bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanical Properties and Leaching Characteristics of Geopolymer‐Solidified/Stabilized Lead‐Contaminated Soil
Authors: Li Yuan-Yuan , Zhang Ting-Ting , Jia Shi-Bo , Liu Jiang , Quan Xian-Hao , Zheng Wei
Published: May 2019

Ordinary Portland cement (OPC) is widely used in the solidification/stabilization of Pb‐contaminated soils. However, many studies have suggested that the high content of Pb would degrade the mechanical properties of OPC‐solidified/stabilized soils. This paper presents a new binder, geopolymer fine aggregate (GFA), composed of ground granulated blast furnace slag, fly ash, CaO, and Na2SiO3. For comparison, OPC was used as a conventional binder. Mechanical properties and leaching characteristics are typically used to evaluate the effects of binders on solidified/stabilized soils. Nevertheless, limited information on the mechanical properties and leaching characteristics of the GFA‐solidified/stabilized soils is available. This study thus investigated the mechanical properties and leaching characteristics of geopolymer‐solidified/stabilized Pb‐contaminated soil. Unconfined compressive strength test, permeability test, synthetic precipitation leaching procedure, simplified bioaccessibility extraction, phytoavailability extraction (with diethylene‐triamine penta‐acetic acid), sequential extraction procedure, mercury intrusion porosimetry, and scanning electron microscopy (SEM) were performed on OPC‐ and GFA‐solidified/stabilized soil. The results showed that the GFA presented a better effect on the mechanical properties and leachability of the solidified/stabilized soils than the OPC‐solidified/stabilized soils. The GFA‐solidified/stabilized soil displayed considerably lower leachability, bioaccessibility, and phytoavailability of Pb and higher mechanical properties and chemical stability than the OPC counterpart. This study demonstrated that GFA had a better effect than OPC on the solidification/stabilization of Pb‐contaminated soils.
Experimental Study on Corrosion of Anchored Rock Mass for Half‐Through Intermittent Joints
Authors: Ding Wantao , Li Mingjiang , Wang Mingbin , Chen Rui , Wang Yang , Chen Lei
Published: May 2019

Make crackled mortar test block to simulate jointed rock mass reinforced by anchor bars. Computational model of corrosion penetration at different load times can be obtained by corrosion acceleration through electrochemistry. Through observation of anchor bar after corrosion, it is found that primary corrosion is mainly pitting; however, with the development of corrosion, corrosion moves along etch pit to the upper and lower surfaces so as to form partial corrosion. Meanwhile, computational formula of pitting ratio is put forward on the basis of mass loss rate. It is found that, through the pulling out experiment of anchor bar corrosion, corrosion has remarkable influence on anchoring performance of anchor bar; meanwhile, different pitting ratios have different influences on trends of ultimate bond strength, for example, when pitting ratio is bigger (between 9% and 30%), the biggest decreasing rate of bond strength is obviously lower than that under lower pitting ratio (from 1.5% to 5%). According to linear fitting of experimental data, the relationship curve of K, ultimate bond strength ratio, and pitting ratio can be obtained so as to provide basis for judgement of anchoring performance loss in practical engineering.
Multiple of Solutions for Nonlocal Elliptic Equations with Critical Exponent Driven by the Fractional p-Laplacian of Order s
Authors: Khiddi M.
Published: May 2019

In this paper, we study the existence of infinitely many weak solutions for nonlocal elliptic equations with critical exponent driven by the fractional p-Laplacian of order s. We show the above result when λ>0 is small enough. We achieve our goal by making use of variational methods, more specifically, the Nehari Manifold and Lusternik-Schnirelmann theory.
Actantial Narrative Schema in Emergency Response Process Modeling for Aircraft Fires
Authors: Luo Xingna , Zhang Qingsong , Jin Yijia
Published: May 2019

Analyzing the emergency response process and time characteristics after aircraft fires is extremely important for airport safety. Due to nonprocess-related elements, the Petri net model of the emergency process is generally complex and difficult to revise and expand. In this study, the actantial model was used to analyze the semantic structure of emergency actions in the Petri net emergency process model, and the actantial-timed Petri net (A-TPN) hybrid model was proposed for problem solving. The emergency response process of aircraft fires was analyzed as a case study to explain the application steps of the A-TPN hybrid model. First, the types of elements should be divided into process-related elements and nonprocess-related elements. Process-related elements include status elements and narrative elements, which are equivalent to the places and transitions in the Petri net model. Second, the workflow constructed by the status and narrative elements is converted into a Petri net. An actantial model is used to analyze the semantic structure of emergency response action narratives. Third, according to the analysis of the actants of the helper and the opponent, emergency action time characteristics are considered to construct the A-TPN hybrid model and analyze the time performance of the emergency response process. In this way, an emergency response plan can be analyzed and promoted for smart development.
Ectopic ACTH Syndrome Emerging 5 Years after the Diagnosis of Neuroendocrine Tumor
Authors: Liu Minghao , Hamele-Bena Diane , Ausiello John , Page-Wilson Gabrielle
Published: May 2019

Ectopic ACTH syndrome (EAS) arising years after the diagnosis of a neuroendocrine tumor (NET) is exceedingly rare. We describe a case of EAS occurring five years after the diagnosis of a metastatic lung NET in a 61-year-old woman. She presented with severe hypokalemia but was not overtly Cushingoid on exam. Serum cortisol was 61mcg/dL after an overnight 1mg dexamethasone suppression test (<1.8mcg/dL) and urinary free cortisol was 7544 mcg/24h (<45mcg/24h), establishing the diagnosis of Cushing’s syndrome. Plasma levels of peptides which have been associated with EAS, Agouti-related peptide (AgRP) and the ACTH precursors POMC (31-kDa) and pro-ACTH (22-kDa), were elevated. Metyrapone was initiated, but hypercortisolism persisted and the patient succumbed to pneumonia shortly after presentation. Retrospective examination of biopsy tissues showed rare ACTH immunoreactivity at the time of initial diagnosis, followed by staining in a greater proportion of cells as the disease progressed, consistent with EAS arising years after the diagnosis of NET. Given the increase in mortality associated with EAS, this unusual case highlights the importance of early detection and raises the possibility that early immunohistochemical stains for ACTH and measurements of ACTH precursors may facilitate the identification of NETs at high risk for EAS.
Changes in Gait Variables in Patients with Intermittent Claudication
Authors: Pietraszewski Bogdan , Woźniewski Marek , Jasiński Ryszard , Struzik Artur , Szuba Andrzej
Published: May 2019

Objective. Intermittent claudication (IC) is a pathological symptom with a particular effect on human gait patterns. Therefore, analyzing these patterns can facilitate rehabilitation or treatment through comparison of the values of kinematic and kinetic variables of patients with the normal values of healthy people. Therefore, the aim of this study was to find differences in the values of gait variables between patients with IC and healthy people. Methods. The study included 98 patients diagnosed with peripheral arterial disease with IC. The patients traveled a distance of 6 m at a voluntary gait velocity. Ground reaction forces while the foot contacted the ground and kinematic variables of lower limb movements were recorded. The values of normal gait variables were computed based on the results obtained in a group of 30 healthy people. Results. Patients used a gait velocity below the norm for healthy people. The velocity during the lower limb swing and the step and stride length in patients with IC were below the norm. Differences were also found in the ranges of motion between patients with IC and healthy people for the pelvic obliquity, pelvic rotation, hip flexion-extension, hip abduction-adduction, hip internal-external rotation, knee flexion-extension, ankle dorsi-plantar flexion, and foot progression angles. Conclusions. The presented kinematic and kinetic characteristics measured by gait variables suggest differences between patients with IC and healthy people. Considering kinematic and kinetic gait variables during the rehabilitation process would facilitate the development of a more economic gait technique (with increased stride length and range of motion in the lower limb joints) to obtain the desired rehabilitation effects. Patients with IC should receive rehabilitation oriented towards improving mobility and increasing muscle strength in selected lower limb joints to increase gait velocity and stride length.
Bearing Fault Identification Method Based on Collaborative Filtering Recommendation Technology
Authors: Wang Guangbin , He Yinghang , Peng Yanfeng , Li Haijiang
Published: May 2019

As the amount of data generated by monitoring the condition of rolling bearings is increasing, it has become a research hotspot in recent years to dig valuable information from massive data and identify unknown bearing states. In Internet technology, the collaborative filtering recommendation technology provides users with an intelligent means of filtering information. Aiming at the difficulty in designing the recommendation system scoring matrix in the field of fault diagnosis, we first obtain the bearing feature matrix based on the wavelet frequency band energy and then design a scoring matrix that accurately describes the bearing state; finally, we design a joint scoring matrix for bearing state identification by combining the matrix of these two different characteristics. After that, a collaborative filtering recommendation system for bearing state identification is proposed based on matrix factorization‐based collaborative filtering and gradient descent algorithm. This method is used to identify and verify two types of fault data of rolling bearing: different position faults and different types of faults on the outer ring. The results show that the accuracy of the two identifications has reached more than 90%.
LncRNA HOXA11-AS Promotes Proliferation and Cisplatin Resistance of Oral Squamous Cell Carcinoma by Suppression of miR-214-3p Expression
Authors: Wang Xiaoyan , Li Hong , Shi Jing
Published: May 2019

Drug resistance to platinum limited therapeutic options for oral squamous cell carcinoma (OSCC). In the current study, we investigated the role of lncRNA HOMEOBOX A11 (HOXA11) antisense RNA (HOXA11-AS) in OSCC resistance to cisplatin (CDDP). We used clinical tissues and OSCC cell lines and induced CDDP resistance in OSCC cells. Gain and loss of function were performed in OSCC-resistant cells. Xenograft mice were also established. HOXA11-AS expression was increased in OSCC clinical tissues and cell lines and upregulated in CDDP-resistant cells. Upregulation of HOXA11-AS promoted proliferation in CDDP-sensitive cells and inhibited CDDP-induced cytotoxicity. In contrast, downregulation of HOXA11-AS decreased proliferation in CDDP-resistant cells and increased CDDP-induced cytotoxicity. Knockdown of HOXA11-AS inhibited the tumor growth in xenograft mice injected by CDDP. Downregulation of HOXA11-AS increased apoptosis and caspase 3 activities in CDDP-resistant OSCC cells. Bioinformatics, reporter assay, and loss and gain of function assay indicated that HOXA11-AS and miR-214-3p could negatively regulate each other. miR-214-3p was decreased in OSCC clinical tissues and cell lines. We further revealed that proto-oncogene serine/threonine-protein kinase (PIM1) was the target of miR-214-3p. PIM1 expression could be negatively regulated by miR-214-3p and positively regulated by HOXA11-AS. Inhibition of PIM1 suppressed anti-miR-214-3p-induced increase of cell proliferation and decrease of apoptosis. In summary, HOXA11-AS was identified to facilitate CDDP-resistance in OSCC and miR-214-3p/PIM1 was found to be the downstream target of HOXA11-AS. The findings highlight the importance of HOXA11-AS/miR-214-3p/PIM1 axis in the drug resistance of OSCC and provide potential targets for improving chemotherapy of OSCC.
Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation
Authors: Kawai Yohei , Narita Yuji , Yamawaki-Ogata Aika , Usui Akihiko , Komori Kimihiro
Published: May 2019

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.
Continuum Damage Modeling of Hydraulic Fracture from Perforations in Horizontal Wells
Authors: Sun Feng , Jia Peng , Xue Shifeng
Published: May 2019

The perforations play an important role in determining the near‐wellbore fracture geometry during the stimulation phase. To address the impact of perforations on fracture geometry in horizontal wells, a 3D coupled hydromechanical finite element model is developed and employed. Based on the theory of continuum damage mechanics, scalar damage variable governs the degradation of the stiffness of the solid. Damage affects the crack element modeling that is used to consider crack behavior and construct a crack‐tracking algorithm to simulate propagation. The model was validated against the analytical solutions and perforation fracture experiments. The results indicate that perforation can be used to control the fracturing pressure and propagation behavior of the initial fracture, which has a further effect on the fracture geometry of near‐wellbore region in horizontal wells. Optimizing perforation parameters can direct the propagation of the initial fracture toward the preferred fracture plane. The results demonstrate an improved capability to depict the 3D near‐wellbore fracture geometry and fracture propagation with a continuum damage model. The model enables the optimization of orientations and perforation parameters, so that most efficient perforating completions can be designed for hydraulic fracture stimulation.
Impacts of Backlash on Nonlinear Dynamic Characteristic of Encased Differential Planetary Gear Train
Authors: Zhu Zengbao , Cheng Longchao , Xu Rui , Zhu Rupeng
Published: May 2019

A multifreedom tensional nonlinear dynamic equation of encased differential planetary gear train with multibacklash and time‐varying mesh stiffness was developed in the present research. The nonlinear dynamic response was obtained by solving the formulated nonlinear dynamic equation, and the impacts of backlash on dynamic characteristics of the gear train were then analyzed by combining time process diagram, phase diagram, and Poincaré section. The results revealed that bilateral shock in meshing teeth was caused due to smaller backlash, thus causing dramatic changes in meshing force; hence, the gears were found to be in a chaotic state. Further, during stable motion state, no contact between intermeshing teeth with bigger backlash was noticed; thus, they were in a stable quasiperiodic motion state in the absence of teeth exciting force. Therefore, in order to avoid a bilateral shock in gears as well as to maintain gear teeth lubrication, a slightly bigger backlash is required. The backlash change in any transmission stage caused significant impacts on gear force and the motion state of its own stage; however, the impact on gear force of another stage was quite small, whereas the impact on the motion state of another stage was quite large.
Tumor-Localized Costimulatory T-Cell Engagement by the 4-1BB/HER2 Bispecific Antibody-Anticalin Fusion PRS-343
Authors: Hinner Marlon J. , Aiba Rachida Siham Bel , Jaquin Thomas J. , Berger Sven , Dürr Manuela Carola , Schlosser Corinna , Allersdorfer Andrea , Wiedenmann Alexander , Matschiner Gabriele , Schüler Julia , Moebius Ulrich , Rothe Christine , Matis Louis , Olwill Shane Anthony
Published: May 2019

Purpose:

4-1BB (CD137) is a key costimulatory immunoreceptor and promising therapeutic target in cancer. To overcome limitations of current 4-1BB–targeting antibodies, we have developed PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 is designed to facilitate T-cell costimulation by tumor-localized, HER2-dependent 4-1BB clustering and activation.

Experimental Design:

PRS-343 was generated by the genetic fusion of 4-1BB–specific Anticalin proteins to a variant of trastuzumab with an engineered IgG4 isotype. Its activity was characterized using a panel of in vitro assays and humanized mouse models. The safety was assessed using ex vivo human cell assays and a toxicity study in cynomolgus monkeys.

Results:

PRS-343 targets 4-1BB and HER2 with high affinity and binds both targets simultaneously. 4-1BB–expressing T cells are efficiently costimulated when incubated with PRS-343 in the presence of cancer cells expressing HER2, as evidenced by increased production of proinflammatory cytokines (IL2, GM-CSF, TNFα, and IFNγ). In a humanized mouse model engrafted with HER2-positive SK-OV-3 tumor cells and human peripheral blood mononuclear cells, PRS-343 leads to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. In IND-enabling studies, PRS-343 was found to be well tolerated, with no overt toxicity and no relevant drug-related toxicologic findings.

Conclusions:

PRS-343 facilitates tumor-localized targeting of T cells by bispecific engagement of HER2 and 4-1BB. This approach has the potential to provide a more localized activation of the immune system with higher efficacy and reduced peripheral toxicity compared with current monospecific approaches. The reported data led to initiation of a phase I clinical trial with this first-in-class molecule.

See related commentary by Su et al., p. 5732
Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia
Authors: Vicioso Yorleny , Gram Hermann , Beck Rose , Asthana Abhishek , Zhang Keman , Wong Derek P. , Letterio John , Parameswaran Reshmi
Published: May 2019

Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti–BAFF-R (VAY736), optimized for natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefit in vivo. However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGFβ). Inhibiting TGFβ signaling in NK cells using the TGFβ receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell–mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.
Addition of a β1-Blocker to Milrinone Treatment Improves Cardiac Function in Patients with Acute Heart Failure and Rapid Atrial Fibrillation
Authors: Kobayashi Shigeki , Myoren Takeki , Kajii Toshiro , Kohno Michiaki , Nanno Takuma , Ishiguchi Hironori , Nishimura Shigehiko , Fukuda Masakazu , Hino Akihiro , Fujimura Tatsuhiro , Ono Makoto , Uchinoumi Hitoshi , Tateishi Hiroki , Mochizuki Mamoru , Oda Tetsuro , Okuda Shinichi , Yoshiga Yasuhiro , Kawano Reo , Yano Masafumi
Published: May 2019

Background: Tachycardia worsens cardiac performance in acute decompensated heart failure (ADHF). We investigated whether heart rate (HR) optimization by landiolol, an ultra-short-acting β1-selective blocker, in combination with milrinone improved cardiac function in patients with ADHF and rapid atrial fibrillation (AF). Methods and Results: We enrolled9 ADHF patients (New York Heart Association classification IV; HR, 138 ± 18 bpm; left ventricular [LV] ejection fraction, 28 ± 8%; cardiac index [CI], 2.1 ± 0.3 L/min–1/m–2; pulmonary capillary wedge pressure [PCWP], 24 ± 3 mm Hg), whose HRs could not be reduced using standard treatments, including diuretics, vasodilators, and milrinone. Landiolol (1.5–6.0 µg/kg–1/min–1, intravenous) was added to milrinone treatment to study its effect on hemodynamics. The addition of landiolol (1.5 µg/kg–1/min–1) significantly reduced HR by 11% without changing systolic blood pressure (BP) and resulted in a significant decrease in PCWP and a significant increase in stroke volume index (SVI), suggesting that HR reduction restores incomplete LV relaxation. Administration of more than 3.0 µg/kg–1/min–1 of landiolol decreased BP, CI, and SVI. Conclusion: The addition of landiolol at doses of <3.0 µg/kg/min to milrinone improved cardiac function in decompensated chronic heart failure with rapid atrial fibrillation by selectively reducing HR.
Detection of Gap and Modulations: Auditory Temporal Resolution Deficits in Adults Who Stutter
Authors: Devaraju Dhatri S. , Maruthy Santosh , Kumar Ajith U.
Published: May 2019

Background: Recent models of speech production suggest a link between speech production and perception. Persons with stuttering are known to have deficits in sensorimotor timing and exhibit auditory processing problems. Most of the earlier studies have focused on assessing temporal ordering in adults who stutter (AWS), but limited attempts have been made to document temporal resolution abilities in AWS. Methods: A group of 16 AWS and 16 age- and gender-matched adults who do not stutter (AWNS) were recruited for the study. Temporal resolution abilities were assessed using the Gap Detection Test and temporal modulation transfer function (TMTF). Results: The results revealed significant differences in TMTF between AWS and AWNS, but no differences were found in the gap detection thresholds. Conclusions: Results suggest that the sensory representations of the temporal modulations are compromised in AWS, which may contribute to the programming of rhythmic movements during speech planning.
Erstellung molekularer Tumorprofile durch Liquid Biopsy - Zukunft für das kolorektale Karzinom
Authors: Lorenzen Sylvie
Published: May 2019

KRAS mutations have been reported as a reliable biomarker for epidermal growth factor receptor (EGFR) targeted therapy and are also associated with poor prognosis in colorectal cancer (CRC) patients. However, limitations of detecting KRAS mutations in tissues are obvious. KRAS mutations in the peripheral blood can be detected as an alternative to tissue analysis. The objective of this meta-analysis was to evaluate the diagnostic value of cfDNA (circulating free DNA) compared with tissues and to investigate the prognostic potential of cfDNA KRAS mutations in CRC patients. Searches were performed in PubMed, Embase, and Cochrane Library for published studies. We extracted true-positive (TP), false-positive (FP), false-negative (FN), true-negative (TN) values, survival rate of CRC patients with mutant and wild-type KRAS and calculated pooled sensitivity and specificity, positive/negative likelihood ratios (PLRs/NLRs), diagnostic odds ratios (DORs), and corresponding 95% confidence intervals (95% Cis). We also generated a summary receiver operating characteristic (SROC) curve to evaluate the overall diagnostic potential. Totally, 31 relevant studies were recruited and used for the meta-analysis on the efficacy of cfDNA testing in detecting KRAS mutations. The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.637 (95% CI: 0.607-0.666), 0.943 (95% CI: 0.930-0.954), 10.024 (95% CI: 6.912-14.535), 0.347 (95% CI: 0.269-0.447), and 37.882 (95% CI: 22.473-63.857), respectively. The area under the SROC curve was 0.9392. Together, the results suggest that detecting KRAS mutations in cfDNA has adequate diagnostic efficacy in terms of specificity. There is a promising role for cfDNA in the detection of KRAS mutations in CRC patients. However, prospective studies with larger patient cohorts are still required before definitive conclusions of the prognostic potential of cfDNA KRAS mutations in CRC patients were drawn.
Attenuation of Severe Generalized Junctional Epidermolysis Bullosa by Systemic Treatment with Gentamicin
Authors: Hammersen Johanna , Neuner Andrea , Wild Florian , Schneider Holm
Published: May 2019

Severe generalized junctional epidermolysis bullosa (JEB), a lethal genodermatosis, is mainly caused by premature termination codons (PTCs) in one of the three genes encoding the anchoring protein laminin-332. Only symptomatic treatment has been established; overcoming PTCs by aminoglycosides may represent an interesting alternative. This retrospective study aimed at assessing for the first time the clinical effects of systemic gentamicin application in infants with severe generalized JEB. Five patients, homozygous or compound-heterozygous for PTCs in the gene LAMB3, were treated with gentamicin which was administered intravenously or by intramuscular injection at doses of 7.5 mg/kg/d for three weeks. Skin biopsies were investigated by immunofluorescence analyses. Clinical effects of the medication were recorded with a parent questionnaire and by assessing weight-for-age charts. Gentamicin application was well tolerated, long hospitalization was not required. Low levels of laminin-332 could be detected in a skin sample obtained after treatment. Gentamicin had a positive impact on skin fragility and daily life in four patients but did not influence weight gain and failed to reverse the lethal course of the disease. Gentamicin injections should be considered regularly in cases of severe generalized JEB caused by PTCs as they may attenuate JEB symptoms without impeding quality of life.
Tumorheterogenität des kolorektalen Karzinoms: Was wir bisher wissen
Authors: Sagaert Xavier , Vanstapel Arno , Verbeek Sanne
Published: May 2019

Das Kolorektalkarzinom ist keine einzelne Erkrankung, sondern umfasst vielmehr eine Gruppe von neoplastischen Erkrankungen. Aufgrund der Heterogenität der Erkrankung sowie des Therapieansprechens und der Prognose ist eine umfangreiche Stratifizierung der Krankheit erforderlich. Daher werden im Pathologiebericht TNM-Stadium, Mikrosatellitenstatus, Tumorgrad, Lymphgefäßeinbruch und andere Parameter bewertet, um das Ausmaß und die Prognose der Erkrankung aufzuzeigen. Ferner wird bei einer Metastasierung der KRAS-, BRAF- und NRAS-Mutationsstatus untersucht, um das Ansprechen auf eine Anti-EGFR-Therapie (EGFR = epidermaler Wachstumsfaktorrezeptor) vorherzusagen. Kürzlich wurden 4 unterschiedliche molekulare Subtypen des Kolorektalkarzinoms beschrieben, die sowohl von prognostischer als auch von therapeutischer Relevanz sind. Darüber hinaus zeigten sich in der Untersuchung des entzündlichen Infiltrats wesentliche Unterschiede hinsichtlich der Anzahl und Lokalisation der Entzündungszellen bei den verschiedenen Kolorektalkarzinomtypen. Die Gesamtheit dieser Parameter ermöglicht eine Stratifizierung der Patienten in verschiedene therapeutische und prognostische Subgruppen. Eine solche Stratifizierung ist jedoch nicht eindeutig, da Tumoren häufig intratumorale Heterogenität aufweisen, bei der verschiedene Subpopulationen innerhalb eines Tumors Unterschiede hinsichtlich Morphologie, entzündlichem Infiltrat, Mutationsstatus oder Genexpressionsprofil zeigen. Der vorliegende Artikel gibt einen Überblick über alle derzeit bekannten Daten zur Tumorheterogenität sowohl auf inter- als auch auf intratumoraler Ebene.
Der Charlson Comorbidity Score - eine Entscheidungshilfe bei der adjuvanten Therapie des fortgeschrittenen Endometriumkarzinoms
Authors: Pölcher Martin
Published: May 2019

Objectives: We sought to evaluate the impact of age-adjusted Charlson comorbidity index (AACCI) score on survival endpoints for women with advanced stage endometrial carcinoma (EC). Methods and Materials: We identified 238 women with stage III EC. AACCI score was calculated and 3 groups were created accordingly; group 1 with a score of 0-2, group 2 with score 3-4, and group 3 with score ≥5. Significant predictors of recurrence-free (RFS), disease-specific (DSS) and overall survival (OS) were analyzed. Results: Median follow-up was 54 months and median age was 65 years. Stage IIIC was the most common stage (69%). The 3 groups were well-balanced except for less utilization of adjuvant chemotherapy in group 3 (p = 0.01). Five-year OS was significantly lower in group 3 compared to groups 1 and 2 (23 vs. 65 and 51%, respectively). Similarly, 5-year RFS was 54, 41, and 33% and DSS was 65, 54, and 35% for groups 1, 2, and 3 respectively. On multivariate analyses, AACCI group 3, cervical stromal involvement, positive peritoneal cytology, and higher tumor grade were predictors for shorter OS. Cervical stromal involvement and higher grade were independent predictors for worse RFS and DSS. Additionally, positive cytology, lymphovascular space invasion, and stage IIIC2 were significantly detrimental for RFS. Conclusions: Our study suggests that comorbidity burden is a strong predictor of worse OS in women with stage III EC. Women with higher AACCI are less likely to receive adjuvant chemotherapy. Comorbidity score can significantly impact survival endpoints for women with advanced EC.
Propranolol Impairs Primary Immune Responses in Rat Experimental Autoimmune Encephalomyelitis
Authors: Pilipović Ivan , Vujnović Ivana , Petrović Raisa , Stojić-Vukanić Zorica , Leposavić Gordana
Published: May 2019

Objective: We examined the effect of β-adrenoceptor (AR) blockade in the preclinical phase of experimental autoimmune encephalomyelitis (EAE), the most commonly used model of multiple sclerosis, on the development of primary CD4+ T-cell responses in draining lymph nodes (dLNs). Methods: CD11b+ cell migration to dLNs, CD4+ T-cell activation/proliferation, and IL-17+ CD4+ (Th17) cell numbers in dLN and spinal cord (SC) were examined in male and female Dark Agouti rats using flow cytometry analysis. Results: Irrespective of sex, in propranolol-treated (PT) rats, migration of CD11b+ antigen-presenting cells from the site of immunization to dLNs was impaired compared with saline-treated controls and consequently the frequency of all CD11b+ cells in dLNs and activated cells among them, too. This correlated with decreased expression of CCL19/21 transcripts in dLNs. Consistently, the frequency of activated/proliferating cells among dLN CD4+ T cells was reduced in PT rats. Additionally, propranolol reduced the number of Th17 cells in dLNs and SC. Consistently, male and female PT rats exhibited a decreased incidence of EAE and prolonged duration of the asymptomatic disease phase. Conclusion: This study suggests that sympathetic dysregulation is involved in the outbreak of clinical EAE.
Sarcoid-Like Lesions Mimicking Pulmonary Metastasis: A Case Series and Review of the Literature
Authors: Eggers Hendrik , Krüger Marcus , Stange Katharina , Jonigk Danny , Biancosino Christian , Rodt Thomas , Fühner Thomas , Murray Tim , Grünwald Viktor , Ivanyi Philipp
Published: May 2019

Background: The association of sarcoid-like lesions and malignancy is well described. Nonetheless, pulmonary lesions in malignant disease are typically presumed metastatic, and do not routinely receive histological validation. Here, we report on pulmonary sarcoid-like lesions identified in patients with a primary malignancy where pulmonary metastatic disease was suspected. Methods: Patients who underwent thoracic surgical procedures for confirmation or treatment of suspected pulmonary metastasis were retrospectively analysed. Results: In 8/186 patients (4.3%), histology revealed sarcoid-like lesions. In these cases, there were no clinical symptoms suggestive of sarcoidosis. All underlying primary malignancies in the sarcoid-like patients were treated with curative intent. The median age of patients with sarcoid-like lesions was 46.3 years (range 26–61). The median interval between primary diagnosis of malignancy and diagnosis of pulmonary lesions was 188 days (range 0–794), with thoracic surgical intervention performed at a median of 250 days (range 183–675). FDG-avidity was demonstrated in the sarcoid-like lesions in 2 out of 3 patients who underwent PET-CT. Conclusion: Sarcoid-like lesions may be challenging to identify and can mimic pulmonary metastases. Therefore, considering sarcoidosis as a differential diagnosis whenever first pulmonary metastasis is suspected is warranted. Carefully considered, histological validation of initial suspected pulmonary metastasis may avoid subsequent over- or undertreatment.
Human Brucellosis: Risks and Prevalence among Iranian Blood Donors Residing in Endemic Areas
Authors: Zadsar Maryam , Shirzadi Mohammad Reza , Zeynali Mohammad , Rasouli Mahboubeh , Karimi Gharib
Published: May 2019

Background: Brucellosis is a common zoonotic infection worldwide. Transmission can be occasionally observed via transfusion or transplantation. This study was designed to survey the seroprevalence of anti-Brucella antibody in blood donors in different endemic provinces. Materials and Methods: A total of 14,706 blood donors from the 5 most prevalent provinces were studied by standard tube agglutination (STA) and any positive subjects were further confirmed by 2-mercaptoethanol agglutination test (2-ME). Significant titres were 80 for STA and 40 for 2-ME. Result: A total of 63 (0.43%) serum samples were STA-positive. Of these, the 2-ME test was reactive in 42 samples. The 2-ME test was reactive in 31 samples with a low titre. However, concomitant STA ≥80 and the titre of ≥40 for the 2-ME test were found in 11 subjects (0.075%), mostly resident in urban areas. Exposure to manure products was identified as a significant risk factor (p = 0.0128). Conclusion: The observed data show a somewhat noticeable prevalence among Iranian blood donors, bringing attention to the importance of pre-donation screening via a questionnaire which supplies answers about occupational history, and any history of exposure or past infections. Further studies to evaluate the frequency and related risk factors in certain populations, in conjunction with implementing stricter regulations in blood donor selection in endemic areas, may be necessary.
Patientenauswahl für die Immun-Checkpoint-Therapie bei fortgeschrittenem nicht kleinzelligem Lungenkarzinom: Bedeutungen für die klinische Praxis
Authors: Schütte Wolfgang , Möller Miriam
Published: May 2019

Immune checkpoint inhibitors targeting PD-1 or PD-L1 represent a standard treatment option for patients with advanced non-small-cell lung cancer. However, a substantial proportion of patients will not benefit from these treatments, and robust biomarkers are required to help clinicians select patients who are most likely to benefit. Here, we discuss the available evidence on the utility of clinical characteristics in the selection of patients with advanced non-small-cell lung cancer as potential candidates for single-agent anti-PD-1/PD-L1 therapy, and provide practical guidance to clinicians on identifying those patients who are most likely to benefit. Recommendations on the use of immune checkpoint inhibitor in clinically challenging populations are also provided.
Oh Schmerz lass nach – ein kurzer Report der ersten Ergebnisse unserer interdisziplinären, integrativen, gynäkologischen Schmerzsprechstunde
Authors: Braun Eva-Marie , Juhasz-Böss Ingolf , Volk Thomas , Braun Benedikt Johannes , Kreutzer Svenja , Solomayer Erich-Franz , Bialas Patric
Published: May 2019

Einleitung: Trotz immer besserer medizinischer und operativer Therapiemaßnahmen bleibt eine adäquate Schmerztherapie für viele gynäkologische Krankheitsbilder eine He­rausforderung. Neue patientenfokussierte Testsysteme können dabei zur Verlaufsbeurteilung und Therapieoptimierung beitragen. Ziel war es, die Pilot-Ergebnisse unserer, in Deutschland einmaligen, interdisziplinären, universitär geführten, integrativen Schmerzsprechstunde anhand neu­ester patientenfokussierter Testsysteme auszuwerten und zur weitergehenden interkollegialen Diskussion vorzustellen. Materialien und Methoden: Retrospektive, monozentrische Analyse der Behandlungsverläufe von Patientinnen einer neuen integrativen und interdisziplinären, gynäkologischen Schmerzsprechstunde mittels patientenfokussiertem Testsystem (PROMIS-29). Ergebnisse: Insgesamt konn­ten die Ergebnisse von 18 Patientinnen analysiert werden. Zur Nachuntersuchung zeigten sich signifikante Verbesserungen in allen Domänen des PROMIS-29. Schlussfolgerung: Die vorgestellte interdisziplinäre, integrative Schmerz­sprechstunde unter Zuhilfenahme patientenfokussierter Testsysteme kann relevante Schmerzdomänen erfassen und erfolgreich therapieren. Weitere Untersuchungen müssen diese neue Art der Verlaufsbeobachtung und gynäkologisch fokussierter Schmerzbehandlung nun mit längeren Nach­sorgeintervallen bestätigen.
Cardiomyopathy in Children: Classification and Diagnosis: A Scientific Statement From the American Heart Association
Authors: Lipshultz Steven E. , Law Yuk M. , Asante-Korang Alfred , Austin Eric D. , Dipchand Anne I. , Everitt Melanie D. , Hsu Daphne T. , Lin Kimberly Y. , Price Jack F. , Wilkinson James D. , Colan Steven D. ,   On behalf of the American Heart Association Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and Council on Genomic and Precision Medicine
Published: May 2019

In this scientific statement from the American Heart Association, experts in the field of cardiomyopathy (heart muscle disease) in children address 2 issues: the most current understanding of the causes of cardiomyopathy in children and the optimal approaches to diagnosis cardiomyopathy in children. Cardiomyopathies result in some of the worst pediatric cardiology outcomes; nearly 40% of children who present with symptomatic cardiomyopathy undergo a heart transplantation or die within the first 2 years after diagnosis. The percentage of children with cardiomyopathy who underwent a heart transplantation has not declined over the past 10 years, and cardiomyopathy remains the leading cause of transplantation for children >1 year of age. Studies from the National Heart, Lung, and Blood Institute–funded Pediatric Cardiomyopathy Registry have shown that causes are established in very few children with cardiomyopathy, yet genetic causes are likely to be present in most. The incidence of pediatric cardiomyopathy is ≈1 per 100 000 children. This is comparable to the incidence of such childhood cancers as lymphoma, Wilms tumor, and neuroblastoma. However, the published research and scientific conferences focused on pediatric cardiomyopathy are sparcer than for those cancers. The aim of the statement is to focus on the diagnosis and classification of cardiomyopathy. We anticipate that this report will help shape the future research priorities in this set of diseases to achieve earlier diagnosis, improved clinical outcomes, and better quality of life for these children and their families.
Higher Body Mass Index in Adolescence Predicts Cardiomyopathy Risk in Midlife
Authors: Robertson Josefina , Schaufelberger Maria , Lindgren Martin , Adiels Martin , Schiöler Linus , Torén Kjell , McMurray John , Sattar Naveed , Åberg Maria , Rosengren Annika
Published: May 2019

Background:

Modifiable lifestyle factors in relation to risk for cardiomyopathy, a common and increasing cause of heart failure in the young, have not been widely studied. We sought to investigate a potential link between obesity, a recognized predictor of early heart failure, in adolescence and being diagnosed with cardiomyopathy in adulthood.

Methods:

This was a nationwide register-based prospective cohort study of 1 668 893 adolescent men (mean age, 18.3 years; SD, 0.7 years) who enlisted for compulsory military service from 1969 to 2005. At baseline, body mass index (BMI), blood pressure, and medical disorders were registered, along with test results for fitness and muscle strength. Cardiomyopathy diagnoses were identified from the National Hospital Register and Cause of Death Register during an up to 46-year follow-up and divided into categories: dilated, hypertrophic, alcohol/drug-induced, and other. Hazard ratios were calculated with Cox proportional hazards models.

Results:

During follow-up (median, 27 years; Q1–Q3, 19–35 years), 4477 cases of cardiomyopathy were identified, of which 2631 (59%) were dilated, 673 (15%) were hypertrophic, and 480 (11%) were alcohol/drug-induced. Increasing BMI was strongly associated with elevated risk of cardiomyopathy, especially dilated, starting at levels considered normal (BMI, 22.5–<25 kg/m
2
; hazard ratio, 1.38 [95% CI, 1.22–1.57]), adjusted for age, year, center, and baseline comorbidities, and with a >8-fold increased risk at BMI ≥35 kg/m
2
compared with BMI of 18.5 to <20 kg/m
2
. For each 1-unit increase in BMI, similarly adjusted hazard ratios were 1.15 (95% CI, 1.14–1.17) for dilated cardiomyopathy, 1.09 (95% CI, 1.06–1.12) for hypertrophic cardiomyopathy, and 1.10 (1.06–1.13) for alcohol/drug-induced cardiomyopathy.

Conclusions:

Even mildly elevated body weight in late adolescence may contribute to being diagnosed with cardiomyopathy in adulthood. The already marked importance of weight control in youth is further strengthened by these findings, as well as greater evidence for obesity as a potential important cause of adverse cardiac remodeling that is independent of clinically evident ischemic heart disease.
Antihypertensive Medication Nonpersistence and Low Adherence for Adults <65 Years Initiating Treatment in 2007–2014
Authors: Tajeu Gabriel S. , Kent Shia T. , Huang Lei , Bress Adam P. , Cuffee Yendelela , Halpern Michael T. , Kronish Ian M. , Krousel-Wood Marie , Mefford Matthew T. , Shimbo Daichi , Muntner Paul
Published: May 2019

Previous evidence suggests modest improvements in antihypertensive medication adherence occurred from 2007 to 2012 among US adults ≥65 years of age. Whether adherence improved over time among adults <65 years of age is unknown. We assessed trends in antihypertensive medication nonpersistence and low adherence among 379 658 commercially insured adults <65 years of age initiating treatment in 2007–2014 using MarketScan claims. Nonpersistence was defined as having no days of medication available to take during the final 90 days of the 365 days following initiation. Among beneficiaries who were persistent to treatment, low adherence was defined by having antihypertensive medication available to take for <80% of the days in the 365 days following initiation (ie, proportion of days covered <80%). In 2007 and 2014, 23.3% and 23.5% of patients were nonpersistent to treatment, respectively, and 42.3% and 40.2% had low adherence, respectively. The relative risks for nonpersistence and low adherence were lower among beneficiaries initiating treatment with an angiotensin-converting enzyme inhibitor (0.95; 95% CI, 0.94–0.97 and 0.97; 95% CI, 0.96–0.98, respectively), angiotensin receptor blocker (0.86; 95% CI, 0.85–0.88 and 0.99; 95% CI, 0.97–1.00, respectively), or multiclass regimen (0.82; 95% CI, 0.80–0.84 and 0.88; 95% CI, 0.86–0.89, respectively), prescribed 90-day versus 30-day prescriptions (0.67; 95% CI, 0.66–0.68 and 0.70; 95% CI, 0.69–0.71, respectively), or who received medications by mail versus at the pharmacy (0.93; 95% CI, 0.90–0.95 and 0.90; 95% CI, 0.88–0.92, respectively). In conclusion, several modifiable factors were associated with lower rates of both antihypertensive medication nonpersistence and low adherence among adults <65 years of age initiating treatment in 2007–2014.
Are We Justified in Conducting Invasive Research on Captive Apes for Their Wild Counterparts?
Authors: Kraska Katlin
Published: May 2019

Wildlife species are threatened for a variety of reasons; research on captive individuals of the same species can, in some circumstances, prevent wild population decline. Such decisions pit conservationists and animal rights advocates against one another—the former are interested in survival of the species and the latter in individual rights. I argue that invasive research on captive animals for the sake of wild animals is justifiable in cases of emergency only if it is the lesser of two evils. This requires that the individual chimpanzee be compensated for harms incurred. I then argue this logic generally does not apply to human beneficiaries of invasive research conducted on chimpanzees. This is not because species membership is morally significant, but because asymmetrical power relations characterized by dependency and vulnerability will always exist between the groups if human interests are at stake. The argument focuses on federal chimpanzee conservation policy.
The Emerging Alliance of Religion and Ecology
Authors: Tucker Mary Evelyn
Published: May 2019

The role of the world's religions may be crucial in rethinking the relationship of humans to the natural world in a mutually enhancing manner. I first acknowledge, although briefly, the scale and complexity of the environmental crisis. Next, I suggest the need for seeking common grounds to work toward a resolution of the crisis. Then I highlight the call for the co-operation and action of the world's religions from particular sectors such as environmental groups, the United Nations, political leaders, scientists, and ethicists. Finally, I document some of the responses and the resources of the world's religions in evoking new attitudes toward nature.
Self and Nature in Heidegger
Authors: Bubbio Paolo Diego
Published: May 2019

This article provides an analysis of the development of the notions of “self” and “nature” through three stages of Heidegger’s thought. The main contention is that Heidegger’s conceptions of the self and nature are indissolubly connected to each other, and that such connection appears through three concerns that represent important elements of continuity: 1) the “irreducibility of the self,” conceived in a non-subjectivist way; 2) the recovery of a non-objectivist “originary” account of nature; 3) the overall commitment to the overcoming of the polarization between subject and object. I argue that there is a parallelism in the way self and nature are addressed in each of the three phases; and that the transformations of the notions are functional to the project of addressing the concerns mentioned earlier. I conclude by addressing the “violence of nature,” which remains a “blind spot” in the philosophy of the later Heidegger.