bluuebunny/crossref_metadata_2025 huggingface dataset:
Radretumab Radioimmunotherapy in Patients with Brain Metastasis: A 124I-L19SIP Dosimetric PET Study
Authors: Poli Gian Luca , Bianchi Claudia , Virotta Giorgio , Bettini Anna , Moretti Renzo , Trachsel Eveline , Elia Giuliano , Giovannoni Leonardo , Neri Dario , Bruno Andrea
Published: May 2013

Radioimmunotherapy (RIT) with 131I-labeled L19SIP (radretumab; a small immunoprotein format antibody directed against the ED-B domain of fibronectin; ∼80 kDa molecular weight) has been investigated in several clinical trials. Here, we describe the use of immuno-PET imaging with iodine-124 (124I)–labeled L19SIP to predict doses delivered to tumor lesions and healthy organs by a subsequent radretumab RIT in patients with brain metastases from solid cancer. Bone marrow doses were evaluated both during the diagnostic phase and posttherapy, measuring activities in blood (germanium detector) and whole body (lanthanum bromide detector). Expected doses for radretumab administration (4,107 MBq/m2) were calculated from data obtained after administration of an average of 167 MBq 124I-L19SIP to 6 patients. To assess lesion average doses, the positron emission tomography (PET) scanner was calibrated for the use of 124I with an International Electrotechnical Commission (IEC) Body Phantom and recovery coefficients were calculated. The average dose to bone red marrow was 0.21 Gy/GBq, with high correlation between provisional and actual posttherapy doses. Although the fraction of injected activity in normal organs was similar in different patients, the antibody uptake in the neoplastic lesions varied by as much as a factor of 60. Immuno-PET with 124I-labeled L19SIP offers significant advantages over conventional 131I imaging, in particular accuracy of dosimetric results. Furthermore, the study indicates that antibody uptake can be highly variable even in different lesions of the same patient and that immuno-PET procedures may guide product development with armed antibodies. Cancer Immunol Res; 1(2); 134–43. ©2013 AACR.
Substantia Nigra Hyperechogenicity as a Marker for Parkinson's Disease: A Population-Based Study
Authors: Mahlknecht Philipp , Seppi Klaus , Stockner Heike , Nocker Michael , Scherfler Christoph , Kiechl Stefan , Willeit Johann , Schmidauer Christoph , Gasperi Arno , Rungger Gregorio , Poewe Werner
Published: May 2013

Background: The clinical diagnosis of Parkinson's disease (PD) is currently anchored in its cardinal motor symptoms. According to hospital-based studies, an enlarged echogenicity in the area of the substantia nigra (SN) assessed with transcranial sonography (TCS) may represent a useful biomarker in the diagnosis of PD. Objective: To evaluate SN hyperechogenicity as a marker for PD in the Bruneck Study cohort, which is representative of the general elderly community. Methods: The diagnostic accuracy of TCS in distinguishing clinically diagnosed PD from nonparkinsonian subjects was assessed in 574 subjects from this cohort. Results: There was a good diagnostic accuracy of TCS in distinguishing PD subjects from nonparkinsonian subjects with an area under the curve value of 0.82. At a receiver-operating characteristic curve analysis-based cutoff value for SN hyperechogenicity of 0.18 cm2, TCS had a sensitivity of 88.2% (95% confidence interval, CI, 64.4-98.0), a specificity of 77.0% (95% CI 72.8-80.6), a positive predictive value of 12.7% (95% CI 7.8-20.0) and a negative predictive value of 99.4% (95% CI 97.8-100.0) for subjects with clinically definite PD at baseline. When analyzing the same population after 5 years with regard to the presence of known and newly diagnosed PD cases, baseline TCS yielded very similar diagnostic accuracy values. Conclusion: SN hyperechogenicity may represent a useful biomarker for PD not only in a hospital-based setting but also in the general community.
Effect of Formoterol on Eosinophil Trans-Basement Membrane Migration Induced by Interleukin-8-Stimulated Neutrophils
Authors: Kawashima Akiko , Suzuki Tomoko , Nishihara Fuyumi , Kobayashi Takehito , Takaku Yotaro , Nakagome Kazuyuki , Soma Tomoyuki , Hagiwara Koichi , Kanazawa Minoru , Nagata Makoto
Published: May 2013

Background: Neutrophils are often increased in the airways of either chronic severe asthma or acute exacerbations. Neutrophils that have migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of patients with asthma and possibly aggravate the disease. In this study, we investigated whether formoterol modified the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8. Methods: Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. Eosinophil TBM was examined using a modified Boyden's chamber technique. Neutrophils were preincubated with or without formoterol (0.1 μM) at 37°C for 30 min. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium containing preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After a 90-minute incubation, the eosinophils that had migrated into the lower chamber were calculated using eosinophil peroxidase assays. Results: A combination of neutrophils and IL-8 significantly induced the eosinophil TBM; formoterol alone had no effect. However, formoterol modestly but significantly attenuated the TBM of eosinophils stimulated with neutrophils and IL-8. Conclusion: These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent, severe asthma. The effect of formoterol likely involves the inhibition of neutrophil activation.
Differential Activation of Eosinophils by Bacteria Associated with Asthma
Authors: Hosoki Koa , Nakamura Akiko , Kainuma Keigo , Sugimoto Mayumi , Nagao Mizuho , Hiraguchi Yukiko , Tanida Hisashi , Tokuda Reiko , Wada Hideo , Nobori Tsutomu , Suga Shigeru , Fujisawa Takao
Published: May 2013

Background: It has been suggested that there is a complex interaction between microbiota and various human diseases. Some bacteria have been reported to be involved in the inception and progression of asthma, and others in the protection against asthma. We know very little about the mechanisms by which bacteria do harm or good with regard to asthma. This study investigated whether bacteria exert differential effects on the functions of eosinophils, major effector cells in airway inflammation in asthma. Methods: Eosinophils were purified from healthy adult volunteers by Percoll density gradient centrifugation and negative immunomagnetic bead selection using anti-CD16 microbeads. Three kinds of heat-killed bacteria that have been implicated in asthma, namely Staphylococcus aureus (SA), Haemophilus influenzae (HI) and a Prevotella sp. (PS), were tested for their effects on the secretion of eosinophil-derived neurotoxin (EDN), the generation of superoxides and the production of cytokines/chemokines. Results: SA, but not HI or PS, induced significant EDN release in a dose-dependent manner. Superoxide generation was significantly enhanced by each of the bacterial species, but most strongly by SA, which induced significantly greater TNF-α production by eosinophils than either HI or PS. Conversely, interleukin 10, an anti-inflammatory cytokine, was more strongly induced by HI and PS than by SA. Conclusions: Bacteria exert differential effects on eosinophils. Based on these results, SA may be involved in the exacerbation of, and HI and PS in the inhibition of, eosinophilic inflammation in asthma.
Pretreatment with Low Levels of FcεRI-Crosslinking Stimulation Enhances Basophil Mediator Release
Authors: Koketsu Rikiya , Yamaguchi Masao , Suzukawa Maho , Tanaka Yusuke , Tashimo Hiroyuki , Arai Hidenori , Nagase Hiroyuki , Matsumoto Kenji , Saito Hirohisa , Ra Chisei , Yamamoto Kazuhiko , Ohta Ken
Published: May 2013

Background: Basophils and mast cells are important initiator/effector cells capable of rapidly responding to IgE-mediated stimulation, but the precise mechanisms regulating their functions in vivo have not been fully identified. In this study, we assessed whether low levels of antigen can modulate activation of basophils and mast cells. Methods: Human basophils and cultured mast cells were pretreated with low concentrations of anti-FcεRI α-chain mAb (CRA-1 mAb), and their cell functions were assessed. Results: Basophils preincubated with CRA-1 mAb at as low as 1 ng/ml for 1 h showed significantly enhanced degranulation in response to various secretagogues such as MCP-1, FMLP, leukotriene B4 and Ca ionophore A23187. FMLP-induced leukotriene C4 production by basophils was also enhanced by CRA-1 mAb pretreatment. Degranulation was further enhanced when CRA-1 mAb-pretreated basophils were additionally treated with IL-3, IL-33 or leptin before stimulation with MCP-1. Priming by subthreshold CRA-1 mAb was a slow process, since 1 h of pretreatment was needed for maximal enhancement. Basophil priming also resulted from preincubation with subthreshold doses of an allergen, Der f 2. In parallel mAb experiments, CRA-1 mAb showed weak priming effects on human umbilical cord blood-derived cultured mast cells; a higher dose, 100 ng/ml, was necessary for this priming. Conclusion: These results indicate that subthreshold doses of CRA-1 mAb or allergens can prime basophils and induce exaggerated responses to various IgE-independent stimuli. This may be a potentially important mechanism that explains environmental allergen-induced exacerbation of IgE-mediated allergic diseases such as asthma.
Alternaria Inhibits Double-Stranded RNA-Induced Cytokine Production through Toll-Like Receptor 3
Authors: Wada Kota , Kobayashi Takao , Matsuwaki Yoshinori , Moriyama Hiroshi , Kita Hirohito
Published: May 2013

Background: Fungi may be involved in asthma and chronic rhinosinusitis (CRS). Peripheral blood mononuclear cells from CRS patients produce interleukin (IL)-5, IL-13 and interferon (IFN)-γ in the presence of Alternaria. In addition, Alternaria produces potent Th2-like adjuvant effects in the airway. Therefore, we hypothesized that Alternaria may inhibit Th1-type defense mechanisms against virus infection. Methods: Dendritic cells (DCs) were generated from mouse bone marrow. The functional responses were assessed by expression of cell surface molecules by FACS (MHC class II, CD40, CD80, CD86 and OX40L). Production of IL-6, chemokine CXCL10 (IP-10), chemokine CXCL11 (I-TAC) and IFN-β was measured by ELISA. Toll-like receptor 3 (TLR3) mRNA and protein expression was detected by quantitative real-time PCR and Western blot. Results:Alternaria and polyinosinic-polycytidylic acid (poly I:C) enhanced cell surface expression of MHC class II, CD40, CD80, CD86 and OX40L, and IL-6 production in a concentration-dependent manner. However, Alternaria significantly inhibited production of IP-10, I-TAC and IFN-β, induced by viral double-stranded RNA (dsRNA) mimic poly I:C. TLR3 mRNA expression and protein production by poly I:C were significantly inhibited by Alternaria. These reactions are likely caused by heat-stable factor(s) in Alternaria extract with >100 kDa molecular mass. Conclusion: These findings suggest that the fungus Alternaria may inhibit production of IFN-β and other cytokines by DCs by suppressing TLR3 expression. These results indicate that Alternaria may inhibit host innate immunity against virus infection.
A Contraction Assay System Using Primary Cultured Mouse Bronchial Smooth Muscle Cells
Authors: Kouyama Satoshi , Otomo-Abe Akemi , Kitamura Noriko , Kaminuma Osamu , Mori Akio
Published: May 2013

Background: Contraction of bronchial smooth muscle is the main mechanism of asthmatic responses. Inflammatory cells such as eosinophils and mast cells produce chemical mediators that induce smooth muscle contraction. To investigate the mechanisms of IgE-independent asthmatic response in murine asthma models, a novel in vitro assay system using primary cultured mouse bronchial smooth muscle cells (BSMC) was explored. Method: Trachea and bronchi were taken from young mice and underwent primary culture. BSMC were expanded in culture and then embedded in a collagen gel. The well-known constrictors leukotriene D4 (LTD4), methacholine and histamine were applied to the BSMC gels. The gel images were captured by an image analyzer and contractile responses were evaluated. Results: LTD4 and methacholine significantly induced the gel contraction in a dose-dependent manner, but histamine did not. Montelukast, a CysLT type ΙΙ receptor antagonist, and atropine, a muscarinic acetylcholine receptor antagonist, inhibited the contractile responses in an agonist-specific manner. Conclusion: A contraction assay system using cultured mouse BSMC was successfully established for the first time. It may go a long way toward identifying bronchoconstricting mediators involved in murine asthma models.
Interleukin-25 Induces Pulmonary Arterial Remodeling via Natural Killer T Cell-Dependent Mechanisms
Authors: Kawashima Saki , Hirose Koichi , Takahashi Kentaro , Tamachi Tomohiro , Ikeda Kei , Tokoyoda Koji , Nakayama Toshinori , Nakajima Hiroshi
Published: May 2013

Background: Recent studies have shown that prolonged Th2-type immune inflammation in the lung induces pulmonary arterial remodeling, in part through the induction of resistin-like molecule α (RELMα) expression. However, the role of interleukin-25 (IL-25; which promotes this inflammation) in the development of the pulmonary arterial remodeling remains unknown. Methods: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with OVA inhalation 3 times a week for 3 weeks. The effects of neutralizing anti-IL-25 antibody on OVA-induced pulmonary arterial remodeling and RELMα expression in the lung were examined. The pulmonary arterial remodeling and RELMα expression in the lung were examined in lung-specific IL-25 transgenic mice (CC10 IL-25 mice) and CC10 IL-25 mice in a natural killer T (NKT) cell-deficient background (CC10 IL-25 NKT-/- mice). Results: Repeated OVA inhalation induced pulmonary arterial wall thickening and the expression of IL-25 and RELMα mRNA in the lung in OVA-sensitized mice. Injection of neutralizing anti-IL-25 antibody inhibited OVA-induced pulmonary arterial wall thickening and RELMα expression in the lung. CC10 IL-25 mice, but not CC10 IL-25 NKT-/- mice, spontaneously developed pulmonary arterial wall thickening and RELMα expression in the lung at 6 months of age. Conclusions: Prolonged expression of IL-25 in the lung induces pulmonary arterial wall thickening by NKT cell-dependent mechanisms.
Esophagitis with Eosinophil Infiltration Associated with Congenital Esophageal Atresia and Stenosis
Authors: Yamada Yoshiyuki , Nishi Akira , Kato Masahiko , Toki Fumiaki , Yamamoto Hideki , Suzuki Norio , Hirato Junko , Hayashi Yasuhide
Published: May 2013

Background: The esophagus is physiologically devoid of eosinophils, so their presence would suggest some underlying pathology. The prevalence of eosinophilic esophagitis (EoE) has steadily increased in Western countries. Previous studies have described EoE in association with congenital esophageal atresia (CEA), which is the most common congenital anomaly of the esophagus. However, the association remains unclear. Methods: We performed a retrospective histological analysis examining for eosinophil infiltration in the esophagus of patients with CEA following surgical repair or congenital esophageal stenosis (CES) who underwent esophageal biopsy or surgical resection in our hospital between 2005 and 2012. Results: There were 6 patients with CEA following surgical repair or CES who had eosinophil-dominant infiltration in the esophagus. All had associated allergic disorders, including food allergies in 4. Moreover, all except for one fulfilled the histological criteria of EoE. Impairment of eosinophil infiltration and symptomatic improvement were observed in those treated with a proton pump inhibitor (PPI), either alone or in combination with steroids after esophageal dilatation. Conclusions: These findings suggest that CEA repair or CES in conjunction with allergic conditions and coexisting gastroesophageal reflux disease (GERD) may induce greater esophageal eosinophilic inflammation. In addition, esophageal dilatation followed by PPI treatment, alone or with steroids, may be a therapeutic strategy that can provide symptomatic relief by reducing eosinophilic inflammation in esophageal strictures or GERD associated with CEA or CES.
Oral Immunotherapy for Allergic Diseases Using Transgenic Rice Seeds: Current State and Future Prospects
Authors: Saeki Mayumi , Nishimura Tomoe , Mori Akio , Hiroi Takachika
Published: May 2013

Allergen-specific immunotherapy (IT) has been shown to provide clinical benefit for patients with allergic diseases. At present, subcutaneous and sublingual ITs are mainly authorized for clinical treatment. Oral administration of allergens seems to be the easiest way to achieve IT, though it has yet to be translated to the clinical setting, mainly due to the requirement of a large amount of allergens. Plants, especially rice seeds, have recently been recognized as superior allergen carriers for oral administration, because of their high productivity, stability and safety. Therefore, in order to establish clinically applicable oral IT, we have been developing transgenic rice seeds (Tg rice), in which major epitopes of cedar pollen allergens or house-dust mites (HDM) are expressed. The efficacy of this orally administered Tg rice was confirmed in murine models of allergic rhinitis and bronchial asthma. In the safety study of the Tg rice, no adverse effects on cynomolgus macaques were observed. In this review, we summarized the current state and future prospects of allergen-specific IT, focusing particularly on oral IT with allergen-expressing Tg rice.
Interleukin-33 Synergistically Enhances Immune Complex-Induced Tumor Necrosis Factor Alpha and Interleukin-8 Production in Cultured Human Synovium-Derived Mast Cells
Authors: Kashiwakura Jun-ichi , Yanagisawa Masahiko , Lee Hyunho , Okamura Yuki , Sasaki-Sakamoto Tomomi , Saito Shu , Tokuhashi Yasuaki , Ra Chisei , Okayama Yoshimichi
Published: May 2013

Background: Substantial evidence suggests that human synovial mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)-33 is believed to play an important role in the pathogenesis of RA. We recently reported that FcγRI is responsible for producing abundant tumor necrosis factor alpha (TNF-α) from cultured synovium-derived MCs (SyMCs) in response to aggregated immunoglobulin G (IgG). However, whether or not IL-33 affects immune complex (IC)-induced synovial MC activation remains unknown. This study sought to evaluate the effect of IL-33 on IC-induced synovial MC activation. Methods: Cultured SyMCs were generated by culturing synovial cells with stem cell factor. ST2 expression was analyzed using FACS and immunohistochemical techniques. Mediators released from the MCs were measured using EIAs or ELISAs. Results: SyMCs obtained from patients with RA or osteoarthritis (OA) expressed ST2 on their surfaces. We confirmed the expression of ST2 in MCs using immunofluorescence staining in joint tissue obtained from RA patients. IC-triggered histamine release was not enhanced by IL-33. However, IL-33 synergistically enhanced IC-induced IL-8 and TNF-α production in SyMCs. Conclusions: ICs and IL-33 may exacerbate inflammation associated with RA by abundantly producing TNF-α and IL-8 from SyMCs.
Existence of Antigen-Specific Immunoglobulin E Is Not Sufficient for Allergic Nasal Eosinophil Infiltration in Mice
Authors: Nishimura Tomoe , Saeki Mayumi , Matsuoka Kunie , Yonekawa Hiromichi , Mori Akio , Hiroi Takachika
Published: May 2013

Background: Immunoglobulin E (IgE) is important for the development of allergic rhinitis (AR), though the contribution of IgE to the infiltration of eosinophils in the nasal mucosa has not been fully elucidated. In this study, antigen-induced sneezing and nasal eosinophil accumulation were comparatively investigated in anti-ovalbumin (OVA)-IgE transgenic (Tg) and wild-type (WT) mice. Methods: Tg and OVA-immunized WT mice were intranasally challenged with OVA. Antigen-specific serum IgE level, sneezing and infiltration of eosinophil into the nasal cavity were then examined. Results: The level of serum OVA-specific IgE in Tg mice was significantly higher than that in antigen-immunized WT mice. Compared to saline challenge, intranasal challenge with OVA significantly induced sneezing in both Tg and immunized WT mice. However, antigen-induced nasal eosinophil infiltration was observed in immunized WT mice but not in Tg mice. Conclusions: IgE-mediated responses might not play a crucial role in antigen-induced eosinophil infiltration in AR.
A Brief Overview of the WHO Classification of Breast Tumors, 4th Edition, Focusing on Issues and Updates from the 3rd Edition
Authors: Sinn Hans-Peter , Kreipe Hans
Published: May 2013

The WHO Classification of Tumors of the Breast, 4th edition, is an update to the 3rd edition that was published in 2003, and covers all neoplastic and preneoplastic lesions of the breast. Changes to the 4th edition include new aspects and changes to the terminology that reflect our present-day knowledge of these lesions. Definitions for histopathological diagnosis are complemented by a description of clinical features, epidemiology, macroscopy, genetics, and prognostic and predictive features. In this review of the WHO classification, we have focused on invasive carcinomas, precursor lesions, and some benign epithelial proliferations.
Locoregional Recurrence and Survival Rates after Breast-Conserving Surgery and Hormonal Therapy in 70-Year-Old or Older Patients with Stage I or IIA Breast Carcinoma
Authors: Soyder Aykut , Özbaş Serdar , Koçak Savaş
Published: May 2013

Background: Data for treatment of elderly women (≥ 70 years) with estrogen receptor-positive early stage breast cancer are available. We have compared different treatment options to determine whether lumpectomy (LU) plus adjuvant hormonal therapy (HT) is as effective as combined LU, HT, and radiotherapy (RT). Method: Medical records of elderly patients over 69 years of age who had been treated for T1N0M0 (stage I) and T2N0M0 (stage IIA) at 2 different medical centers between March 2004 and January 2011 were assessed, and 35 patients were included in this study. 21 of these patients underwent only breast-conserving surgery (BCS) and HT (Group 1: T1N0M0-Group 1a, n = 16; T2N0M0-Group 1b, n = 5) and the others either BCS, HT and RT (Group 2, n = 4) or BCS, chemotherapy (CT), HT and RT (Group 3, n = 10). Adjuvant HT for all the patients comprised aromatase inhibitors. Results: The mean follow-up period for Groups 1, 2 and 3 were 32.2, 31.3 and 20.4 months, respectively. No locoregional recurrence or cancer-specific mortality occurred in any of these patients; 1 patient from Group 1 died of a different cause. Discussion: The BCS+HT regimen seems to be an efficient treatment option for early stage breast cancer in selected 70-year-old and older patient groups.
Patient's Anastrozole Compliance to Therapy (PACT) Program: Baseline Data and Patient Characteristics from a Population-Based, Randomized Study Evaluating Compliance to Aromatase Inhibitor Therapy in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer
Authors: Harbeck Nadia , Blettner Maria , Hadji Peyman , Jackisch Christian , Lück Hans-Joachim , Windemuth-Kieselbach Christine , Zaun Silke , Haidinger Renate , Schmitt Doris , Schulte Hilde , Nitz Ulrike , Kreienberg Rolf
Published: May 2013

Background: The Patient's Anastrozole Compliance to Therapy (PACT) program is a large randomized study designed to assess whether the provision of educational materials (EM) could improve compliance with aromatase inhibitor therapy in postmenopausal women with early, hormone receptor-positive breast cancer. Patients and Methods: The PACT study presented a large, homogeneous dataset. The baseline analysis included patient demographics and initial treatments and patient perceptions about treatment and quality of life. Results: Overall, 4,923 patients were enrolled at 109 German breast cancer centers/clinics in cooperation with 1,361 office-based gynecologists/oncologists. 4,844 women were randomized 1:1 to standard therapy (n = 2,402) or standard therapy plus EM (n = 2,442). Prior breast-conserving surgery and mastectomy had been received by 76% and 24% of the patients, respectively. Radiotherapy was scheduled for 85% of the patients, adjuvant chemotherapy for 38%. Reflecting the postmenopausal, hormone-sensitive nature of this population, only 285 patients (7%) had received neoadjuvant chemotherapy. Conclusions: A comparison with epidemiological data from the West German Breast Center suggests that the patients in the PACT study are representative of a general postmenopausal early breast cancer population and that the findings may be applicable to ‘real-world' Germany and beyond. Compliance data from PACT are eagerly anticipated.
Effect of Endocrine Therapy on Quality of Life and Cognitive Functions in Patients with Breast Cancer
Authors: Kilickap Saadettin , Hayran Mutlu , Cakir Banu , Cilingiroglu Nesrin , Erman Mustafa , Buyukdamgaci Guldal , Ozisik Yavuz
Published: May 2013

Background: The use of endocrine therapy (ET) in postmenopausal breast cancer patients may affect their cognitive status. This study aims to assess the effects of tamoxifen and aromatase inhibitors (AIs) on quality of life (QoL) and cognitive functions in breast cancer patients. Patients and Methods: The study included 101 patients receiving tamoxifen, 97 patients receiving AIs, and 95 patients without any ET. All patients completed both the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the Short Form-12 (SF-12) questionnaires. Results: The patients' characteristics were similar between the groups. The mean duration of ET was 2.6 years for tamoxifen and 2.5 years for AIs. EORTC QLQ-C30 global scores and cognitive functioning scores as well as SF-12 mental scorings (mcs) were found not significantly different between patients without any ET and those receiving tamoxifen or AIs (p = 0.529, p = 0.333, and p = 0.452, respectively). SF-12 mcs correlated moderately with EORTC QLQ-C30 global scores for the 3 treatment groups (all p values < 0.001). Conclusion: Our study suggests that QoL and cognitive functions are similar in patients receiving AIs or tamoxifen. Moreover, it appears that these parameters also do not differ in patients with respect to the use of ET.
Predictors of Mild Cognitive Impairment in Early-Stage Parkinson's Disease
Authors: Hanna-Pladdy Brenda , Jones Katherine , Cabanban Romeo , Pahwa Rajesh , Lyons Kelly E.
Published: May 2013

Aim: The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles. Methods: Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states. Results: Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state. Conclusion: Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD.
Successful Treatment of Diffuse Normolipemic Plane Xanthoma with Probucol
Authors: Miyagawa Fumi , Fukumoto Takaya , Kobayashi Nobuhiko , Asada Hideo
Published: May 2013

We report on a 70-year-old woman with diffuse normolipemic plane xanthoma (DNPX) who developed macular yellowish patches on the eyelids, both cheeks, and the nose. Histology revealed the accumulation of CD68-positive foam cells and Touton giant cells in the superficial dermis. Plasma lipid levels were within normal limits. The patient had no underlying hematological diseases. Her extensive lesions precluded surgical excision. The patient was given oral probucol instead, which resulted in a significant reduction of the lesions after 2 weeks. The lesions almost disappeared within 8 months. Plane xanthoma is primarily treated with excisional or abrasive therapies; however, probucol can be a safe and effective alternative therapy for DNPX.
13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence, Controversies, Consensus - Opinion of a German Team of Experts (Zurich 2013)
Authors: Untch* Michael , Gerber Bernd , Harbeck Nadia , Jackisch Christian , Marschner Norbert , Möbus Volker , von Minckwitz Gunter , Loibl* Sibylle , Beckmann Matthias W. , Blohmer Jens-Uwe , Costa Serban-Dan , Decker Thomas , Diel Ingo , Dimpfl Thomas , Eiermann Wolfgang , Fehm Tanja , Friese Klaus , Jänicke Fritz , Janni Wolfgang , Jonat Walter , Kiechle Marion , Köhler Uwe , Lück Hans-Joachim , Maass Nicolai , Possinger Kurt , Rody Achim , Scharl Anton , Schneeweiss Andreas , Thomssen Christoph , Wallwiener Diethelm , Welt Anja
Published: May 2013

The International Consensus Conference on the treatment of primary breast cancer takes place every two years in St. Gallen, Switzerland. The panel in St. Gallen is composed of international experts from different countries. From a German perspective, it seems reasonable to interpret the voting results in the light of AGO-recommendations and S3-guidelines for everyday practice in Germany. Consequently, a team of eight breast cancer experts, of whom two are members of the international St. Gallen panel, commented on the voting results of the St. Gallen Consensus Conference (2013). The main topics at this year's St. Gallen conference were surgical issues of the breast and axilla, radio-therapeutic and systemic treatment options, and the clinical relevance of tumour biology. The clinical utility of multigene assays for supporting individual treatment decisions was also intensively discussed.
Change in Proportional Protein Intake in a 10-Week Energy-Restricted Low- or High-Fat Diet, in Relation to Changes in Body Size and Metabolic Factors
Authors: Stocks Tanja , Taylor Moira A. , Ängquist Lars , MacDonald Ian A. , Arner Peter , Holst Claus , Oppert Jean-Michel , Martinez J.Alfredo , Rössner Stephan , Polak Jan , Langin Dominique , Saris Wim H.M. , Astrup Arne , Sørensen Thorkild I.A.
Published: May 2013

Objective: To investigate in a secondary analysis of a randomised trial the effects of a low-/high-fat diet and reported change from baseline in energy% from protein (prot%), in relation to changes in body size and metabolic factors. Methods: Obese adults (n = 771) were randomised to a 600 kcal energy-deficient low-fat (20-25 fat%) or high-fat (40-45 fat%) diet over 10 weeks. Dietary intake data at baseline and during the intervention were available in 585 completers. We used linear regression to calculate the combined effects of randomised group and groups of prot% change (<-2 /-2 to 2/>2) on outcomes. Results: The low-fat group with >2 prot% increase lost 1.1 kg more weight (p = 0.03) and reduced cholesterol by 0.25 mmol/l more (p = 0.003) than the high-fat group with >2 prot% decrease. These differences were 2.5-fold and 1.8-fold greater than the differences between the low-fat and high-fat groups while not considering prot% change. The high-fat group reduced plasma triglycerides more than the low-fat group, but not compared to those in the low-fat group with >2 units prot% increase (p fat-protein interaction = 0.01). Conclusions: Under energy restriction, participants on a low-fat diet who had increased the percentage energy intake from protein showed the greatest reduction in weight and cholesterol, and a triglyceride reduction equally large to that of participants on a high-fat diet.
Successful Self-Expandable Metallic Stent Placement for a Case of Distal Rectal Stenosis due to Gastric Cancer Metastasis
Authors: Okugawa Takuya , Oshima Tadayuki , Ikeo Koichi , Kondo Takashi , Tomita Toshihiko , Fukui Hirokazu , Watari Jiro , Miwa Hiroto
Published: May 2013

A 47-year-old woman was diagnosed as having advanced gastric cancer with malignant ascites. Despite chemotherapy, recurrent peritoneal dissemination was seen 1.5 years after operation. A computed tomography scan revealed rectal stenosis due to Schnitzler's metastasis. When the distance from the distal end of the obstruction to the anal verge is less than 5 cm, stent replacement has been said to be contraindicated due to the development of anal pain and foreign body sensation. Although the distance from the distal end of the obstruction to the anal verge was 4 cm in this case, a WallFlex™ colonic stent could be placed. She stayed home, and luminal patency remained until she died 270 days after stent insertion. This report demonstrates that rectal obstruction located less than 5 cm from the anal verge due to Schnitzler's metastasis could be treated by stenting without any symptomatic or technical complications.
Nonpharmacologic Control of Postoperative Supraventricular Arrhythmias Using AV Nodal Fat Pad Stimulation in a Young Animal Open Heart Surgical Model
Authors: Moak Jeffrey P. , Mercader Marco A. , He Dingchao , Trachiotis Gregory , Langert Joshua , Blicharz Andy , Montaque Erin , Li Xiyan , Cheng Yao I. , McCarter Robert , Bornzin Gene A. , Martin Gerard R. , Jonas Richard A.
Published: May 2013

Background—

Supraventricular arrhythmias (junctional ectopic tachycardia [JET] and atrial tachyarrhythmias) frequently complicate recovery from open heart surgery in children and can be difficult to manage. Medical treatment of JET can result in significant morbidity. Our goal was to develop a nonpharmacological approach using autonomic stimulation of selective fat pad (FP) regions of the heart in a young canine model of open heart surgery to control 2 common postoperative supraventricular arrhythmias.

Methods and Results—

Eight mongrel dogs, varying in age from 5 to 8 months and weighting 22±4 kg, underwent open heart surgery replicating a nontransannular approach to tetralogy of Fallot repair. Neural stimulation of the right inferior FP was used to control the ventricular response to supraventricular arrhythmias. Right inferior FP stimulation decreased baseline AV nodal conduction without altering sinus cycle length. AV node Wenckebach cycle length prolonged from 270±33 to 352±89 ms,
P
=0.02. Atrial fibrillation occurred in 7 animals, simulating a rapid atrial tachyarrhythmias. FP stimulation slowed the ventricular response rate from 166±58 to 63±29 beats per minute,
P
<0.001. Postoperative JET occurred in 7 dogs. FP stimulation slowed the ventricular rate during postoperative JET from 148±31 to 106±32 beats per minute,
P
<0.001, and restored sinus rhythm in 7/7 dogs.

Conclusions—

Right inferior FP stimulation had a selective effect on the AV node, and slowed the ventricular rate during postoperative JET and atrial tachyarrhythmias in our young canine open heart surgery model. FP stimulation may be a useful new technique for managing children with JET and atrial tachyarrhythmias.
Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment
Authors: Villa-Bellosta Ricardo , Rivera-Torres José , Osorio Fernando G. , Acín-Pérez Rebeca , Enriquez José A. , López-Otín Carlos , Andrés Vicente
Published: May 2013

Background—

Progerin is a mutant form of lamin A responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder characterized by excessive atherosclerosis and vascular calcification that leads to premature death, predominantly of myocardial infarction or stroke. The goal of this study was to investigate mechanisms that cause excessive vascular calcification in HGPS.

Methods and Results—

We performed expression and functional studies in wild-type mice and knock-in
Lmna

G609G/+

mice expressing progerin, which mimic the main clinical manifestations of HGPS.
Lmna

G609G/+

mice showed excessive aortic calcification, and primary aortic vascular smooth muscle cells from these progeroid animals had an impaired capacity to inhibit vascular calcification. This defect in progerin-expressing vascular smooth muscle cells is associated with increased expression and activity of tissue-nonspecific alkaline phosphatase and mitochondrial dysfunction, which leads to reduced ATP synthesis. Accordingly,
Lmna

G609G/+

vascular smooth muscle cells are defective for the production and extracellular accumulation of pyrophosphate, a major inhibitor of vascular calcification. We also found increased alkaline phosphatase activity and reduced ATP and pyrophosphate levels in plasma of
Lmna

G609G/+

mice without changes in phosphorus and calcium. Treatment with pyrophosphate inhibited vascular calcification in progeroid mice.

Conclusions—

Excessive vascular calcification in
Lmna

G609G

mice is caused by reduced extracellular accumulation of pyrophosphate that results from increased tissue-nonspecific alkaline phosphatase activity and diminished ATP availability caused by mitochondrial dysfunction in vascular smooth muscle cells. Excessive calcification is ameliorated on pyrophosphate treatment. These findings reveal a previously undefined pathogenic process in HGPS that may also contribute to vascular calcification in normal aging, because progerin progressively accumulates in the vascular tissue of individuals without HGPS.
Pharmacogenomic Association of Nonsynonymous SNPs in
SIGLEC12
,
A1BG
, and the Selectin Region and Cardiovascular Outcomes
Authors: McDonough Caitrin W. , Gong Yan , Padmanabhan Sandosh , Burkley Ben , Langaee Taimour Y. , Melander Olle , Pepine Carl J. , Dominiczak Anna F. , Cooper-DeHoff Rhonda M. , Johnson Julie A.
Published: May 2013

We sought to identify novel pharmacogenetic markers associated with cardiovascular outcomes in patients with hypertension on antihypertensive therapy. We genotyped a 1:4 case:control cohort (n=1345) on the Illumina HumanCVD Beadchip from the INternational VErapamil SR–Trandolapril STudy (INVEST), where participants were randomized to a β-blocker strategy or a calcium channel blocker strategy. Genome-spanning single nucleotide polymorphism (SNP)×treatment interaction analyses of nonsynonymous SNPs were conducted in white and Hispanic race/ethnic groups. Top hits from whites were tested in Hispanics for consistency. A genetic risk score was constructed from the top 3 signals and tested in the Nordic Diltiazem study.
SIGLEC12
rs16982743 and
A1BG
rs893184 had a significant interaction with treatment strategy for adverse cardiovascular outcomes (INVEST whites and Hispanics combined interaction
P
=0.0038 and 0.0036, respectively). A genetic risk score, including rs16982743, rs893184, and rs4525 in
F5
, was significantly associated with treatment-related adverse cardiovascular outcomes in whites and Hispanics from the INVEST study and in the Nordic Diltiazem study (meta-analysis interaction
P
=2.39×10
−5
). In patients with a genetic risk score of 0 or 1, calcium channel blocker treatment was associated with lower risk (odds ratio [95% confidence interval]=0.60 [0.42–0.86]), and in those with a genetic risk score of 2 to 3, calcium channel blocker treatment was associated with higher risk (odds ratio [95% confidence interval]=1.31 [1.08–1.59]). These results suggest that cardiovascular outcomes may differ based on
SIGLEC12, A1BG
,
F5
genotypes, and antihypertensive treatment strategy. These specific genetic associations and our risk score provide insight into a potential approach to personalized antihypertensive treatment selection.
Serum Uric Acid Level, Longitudinal Blood Pressure, Renal Function, and Long-Term Mortality in Treated Hypertensive Patients
Authors: Dawson Jesse , Jeemon Panniyammakal , Hetherington Lucy , Judd Caitlin , Hastie Claire , Schulz Christin , Sloan William , Muir Scott , Jardine Alan , McInnes Gordon , Morrison David , Dominiczak Anna F. , Padmanabhan Sandosh , Walters Matthew
Published: May 2013

Uric acid may have a role in the development of hypertension and renal dysfunction. We explored the relationship among longitudinal blood pressure, renal function, and cardiovascular outcomes in a large cohort of patients with treated hypertension. We used data from the Glasgow Blood Pressure Clinic database. Patients with a baseline measure of serum uric acid and longitudinal measures of blood pressure and renal function were included. Mortality data were obtained from the General Register Office for Scotland. Generalized estimating equations were used to explore the relationship among quartiles of serum uric acid, blood pressure, and estimated glomerular filtration rate. Cox proportional hazard models were developed to assess mortality relationships. In total, 6984 patients were included. Serum uric acid level did not influence the longitudinal changes in systolic or diastolic blood pressure but was related to change in glomerular filtration rate. In comparison with patients in the first quartile of serum uric acid, the relative decrease in glomerular filtration rate in the fourth was 10.7 (95% confidence interval, 7.9–13.6 mL/min per 1.73 m
2
) in men and 12.2 (95% confidence interval, 9.2–15.2 mL/min per 1.73 m
2
) in women. All-cause and cardiovascular mortality differed across quartiles of serum uric acid in women only (
P
<0.001; hazard ratios for all-cause mortality 1.38 [95% confidence interval, 1.14–1.67] for the fourth quartile of serum uric acid compared with the first). Serum uric acid level was not associated with longitudinal blood pressure control in adults with treated hypertension but was related to decline in renal function and mortality in women.
Review of the Balkan Isophya (Orthoptera: Phaneropteridae) with particular emphasis on the Isophya modesta group and remarks on the systematics of the genus based on morphological and acoustic data
Authors: CHOBANOV DRAGAN P. , GRZYWACZ BEATA , IORGU IONUŢ Ş. , CΙPLAK BATTAL , ILIEVA MAYA B. , WARCHAŁOWSKA-ŚLIWA ELŻBIETA
Published: May 2013

A critical review of the taxonomy and systematics of the genus Isophya from the Balkan Peninsula, together with a revision of the I. modesta group, including its representatives outside the Balkans, has been made using morphological, bioacoustic and karyological data. As a result, the following taxonomic considerations have been proposed: (1) the status of two taxa has been reconsidered: Isophya rhodopensis leonorae Kaltenbach, stat.n., I. rhodopensis petkovi Peshev, stat.n.; (2) five synonymies have been established: I. hospodar (Saussure) = I. hospodar medimontana Nedelkov, syn.n.; I. plevnensis Peshev, sensu novo = I. pravdini pravdini Peshev, syn.n.; I. rhodopensis leonorae Kaltenbach = I. kisi Peshev, syn.n.; I. obtusa = I. pravdini bazyluki Peshev, syn.n.; I. modesta Frivaldszky = I. modesta intermedia Kis syn.n. The descriptions of the taxa under consideration are supplemented with unpublished morphological and/or bioacoustic data. An updated list of the taxa occurring on the Balkans includes 24 taxa (21 species, including the doubtful data on I. camptoxypha). A dichotomic and tabulated key for recognition and maps of distribution of the established taxa are presented.
Hotspots of new species discovery: new mite species described during 2007 to 2012
Authors: LIU DONG , YI TIAN-CI , XU YUN , ZHANG ZHI-QIANG
Published: May 2013

The type localities of new mite species described in two journals (Systematic & Applied Acarology and Zootaxa) during the last six years (2007–2012) were surveyed to detect hotspots of new mite species discovery. Among the 642 papers examined, 71% of them contain new species, with 148 new species in 2007, 207 in 2008, 234 in 2009, 208 in 2010, 333 in 2011 and 249 in 2012. Systematic & Applied Acarology published about 3% of the total new species indexed by Zoological Record during 2007–2012, whereas Zootaxa published about 35% of the total. The 1379 new species are distributed unevenly among 150 mite families; the top 15 families accounted for 55% of all the species, and 86 of the 150 families have 1–3 species each. The top family is the Eriophyidae, which alone accounted for nearly 15% of the total new species. Geographically, the new species were described from 92 countries and their distribution among these countries is highly uneven. The top 10 countries accounted for 62% of all the new species and the top country, China, alone accounted for 18% of the total. The average number of new species per country is 15 and no more than a fifth of the countries are above the average, and 40% of the countries have only 1–3 new species each. The top country for each continent is China (248 species) for Asia, Australia (166 species) for Oceania, Brazil (76 species) for South America, Kenya (51 species) for Africa, USA (51 species) for North America and Russia (42 species) for Europe. Increased efforts in discovering and describing new species are much needed for biodiversity-rich countries in South America, Southeast Asia and Africa.
High-Resolution Doppler Lidar Observations of Transient Downslope Flows and Rotors
Authors: Kühnlein Christian , Dörnbrack Andreas , Weissmann Martin
Published: May 2013

The authors present observations of the temporal evolution of downslope windstorms with rotors and internal hydraulic jumps of unprecedented detail and spatiotemporal coverage. The observations were carried out by means of a coherent Doppler lidar in the lee of the southern Sierra Nevada range during the sixth intensive observational period of the Terrain-induced Rotor Experiment (T-REX) in 2006. Two representative flow regimes are analyzed and juxtaposed in this paper. The first case shows pulses of high-momentum air that propagate eastward through the valley with an internal hydraulic jump on the leading edge. The region downstream of the transient internal hydraulic jump is characterized by turbulence but no coherent rotor circulation was observed. During the second case, the strongest windstorm of the field campaign T-REX occurred. The observed features of this event resemble the classical notion of a rotor. Altogether, the Doppler lidar observations of both downslope flow events reveal a complex, turbulent flow that is highly transient, intermittent, 3D, and interacts with a significant along-valley flow.