: Evidence has accumulated that EoE represents a T-helper (Th) 2-type inflammatory disease, in which allergens play a role in triggering the disease. The majority of the patients suffer from concurrent allergic rhinitis, asthma, and eczema, and have a history of atopy. The chronic inflammatory response in EoE is associated with tissue damage and remodeling, both of which lead to esophageal dysfunction and bolus impaction. The new insights into the pathophysiology have resulted in the development of the first pharmacological therapies of EoE.
Remodeling and Fibrosis in Chronic Eosinophil Inflammation
Authors: Aceves Seema S.
Published: March 2014

Chronic eosinophilic inflammation has been associated with tissue remodeling in a number of disease states including the hypereosinophilic syndrome (HES), asthma, and, more recently, eosinophilic esophagitis (EoE). Remodeling occurs in the epithelial and subepithelial esophageal tissue, and includes basal zone hyperplasia, epithelial mesenchymal transition, fibrosis, angiogenesis, and smooth muscle hypertrophy/hyperplasia. Previously, research on the clinical impacts of tissue remodeling has been limited by a paucity of human tissue. However, in EoE, recurrent biopsies are required for diagnosis and management. As such, investigators are able to study the associations between tissue changes and clinical disease features. A number of profibrotic and proangiogenic factors are elevated in EoE, including TGF-β1, CCL-18, FGF-9, VEGF, and VCAM-1. Both eosinophils and mast cells produce a number of these factors. TGF-β1 appears to be a master regulator of end-organ dysfunction in EoE and can cause esophageal epithelial mesenchymal transition, fibrosis, and smooth muscle contraction. The requirement for eosinophils, the eosinophilopoietic interleukin, IL-5, and the canonical TGF-β1 signaling pathway for EoE-associated fibrosis, has been invoked using gene-deficient mice. The clinical consequences of eosinophil-associated tissue fibrosis can be devastating, such as endomyocardial fibrosis and heart failure in HES. In EoE, tissue remodeling appears to be the mechanism for multiple cardinal disease complications including esophageal rigidity, strictures, narrowing, and food impactions, as well as the clinical hallmark of dysphagia. Therapies that may be able to reduce or reverse EoE-associated remodeling include topical corticosteroids, anti-IL-5, and food antigen avoidance.
Genetics of Eosinophilic Esophagitis
Authors: Sherrill Joseph D. , Blanchard Carine
Published: March 2014

Eosinophilic esophagitis (EoE) is a complex genetic disorder characterized by eosinophilic inflammation within the esophagus. Multiple epidemiological studies estimate the prevalence of EoE is 4 in 10,000, with a higher disease prevalence in individuals of European ancestry and in males, highlighting a genetic etiology of the disease. EoE has often been noted to occur in multiple family members, particularly siblings, in a non-Mendelian pattern, indicating the heritable component of EoE is likely complex in nature. Although EoE is a newly diagnosed disorder involving a complex polygenic etiology, much progress has been made towards identifying the molecular pathways contributing to the disease pathogenesis and the genetic variants associated with disease susceptibility using a variety of approaches (genome-wide and candidate gene) as well as study designs (case-control and family-based cohorts). Here, we discuss the major scientific findings that have shaped the current molecular and genetic landscape of EoE as well as the major obstacles in the discovery of disease causal variants in complex disorders.
Historical Aspects of Eosinophilic Esophagitis: From Case Reports to Clinical Trials
Authors: Attwood Stephen , Sabri Shariq
Published: March 2014

Eosinophilic esophagitis (EoE) is a clinicopathological condition characterized clinically by symptoms of esophageal dysfunction in the absence of acid reflux, with typical endoscopic findings and eosinophilia on biopsy. This article looks into the historical clinical recognition and description of EoE, in particular clinical manifestations, natural history, and epidemiology. Additionally, the evolution of endoscopic recognition and development of clinical trials are described: EoE is an isolated disease of the esophagus, although it is associated with other antigen-driven diseases such as asthma, rhinitis, and atopic dermatitis. After initial case reports which were mostly not typical of the disease state now described, the first case series were described in 1993 and 1994 in adults, and 1995 in children. Although rarely seen before 2000, the disease is now commonly recognized. Randomized clinical trials have now been performed on topical steroids, and on biological agents targeted against IL-5, IL-13, and other mediators. Therapy with dilatation may be best guided by measures of compliance and distensibility. Work is needed on biomarkers of the disease's severity and progression, and predictive indexes of complications. EoE is a relatively new disease of increasing importance. It represents an important diagnosis in patients with upper gastrointestinal symptoms and must be considered in all patients with dysphagia where the diagnosis is not certain and in all patients who have an assumed diagnosis of reflux but are not responding to standard reflux therapy.
Role of Advanced Diagnostics for Eosinophilic Esophagitis
Authors: Hirano Ikuo
Published: March 2014

In eosinophilic esophagitis (EoE), diagnostic tests aid in the identification of pathophysiologic consequences and accurate detection of the disease. The EoE Endoscopic Reference Score (EREFS) classifies and grades the severity of the five major endoscopically identified esophageal features of EoE (edema, rings, exudates, furrows and strictures). The EREFS may be useful in the evaluation of disease severity and as an objective outcome of response to therapy. pH monitoring identifies the presence of abnormal degrees of acid exposure in the esophagus that characterizes gastroesophageal reflux disease. The presence of acid reflux, however, does not indicate that the reflux is responsible for esophageal eosinophilia. Esophageal manometry has not demonstrated a characteristic abnormality with sufficient sensitivity to make the test of diagnostic value in clinical practice. On the other hand, manometric characteristics of esophageal pressurization and longitudinal muscle dysfunction may help identify important pathophysiologic consequences of EoE. Esophageal impedance testing has demonstrated increased baseline mucosal impedance that correlates with increased epithelial permeability in EoE. Reduced mucosal integrity may provide intraluminal allergens access to antigen-presenting cells, serving as an early event in the pathogenesis of EoE. The functional luminal impedance probe (FLIP) provides quantitative assessment of esophageal mural compliance, a physiologic correlate of remodeling in EoE. Studies using FLIP have associated reductions in esophageal distensibility in EoE with the important outcome of food impaction risk. Finally, confocal endomicroscopy, multiphoton fluorescence microscopy and novel eosinophil-enhancing contrast agents are emerging methods that may allow for in vivo visualization of esophageal eosinophilic inflammation, thereby improving the detection and understanding of this emerging disease.
Value of Allergy Tests for the Diagnosis of Food Allergy
Authors: Ballmer-Weber Barbara K.
Published: March 2014

Eosinophilic esophagitis (EoE) is a chronic T helper 2-type inflammatory disorder. Concurrent allergic diseases have been observed in EoE cases at a high prevalence. The observation that EoE responds to dietary treatment suggests that EoE is an antigen-driven process. However, the pathogenesis by which allergens mediate the eosinophilic disease in the esophagus needs further clarification. In immediate-type food allergy, diagnosis is based on a careful case history followed by a search for food-specific IgE either by skin testing [skin prick test (SPT)] or in vitro (e.g. ImmunoCAP). In children with atopic dermatitis and a food allergy to milk, eggs, peanuts, fish or wheat, the SPT and in vitro determination of specific IgE show excellent sensitivity and negative predictive values, whereas the positive predictive values are low. In pollen-related secondary food allergy, sensitivity and negative predictive values of IgE testing is much lower. Consequently, oral food provocation is the gold standard for the diagnosis of food allergy. Similarly, in EoE patients, SPT, atopy patch test and in vitro determination of IgE to foods do not reliably predict food allergy, and the average positive predictive values of these allergy tests are below 50%. In conclusion, the value of allergy tests to identify triggering foods are limited, and triggering foods have to be identified by an elimination diet and consequent reintroduction of single foods under biopsy control. However, due to the high prevalence of concurrent allergic diseases among EoE patients, an allergy work-up is urgently indicated in each patient with EoE.
Eosinophilic Esophagitis - Treatment of Eosinophilic Esophagitis with Drugs: Corticosteroids
Authors: von Arnim Ulrike , Malfertheiner Peter
Published: March 2014

Eosinophilic esophagitis (EoE) is defined as a chronic immune/antigen-mediated esophageal disease characterized by clinical symptoms of esophageal dysfunction and histologically by eosinophil-predominant infiltration of the esophagus mucosa. Treatment of EoE should therefore lead to improvement of clinical symptoms and a histological decrease of eosinophilic inflammation. Topical corticosteroids (tCS; fluticasone, budesonide) have been demonstrated to be effective in treating EoE and therefore represent first-line therapy. To date, there is no approved therapy in the world for EoE. This is the reason why EoE patients are treated with medication such as inhalers or aqueous nebulizer solutions, which have to be swallowed. After administration, patients are not allowed to eat or drink for 45 min in order for the esophagus to become well coated so that the topical anti-inflammatory effect is maximized. For adults there are different dose ranges: fluticasone propionate 440-880 μg/day twice daily, budesonide 2 mg/day divided dose for inducing remission over a period of 4 to 8 weeks. Since EoE is a chronic disease known to relapse after termination of medication, maintenance therapy seems to be valuable, but there is no evidence from controlled studies with long-term follow-up. In several randomized trials, both tCS have been able to show a good safety profile. Candida esophagitis and oral candidiasis present the most common side effects of topical steroid therapy. At the moment, no data about tCS and long-term safety in EoE are available.
Treatment of Eosinophilic Esophagitis by Dilation
Authors: Schoepfer Alain
Published: March 2014

Treatment options for eosinophilic esophagitis (EoE) include drugs, diets and esophageal dilation. Esophageal dilation can be performed using either through-the-scope balloons or wire-guided bougies. Dilation can lead to long-lasting symptom improvement in EoE patients presenting with esophageal strictures. Esophageal strictures are most often diagnosed when the 8- to 9-mm outer diameter adult gastroscope cannot be passed any further or only against resistance. A defined esophageal diameter to be targeted by dilation is missing, but the majority of patients have considerable symptomatic improvement when a diameter of 16-18 mm has been reached. A high complication rate, especially regarding esophageal perforations, has been reported in small case series until 2006. Several large series were published in 2007 and later that demonstrated that the complication risk (especially esophageal perforation) was much lower than what was reported in earlier series. The procedure can therefore be regarded as safe when some simple precautions are followed. It is noteworthy that esophageal dilation does not influence the underlying eosinophil-predominant inflammation. Patients should be informed before the procedure that postprocedural retrosternal pain may occur for some days, but that it usually responds well to over-the-counter analgesics such as paracetamol. Dilation-related superficial lacerations of the mucosa should not be regarded and reported as complications, but instead represent a desired effect of the therapy. Patient tolerance and acceptance for esophageal dilation have been reported to be good.
Unmet Therapeutic Needs in Eosinophilic Esophagitis
Authors: Aceves Seema S.
Published: March 2014

Eosinophilic esophagitis (EoE) is a clinicopathologic disease of increasing prevalence in children and adults worldwide. EoE is defined by a robust, acid-resistant, often panesophageal eosinophilia. Disease complications include food impactions and strictures. While much has been learned since it was first described in the late 1970s, there are still a number of unmet clinical needs. This review provides an overview of these and addresses our current state of progress in meeting these challenges. The best diagnostic criteria, the least invasive mechanisms for procuring tissue, the best therapeutic intervention, and an understanding of how therapies affect EoE natural history remain to be systematically addressed. In addition, the classification of EoE subjects by phenotype, genotype, and/or endotype is required but dependent upon further large-scale systematic studies.
Borderline Indications and Selection of Gastroesophageal Reflux Disease Patients: ‘Is Surgery Better than Medical Therapy'?
Authors: Lundell Lars
Published: March 2014

Modern medical therapies for gastroesophageal reflux disease (GERD) are totally dedicated to the control of the acid component of the refluxate. In chronic erosive GERD, antireflux surgery has proven to be very efficacious and superior to traditional medical therapies, such as H2 blockers. The introduction of proton pump inhibitors (PPIs), however, substantially improved medical therapy. Still, treatment failures are inevitable regardless of which of these two effective therapies is chosen. Some recent reports have presented conflicting results from trials comparing antireflux surgery and PPIs. This may be due to differences in trial designs as well as in the structure and content of the therapeutic strategies that are compared. The study with the longest clinical follow-up by far is the SOPRAN study comparing open antireflux surgery and omeprazole. The protocol provides for a follow-up period of more than a decade and the clinical outcomes have recently been published. There has always been concern about the long-term effectiveness of reflux prevention whether by surgery or PPI therapy. It is likely that a marker for an emerging risk for recurrence of GERD is abnormal acid reflux as assessed by ambulatory 24-hour pH-metry. The LOTUS trial compared maintenance therapy provided by esomeprazole (dose-adjusted when required) with standardized laparoscopic antireflux surgery in patients with good response to acid suppressive therapy. An operation is suitable when symptoms are poorly controlled despite medication, especially for patients who suffer large-volume regurgitation and those who wake at night coughing and choking and who regurgitate acidic fluid or food into their throat and airways. Regurgitation into the throat upon stooping or exercising can limit a patient's ability to work, play sports or even do simple housework. A few patients cannot tolerate medical treatment. If surgery is to be a good option, it must be ensured that the right surgeon performs a standardized operation for the right indications on the right patient and provides good preoperative counseling and testing along with postoperative support. When a patient is refractory to medical treatment, the diagnosis of GERD should be reconsidered before surgery is advised; extradigestive manifestations should be accounted for with care. Conclusions: Laparoscopic fundoplication (LF) substantially improves GERD symptoms, although in some individuals symptoms return and acid-suppressive medication use increases. Limited data suggest that LF is less effective at reducing symptoms in partial responders to medical therapy than in complete responders. This may affect cost arguments for using fundoplication surgery rather than acid-suppressive medications, as data are based largely on complete responders.
Does Barrett's Esophagus Regress after Surgery (or Proton Pump Inhibitors)
Authors: Spechler Stuart Jon
Published: March 2014

Barrett's esophagus, the condition in which metaplastic columnar epithelium that predisposes to cancer development replaces the squamous epithelium that normally lines the distal esophagus, is a complication of gastroesophageal reflux disease (GERD). Metaplasia is a potentially reversible condition, and partial regression of Barrett's metaplasia has been documented with effective medical or surgical therapy for GERD. The important issue for patient management is not whether antireflux treatment causes Barrett's esophagus to regress, but rather whether antireflux therapy prevents cancer in Barrett's esophagus. Proton pump inhibitors (PPIs) would be expected to prevent this cancer because they heal reflux esophagitis, reduce exposure to a potential carcinogen (acid), and might prevent acid-induced proliferation and cancer-promoting cytokine secretion by esophageal epithelial cells. Furthermore, observational studies have shown that PPI use is associated with a decreased incidence of neoplasia in Barrett's esophagus. In theory, successful antireflux surgery, which eliminates the reflux of both acid and bile, should be better for cancer prevention than medical therapy, which only decreases the reflux of acid. However, high-quality studies show no significant difference in cancer incidence between medically and surgically treated patients with GERD and Barrett's esophagus. Furthermore, for individual patients with nondysplastic Barrett's metaplasia, the cancer risk is so small and the number needed to treat for cancer prevention with surgery so large, that it does not matter whether or not surgery provides a tiny margin of extra protection against cancer beyond that provided by medical therapy. The cost and risks of the operation overwhelm any small, additional cancer protective benefit. Antireflux surgery is very effective at controlling the endoscopic signs and symptoms of GERD, but the operation should not be recommended to patients solely with the rationale that it protects against cancer better than medical therapy.
The Current Evidence in Support of Multimodal Treatment of Locally Advanced, Potentially Resectable Esophageal Cancer
Authors: Zacherl Johannes
Published: March 2014

Background: Treatment of locally advanced resectable esophageal cancer is challenging. In the past three decades surgical treatment has become safer, chemotherapy more powerful and radiation techniques more precise. Today's stage-dependent treatment relies on modern diagnostic tools such as multidetector helical CT, high-frequency endoscopic ultrasound, PET, image fusion techniques and MRI. Specialists cooperate on multidisciplinary tumor boards that follow transparent decision trees based on the newest evidence. Methods: Results of recent randomized controlled trials are examined with emphasis on their reliability and comparability. Results: Patients with esophagogastric cancer undergoing neoadjuvant chemotherapy, perioperative chemotherapy and neoadjuvant radiochemotherapy plus esophagectomy had a higher R-0 resection rate, fewer involved lymph nodes and better overall survival than with esophagectomy alone. While perioperative morbidity and mortality were not remarkably enhanced by neoadjuvant chemotherapy, several trials showed an increase of mortality after neoadjuvant radiochemotherapy. Adenocarcinoma seems to respond better to chemotherapy than squamous cell cancer, and squamous cell cancer seems to respond better to radiochemotherapy than adenocarcinoma. Conclusion: On the basis of the results of randomized trials, preoperative treatment of esophageal cancer shows a survival benefit and should be recommended as the standard treatment strategy in advanced esophageal cancer. While preoperative radiochemotherapy is the standard for advanced squamous cell cancer, both chemotherapy and radiochemotherapy may be adopted for neoadjuvant/perioperative treatment of adenocarcinoma depending on the patient's general condition. Markers to predict response are urgently needed since only responders benefit from multimodal treatment and nonresponders suffer potential harm when surgery is delayed.
Mild Cognitive Impairment with Associated Inflammatory and Cortisol Alterations as Independent Risk Factor for Postoperative Delirium
Authors: Kazmierski Jakub , Banys Andrzej , Latek Joanna , Bourke Julius , Jaszewski Ryszard , Sobow Tomasz , Kloszewska Iwona
Published: March 2014

Aims: The present study aimed to determine the impact of mild cognitive impairment (MCI) on the development of postoperative delirium and, secondly, to assess the association between MCI and raised perioperative cortisol, cytokine, cobalamin and homocysteine levels. Methods: The study recruited 113 consecutive adult patients scheduled for cardiac surgery with cardiopulmonary bypass. The patients were examined preoperatively with the Montreal Cognitive Assessment and Trail Making Test. A diagnosis of MCI was established based upon the criteria of the National Institute on Aging and Alzheimer's Association. Patients were screened for delirium within the first 5 days postoperatively. Results: MCI was diagnosed in 24.8% of the patients, whereas the frequency of delirium was 36%. A multivariate analysis demonstrated that individuals with MCI were at a significantly higher risk of postoperative delirium (OR = 6.33, p = 0.002). Preoperative cortisol, postoperative cortisol and IL-2 plasma levels were higher in the MCI group as compared to non-MCI subjects. Conclusion: MCI is associated with a higher risk of postoperative delirium. Perioperative cortisol and inflammatory alterations observed in MCI may provide a physiological explanation for this increased risk.
Circulating Autoantibodies and Autoimmune Comorbidities in Vitiligo Patients: A Multicenter Italian Study
Authors: Ingordo Vito , Cazzaniga Simone , Raone Beatrice , Digiuseppe Maria Donata , Musumeci Maria Letizia , Fai Dario , Pellegrino Michele , Pezzarossa Enrico , Di Lernia Vito , Battarra Vincenzo Claudio , Sirna Riccardo , Patrizi Annalisa , Naldi Luigi
Published: March 2014

Background: Autoimmune comorbidities and circulating autoantibodies have been observed in vitiligo patients, but differences in rate are present according to countries in which the studies were performed, perhaps owing to ethnic diversities or different trigger factors. Objective: To estimate the prevalence of circulating autoantibodies and overt autoimmune diseases in a fairly large sample of Italian vitiligo patients. Methods: 175 outpatients affected by vitiligo and referred to nine dermatological centers were included in the study. Patients were offered routine blood test, serological testing for thyroid function and search for autoantibodies. Results: At least one circulating autoantibody was detected in 61 (41.8%) of 146 subjects who underwent laboratory tests. Anti-thyroperoxidase (25.6%), anti-thyroglobulin (23.4%), antinuclear antibodies (16.8%) and anti-gastric parietal cell antibodies (7.8%) were the most noticed autoantibodies. 74 (41.5%) autoimmune comorbidities, mainly autoimmune thyroiditis (37%), were reported. Conclusion: The prevalence of autoimmune comorbidities and circulating autoantibodies in this study was in agreement with other surveys conducted on Caucasian patients.
Evaluation of Emotional Blunting in Behavioral Variant Frontotemporal Dementia Compared to Alzheimer's Disease
Authors: Karve Simantini , Barsuglia Joseph P. , Mather Michelle J. , Jimenez Elvira E. , Shapira Jill , Mendez Mario F.
Published: March 2014

Background: Emotional blunting is a major clinical feature of behavioral variant frontotemporal dementia (bvFTD). Assessing the change in emotional blunting may facilitate the differential diagnosis of this disorder and can quantify a major source of distress for the patients' caregivers and families. Methods: We evaluated investigator ratings on the Scale for Emotional Blunting (SEB) for 13 patients with bvFTD versus 18 patients with early-onset Alzheimer's disease (AD). The caregivers also performed SEB ratings for both the patients' premorbid behavior (before dementia onset) and the patients' behavior on clinical presentation (after dementia onset). Results: Before the onset of dementia, the caregivers reported normal SEB scores for both dementia groups. After the onset of dementia, both caregivers and investigators reported greater SEB scores for the bvFTD patients compared to the AD patients. The patients were rated to be much more emotionally blunted by the bvFTD caregivers than by the investigators. A change of ≥15 in the caregiver SEB ratings suggests bvFTD. The change in caregiver SEB ratings was positively correlated with bifrontal hypometabolism on FDG-PET scans. Conclusions: Changes in the caregiver assessment of emotional blunting with dementia onset can distinguish patients with bvFTD from those with AD, and they may better reflect the impact of emotional blunting than similar assessments made by clinicians/investigators.