bluuebunny/crossref_metadata_2025 huggingface dataset:
Celiac Disease and Endocrine Autoimmunity
Authors: Kahaly George J. , Schuppan Detlef
Published: April 2015

Background: Celiac disease (CD) is a small-intestinal inflammatory disease that is triggered by the ingestion of the storage proteins (gluten) of wheat, barley and rye. Key Messages: Endocrine autoimmunity is prevalent in patients with CD and their relatives. The genes that predispose to endocrine autoimmune diseases, e.g. type 1 diabetes, autoimmune thyroid diseases, and Addison's disease, i.e. DR3-DQ2 and DR4-DQ8, are also the major genetic determinants of CD, which is the best understood HLA-linked disease. Thus, up to 30% of first-degree relatives both of patients with CD and/or endocrine autoimmunity are affected by the other disease. In CD, certain gluten proteins bind with high affinity to HLA-DQ2 or -DQ8 in the small-intestinal mucosa, to activate gluten-specific T cells which are instrumental in the destruction of the resorptive villi. Here, the autoantigen tissue transglutaminase increases the T cell response by generating deamidated gluten peptides that bind more strongly to DQ2 or DQ8. Classical symptoms such as diarrhea and consequences of malabsorption like anemia and osteoporosis are often absent in patients with (screening-detected) CD, but this absence does not significantly affect these patients' incidence of endocrine autoimmunity. Moreover, once autoimmunity is established, a gluten-free diet is not able to induce remission. However, ongoing studies attempt to address how far a gluten-free diet may prevent or retard the development of CD and endocrine autoimmunity in children at risk. Conclusions: The close relationship between CD and endocrine autoimmunity warrants a broader immune genetic and endocrine screening of CD patients and their relatives.
Novel Treatments for Celiac Disease: Glutenases and Beyond
Authors: Kaukinen Katri , Lindfors Katri
Published: April 2015

Currently, the only effective treatment for celiac disease is a strict lifelong gluten-free diet. However, gluten-free dieting is restrictive, difficult to maintain and nutritionally less than optimal. The improved knowledge on celiac disease pathogenesis has enabled researchers to suggest alternative strategies to treat the disorder. The drug development poses a challenge as any novel drug for celiac disease should be simultaneously effective and as safe as the gluten-free diet. The rationale behind enzyme supplementation therapy as a future treatment option for celiac patients lies in the fact that gluten is only poorly digested by gastrointestinal proteases. Due to incomplete degradation in the gastrointestinal tract, fairly long gluten peptides enter the small-intestinal lumen and come into contact with the mucosal epithelium, and in celiac disease patients this encounter launches deleterious downstream effects. Enzyme supplement therapy using either bacterial or fungal endopeptidases or proteases from germinating cereals has been proposed to promote complete digestion of prolamins and destroy disease-inducing gluten peptides. A major advantage of these glutenases is that they work in the lumen of the small intestine and do not themselves take part in the immunological cascade of events in the lamina propria, thus being unlikely to cause harmful side effects to the host. Studies to test this rationale, e.g. with Aspergillus niger prolyl endoprotease and a combination enzyme product ALV003, are already ongoing. The development of a novel medication for celiac disease is still in its early days, and thus the conventional dietary treatment will hold its place for the time being.
Celiac Disease: Prevention in Children
Authors: Mearin M. Luisa
Published: April 2015

Several studies have suggested a protective role of breastfeeding and/or the timing and quantity of gluten introduction in the subsequent development of celiac disease. Especially, prolonged breastfeeding during the introduction of gluten-containing feeding has been associated with a reduced risk of developing celiac disease in infancy. The mentioned results suggest the existence of a ‘window of opportunity' between 4 and 6 months of age in which gluten can be introduced in small amounts. Therefore, the European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends avoiding gluten introduction before the age of 4 months and after the age of 7 months and that gluten should be preferably introduced during ongoing breastfeeding. However, the influence of breastfeeding in the development of celiac disease is not clear, since some studies report prevention and others do not, and the studies reporting a protective effect of breastfeeding do not make clear if it concerns prevention of the disease or delays the onset of symptoms. In addition, most of the studies on this topic have been observational and retrospective. For these reasons, prospective studies are needed to understand the relationship between early nutrition in particular and environmental factors in general, concerning the development and possible prevention of celiac disease. Some of these studies are ongoing. One example is the European multicenter PreventCD project (www.preventcoeliacdisease.com) among infants with a first-degree family member with celiac disease carrying HLA-DQ2 and/or -DQ8, randomized to a double-blind dietary intervention with 100 mg of gluten daily or placebo between the age of 4-6 months. All included children are already 3 years old, and the first analyses are being prepared (http://www.trialregister.nl).
Eosinophilic Enteritis
Authors: Pineton de Chambrun Guillaume , Desreumaux Pierre , Cortot Antoine
Published: April 2015

Background: Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathology of the intestinal mucosa. Key Messages: The etiology of eosinophilic enteritis remains obscure. There is growing evidence to support the role of aeroallergens and food allergens in the pathogenesis of this disorder as children and adults with EGIDs often have positive skin testing for food allergens and a familial history of allergic diseases. Moreover, significant progress has been made in elucidating that EGIDs involve mechanisms that fall between pure IgE-mediated and delayed Th2 type responses. Preclinical studies have identified a contributory role for the cytokine IL-5 and eotaxin chemokines, providing a rationale for specific disease therapy. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating or ascites, and its diagnosis requires a high degree of clinical likelihood given the nonspecific presentation and physical examination findings. The Klein classification arbitrarily divided patients with eosinophilic enteritis into those with predominantly mucosal, muscle layer or subserosal disease relying on the concept that clinical presentation is dependent on the predominant involved layer of the gastrointestinal tract. Main therapeutic options are represented by oral corticosteroids for a short period with good efficacy. Antihistaminic drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. Conclusion: Eosinophilic enteritis is generally considered as a benign disease with no relapse, but half of the patients may present a more complex natural history characterized by unpredictable relapses and a chronic course.
Enteropathy-Associated T-Cell Lymphoma: Improving Treatment Strategies
Authors: Nijeboer P. , Malamut G. , Mulder C.J. , Cerf-Bensussan N. , Sibon D. , Bouma G. , Cellier C. , Hermine O. , Visser O.
Published: April 2015

Enteropathy-associated T-cell lymphoma (EATL) is a rare and usually rapidly fatal intestinal T-cell non-Hodgkin lymphoma. It arises from intraepithelial lymphocytes and has a high association with coeliac disease. The high mortality of EATL is associated not only with the very aggressive and often chemotherapy-refractory nature of the lymphoma. The poor condition of patients due to prolonged and severe malnutrition compromises the ability to deliver chemotherapy. There are no standardized treatment protocols, and the optimal therapy for EATL remains unclear. The primary step of treatment consists of local debulking, preferably as early as possible after EATL diagnosis. Morbidity and mortality seem to rise with advanced stages of disease due to tumour size progression, worse nutritional status and a higher risk of emergency surgery due to perforation. Standard induction therapy for EATL is anthracycline-based chemotherapy, preferably resumed between 2 and 5 weeks after surgery (depending on clinical condition). Intensification of therapy using high-dose chemotherapy followed by consolidation with BEAM and autologous stem cell transplantation is associated with better outcome. Notably, this treatment strategy has only been applied in patients eligible for this aggressive regimen which might reflect selection bias. Unfortunately, prognosis of EATL remains poor; 5-year survival varies from 8 to 60% depending on the eligibility to receive additional steps of therapy. New treatment strategies are urgently needed for a better prognosis of this lethal complication of coeliac disease. Brentuximab vedotin (anti-CD30) might be promising when added to conventional chemotherapy and is suggested as upfront treatment in EATL.
Drug-Induced Enteropathy
Authors: Marietta Eric V. , Cartee Amanda , Rishi Abdul , Murray Joseph A.
Published: April 2015

Background/Aims: Many medications can cause diarrhea by increasing motility, inflammation or enteropathy. Olmesartan and mycophenolic acid (CellCept) are drugs that are capable of increasing inflammation and enteropathy in some individuals and, if not recognized, can lead to chronic diarrhea. It is this type of drug-induced diarrhea that is the focus of this review. Methods: A summary of our findings (recent and earlier published) as well as a review of published works from other centers were conducted. Results: There is increasing evidence that olmesartan use is associated with enteropathy in a small number of individuals who use angiotensin receptor II blockers, and that this enteropathy is characterized by severe diarrhea capable of inducing severe dehydration and, in some instances, failure of organs such as the kidney. Typical patient demographics are Caucasian individuals who are older (>50 years old) and obese or overweight prior to weight loss. Prolonged exposure to olmesartan use for 1-2 years is typical, although case reports of irbesartan and valsartan have been reported as well. Discontinuing olmesartan leads to improvement of symptoms; however, the period for healing is variable, with some patients requiring steroid therapy and even prolonged parental nutrition support. In addition, many histological features of olmesartan-associated enteropathy are also present in celiac disease, including villi shortening and lymphocyte infiltration. Other drug-associated enteropathies have also been reported with mycophenolate mofetil used in transplantation. Conclusions: Of the drug-associated enteropathies discussed in this review, olmesartan can generate the most severe symptoms, albeit quite rare. Therefore, with patients who present with severe diarrhea and weight loss, one should consider olmesartan-associated enteropathy. In addition, many of the features associated with olmesartan-associated enteropathy are also found in celiac disease enteropathy; as such, one should review any celiac disease diagnosis for any use of olmesartan at the time of diagnosis.
Other Dietary Confounders: FODMAPS et al.
Authors: Gibson Peter R. , Muir Jane G. , Newnham Evan D.
Published: April 2015

Background: While it is well documented and widely appreciated that ingestion of wheat (and less so rye and barley) is associated with gastrointestinal symptoms such as bloating or abdominal pain, the component of wheat to which such an effect is attributed is less well established. Key Messages: Wheat is a complex of proteins (80% gluten, 20% metabolic proteins), carbohydrates (starch, non-starch polysaccharides, fructans), lipids and other components. The majority of attention has focused on gluten as the culprit in triggering symptoms, but re-challenge studies have nearly all used wheat flour-related products (such as bread) as the stimulus. When carbohydrate-deplete gluten was used as the challenge agent, gluten-specific feelings of depression and not gut symptoms were observed in those who fulfilled strict criteria of ‘non-coeliac gluten sensitivity', thereby underlining the complexity of cereals and of undertaking research in this area. Candidate components other than gluten include poorly absorbed oligosaccharides (mainly fructans), non-gluten wheat proteins such as amylase-trypsin inhibitors or wheat germ agglutinin, and exorphins released during the digestion of gluten. Specific biological and/or clinical effects associated with gluten-free diets or wheat ingestion need to be carefully dissected before attribution to gluten can be claimed. Conclusions: Currently, coeliac disease is the only common condition that has been unequivocally linked to gluten. Inaccurate attribution will be associated with suboptimal therapeutic advice and at least partly underlies the current gluten-free epidemic gripping the Western world.
Serum Markers in the Clinical Management of Celiac Disease
Authors: Adriaanse Marlou , Leffler Daniel A.
Published: April 2015

The advent of highly reliable noninvasive celiac diagnostic tests has transformed the field of celiac disease, from diagnosis, to evaluation of epidemiology, to clinical and translational research. Serologic tests in their modern forms are highly sensitive and specific for diagnosis, allowing for consideration of avoidance of diagnostic intestinal biopsy in some settings. On the other hand, as predictors of intestinal damage and for use in monitoring disease activity, currently available noninvasive tests have been disappointing. Serologic tests, while a measure of disease activity, do not correlate well with histology or symptomatology, and it is unclear if they predict long-term risk. Additionally, while the many clinically available tests have improved accessibility, they can have widely different cutoff levels and overall performance, making the comparison of levels in individual patients over time and across populations quite difficult. In the future, we can expect to see improvement in the currently available serologic tests including tissue transglutaminase and deamidated gliadin peptide with expansion of the dynamic range of the tests, and the celiac care community should push for a standardization of assays that would simplify research and patient care. Additionally, current serologic tests are measures of the adaptive immune response in celiac disease but do not directly measure intestinal inflammation. Promising work on intestinal fatty acid-binding protein and other assays which directly measure intestinal damage may complement traditional serologic tests and further improve our ability to noninvasively diagnose and monitor celiac disease. The coming years hold promise for the continuing evolution of serum-based tests in celiac disease with the possibility of substantial improvement of patient care and clinical research.
Demographic, Hematologic, and Clinical Features of Myelodysplastic Syndrome Patients: Results from the First Polish Myelodysplastic Syndrome Registry
Authors: Mądry Krzysztof , Machowicz Rafał , Waszczuk-Gajda Anna , Drozd-Sokołowska Joanna , Hołowiecka Beata Stella , Wiater Elżbieta , Mital Andrzej , Obara Agata , Szmigielska-Kapłon Anna , Kołkowska-Leśniak Agnieszka , Sikorska Anna , Subocz Edyta , Mendrek Włodzimierz , Szczepańska Magdalena , Biedroń Monika , Jachalska Anna , Wasilewska Ewa , Wojciechowska Małgorzata , Guzicka-Kazimierczak Renata , Kopacz Agnieszka , Katinas Katarzyna , Kruger Witold , Dawidowska Anna , Salamańczuk Zoriana , Zawirska Daria , Świderska Alina , Jędrzejczak Wiesław Wiktor , Dwilewicz-Trojaczek Jadwiga
Published: April 2015

Epidemiological studies on myelodysplastic syndromes (MDS) in Middle-Eastern Europe are scarce. No data about the demographic, clinical, and laboratory features of Polish MDS patients have been published. The aim of this study was to assess the epidemiological data and toxic exposure of Polish MDS patients and their association with hematological parameters and clinical outcomes. For 15 months, 966 living MDS patients were enrolled at 24 centers (12 university and 12 community hospitals). Follow-up was conducted for the next 55 months. The percentage of patients older than 80 years (16%) was between the values for Eastern and Western countries. In patients younger than 55 years, a female predominance was observed (male/female ratio 0.70:1 vs. 1.29:1; p < 0.001). Female patients had higher platelet counts (160 × 109/l vs. 111 × 109/l; p < 0.001). Patients exposed to chemicals were younger than patients without such exposure; their median age at MDS diagnosis was 66 vs. 70 years (p = 0.037). Smokers had significantly lower hemoglobin concentrations (8.6 vs. 9.1 g/dl; p = 0.032) and lower platelet counts (99 × 109/l vs. 137 × 109/l; p < 0.001) than nonsmokers. We provide the first description of the characteristics of Polish MDS patients. Females predominated in the group aged <60 years and they had higher platelet counts. The course of the disease is affected by toxic exposure and smoking.
Therapy in RCDII: Rationale for Combination Strategies?
Authors: Nijeboer Petula , Malamut Georgia , Bouma Gerd , Cerf-Bensussan Nadine , Koning Frits , van Bergen Jeroen , Cellier Christophe , Mulder Chris J.J.
Published: April 2015

Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Rα. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRγδ phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common γ-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy-associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention.
Platelets from flowing blood attach to the inflammatory chemokine CXCL16 expressed in the endothelium of the human vessel wall
Authors: Santos Sascha Meyer dos , Blankenbach Kira , Scholich Klaus , Dörr Angela , Monsefi Nadejda , Keese Michael , Linke Bona , Deckmyn Hans , Nelson Karen , Harder Sebastian
Published: April 2015

Endothelial chemokine CXC motif ligand 16 (CXCL16) expression is associated with atherosclerosis, while platelets, particularly those attaching to atherosclerotic plaque, contribute to all stages of athero-sclerotic disease. This investigation was designed to examine the role of CXCL16 in capturing platelets from flowing blood. CXCL16 was expressed in human atherosclerotic plaques, and lesion severity in human carotid endarterectomy specimens was positively correlated with CXCL16 levels. CXCL16 expression in plaques was co-localised with platelets deposited to the endothelium. Immobilised CXCL16 promoted CXCR6-dependent platelet adhesion to the human vessel wall, endothelial cells and von Willebrand factor during physiologic flow. At low shear, immobilised CXCL16 captured platelets from flowing blood. It also induced irreversible platelet aggregation and a rise in intra-platelet calcium levels. These results demonstrate that endothelial CXCL16’s action on platelets is not only limited to platelet activation, but that immobilised CXCL16 also acts as a potent novel platelet adhesion ligand, inducing platelet adhesion to the human vessel wall.
Enhanced Classification of Brugada Syndrome–Associated and Long-QT Syndrome–Associated Genetic Variants in the
SCN5A
-Encoded Na
v
1.5 Cardiac Sodium Channel
Authors: Kapplinger Jamie D. , Giudicessi John R. , Ye Dan , Tester David J. , Callis Thomas E. , Valdivia Carmen R. , Makielski Jonathan C. , Wilde Arthur A. , Ackerman Michael J.
Published: April 2015

Background—

A 2% to 5% background rate of rare
SCN5A
nonsynonymous single nucleotide variants (nsSNVs) among healthy individuals confounds clinical genetic testing. Therefore, the purpose of this study was to enhance interpretation of
SCN5A
nsSNVs for clinical genetic testing using estimated predictive values derived from protein-topology and 7 in silico tools.

Methods and Results—

Seven in silico tools were used to assign pathogenic/benign status to nsSNVs from 2888 long-QT syndrome cases, 2111 Brugada syndrome cases, and 8975 controls. Estimated predictive values were determined for each tool across the entire
SCN5A
-encoded Na
v
1.5 channel as well as for specific topographical regions. In addition, the in silico tools were assessed for their ability to correlate with cellular electrophysiology studies. In long-QT syndrome, transmembrane segments S3–S5+S6 and the DIII/DIV linker region were associated with high probability of pathogenicity. For Brugada syndrome, only the transmembrane spanning domains had a high probability of pathogenicity. Although individual tools distinguished case- and control-derived
SCN5A
nsSNVs, the composite use of multiple tools resulted in the greatest enhancement of interpretation. The use of the composite score allowed for enhanced interpretation for nsSNVs outside of the topological regions that intrinsically had a high probability of pathogenicity, as well as within the transmembrane spanning domains for Brugada syndrome nsSNVs.

Conclusions—

We have used a large case/control study to identify regions of Na
v
1.5 associated with a high probability of pathogenicity. Although topology alone would leave the variants outside these identified regions in genetic purgatory, the synergistic use of multiple in silico tools may help promote or demote a variant’s pathogenic status.
Quantitative Assessment of Pericardial Delayed Hyperenhancement Predicts Clinical Improvement in Patients With Constrictive Pericarditis Treated With Anti-Inflammatory Therapy
Authors: Cremer Paul C. , Tariq Muhammad U. , Karwa Abhishek , Alraies M. Chadi , Benatti Rodolfo , Schuster Andres , Agarwal Shikhar , Flamm Scott D. , Kwon Deborah H. , Klein Allan L.
Published: April 2015

Background—

Delayed hyperenhancement (DHE) of the pericardium usually represents ongoing inflammation and may identify patients with constrictive pericarditis that will improve with anti-inflammatory therapy. However, a quantitative assessment of pericardial DHE has not been performed, and the hierarchical relationship among clinical factors, inflammatory markers, and pericardial DHE is unknown.

Methods and Results—

We identified 41 consecutive patients with constrictive pericarditis who had a cardiovascular magnetic resonance study with DHE prior to the initiation of anti-inflammatory medications. Pericardial inflammation was quantified on short-axis DHE sequences by contouring the pericardium, selecting normal septal myocardium as a reference region, and then quantifying the pericardial signal that was >6 SD above the reference. Our primary outcome was clinical improvement with anti-inflammatory therapy. The mean age of our patients was 58 years, most patients were male (83%) with New York Heart Association Class II or III (59%) heart failure, and the median follow-up was 1 year. Chest pain, lower New York Heart Association class, higher Westergren sedimentation rates, and increased pericardial DHE were all significantly associated with clinical improvement (
P
<0.01 for all). When quantitative pericardial DHE was added to a model that included age, chest pain, New York Heart Association class, and Westergren sedimentation rates, the global χ
2
improved significantly (
P
=0.04 for DHE), and the area under the receiver operating characteristic curve was 0.96.

Conclusions—

In patients with constrictive pericarditis treated with anti-inflammatory therapy, a quantitative assessment of pericardial DHE can provide incremental information to predict clinical improvement when added to clinical factors and Westergren sedimentation rates.
Pathogenesis of the Limb Manifestations and Exercise Limitations in Peripheral Artery Disease
Authors: Hiatt William R. , Armstrong Ehrin J. , Larson Christopher J. , Brass Eric P.
Published: April 2015

Patients with peripheral artery disease have a marked reduction in exercise performance and daily ambulatory activity irrespective of their limb symptoms of classic or atypical claudication. This review will evaluate the multiple pathophysiologic mechanisms underlying the exercise impairment in peripheral artery disease based on an evaluation of the current literature and research performed by the authors. Peripheral artery disease results in atherosclerotic obstructions in the major conduit arteries supplying the lower extremities. This arterial disease process impairs the supply of oxygen and metabolic substrates needed to match the metabolic demand generated by active skeletal muscle during walking exercise. However, the hemodynamic impairment associated with the occlusive disease process does not fully account for the reduced exercise impairment, indicating that additional pathophysiologic mechanisms contribute to the limb manifestations. These mechanisms include a cascade of pathophysiological responses during exercise-induced ischemia and reperfusion at rest that are associated with endothelial dysfunction, oxidant stress, inflammation, and muscle metabolic abnormalities that provide opportunities for targeted therapeutic interventions to address the complex pathophysiology of the exercise impairment in peripheral artery disease.
Epidemiology of Peripheral Artery Disease
Authors: Criqui Michael H. , Aboyans Victor
Published: April 2015

New data on the epidemiology of peripheral artery disease (PAD) are available, and they should be integrated with previous data. We provide an updated, integrated overview of the epidemiology of PAD, a focused literature review was conducted on the epidemiology of PAD. The PAD results were grouped into symptoms, diagnosis, prevalence, and incidence both in the United States and globally, risk factors, progression, coprevalence with other atherosclerotic disease, and association with incident cardiovascular morbidity and mortality. The most common symptom of PAD is intermittent claudication, but noninvasive measures, such as the ankle-brachial index, show that asymptomatic PAD is several times more common in the population than intermittent claudication. PAD prevalence and incidence are both sharply age-related, rising >10% among patients in their 60s and 70s. With aging of the global population, it seems likely that PAD will be increasingly common in the future. Prevalence seems to be higher among men than women for more severe or symptomatic disease. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease, with some differences in the relative importance of factors. Smoking is a particularly strong risk factor for PAD, as is diabetes mellitus, and several newer risk markers have shown independent associations with PAD. PAD is strongly associated with concomitant coronary and cerebrovascular diseases. After adjustment for known cardiovascular disease risk factors, PAD is associated with an increased risk of incident coronary and cerebrovascular disease morbidity and mortality.
Apolipoprotein E Enhances MicroRNA-146a in Monocytes and Macrophages to Suppress Nuclear Factor-κB–Driven Inflammation and Atherosclerosis
Authors: Li Kang , Ching Daniel , Luk Fu Sang , Raffai Robert L.
Published: April 2015

Rationale:

Apolipoprotein E (apoE) exerts anti-inflammatory properties that protect against atherosclerosis and other inflammatory diseases. However, mechanisms by which apoE suppresses the cellular activation of leukocytes commonly associated with atherosclerosis remain incompletely understood.

Objective:

To test the hypothesis that apoE suppresses inflammation and atherosclerosis by regulating cellular microRNA levels in these leukocytes.

Methods and Results:

An assessment of apoE expression among such leukocyte subsets in wild-type mice revealed that only macrophages and monocytes express apoE abundantly. An absence of apoE expression in macrophages and monocytes resulted in enhanced nuclear factor-κB signaling and an exaggerated inflammatory response on stimulation with lipopolysaccharide. This correlated with reduced levels of microRNA-146a, a critical negative regulator of nuclear factor-κB signaling. Ectopic apoE expression in
Apoe
–/–
macrophages and monocytes raised miR-146a levels, whereas its silencing in wild-type cells had an opposite effect. Mechanistically, apoE increased the expression of transcription factor purine-rich PU-box–binding protein 1, which raised levels of pri-miR-146 transcripts, demonstrating that apoE exerts transcriptional control over miR-146a. In vivo, even a small amount of apoE expression in macrophages and monocytes of hypomorphic apoE mice led to increased miR-146a levels, and inhibited macrophage proinflammatory responses, Ly-6C
high
monocytosis, and atherosclerosis in the settings of hyperlipidemia. Accordingly, cellular enrichment of miR-146a through the systemic delivery of miR-146a mimetics in
Apoe
–/–
Ldlr
–/–
and
Ldlr
–/–
mice attenuated monocyte/macrophage activation and atherosclerosis in the absence of plasma lipid reduction.

Conclusions:

Our data demonstrate that cellular apoE expression suppresses nuclear factor-κB–mediated inflammation and atherosclerosis by enhancing miR-146a levels in monocytes and macrophages.
Contributions of Increasing Obesity and Diabetes to Slowing Decline in Subclinical Coronary Artery Disease
Authors: Smith Carin Y. , Bailey Kent R. , Emerson Jane A. , Nemetz Peter N. , Roger Véronique L. , Palumbo Pasquale J. , Edwards William D. , Leibson Cynthia L.
Published: April 2015

Background

Our previous study of nonelderly adult decedents with nonnatural (accident, suicide, or homicide) cause of death (96% autopsy rate) between 1981 and 2004 revealed that the decline in subclinical coronary artery disease (
CAD
) ended in the mid‐1990s. The present study investigated the contributions of trends in obesity and diabetes mellitus to patterns of subclinical
CAD
and explored whether the end of the decline in
CAD
persisted.

Methods and Results

We reviewed provider‐linked medical records for all residents of Olmsted County,
Minnesota
, who died from nonnatural causes within the age range of 16 to 64 years between 1981 and 2009 and who had
CAD
graded at autopsy. We estimated trends in
CAD
risk factors including age, sex, systolic blood pressure, diabetes (qualifying fasting glucose or medication), body mass index, smoking, and diagnosed hyperlipidemia. Using multiple regression, we tested for significant associations between trends in
CAD
risk factors and
CAD
grade and assessed the contribution of trends in diabetes and obesity to
CAD
trends. The 545 autopsied decedents with recorded
CAD
grade exhibited significant declines between 1981 and 2009 in systolic blood pressure and smoking and significant increases in blood pressure medication, diabetes, and body mass index ≥30 kg/m
2
. An overall decline in
CAD
grade between 1981 and 2009 was nonlinear and ended in 1994. Trends in obesity and diabetes contributed to the end of
CAD
decline.

Conclusions

Despite continued reductions in smoking and blood pressure values, the previously observed end to the decline in subclinical
CAD
among nonelderly adult decedents was apparent through 2009, corresponding with increasing obesity and diabetes in that population.
Heart Rate at Hospital Discharge in Patients With Heart Failure Is Associated With Mortality and Rehospitalization
Authors: Laskey Warren K. , Alomari Ihab , Cox Margueritte , Schulte Phillip J. , Zhao Xin , Hernandez Adrian F. , Heidenreich Paul A. , Eapen Zubin J. , Yancy Clyde , Bhatt Deepak L. , Fonarow Gregg C. ,   the AHA Get With The Guidelines‐Heart Failure Program
Published: April 2015

Background

Whether heart rate upon discharge following hospitalization for heart failure is associated with long‐term adverse outcomes and whether this association differs between patients with sinus rhythm (
SR
) and atrial fibrillation (
AF
) have not been well studied.

Methods and Results

We conducted a retrospective cohort study from clinical registry data linked to Medicare claims for 46 217 patients participating in Get With The Guidelines
®
–Heart Failure. Cox proportional‐hazards models were used to estimate the association between discharge heart rate and all‐cause mortality, all‐cause readmission, and the composite outcome of mortality/readmission through 1 year. For
SR
and
AF
patients with heart rate ≥75, the association between heart rate and mortality (expressed as hazard ratio [
HR
] per 10 beats‐per‐minute increment) was significant at 0 to 30 days (
SR
:
HR
1.30, 95%
CI
1.22 to 1.39;
AF
:
HR
1.23, 95%
CI
1.16 to 1.29) and 31 to 365 days (
SR
:
HR
1.15, 95%
CI
1.12 to 1.20;
AF
:
HR
1.05, 95%
CI
1.01 to 1.08). Similar associations between heart rate and all‐cause readmission and the composite outcome were obtained for
SR
and
AF
patients from 0 to 30 days but only in the composite outcome for
SR
patients over the longer term. The
HR
from 0 to 30 days exceeded that from 31 to 365 days for both
SR
and
AF
patients. At heart rates <75, an association was significant for mortality only for both
SR
and
AF
patients.

Conclusions

Among older patients hospitalized with heart failure, higher discharge heart rate was associated with increased risks of death and rehospitalization, with higher risk in the first 30 days and for
SR
compared with
AF
.
Exercise Blood Pressure and the Risk for Future Hypertension Among Normotensive Middle‐Aged Adults
Authors: Berger Assaf , Grossman Ehud , Katz Moshe , Kivity Shaye , Klempfner Robert , Segev Shlomo , Goldenberg Ilan , Sidi Yehezkel , Maor Elad
Published: April 2015

Background

The aim of the present study was to examine whether exercise blood pressure can be used to predict the development of hypertension in normotensive middle‐aged adults.

Methods and Results

We investigated 7082 normotensive subjects who were annually screened in a tertiary medical center and completed maximal treadmill exercise tests at each visit. After the initial 3 years, subjects were divided into approximate quartiles according to their average exercise systolic and diastolic blood pressure responses (≤158; 158 to 170; 170 to 183; ≥183 mm Hg for systolic blood pressure and ≤73; 73 to 77; 77 to 82; ≥82 mm Hg for diastolic blood pressure). Mean age of the study population was 48±9 years and 73% were men. Average baseline resting blood pressure was 120/77±12/7 mm Hg. During a follow‐up of 5±3 years, 1036 (14.6%) subjects developed hypertension. The cumulative probability of new‐onset hypertension at 5 years was significantly increased with increasing quartiles of exercise systolic blood pressure (5%, 9%, 17%, and 35%, respectively;
P
<0.001), with a similar association shown for diastolic blood pressure. After adjustment for baseline resting blood pressure and clinical parameters, each 5‐mm Hg increments in exercise either systolic or diastolic blood pressures were independently associated with respective 11% (
P
<0.001) and 30% (
P
<0.001) increased risk for the development of hypertension.

Conclusions

In normotensive middle‐aged individuals, blood pressure response to exercise is associated with future development of hypertension.
Socio-demographic Differences in Environmental Concern and Willingness to Pay for Addressing Global Climate Change in Pakistan
Authors: Rasool Faiz , Ogunbode Charles A.
Published: April 2015

Previous research indicates that socio-demographic attributes are important predictors of environmental concern. However, this research mainly focused on Western societies, with minimal representation of non-Western contexts. In this article, we argue that a stronger representation of non-Western societies is necessary for a more global understanding of pro-environmentalism. On this basis, we explored socio-demographic differences in environmental concern and willingness to pay for addressing climate change in Pakistan. We aimed to assess demographic trends in public perceptions of environmental problems in the Pakistan, and their level of convergence with Western-derived theories of the social bases of environmental concern. Although our findings are largely congruent with trends previously observed in Western contexts, we found some divergent demographic patterns in environmental concern among Pakistanis that are likely the result of a number of contextual influences that prevail in Pakistan and other similar developing countries.
Urban Government Performance in the Eyes of Chinese Urban Residents
Authors: Zhong Yang , Chen Yongguo , Feng Fei , Wang Kuiming
Published: April 2015

Urban China always plays important political role in contemporary Chinese history. Urban residents, especially in provincial capital cities, are better educated and live in political, economic and social centers in China. Their support is indispensable for the current government in China. Utilizing a large-scale survey data this study explores sources of subjective evaluation of local municipal government policy performance among Chinese urban residents in ten large Chinese cities. Descriptively, this study finds moderate satisfaction with city government performance among Chinese urbanites, which seems to lend support to Chinese government’s performance-based political legitimacy and explains relative political stability in China. Analytically, it is found that, while perceived public participation in municipal policy-making process, perceived government transparency, and personal life satisfaction increase Chinese urban residents’ positive evaluation of government performance, perceived official corruption, democratic orientation and level of political interest lead to negative evaluation of government performance among Chinese urbanites.
Acute toxicity and accumulation of microcystin-leucine-arginine in the crayfish Procambarus clarkii (Girard, 1852)
Authors: An Zhenhua , An Zhenhua , Sun Longsheng , An Zhenhua , Sun Longsheng , Wang Ping
Published: April 2015

The aim of this study was to determine the acute toxicity effect and the accumulation of microcystin-leucine-arginine (MC-LR) on the crayfish Procambarus clarkii (Girard, 1852). Juvenile P. clarkii (5.47 ± 1.3 g) were cultured under 5 different MC-LR concentrations (0.3, 0.6, 1.2, 2.4, 4.8 mg/l), then the acute toxicity effect was observed. The median lethal concentration (LC50) of MC-LR on juvenile P. clarkii was 3.741 mg/l at 24 h, 1.494 mg/l at 48 h, 0.817 mg/l at 72 h and 0.567 mg/l at 96 h. Accumulation of MC-LR was measured in different organs of mature P. clarkii (58.7 ± 3.8 g) exposed to 0.3 mg/l MC-LR for 120 h. The detected MC-LR concentration decreased in the sequence: hepatopancreas > ovary > abdominal muscle > intestine. Hepatopancreas and ovary were found to be the main targets of the toxin. The results suggested that the MC-LR produced by cyanobacteria blooms could not only reduce the survival rate of juvenile P. clarkii but also affect the fecundity of mature crayfish. This research also provides a reference basis for the detection and assessment of the pollution of water bodies in P. clarkii culture.
Oral Preaching and Written Sermons in the Middle Ages
Authors: Regev Shaul
Published: April 2015

Our knowledge of the nature of medieval Jewish public sermons is limited and our conclusions mostly inferential. Nonetheless, based upon the sermon literature and through analysis of various introductions and manuals for preachers of the time, we can fairly accurately reconstruct the oral sermon. We know where and when sermons were delivered, their content, the characteristics of the various preachers, the expectations of the listeners and the efforts the preachers made to make their sermons appealing to a diverse audience. Inevitably, over the course of centuries, both the form and the content of sermons changed. This was in response to the shifting needs and desires of audiences and reflects the changes in orientation of the various periods, such as the move from philosophically based sermons to those with Kabbalistic or Halakhic content.
On Pyrrhonism, Stances, and Believing What You Want
Authors: Bett Richard
Published: April 2015

The paper considers the relations between the Pyrrhonism of Sextus Empiricus and epistemological voluntarism, as applied both to epistemic stances and to individual beliefs. In the first part, the main question is whether ancient skepticism is congenial to the idea of alternative epistemic stances (and hence, potentially, to voluntarism about them). The answer proposed is that skepticism does not in fact recognize this possibility. However, this is not due to any essential features of skepticism itself; rather, it is because, like ancient Greek philosophy in general, the stance skepticism in fact unquestioningly assumes is that of realism. In the second part, the focus is more directly on voluntarism and its compatibility with skepticism. The difficulty with bringing these two together, it is argued, is that, while voluntarism gives one license to hold either of two opposing beliefs, skepticism is in the business of subverting beliefs; in this respect their orientations are in opposite directions. A closing suggestion is that if there is any place where ancient skepticism and voluntarism might meet, it is not in the Pyrrhonist tradition, but in the mitigated skepticism of the late Academy, which allowed the holding of (albeit tentative) beliefs.
Skepticism, Suspension of Judgment, and Norms for Belief
Authors: Perin Casey
Published: April 2015

According to Sextus Empiricus, the Skeptic suspends judgment in response to equipollence. This fact has two significant implications. First, the Skeptic has at most indirect control over his suspension of judgment and so does not suspend judgment at will. Second, the skeptic accepts the norm of truth for belief. This is a norm according to which one ought to believe that p only if p is true. However, there are passages in the Outlines of Pyrrhonism that imply the Skeptic accepts the norm of utility for belief. This is a norm according to which one ought to believe that p only if the belief that p promotes one’s tranquility. I first argue that if the Skeptic suspends judgment in response to equipollence, then a pragmatic reason can’t be the reason for which the Skeptic suspends judgment. I then argue that the norms of truth and utility for belief are incompatible just in the sense that the acceptance of the one precludes the acceptance of the other. If Sextus describes the Skeptic as accepting both of these norms for belief, as I argue he does, his conception of Skepticism in the Outlines is not coherent.
Suspension of Belief and Epistemologies of Science
Authors: Chakravartty Anjan
Published: April 2015

Epistemological disputes in the philosophy of science often focus on the question of how restrained or expansive one should be in interpreting our best scientific theories and models. For example, some empiricist philosophers countenance only belief in their observable content, while realists of different sorts extend belief (in incompatible ways, reflecting their different versions of realism) to strictly unobservable entities, structures, events, and processes. I analyze these disputes in terms of differences regarding where to draw a line between domains in which one has warrant for belief and those in which one should suspend belief and thus remain sceptical. I consider and defend the idea that the precise location of this line is subject to a form of epistemic voluntarism, and argue that a Pyrrhonian reading of the basis of such voluntaristic choice is both natural and transformative of our understanding of these debates.
A review of Billaea Robineau-Desvoidy of the eastern Palearctic and Oriental regions (Diptera: Tachinidae)
Authors: ZHANG CHUN-TIAN , SHIMA HIROSHI , WANG QIANG , TSCHORSNIG HANS-PETER
Published: April 2015

The species of Billaea Robineau-Desvoidy (Diptera, Tachinidae) from the eastern Palearctic and Oriental regions are        revised. Ten described species are recognized, viz. B. atkinsoni (Baranov) (new records for Japan, Laos, Malaysia, Pakistan and Thailand), B. ficorum (Townsend), B. fortis (Rondani), B. impigra Kolomiets (new record for China), B. kolomyetzi Mesnil, B. malayana Malloch, B. morosa Mesnil, B. robusta Malloch, B. steini (Brauer et Bergenstamm) and B. triangulifera (Zetterstedt) and nine species are described as new to science, B. brevicauda Zhang et Shima sp. nov.       (China), B. carinata Zhang et Shima sp. nov. (China), B. chinensis Zhang et Shima sp. nov. (China and Vietnam), B. flava Zhang et Wang sp. nov. (China), B. kurahashii Zhang et Shima sp. nov. (Laos and Thailand), B. micronychia Zhang et Shima sp. nov. (China and Japan; previously misidentified from China as B. irrorata (Meigen)), B. papei Zhang et Shima sp. nov. (Malaysia), B. setigera Zhang et Shima sp. nov. (China) and B. verticalis Shima et Zhang sp. nov. (China). Billaea fasciata (Townsend, 1928) is treated as a junior synonym of B. ficorum (Townsend, 1916), syn. nov. Billaea irrorata is no longer recorded from the eastern Palearctic. A key to 19 species of Billaea from the eastern Palearctic and Oriental regions and 101 figures of male terminalia, bodies, heads and abdomens are given.