bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory Effects of Urothelium‐related Factors
Authors: Guan Na N. , Gustafsson Lars E. , Svennersten Karl
Published: April 2017

The urothelium of the bladder has long been recognized as a protective barrier between detrusor and urine. In recent years, it has become more evident that the urothelium plays a role as an active source of mediators. The urothelium can release neurotransmitters and modulators such as acetylcholine, ATP, nitric oxide, prostaglandins and neuropeptides. They exert both excitatory and inhibitory effects in modulating urinary tract motility. In addition, several studies have reported the existence of an urothelium‐derived unknown inhibitory factor in the urinary bladder. By the use of a new serial cascade superfusion bioassay on guinea pig ureter, recent studies confirm that the guinea pig bladder urothelium releases a substance with inhibitory bioactivity, which was resistant to treatment with nitric oxide synthase inhibitor and cyclooxygenase inhibitor and to adenosine A1/A2 receptor blockade. Lately, a marked and quickly inactivated novel release of PGD2 from the bladder urothelium was discovered, together with localization of prostaglandin D synthase therein. PGD2 was found to have an inhibitory influence on nerve‐induced contractions in guinea pig urinary bladder and on spontaneous contractions in the out‐flow region. An altered release of excitatory and inhibitory factors is likely to play an important part in bladder motility disturbances, of which the prostanoids are a notable group. Due to the fact that the bladder is relaxed 99% of the time, not only excitatory mechanisms in the bladder are necessary to study, but also inhibitory mechanisms need considerable attention, which will contribute to the discovery of new targets to treat bladder motility disorders.
Wrongness, Responsibility, and Conscientious Refusals in Health Care
Authors: Liberman Alida
Published: April 2017

In this article, I address what kinds of claims are of the right kind to ground conscientious refusals. Specifically, I investigate what conceptions of moral responsibility and moral wrongness can be permissibly presumed by conscientious objectors. I argue that we must permit HCPs to come to their own subjective conclusions about what they take to be morally wrong and what they take themselves to be morally responsible for. However, these subjective assessments of wrongness and responsibility must be constrained in several important ways: they cannot involve empirical falsehoods, objectionably discriminatory attitudes, or unreasonable normative beliefs. I argue that the sources of these constraints are the basic epistemic, relational, and normative competencies needed to function as a minimally decent health‐care professional. Finally, I consider practical implications for my framework, and argue that it shows us that the objection raised by the plaintiffs in Zubik v. Burwell is of the wrong sort.
The unique immunological features of heparin‐induced thrombocytopenia
Authors: Staibano Phillip , Arnold Donald M. , Bowdish Dawn M. E. , Nazy Ishac
Published: April 2017

Heparin‐induced thrombocytopenia (HIT) is a serious drug reaction that leads to a decrease in platelet count and a high risk of thrombosis. HIT patients produce pathogenic immunoglobulin G (IgG) antibodies that bind to complexes of platelet factor‐4 (PF4) and heparin. HIT immune complexes crosslink Fc‐receptors resulting in platelet and monocyte activation. These events lead to the release of procoagulant chemokines and tissue factor, which together create an intensely prothrombotic state. HIT represents an atypical immune response because it has features of both T cell‐dependent and T cell‐independent mechanisms. The disorder is characterized by newly formed anti‐PF4/heparin IgG antibodies, which are characteristic of a T cell‐dependent mechanism; however, re‐exposure to heparin, months after HIT, does not lead to a memory response, which is consistent with a T cell‐independent mechanism. In this review, we discuss the immunobiological events that can explain these features, including the role for T cell‐dependent and T cell‐independent mechanisms in HIT antibody generation, the immunogenic characteristics of the PF4/heparin antigen, and the concept of a temporary loss in immune regulation contributing to the onset of HIT. We also present a novel immunobiological model to explain the atypical immune response that is characteristic of HIT.
Tectonic uplift of the Xichang Basin (SETibetan Plateau) revealed by structural geology and thermochronology data
Authors: Deng Bin , Liu Shugen , Jiang Lei , Zhao Gaoping , Huang Rui , Li Zhiwu , Li Jinxi , Jansa Luba
Published: April 2017

The Xichang Basin in southeastern Tibet provides crucial information about formation and tectonic processes affecting the eastern Tibetan Plateau. To determine when and how the uplift developed, we conducted detailed studies of structures and obtained thermochronology data from the Xichang Basin and its periphery. The Xichang Basin is characterized by gentle deformation of the strata, segmented by an E‐vergent boundary thrust fault. Two stages of deformation, strike‐slip followed by an E‐W oriented shortening resulted in oblique shortening between the southeastern Tibetan Plateau and the Sichuan Basin. New apatite fission‐track data interpreted together with (U‐Th)/He data confirm a simple burial/heating and exhumation/cooling history across the Xichang Basin and its periphery. Subsidence and burial of the Xichang Basin peaked between 80–30 Ma, followed by mountain building with a protracted cooling starting at around 40–20 Ma, with rates ofca. 2.0–8.0 °C Myr−1(i.e. 0.1–0.3 mm year−1). Our data indicate that the Xichang Basin has experiencedca. 2.5–5 km of exhumation, much more intensive than theca. 1–2 km of exhumation inferred for the southwestern Sichuan Basin. Restored balanced cross‐sections of post‐Late‐Triassic strata along aca. 250 km traverse indicateca. 10–20% east‐west shortening strain (i.e.ca. 20–30 km) at the southeastern Tibetan Plateau during Cenozoic time. Study of crustal thickening and erosion supports a tectonic shortening mechanism to account for the uplift of the Xichang Basin on the southeastern Tibetan Plateau.
Reproductive senescence: new perspectives in the wild
Authors: Lemaître Jean‐François , Gaillard Jean‐Michel
Published: April 2017

According to recent empirical studies, reproductive senescence, the decline in reproductive success with increasing age, seems to be nearly ubiquitous in the wild. However, a clear understanding of the evolutionary causes and consequences of reproductive senescence is still lacking and requires new and integrative approaches. After identifying the sequential and complex nature of female reproductive senescence, we show that the relative contributions of physiological decline and alterations in the efficiency of parental care to reproductive senescence remain unknown and need to be assessed in the light of current evolutionary theories of ageing. We demonstrate that, although reproductive senescence is generally studied only from the female viewpoint, age‐specific female reproductive success strongly depends on male–female interactions. Thus, a reduction in male fertilization efficiency with increasing age has detrimental consequences for female fitness. Lastly, we call for investigations of the role of environmental conditions on reproductive senescence, which could provide salient insights into the underlying sex‐specific mechanisms of reproductive success. We suggest that embracing such directions should allow building new bridges between reproductive senescence and the study of sperm competition, parental care, mate choice and environmental conditions.
Diversity of arbuscular mycorrhizal fungi in Brazil's Caatinga and experimental agroecosystems
Authors: Pontes Juliana S. , Oehl Fritz , Marinho Frederico , Coyne Danny , Silva Danielle Karla Alves da , Yano‐Melo Adriana M. , Maia Leonor C.
Published: April 2017

Cowpea (Vigna unguiculata) is a nutritious legume crop for both its grain and leaves and comprises an important component in both human and animal nutrition. In Brazil, the use of mulch, such as coconut fiber, and organic fertilizers to maximize cowpea production offers an alternative to conventional mineral fertilizer strategies. Farming practices affect the diversity and activity of soil microorganisms, including arbuscular mycorrhizal fungi (AMF), important plant growth promoters for legumes. Our objective was to determine the effect of mulching with coconut fiber and manure on AMF diversity in cowpea. Soil samples were collected from an Experimental Station in Petrolina, NE Brazil: one Caatinga (natural dry‐forest vegetation), one fallow, and one experimental site established in the fallow area and cultivated with cowpea receiving cattle manure and four doses (0, 12, 24, 48 t/ha) of coconut fiber. AMF species richness, abundance, and diversity were evaluated. Sixty‐four AMF species were recorded, with predominance of Glomeraceae and Acaulosporaceae. Highest species richness (47) was recovered from the Caatinga but AMF diversity was also high in the cultivated sites, demonstrating the importance of mycotrophic plants, such as cowpea, in crop production systems for the maintenance of AMF species richness. Although several species, such as Claroideoglomus etunicatum, Acaulospora scrobiculata, Glomus trufemii, and Paraglomus pernambucanum, revealed pronounced sporulation patterns, even high doses of coconut fiber did not affect AMF richness and diversity, compared to fallow. Consequently, cultivation of mycotrophic plants and use of organic manures are able to maintain high AMF species richness in tropical agroecosystems.
Downregulation of Talin1 promotes hepatocellular carcinoma progression through activation of the ERK1/2 pathway
Authors: Chen Peijuan , Lei Ling , Wang Jian , Zou Xuejing , Zhang Dongyan , Deng Ling , Wu Dehua
Published: April 2017

Talin1 is an adaptor protein that conjugates integrins to the cytoskeleton and regulates integrins and focal adhesion signaling. Several studies have found that Talin1 is overexpressed in several tumor types and promotes tumor progression. However, the explicit role of Talin1 in hepatocellular carcinoma (HCC) progression is still unclear and its functional mechanism remains largely unknown. In this study, we showed a trend of gradually decreasing expression of Talin1 from normal liver tissues to hepatocirrhosis, liver hyperplasia, the corresponding adjacent non‐tumor, primary HCC, and eventually metastatic foci, indicating that Talin1 may correlate with HCC initiation to progression. Talin1 was significantly downregulated in HCC tissues compared with adjacent non‐tumor tissues and low Talin1 expression was associated with HCC progression and poor prognosis. Furthermore, Talin1 knockdown induced epithelial–mesenchymal transition and promoted migration and invasion in SK‐Hep‐1 cells and HepG2 cells. Mechanistically, we found that the ERK pathway was responsible for these promoting effects of Talin1 knockdown in HCC cells. The promoting effects of Talin1 knockdown on epithelial–mesenchymal transition, migration, and invasion were reversed by U0126, a specific ERK1/2 inhibitor. Taken together, our results suggested that Talin1 might serve as a tumor suppressor in HCC and a potential prognostic biomarker for HCC patients.
Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells
Authors: Liu Yongchen , Wang Zheng , Li Maolan , Ye Yuanyuan , Xu Yi , Zhang Yichi , Yuan Ruiyan , Jin Yunpeng , Hao Yajuan , Jiang Lin , Hu Yunping , Chen Shili , Liu Fatao , Zhang Yijian , Wu Wenguang , Liu Yingbin
Published: April 2017

Metformin is the most commonly used drug for type 2 diabetes and has potential benefit in treating and preventing cancer. Previous studies indicated that membrane proteins can affect the antineoplastic effects of metformin and may be crucial in the field of cancer research. However, the antineoplastic effects of metformin and its mechanism in gallbladder cancer (GBC) remain largely unknown. In this study, the effects of metformin on GBC cell proliferation and viability were evaluated using the Cell Counting Kit‐8 (CCK‐8) assay and an apoptosis assay. Western blotting was performed to investigate related signaling pathways. Of note, inhibition, knockdown and upregulation of the membrane protein Chloride intracellular channel 1 (CLIC1) can affect GBC resistance in the presence of metformin. Our data demonstrated that metformin apparently inhibits the proliferation and viability of GBC cells. Metformin promoted cell apoptosis and increased the number of early apoptotic cells. We found that metformin can exert growth‐suppressive effects on these cell lines via inhibition of p‐Akt activity and the Bcl‐2 family. Notably, either dysfunction or downregulation of CLIC1 can partially decrease the antineoplastic effects of metformin while upregulation of CLIC1 can increase drug sensitivity. Our findings provide experimental evidence for using metformin as an antitumor treatment for gallbladder carcinoma.
Clinicopathological analysis of methotrexate‐associated lymphoproliferative disorders: Comparison of diffuse large B‐cell lymphoma and classical Hodgkin lymphoma types
Authors: Gion Yuka , Iwaki Noriko , Takata Katsuyoshi , Takeuchi Mai , Nishida Keiichiro , Orita Yorihisa , Tachibana Tomoyasu , Yoshino Tadashi , Sato Yasuharu
Published: April 2017

Patients with rheumatoid arthritis often develop methotrexate‐associated lymphoproliferative disorders (MTX‐LPD) during MTX treatment. MTX‐LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non‐spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX‐LPD (diffuse large B‐cell lymphoma [DLBCL]‐type [n = 34] and classical Hodgkin lymphoma [CHL]‐type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL‐type MTX‐LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL‐type MTX‐LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL‐type and CHL‐type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX‐LPD may be a factor for spontaneous or non‐spontaneous regression after discontinuation of MTX.
Antibacterial and antitubercular evaluation of dihydronaphthalenone‐indole hybrid analogs
Authors: V Praveen Kumar , J Renjitha , C T Fathimath Salfeena , K T Ashitha , S. Keri Rangappa , Varughese Sunil , Balappa Somappa Sasidhar
Published: April 2017

A new series of indole appended dihydronaphthalenone hybrid analogs (5a–t) have been synthesized through the Lewis acid catalyzed Michael addition of indoles to the arylidene/hetero arylidene ketones. All the synthesized derivatives are well characterized through the 1H‐NMR, 13C‐NMR, HRMS spectroscopic techniques, compound 5r was further confirmed through single crystal X‐ray analysis and screened for antibacterial and antitubercular activities. Among the synthesized compounds, the minimum inhibition concentration of 5l (against Escherichia coli) and 5o & 5p (against E. coli & Staphylococcus aureus) was found to be as low as 3.12 μg/ml as compared to the standard antibacterial drug ciprofloxacin 2.5 μg/ml. In antitubercular activity, compounds 5o and 5p with minimum inhibition concentration 6.25 μg/ml were found to be comparable with that of the drugs Pyrazinamide 5 μg/ml and Streptomycin 5 μg/ml. Compounds 5i, 5j, 5m, 5n, 5q, and 5r also showed promising activity against group of organisms tested.
Therapeutic potential of chemically modified siRNA: Recent trends
Authors: Selvam Chelliah , Mutisya Daniel , Prakash Sandhya , Ranganna Kasturi , Thilagavathi Ramasamy
Published: April 2017

Small interfering RNAs (siRNAs) are one of the valuable tools to investigate the functions of genes and are also used for gene silencing. It has a wide scope in drug discovery through in vivo target validation. siRNA therapeutics are not optimal drug‐like molecules due to poor bioavailability and immunogenic and off‐target effects. To overcome the challenges associated with siRNA therapeutics, identification of appropriate chemical modifications that improves the stability, specificity and potency of siRNA is essential. This review focuses on the various chemical modifications and their implications in siRNA therapy.
tRF‐Leu‐CAG promotes cell proliferation and cell cycle in non‐small cell lung cancer
Authors: Shao Yang , Sun Qiangling , Liu Xiaomin , Wang Ping , Wu Renqi , Ma Zhongliang
Published: April 2017

tRNA‐derived RNA fragments (tRFs), non‐coding single‐stranded RNAs with 14–35 nt in length, were found to play important roles in gene regulation, even in carcinogenesis. In this study, we investigated the expression of tRF‐Leu‐CAG in human non‐small cell lung cancer (NSCLC) and its function in the cell proliferation and cell cycle of NSCLC. The expression level of tRF‐Leu‐CAG was detected in NSCLC tissues, cell lines, and sera. tRF‐Leu‐CAG RNA levels were higher in NSCLC tumor tissues than in normal tissues, and also upregulated in NSCLC cell lines. A significant relationship was observed between stage progression and tRF‐Leu‐CAG in NSCLC sera. We found that in H1299 cells, inhibition of tRF‐Leu‐CAG suppressed cell proliferation and impeded cell cycle. AURKA was also repressed with the knockdown of tRF‐Leu‐CAG. Thus, our study revealed that tRF‐Leu‐CAG may be involved in regulating AURKA and could be a new diagnostic marker and potential therapeutic target in NSCLC.
Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial
Authors: Kitaoka Taichi , Tajima Toshihiro , Nagasaki Keisuke , Kikuchi Toru , Yamamoto Katsusuke , Michigami Toshimi , Okada Satoshi , Fujiwara Ikuma , Kokaji Masayuki , Mochizuki Hiroshi , Ogata Tsutomu , Tatebayashi Koji , Watanabe Atsushi , Yatsuga Shuichi , Kubota Takuo , Ozono Keiichi
Published: April 2017

Objective

Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan.

Design

Open‐label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015.

Patients

Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1).

Measurements

Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development.

Results

Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low‐calcium and/or low‐phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved.

Conclusion

Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.
Genetics of hypertrophic cardiomyopathy: A review of current state
Authors: Sabater‐Molina M. , Pérez‐Sánchez I. , Hernández del Rincón J.P. , Gimeno J.R.
Published: April 2017

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. HCM is a highly complex and heterogeneous disease regarding not only the number of associated mutations but also the severity of phenotype, symptom burden, and the risk of complications, such as heart failure and sudden death. The penetrance is incomplete and it is age and gender dependent. It is accepted as a disease of the sarcomere. Sixty percent of HCM cases carry mutations in 1 of 8 sarcomere protein genes, mainly non‐sense MYBPC3 and missense MYH7 variants. Young patients with severe phenotype and other clinical features are included in proposed scores for prediction of high positive genetic result. The number of genes reported as disease‐causing has increased in the last few years, in some cases without robust evidence. Currently available in silico tools are not always useful for differentiation between benign and deleterious variants. There is enough information on genotype‐phenotype correlations to start understanding the mechanisms of the disease. Genetic and environmental modifiers have been explored with some interesting insights from miRNA studies with potential as biomarkers and therapeutic agents. There is an additional value of genetic testing in HCM for prognosis. Knowledge about genetics and functional studies are the basis of near future therapies.
Galactose‐1‐phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long‐term complications and allelic variants
Authors: Viggiano E. , Marabotti A. , Politano L. , Burlina A.
Published: April 2017

Galactosemia type 1 is an autosomal recessive disorder of galactose metabolism, determined by a deficiency in the enzyme galactose‐1‐phosphate uridyltransferase (GALT). GALT deficiency is classified as severe or variant depending on biochemical phenotype, genotype and potential to develop acute and long‐term complications. Neonatal symptoms usually resolve after galactose‐restricted diet; however, some patients, despite the diet, can develop long‐term complications, in particular when the GALT enzyme activity results absent or severely decreased. The mechanisms of acute and long‐term complications are still discussed and several hypotheses are presented in the literature like enzymatic inhibition, osmotic stress, endoplasmic reticulum stress, oxidative stress, defects of glycosylation or epigenetic modification. This review summarizes the current knowledge of galactosemia, in particular the putative mechanisms of neonatal and long‐term complications and the molecular genetics of GALT deficiency.
Large gene panel sequencing in clinical diagnostics—results from 501 consecutive cases
Authors: Pajusalu S. , Kahre T. , Roomere H. , Murumets Ü. , Roht L. , Simenson K. , Reimand T. , Õunap K.
Published: April 2017

Background

In addition to whole exomes, large gene panels of clinically associated genes are used as high‐throughput sequencing tests in many clinical centers, but their clinical utility has been much less investigated.

Materials and Methods

Here we report the results of the 501 first unselected cases for whom TruSight One panel (Illumina Inc., San Diego, California) was sequenced as a clinical diagnostic test for a variety of indications in our department. The analysis was restricted to virtual subpanels based on referral forms, where doctors were asked to list candidate genes or select one from predefined larger panels.

Results

A probable or definite pathogenic finding was reported in 26.3% of cases. In 238 samples for whom 1 to 9 genes were requested for analysis, the diagnostic yield was significantly higher compared to other 263 cases for whom larger subpanels were requested (31.5% vs 21.7%, respectively, P = .016). Detected mutations included single nucleotide variants, small insertions and deletions, and larger copy number variants. Out of 157 reported mutations, 67 were previously undescribed.

Conclusion

The clinical utility of large gene panel sequencing in the context of other genetic diagnostic tests is discussed in detail.
Guided bone regeneration with particulate vs. block xenogenic bone substitutes: a pilot cone beam computed tomographic investigation
Authors: Benic Goran I. , Thoma Daniel S. , Jung Ronald E. , Sanz-Martin Ignacio , Unger Silvan , Cantalapiedra Antonio , Hämmerle Christoph H.F.
Published: April 2017

Aim

To test whether an equine bone substitute block used for guided bone regeneration (GBR) of peri‐implant defects differs from bovine block or particulate bone substitutes regarding the hard and soft tissue contours of the augmented ridge.

Material & Methods

Two semi‐saddle bone defects were prepared in each side of the mandible of eight dogs, and one titanium implant was inserted into every defect. The defects were randomly allocated to receive one of the following treatments: bone augmentation by GBR using (1) particulate deproteinized bovine bone mineral (DBBM) + a collagen membrane (CM), (2) block DBBM + CM, (3) equine bone substitute block + CM, and (4) empty controls. After 4 months, the jaws were scanned by means of cone beam computed tomography (CBCT). CBCT analysis was performed in one central and two lateral (mesial and distal) regions of interest (ROI) of each site evaluating the horizontal thickness of the augmented hard tissue (HThard tisue) and the total thickness of hard and soft tissue (HTtotal). The Wilcoxon‐Pratt signed rank test was used for statistical analysis.

Results

In the majority of ROIs, equine and bovine blocks rendered significantly higher values in HThard tissue and HTtotal than controls (P < 0.05). Generally, equine blocks reached the highest values in HThard tissue and HTtotal followed by DBBM blocks and particulate DBBM. The differences in HThard tissue and HTtotal between GBR groups were not statistically significant (P > 0.05). In the central ROI, HThard tissue at the level of the implant shoulder measured 1.7 ± 1.4 mm for equine blocks, 1.7 ± 1.0 mm for DBBM blocks, 0.9 ± 1.2 mm for particulate DBBM, and 0 ± 0 mm for controls. The corresponding values in the lateral ROI reached 1.9 ± 1.1 mm for equine blocks, 1.2 ± 0.8 mm for DBBM blocks, 1.0 ± 0.9 mm for particulate DBBM, and 0 ± 0 mm for controls.

Conclusions

GBR with bone substitute blocks lead to higher ridge dimensions than empty controls. The equine block with CM rendered the most favorable outcomes in hard and soft tissue contours followed by DBBM block and DBBM granulate with CM.
Analyse der Mobilitätsbereitschaft von Patienten unter Berücksichtigung individueller Merkmale und zweier Beispielindikationen
Authors: Augustin Jobst , Schäfer Ines , Augustin Matthias , Zander Nicole
Published: April 2017

Hintergrund

In der Versorgungsplanung wird davon ausgegangen, dass Patienten den nächstgelegenen Arzt aufsuchen. Die Praxis zeigt jedoch, dass beim Arztbesuch oftmals ein höherer Aufwand in Kauf genommen wird, als notwendig. Es soll der Frage nachgegangen werden, unter welchen Umständen ein Patient einen Mehraufwand in Kauf nimmt und welchen Einfluss soziodemographische und klinische Merkmale haben.

Methodik

Die Datenerhebung erfolgte mittels einer multizentrischen Querschnittsstudie am Beispiel niedergelassener und in einer Universitätsklinik tätigen Dermatologen in Hamburg. Es wurden n = 309 Patienten mit Psoriasis und chronischen Wunden u. a. zu ihrem Mobilitätsverhalten und Krankheitsbild befragt. Die Datenauswertung erfolgte anhand deskriptiver und multivariater Verfahren.

Ergebnisse

Eine hohe Bereitschaft, einen Mehraufwand in Kauf zu nehmen, wird vor allem durch die Kompetenz sowie das Leistungsangebot des Arztes bestimmt. Vergleiche beider Diagnosen zeigten, dass Psoriasis‐Patienten prinzipiell weitere Anfahrtswege hatten als die Wundpatienten. Unter den Psoriasis‐Patienten konnte u. a. der Schulabschluss als signifikanter Prädiktor für den Mehraufwand ermittelt werden. Bei den Wundpatienten war beispielsweise die Wundgröße (Schweregrad) ausschlaggebend.

Schlussfolgerungen

Es zeigte sich ein komplexes Mobilitätsverhalten der Patienten, das von zahlreichen persönlichen, aber auch klinischen Merkmalen beeinflusst wird. Je nach Diagnose und individuellen Präferenzen kann der Mehraufwand u. a. durch den Schweregrad der Erkrankung erklärt werden. Weitere Analysen sind notwendig, um detailliertere Aussagen zu erhalten.
Subklinische Enthesitis bei Nagelpsoriasis‐Patienten: eine Fall‐Kontroll‐Studie
Authors: Klaassen Karlijn M.G. , Ploegmakers Marieke J.M. , van de Kerkhof Peter C.M. , Klein Willemijn M. , Pasch Marcel C.
Published: April 2017

Hintergrund

Bei Patienten mit Nagelpsoriasis ist die Prävalenz der Psoriasis‐Arthritis erhöht. Die pathogenetische Beziehung zwischen diesen beiden Störungen ist jedoch noch unklar. Als Epizentrum der Krankheiten wurden Enthesen vorgeschlagen, die die Pathogenese auf anatomischer Ebene erklären könnten.

Zielsetzung

Aufklärung der Hypothese einer anatomischen Verbindung zwischen Nagelpsoriasis und Psoriasis‐Arthritis mit der Extensor‐Enthese des distalen Interphalangealgelenkes als Epizentrum.

Verfahren

Wir führten eine Querschnitts‐Kohortenstudie durch, bei der die Enthesen der distalen interphalangealen (DIP)‐Gelenke von Patienten mit Fingernagel‐­Psoriasis (n = 54), von Psoriasis‐Patienten ohne Nagelbeteiligung (n = 32), und von gesunden Kontrollpersonen (n = 32) mit dreidimensionalem Ultraschall visualisiert wurden. ­Patienten mit Nagelpsoriasis unterzogen sich nach einem Jahr erneut bildgebenden Untersuchungen.

Ergebnisse

Personen mit Nagelpsoriasis hatten signifikant stärkere radiale Enthesien als Psoriasis‐Patienten ohne Nagelbeteiligung. Allerdings gab es keine signifikanten Unterschiede bezüglich der Enthesenstärke zwischen betroffenen und nicht betroffenen benachbarten Nägeln (1,297 mm vs. 1,253 mm, p = 0,13). Die Nachuntersuchung nach einem Jahr zeigte keine signifikanten Unterschiede in der Stärke der Enthesen in Korrelation mit der Nagelpsoriasis‐Aktivität.

Schlussfolgerungen

Die vorliegende Studie liefert Hinweise auf eine subklinische Enthesitis auf der Ebene des DIP‐Gelenks bei Patienten mit Nagelpsoriasis. Allerdings konnte eine anatomische Korrelation zwischen Nagelpsoriasis und Psoriasis‐Arthritis nicht bestätigt werden.
Factors associated with improved glycemic control following continuous subcutaneous insulin infusion therapy in patients with type 2 diabetes uncontrolled with bolus‐basal insulin regimens: An analysis from the OpT2mise randomized trial
Authors: Metzger Muriel , Castañeda Javier , Reznik Yves , Giorgino Francesco , Conget Ignacio , Aronson Ronnie , de Portu Simona , Runzis Sarah , Lee Scott W. , Cohen Ohad
Published: April 2017

This analysis investigated factors associated with the decrease in HbA1c in patients receiving continuous subcutaneous insulin infusion (CSII) in the OpT2mise randomized trial. In this study, patients with type 2 diabetes and HbA1c >8% following multiple daily injections (MDI) optimization were randomized to receive CSII (n = 168) or MDI (n = 163) for 6 months. Patient‐related and treatment‐related factors associated with decreased HbA1c in the CSII arm were identified by univariate and multivariate analyses. CSII produced a significantly greater reduction in HbA1c than MDI, and the treatment difference increased with baseline HbA1c. In the CSII arm, the only factors significantly associated with decreased HbA1c were higher baseline HbA1c (P < .001), geographical region (P < .001), higher educational level (P = .012), higher total cholesterol level (P = .002), lower variability of baseline glucose values on continuous glucose monitoring (P < .001) and the decrease in average fasting self‐monitored blood glucose at 6 months (P < .001). These findings suggest that CSII offers an option to improve glycemic control in a broad range of patients with type 2 diabetes in whom control cannot be achieved with MDI.

OpT2mise ClinicalTrials.gov number: NCT01182493 (https://clinicaltrials.gov/).
Market basket analysis of grasshopper (Orthoptera: Acrididae) assemblages in eastern Wyoming: a 17‐year case study using associative analysis for ecological insights into grasshopper outbreaks
Authors: SMITH DOUGLAS I. , CURRAN MICHAEL F. , LATCHININSKY ALEXANDRE V.
Published: April 2017

1. This study utilised an associative analysis (AA) technique named market basket analysis (MBA) to investigate whether particular grasshopper (Orthoptera: Acrididae) species associations are common during outbreaks (>9.6 grasshoppers m−2) that last >3 years. This study is the first of its kind to use MBA on animal communities.

2. A subset of the 17 years of grasshopper density data from the Wyoming Grasshopper Survey Dataset was used to explore associations among grasshopper species.

3. Associations of certain species were found with over 80% confidence. Life‐history traits of those species commonly found together were examined and compared (a posteriori), creating opportunities to hypothesise certain ecological relationships (e.g. interspecific competition, indirect mutualism) for future studies.

4. This case study shows that further MBA analysis of grasshopper assemblages should prove useful in discovering ecological relationships of grasshopper species during outbreaks. Preliminary examples are demonstrated.
Genomewide association study on monoclonal gammopathy of unknown significance (MGUS)
Authors: Thomsen Hauke , Campo Chiara , Weinhold Niels , da Silva Filho Miguel Inacio , Pour Luděk , Gregora Evžen , Vodicka Pavel , Vodickova Ludmila , Hoffmann Per , Nöthen Markus M , Jöckel Karl‐Heinz , Langer Christian , Hajek Roman , Goldschmidt Hartmut , Hemminki Kari , Försti Asta
Published: April 2017

Objectives

To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM).

Methods

We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta‐analysis were also tested in the MGUS GWAS.

Results

In GWAS, we identified 10 loci contributing to development of MGUS at P‐value threshold of 10−5. The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10−9), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS.

Conclusions

These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
An examination of biochemical parameters and their association with response to ketogenic dietary therapies
Authors: Schoeler Natasha E. , Bell Gail , Yuen Alan , Kapelner Adam D. , Heales Simon J. R. , Cross J. Helen , Sisodiya Sanjay
Published: April 2017

Objective

In the absence of specific metabolic disorders, accurate predictors of response to ketogenic dietary therapies (KDTs) for treating epilepsy are largely unknown. We hypothesized that specific biochemical parameters would be associated with the effectiveness of KDT in humans with epilepsy. The parameters tested were β‐hydroxybutyrate, acetoacetate, nonesterified fatty acids, free and acylcarnitine profile, glucose, and glucose‐ketone index (GKI).

Methods

Biochemical results from routine blood tests conducted at baseline prior to initiation of KDT and at 3‐month follow‐up were obtained from 13 adults and 215 children with KDT response data from participating centers. One hundred thirty‐two (57%) of 228 participants had some data at both baseline and 3 months; 52 (23%) of 228 had data only at baseline; 22 (10%) of 228 had data only at 3 months; and 22 (10%) of 228 had no data. KDT response was defined as ≥50% seizure reduction at 3‐month follow‐up.

Results

Acetyl carnitine at baseline was significantly higher in responders (p < 0.007). It was not associated with response at 3‐month follow‐up. There was a trend for higher levels of free carnitine and other acylcarnitine esters at baseline and at 3‐month follow‐up in KDT responders. There was also a trend for greater differences in levels of propionyl carnitine and in β‐hydroxybutyrate measured at baseline and 3‐month follow‐up in KDT responders. No other biochemical parameters were associated with response at any time point.

Significance

Our finding that certain carnitine fractions, in particular baseline acetyl carnitine, are positively associated with greater efficacy of KDT is consistent with the theory that alterations in energy metabolism may play a role in the mechanisms of action of KDT.
Derivation and initial validation of a surgical grading scale for the preliminary evaluation of adult patients with drug‐resistant focal epilepsy
Authors: Dugan Patricia , Carlson Chad , Jetté Nathalie , Wiebe Samuel , Bunch Marjorie , Kuzniecky Ruben , French Jacqueline
Published: April 2017

Objective

Presently, there is no simple method at initial presentation for identifying a patient's likelihood of progressing to surgery and a favorable outcome. The Epilepsy Surgery Grading Scale (ESGS) is a three‐tier empirically derived mathematical scale with five categories: magnetic resonance imaging (MRI), electroencephalography (EEG), concordance (between MRI and EEG), semiology, and IQ designed to stratify patients with drug‐resistant focal epilepsy based on their likelihood of proceeding to resective epilepsy surgery and achieving seizure freedom.

Methods

In this cross‐sectional study, we abstracted data from the charts of all patients admitted to the New York University Langone Medical Center (NYULMC) for presurgical evaluation or presented in surgical multidisciplinary conference (MDC) at the NYU Comprehensive Epilepsy Center (CEC) from 1/1/2007 to 7/31/2008 with focal epilepsy, who met minimal criteria for treatment resistance. We classified patients into ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favorable candidates). Three cohorts were evaluated: all patients, patients presented in MDC, and patients who had resective surgery. The primary outcome measure was proceeding to surgery and seizure freedom.

Results

Four hundred seven patients met eligibility criteria; 200 (49.1%) were presented in MDC and 113 (27.8%) underwent surgery. A significant difference was observed between Grades 1 and 3, Grades 1 and 2, and Grades 2 and 3 for all presurgical patients, and those presented in MDC, with Grade 1 patients having the highest likelihood of both having surgery and becoming seizure‐free. There was no difference between Grades 1 and 2 among patients who had resective surgery.

Significance

These results demonstrate that by systematically using basic information available during initial assessment, patients with drug‐resistant epilepsy may be successfully stratified into clinically meaningful groups with varied prognosis. The ESGS may improve communication, facilitate decision making and early referral to a CEC, and allow patients and physicians to better manage expectations.
Psychiatric lifetime diagnoses are associated with a reduced chance of seizure freedom after temporal lobe surgery
Authors: Koch‐Stoecker Steffi C. , Bien Christian G. , Schulz Reinhard , May Theodor W.
Published: April 2017

Objective

To examine whether psychiatric comorbidity is a predictor of long‐term seizure outcome following temporal lobe epilepsy surgery.

Methods

A sample of 434 adult patients who received temporal lobe resection to treat epilepsy between 1991 and 2009 and were psychiatrically assessed before surgery were followed for 2 years to assess seizure outcome. Stepwise multivariate logistic regression analyses were used to assess the impact of psychiatric variables on complete seizure freedom (Engel class IA), and freedom from disabling seizures (Engel class I). Lifetime histories of three psychiatric syndromes (PS: psychosis; depression; other) and five personality disorders (PD: DSM‐IV Clusters A, B, and C; organic personality disorder; other) were considered as predictors, complemented by age at onset, duration of epilepsy, type of lesion (mesiotemporal sclerosis vs. other), and year of surgery.

Results

Seizure‐freedom rates were significantly higher (p < 0.001) in patients with no history of PS or PD (N = 138; Engel class IA: 61.6%; Engel class I: 87.7%) than in those with any PS or PD (N = 296; Engel class IA: 39.5%; Engel class I: 58.8%). Particularly low seizure‐freedom rates were found in patients with a diagnosis of psychosis (N = 32, Engel class IA: 21.9%; Engel class I: 40.6%), organic PD (N = 48, Engel class IA: 25.0%; Engel class I: 35.4%) or a double diagnosis of PS plus PD (N = 97; Engel class IA: 27.8%; Engel class I: 45.5%). No other variables emerged as significant risk factors in multivariate logistic regression analyses.

Significance

Patients with and without psychiatric comorbidities can benefit from temporal lobe epilepsy surgery; however, psychiatric comorbidities are negatively associated with postoperative seizure‐freedom rates. Surgical outcome is related to the type and extent of preoperative psychiatric morbidity, which underscores the prognostic value of presurgical psychiatric evaluation. The data support the argument that there are common pathogenetic mechanisms underlying both epilepsy and psychiatric conditions.
Intracerebral delivery of the M2 polarizing cytokine interleukin 13 using mesenchymal stem cell implants in a model of temporal lobe epilepsy in mice
Authors: Ali Idrish , Aertgeerts Stephanie , Le Blon Debbie , Bertoglio Daniele , Hoornaert Chloe , Ponsaerts Peter , Dedeurwaerdere Stefanie
Published: April 2017

Objectives

Neuroinflammation plays a critical role in the pathophysiology of mesial temporal lobe epilepsy. We aimed to evaluate whether intracerebral transplantation of interleukin 13–producing mesenchymal stem cells (IL‐13 MSCs) induces an M2 microglia/macrophage activation phenotype in the hippocampus with an epileptogenic insult, thereby providing a neuroprotective environment with reduced epileptogenesis.

Methods

Genetically engineered syngeneic IL‐13 MSCs or vehicle was injected within the hippocampus 1 week before the intrahippocampal kainic acid–induced status epilepticus (SE) in C57BL/6J mice. Neuroinflammation was evaluated at disease onset as well as during the chronic epilepsy period (9 weeks). In addition, continuous video–electroencephalography (EEG) (vEEG) monitoring was obtained during the chronic epilepsy period (between 6 and 9 weeks after SE).

Results

Evaluation of vEEG recordings suggested that IL‐13 MSC grafts did not affect the severity and duration of SE or the seizure burden during the chronic epilepsy period, when compared to the vehicle treated SE mice. An M2‐activation phenotype was induced in microglia/macrophages that infiltrated the ‐13 MSC graft site, as evidenced by the arginase1 expression at the graft site at both the 2‐week and 9‐week time‐points. However, M2‐activated immune cells were rarely observed outside the graft site and, accordingly, the neuroinflammatory response or cell loss related to SE induction was not altered by IL‐13 MSC grafting. Moreover, an increase in the proportion of F4/80+ cells was observed in the IL‐13 MSC group compared to the controls.

Significance

Our data suggest that MSC‐based IL‐13 delivery to induce M2 glial activation does not provide any neuroprotective or disease‐modifying effects in a mouse model of epilepsy. Moreover, use of cell grafting to deliver bioactive compounds for modulating neuroinflammation may have confounding effects in disease pathology of epilepsy due to the additional immune response generated by the grafted cells.
Budgetary Stewardship, Innovation and Working Culture: Identifying the Missing Ingredient in English and Welsh Local Authorities’ Recipes for Austerity Management
Authors: Ferry Laurence , Coombs Hugh , Eckersley Peter
Published: April 2017

Drawing on fieldwork with 70 local authorities in England and Wales, this paper builds on previous studies of austerity management by highlighting the importance of organisational cultures to achieving strategic objectives. It finds that, in line with their prevailing ‘belief system’ of budgetary stewardship, local authorities in both countries are holding down input costs to deal with austerity. However, the scale of funding cuts means that this strategy is unlikely to be successful over the longer term. Instead, they need greater freedom to generate revenue, in order to facilitate innovation and develop more sustainable business practices and service models.
The Strategic Options of Supreme Audit Institutions: The Case of Four Nordic Countries
Authors: Jeppesen Kim K. , Carrington Thomas , Catasús Bino , Johnsen Åge , Reichborn‐Kjennerud Kristin , Vakkuri Jarmo
Published: April 2017

Based on the theory of professional competition, this paper identifies and investigates four strategic options of supreme audit institutions (SAIs) through a case study of four Nordic national audit offices: a performance auditing strategy; a financial auditing strategy; a portfolio strategy; and a hybrid strategy. The analysis of the Nordic SAIs shows that while one SAI appears to have adopted a hybrid strategy, the portfolio strategy has been chosen by the three other SAIs, although with some variations in the portfolio. The paper concludes by discussing the implications of these strategic options for public sector auditing.
Neutrophil extracellular traps can serve as platforms for processing and activation of IL‐1 family cytokines
Authors: Clancy Danielle M. , Henry Conor M. , Sullivan Graeme P. , Martin Seamus J.
Published: April 2017

Activated neutrophils can undergo a mode of regulated cell death, called NETosis, that results in the extrusion of chromatin into the extracellular space, thereby acting as extracellular traps for microorganisms. Neutrophil‐derived extracellular traps (NETs) are comprised of DNA decorated with histones, antimicrobial proteins and neutrophil granule proteases, such as elastase and cathepsin G (Cat G). NET‐associated factors are thought to enhance the antimicrobial properties of these structures and localisation of antimicrobial molecules on NETs may serve to increase their local concentration. Because neutrophil‐derived proteases have been implicated in the processing and activation of several members of the extended interleukin (IL)‐1 family, we wondered whether neutrophil NETs could also serve as platforms for the activation of proinflammatory cytokines. Here, we show that neutrophil NETs potently processed and activated IL‐1α as well as IL‐36 subfamily cytokines through NET‐associated Cat G and elastase. Thus, in addition to their role as antimicrobial traps, NETs can also act as local sites of cytokine processing and activation.
An Empirical Study of International Spillover of Sovereign Risk to Bank Credit Risk
Authors: Poon Winnie P. H. , Shen Jianfu , Burnett John E.
Published: April 2017

The severity and complexity of the recent financial crisis has motivated the need for understanding the relationships between sovereign ratings and bank credit ratings. This is the first study to examine the impact of the “international” spillover of sovereign risk to bank credit risk through both a ratings channel and an asset holdings channel. In the first case, the downgrade of sovereign ratings in GIIPS (Greece, Italy, Ireland, Portugal, and Spain) countries leads to rating downgrades of banks in the peripheral countries. The second channel indicates that larger asset holdings of GIIPS debt increases the credit risk of cross‐border banks, and hence, the probabilities of downgrade.