bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathogenesis of the Metabolic Syndrome: Insights from Monogenic Disorders
Authors: Murphy Rinki , Carroll Richard W. , Krebs Jeremy D.
Published: May 2013

Identifying rare human metabolic disorders that result from a single-gene defect has not only enabled improved diagnostic and clinical management of such patients, but also has resulted in key biological insights into the pathophysiology of the increasingly prevalent metabolic syndrome. Insulin resistance and type 2 diabetes are linked to obesity and driven by excess caloric intake and reduced physical activity. However, key events in the causation of the metabolic syndrome are difficult to disentangle from compensatory effects and epiphenomena. This review provides an overview of three types of human monogenic disorders that result in (1) severe, non-syndromic obesity, (2) pancreatic beta cell forms of early-onset diabetes, and (3) severe insulin resistance. In these patients with single-gene defects causing their exaggerated metabolic disorder, the primary defect is known. The lessons they provide for current understanding of the molecular pathogenesis of the common metabolic syndrome are highlighted.
Residual ISI Obtained by Blind Adaptive Equalizers and Fractional Noise
Authors: Pinchas Monika
Published: May 2013

Recently, a closed-form approximated expression was derived by the same author for the achievable residual intersymbol interference (ISI) case that depends on the step-size parameter, equalizer’s tap length, input signal statistics, signal-to-noise ratio (SNR), and channel power. But this expression was obtained by assuming that the input noise is a white Gaussian process where the Hurst exponent (H) is equal to 0.5. In this paper, we derive a closed-form approximated expression (or an upper limit) for the residual ISI obtained by blind adaptive equalizers valid for fractional Gaussian noise (fGn) input where the Hurst exponent is in the region of0.5≤H<1. Up to now, the statistical behaviour of the residual ISI was not investigated. Furthermore, the convolutional noise for the latter stages of the deconvolutional process was assumed to be a white Gaussian process (H=0.5). In this paper, we show that the Hurst exponent of the residual ISI is close to one, almost independent of the SNR or equalizer’s tap length but depends on the step-size parameter. In addition, the convolutional noise obtained in the steady state is a noise process having a Hurst exponent depending on the step-size parameter.
Neuropilin-2 Promotes Extravasation and Metastasis by Interacting with Endothelial α5 Integrin
Authors: Cao Ying , Hoeppner Luke H. , Bach Steven , E Guangqi , Guo Yan , Wang Enfeng , Wu Jianmin , Cowley Mark J. , Chang David K. , Waddell Nicola , Grimmond Sean M. , Biankin Andrew V. , Daly Roger J. , Zhang Xiaohui , Mukhopadhyay Debabrata
Published: May 2013

Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we show that neuropilin-2 (NRP-2), a multifunctional nonkinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with α5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis. Cancer Res; 73(14); 4579–90. ©2013 AACR.
The Ubiquitin–CXCR4 Axis Plays an Important Role in Acute Lung Infection–Enhanced Lung Tumor Metastasis
Authors: Yan Libo , Cai Qingchun , Xu Yan
Published: May 2013

Purpose: Our goals were to test the effect of acute lung infection on tumor metastasis and to investigate the underlying mechanisms.

Experimental Design: We combined bacteria-induced and lipopolysaccharide (LPS)-induced acute lung injury/inflammation (ALI) mouse models with mouse metastatic models to study the effect of acute inflammation on lung metastasis in mice. The mechanisms were investigated in ex vivo, in vitro, and in vivo studies.

Results: Both bacteria- and LPS-induced ALI significantly enhanced lung metastasis of four tail vein–injected mouse tumor cell lines. Bacteria also enhanced lung metastasis when 4T1 cells were orthotopically injected. The bronchoalveolar lavage fluid (BALF) from LPS- or bacteria-injected mice stimulated migration of tumor cells. In vivo tracking of metastatic RM-9 cells showed that bacterial injection enhanced early dissemination of tumor cells to the lung. The majority of the BALF migratory activity could be blocked by AMD3100, a chemokine receptor 4 (CXCR4) inhibitor. All tested cell lines expressed CXCR4. The levels of extracellular ubiquitin, but not stromal cell–derived factor-1, in BALF were significantly increased by LPS. Ubiquitin was able to induce AMD3100-sensitive migration of tumor cells. Finally, the antibacterial agent amoxicillin and the CXCR4 inhibitor AMD3100 blocked the enhancement effect of bacterial infection on tumor metastasis.

Conclusions: Acute lung infection dramatically increased cancer cell homing to the lung and lung metastasis. This change may be due to an alteration of the lung microenvironment and preparation of a favorable metastatic “niche.” This effect was seen in multiple cancer types and thus may have broad applications for cancer patients in prevention and/or treatment of metastasis. Clin Cancer Res; 19(17); 4706–16. ©2013 AACR.
Adoptive Transfer of Tumor-Infiltrating Lymphocytes in Patients with Metastatic Melanoma: Intent-to-Treat Analysis and Efficacy after Failure to Prior Immunotherapies
Authors: Besser Michal J. , Shapira-Frommer Ronnie , Itzhaki Orit , Treves Avraham J. , Zippel Douglas B. , Levy Daphna , Kubi Adva , Shoshani Noa , Zikich Dragoslav , Ohayon Yaara , Ohayon Daniel , Shalmon Bruria , Markel Gal , Yerushalmi Ronit , Apter Sara , Ben-Nun Alon , Ben-Ami Eytan , Shimoni Avichai , Nagler Arnon , Schachter Jacob
Published: May 2013

Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies.

Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning.

Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment.

Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. Clin Cancer Res; 19(17); 4792–800. ©2013 AACR.
Combined Targeting of mTOR and AKT Is an Effective Strategy for Basal-like Breast Cancer in Patient-Derived Xenograft Models
Authors: Xu Siguang , Li Shunqiang , Guo Zhanfang , Luo Jingqin , Ellis Matthew J. , Ma Cynthia X.
Published: May 2013

Basal-like breast cancer is an aggressive disease for which targeted therapies are lacking. Recent studies showed that basal-like breast cancer is frequently associated with an increased activity of the phosphatidylinositol 3-kinase (PI3K) pathway, which is critical for cell growth, survival, and angiogenesis. To investigate the therapeutic potential of PI3K pathway inhibition in the treatment of basal-like breast cancer, we evaluated the antitumor effect of the mTOR inhibitor MK-8669 and AKT inhibitor MK-2206 in WU-BC4 and WU-BC5, two patient-derived xenograft models of basal-like breast cancer. Both models showed high levels of AKT phosphorylation and loss of PTEN expression. We observed a synergistic effect of MK-8669 and MK-2206 on tumor growth and cell proliferation in vivo. In addition, MK-8669 and MK-2206 inhibited angiogenesis as determined by CD31 immunohistochemistry. Biomarker studies indicated that treatment with MK-2206 inhibited AKT activation induced by MK-8669. To evaluate the effect of loss of PTEN on tumor cell sensitivity to PI3K pathway inhibition, we knocked down PTEN in WU-BC3, a basal-like breast cancer cell line with intact PTEN. Compared with control (GFP) knockdown, PTEN knockdown led to a more dramatic reduction in cell proliferation and tumor growth inhibition in response to MK-8669 and MK-2206 both in vitro and in vivo. Furthermore, a synergistic effect of these two agents on tumor volume was observed in WU-BC3 with PTEN knockdown. Our results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer with loss of PTEN. Mol Cancer Ther; 12(8); 1665–75. ©2013 AACR.
Chemotherapy for Liver Metastasis Originating from Colorectal Cancer with Portal Vein Tumor Thrombosis: A Case Report
Authors: Kawasaki Atsushi , Mimatsu Kenji , Oida Takatsugu , Kano Hisao , Kuboi Youichi , Fukino Nobutada , Kida Kazutoshi , Amano Sadao
Published: May 2013

The patient was a male in his 70s with a history of chronic renal failure and dilated cardiomyopathy. In January 2011, he underwent abdominoperineal resection of the rectum, right hepatic lobectomy, and resection of a portal vein tumor thrombus with a diagnosis of rectal cancer and metastatic liver cancer accompanied by portal vein tumor thrombosis. Although 5-fluorouracil + l-leucovorin therapy (RPMI regimen) was carried out as postoperative adjuvant chemotherapy, the tumor marker (CEA and VA19-9) levels increased 8 months after surgery. Since the functions of major organs were impaired, UFT® + UZEL® therapy was started. The tumor marker levels decreased temporarily, but increased again 12 months after surgery, and so intravenous instillation of panitumumab was initiated. Nine administrations have been performed to date, with no increase in tumor marker levels or exacerbation of the condition. Also, no grade 2 or severer adverse event has been noted according to CTCAE v.4.0. The experience with this patient suggests the possibility that exacerbation of the condition of patients with liver metastasis of colorectal cancer accompanied by portal vein tumor thrombosis with abnormalities in the functions of major organs can be controlled temporarily by the administration of panitumumab alone.
‘Small Changes' to Diet and Physical Activity Behaviors for Weight Management
Authors: Hills Andrew P. , Byrne Nuala M. , Lindstrom Rachel , Hill James O.
Published: May 2013

Obesity is associated with numerous short- and long-term health consequences. Low levels of physical activity and poor dietary habits are consistent with an increased risk of obesity in an obesogenic environment. Relatively little research has investigated associations between eating and activity behaviors by using a systems biology approach and by considering the dynamics of the energy balance concept. A significant body of research indicates that a small positive energy balance over time is sufficient to cause weight gain in many individuals. In contrast, small changes in nutrition and physical activity behaviors can prevent weight gain. In the context of weight management, it may be more feasible for most people to make small compared to large short-term changes in diet and activity. This paper presents a case for the use of small and incremental changes in diet and physical activity for improved weight management in the context of a toxic obesogenic environment.
Recurrent Stereotyped Episodes in Cerebral Amyloid Angiopathy: Response to Migraine Prophylaxis in Two Patients
Authors: Paterson R.W. , Uchino K. , Emsley H.C. , Pullicino P.
Published: May 2013

Background: Cerebral amyloid angiopathy (CAA) typically presents with cognitive decline or symptomatic intracerebral hemorrhage, but episodes of recurrent stereotyped limb attacks have also been reported. Methods: Retrospective review of the medical records of 4 patients referred to the general neurology services and a specialist stroke center with clinically probable CAA. Results: Four subjects, all Caucasian, mean age 74 years, were followed up over a mean duration of 20 months. They all experienced recurrent prolonged stereotyped attacks of sensory symptoms, lasting 5-30 min, that resolved completely between attacks. Three subjects developed intracerebral hemorrhage, and 2 had an irreversible rapid cognitive decline. Two patients experienced symptomatic improvement with migraine prophylaxis (verapamil or topiramate). Conclusions: Recurrent stereotyped prolonged attacks with sensory and motor elements can predate the development of intracerebral hemorrhage in individuals with clinically probable CAA. When evaluating patients with such attacks, neurologists need to consider CAA as a possible mimic of transient ischemic attacks. We suggest a trial of migraine prophylaxis for symptomatic management.
Regulation of IgE-Dependent Zinc Release from Human Mast Cells
Authors: Nakashima-Kaneda Kazuko , Matsuda Akira , Mizuguchi Hiroyuki , Sasaki-Sakamoto Tomomi , Saito Hirohisa , Ra Chisei , Okayama Yoshimichi
Published: May 2013

Background: Zinc (Zn) affects many aspects of immune function, including thymic development and the activities of immune cells. Zn is also involved in many steps of high-affinity IgE receptor (FcεRI)-induced mast cell (MC) activation, which is required for degranulation and cytokine production. Intracellular Zn levels increase in mouse MCs after FcεRI stimulation. We previously reported that Zn distribution in a human MC line, LAD2, changed dramatically following FcεRI aggregation with synchrotron radiation microbeams. However, the kinetics of Zn distribution and the underlying mechanisms following FcεRI cross-linking remain unknown. Methods: We used cord-blood-derived MCs and LAD2 cells. Degranulation was assessed by β-hexosaminidase (β-hex) release. Extracellular Zn levels were determined by inductively coupled plasma atomic emission spectrometry or based on the fluorescence intensity of a Zn indicator. We also used RNAi to knockdown ZnT1 expression. mRNA expression levels were determined by real-time RT-PCR. Results: Zn was rapidly released from human MCs after FcεRI aggregation. The kinetics and optimal conditions for FcεRI cross-linking for Zn release were different from those for degranulation. Treating LAD2 cells with an intracellular Ca2+ chelator significantly inhibited IgE-mediated β-hex release but not Zn release. We investigated IgE-mediated β-hex and Zn release with specific inhibitors of signaling pathways. Zn and β-hex release were partly correlated with but also partly independent of IgE. Knockdown of the Zn efflux transporter, ZnT1, significantly inhibited Zn release from human MCs. Conclusions: Our results indicate that IgE-dependent Zn release from human MCs involves signaling cascades that are distinct from those of degranulation. Thus, Zn may have a unique function as a mediator of allergic inflammation.
Total and Antigen- (Fungi, Mites and Staphylococcal Enterotoxins) Specific IgEs in Nasal Polyps Is Related to Local Eosinophilic Inflammation
Authors: Matsuwaki Yoshinori , Uno Keisuke , Okushi Tetsushi , Otori Nobuyoshi , Moriyama Hiroshi
Published: May 2013

Background: Total and specific immunoglobulin E (IgE) in nasal polyps (NP) is related to local eosinophilic inflammation. However, it remains unclear which antigens cause a stronger accumulation of eosinophils in NP. We investigated whether local IgEs to specific antigens correlated with local eosinophil accumulation. Methods: Total IgE, antigen-specific IgEs [5 species of fungi, staphylococcal enterotoxins A and B (SEA and SEB), cedar pollen, ragweed pollen and house-dust mites] and eosinophil cationic protein (ECP) were measured in sinus mucosa homogenates and serum from 29 patients with chronic rhinosinusitis with NP (CRSwNP), 8 patients with allergic fungal rhinosinusitis (AFRS) and 8 control subjects without CRS. The level of ECP in NP was analyzed for correlations with the total and specific IgE levels in the serum and NP. Results: In CRSwNP, antigen-specific IgEs [Alternaria > mite (Dp) > Aspergillus > SEB > Penicillium > mite (Df), but not the other fungi, SEA or pollens] in the sinus mucosa correlated significantly with the local ECP. In AFRS, antigen-specific IgEs [Penicillium > mite (Df) > Alternaria, but not the other fungi, SEs or pollens] in the sinus mucosa correlated significantly with the local ECP. Conclusions: Local total IgE and antigen (fungi, mites and SEs)-specific IgEs in NP are related to the local eosinophilic inflammation of AFRS and CRSwNP.
Contribution of CD4+ T Cells and Dendritic Cells to Female-Dominant Antigen-Induced T Helper Type 2 Cytokine Production by Bronchial Lymph Node Cells
Authors: Okuyama Kaori , Suenaga Masatoshi , Furuki Shyunya , Kawano Tasuku , Ohkawara Yuichi , Takayanagi Motoaki , Kikuchi Toshiaki , Ohno Isao
Published: May 2013

Background: After puberty, asthma severity is higher in women than in men. The underlying mechanisms of this gender difference are not fully understood. In murine models of allergic asthma, more severe airway inflammation in female mice is associated with higher levels of T helper type 2 (Th2) cytokines. The aim of this study was to investigate the contributions of CD4+ T cells and dendritic cells (DCs) to the differences in Th2 cytokine production between sexes. Methods: Bronchial lymph node (BLN) cells from ovalbumin (OVA)-sensitized male and female C57BL/6 mice were stimulated with OVA and anti-CD3/CD28 antibodies. The CD4+ T cells and DCs purified from BLN cells were cocultured with OVA in a sex-matched or mismatched fashion. The CD4+ T cells were also stimulated with anti-CD3/CD28 antibodies. The concentrations of interleukin (IL)-5, IL-4, IL-13 and interferon (IFN)-γ in the culture supernatants were measured. Results: The concentrations of IL-5, IL-4 and IL-13, but not IFN-γ, were significantly higher in female BLN cells stimulated with OVA than in male BLN cells. Sex differences were also observed in the CD4+ T cells stimulated with anti-CD3/CD28 antibodies, whereas only IL-4 was significantly different in the BLN cells stimulated with antibodies. IL-5 production by OVA-stimulated male and female CD4+ T cells, but not IL-4 or IL-13 production, was significantly increased in the coculture with female DCs when compared to the male DCs. Conclusions: The differences in Th2 cytokine production between sexes by the BLN cells may be attributable, at least in part, to the differing functions of CD4+ T cells and DCs between sexes.
Elevated Macrophage Inflammatory Protein 1α and Interleukin-17 Production in an Experimental Asthma Model Infected with Respiratory Syncytial Virus
Authors: Ishioka Taisei , Yamada Yoshiyuki , Kimura Hirokazu , Yoshizumi Masakazu , Tsukagoshi Hiroyuki , Kozawa Kunihisa , Maruyama Kenichi , Hayashi Yasuhide , Kato Masahiko
Published: May 2013

Background: Respiratory syncytial virus (RSV) infection is associated with both the development and exacerbation of bronchial asthma. We examined eosinophil infiltration and the cytokine profiles of both airway and peripheral blood in antigen-sensitized mice infected with RSV to investigate the pathogenesis of exacerbations of asthma due to RSV infection. Methods: Ovalbumin (OVA)-sensitized mice were challenged by OVA inhalation 3 times and then infected with RSV [105 TCID50 (50% of tissue culture infectious dose)/25 g body weight] or mock infection immediately after the last challenge. Animals from each group, namely, the control (PBS instead of OVA inhalation plus mock infection), RSV (PBS plus RSV), OVA (OVA plus mock) and OVA/RSV (OVA plus RSV) were analyzed. Analysis included evaluation of airway responsiveness to methacholine, pathological findings in the airway by hematoxylin and eosin (HE) and Luna staining, bronchoalveolar fluid (BALF) and peripheral leukocytes counts, and concentrations of multiple cytokines/chemokines in both BALF and serum. Results: Airway responsiveness was significantly enhanced in the OVA and OVA/RSV groups compared with the control group. Levels of tissue and BALF eosinophils were higher in the OVA and OVA/RSV groups than in the RSV or control group. Significantly higher levels of macrophage inflammatory protein (MIP)-1α in BALF were observed in the OVA/RSV group compared with the 3 other groups. Production of serum IL-17 was also significantly elevated in the OVA/RSV group compared with the control or OVA group. Conclusions: These findings suggest that MIP-1α and IL-17 may play important roles in acute exacerbation of asthma induced by RSV in an animal model.
Eosinophils: Multifunctional and Distinctive Properties
Authors: Kita Hirohito
Published: May 2013

The eosinophil is a granulocyte prominent in allergic diseases and inflammatory responses against helminthic parasites. The eosinophil was named by Paul Ehrlich in 1879, and derives from the intense staining of its granules with the acidic dye eosin. It has been the subject of extensive investigation ever since. It is strongly associated with human diseases involving mucosal surfaces, such as allergic asthma, atopic dermatitis and gastrointestinal disorders. Eosinophils are likely involved in tissue homeostasis, modulation of adaptive immune responses, innate immunity to certain microbes and pathological changes in allergic disorders. Thus, the eosinophil is considered a multifunctional leukocyte that contributes to a wide variety of physiological and pathological processes, depending on its location and activation status. Further studies will be necessary to better understand the biology of this extraordinary leukocyte and to reveal the importance of the cell in human health and disease.
Correction of Poland's Syndrome: Case Report and Review of the Current Literature
Authors: Lantzsch Tilmann , Lampe Dieter , Kantelhardt Eva J.
Published: May 2013

Background: Poland's syndrome, a rare congenital anomaly, consists of unilateral absence of the pectoralis major muscle, ipsilateral brachysyndactyly, and occasionally associated other malformations of the anterior chest wall, mamilla, and mamma. Case Report: In the case of a 32-year-old woman, marked hypoplasia of the right breast and the right nipple, malformation of the right upper limb with brachysyndactyly and microdactyly were noted, all present since birth. This paper describes the surgical technique and possible complications of reconstruction of the chest wall deformity with a solid silicone implant and a latissimus dorsi flap. The current literature on the topic is reviewed. Conclusion: The surgical method with autologous material and implants is a sufficient technique for chest wall reconstruction and gives a good long-term result in case of Poland's syndrome.
Role of Galactography in the Early Diagnosis of Breast Cancer
Authors: Berná-Serna Juan D. , Torres-Ales Carolina , Berná-Mestre Juan D. , Polo Luis
Published: May 2013

Background: The purpose of this study was to evaluate the usefulness of galactography (GL) in the early diagnosis of breast cancer in patients with pathologic nipple discharge (PND). Patients and Methods: We retrospectively studied all galactograms obtained in 117 women with PND, who subsequently had a biopsy. The findings detected in the galactograms of the patients in this study were assigned to different categories of the Galactogram Image Classification System (GICS): GICS 2, benign; GICS 3, probably benign; GICS 4, suspicious for malignancy; and GICS 5, highly suspicious for malignancy. Results: The galactograms were classified into GICS 2 (29 cases; 24.7%), GICS 3 (42 cases; 35.8%), GICS 4 (30 cases; 25.6%), and GICS 5 (16 cases; 13.6%). A good correlation was observed between histological diagnosis and GICS categories (p < 0.05). All cases diagnosed with carcinoma (n = 18) were classified in GICS categories 4-5: ductal carcinoma in situ in 14 cases (11.9%) and invasive carcinoma in 4 cases (3.4%). Conclusion: GL is a useful procedure in the early diagnosis of breast cancer in patients with PND.
Dose-Dependent Vitamin C Uptake and Radical Scavenging Activity in Human Skin Measured with in vivo Electron Paramagnetic Resonance Spectroscopy
Authors: Lauer Anna-Christina , Groth Norbert , Haag Stefan F. , Darvin Maxim E. , Lademann Jürgen , Meinke Martina C.
Published: May 2013

Vitamin C is a potent radical scavenger and a physiological part of the antioxidant system in human skin. The aim of this study was to measure changes in the radical-scavenging activity of human skin in vivo due to supplementation with different doses of vitamin C and at different time points. Therefore, 33 volunteers were supplemented with vitamin C or placebo for 4 weeks. The skin radical-scavenging activity was measured with electron paramagnetic resonance spectroscopy. After 4 weeks, the intake of 100 mg vitamin C/day resulted in a significant increase in the radical-scavenging activity by 22%. Intake of 180 mg/day even resulted in a significant increase of 37%. No changes were found in the placebo group. A part of the study population was additionally measured after 2 weeks: in this group radical scavenging had already reached maximal activity after 2 weeks. In conclusion, orally administered vitamin C increases the radical-scavenging activity of the skin. The effect occurs fast and is enhanced with higher doses of vitamin C.
St. Gallen 2013: Brief Preliminary Summary of the Consensus Discussion
Authors: Harbeck Nadia , Thomssen Christoph , Gnant Michael
Published: May 2013

The 2013 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-based, globally valid treatment recommendations for breast cancer care, with a broad spectrum of acceptable clinical practice. This report summarizes the results of the 2013 international panel voting procedures with regard to loco-regional and endocrine treatment, chemotherapy, targeted therapy as well as adjuvant bisphosphonate use. This report is not aimed to replace the official St. Gallen Consensus publication, some recommendations may even be altered in the final paper, but should serve a preliminary rapid report of this important meeting.
Comparison of Echocardiographic and Cardiac Magnetic Resonance Imaging in Hypertrophic Cardiomyopathy Sarcomere Mutation Carriers Without Left Ventricular Hypertrophy
Authors: Valente Anne Marie , Lakdawala Neal K. , Powell Andrew J. , Evans Sarah P. , Cirino Allison L. , Orav E. John. , MacRae Calum A. , Colan Steven D. , Ho Carolyn Y.
Published: May 2013

Background—

Left ventricular hypertrophy (LVH) typically manifests during or after adolescence in sarcomere mutation carriers at risk for developing hypertrophic cardiomyopathy. Guidelines recommend serial imaging of mutation carriers without LVH (G+/LVH−) to monitor for phenotypic evolution, but the optimal strategy is undefined. Compared with echocardiography (echo), cardiac MRI (CMR) offers improved endocardial visualization and potential to assess scar. However, the incremental advantage offered by CMR for early diagnosis of hypertrophic cardiomyopathy is unclear. Therefore, we systematically compared echo and CMR in G+/LVH− subjects.

Methods and Results—

A total of 40 sarcomere mutation carriers with normal echo wall thickness (<12 mm or
z
score <2.5 in children) underwent concurrent CMR. Mean age was 21.7±11.1 years, 55% were female. If left ventricular wall thickness seemed nonuniform, the size and location of relatively thickened segments were noted. Late gadolinium enhancement was assessed with CMR. Diagnostic agreement between echo and CMR was good (90%), although CMR measurements of left ventricular wall thickness were ≈19% lower than echo. Four subjects had mild hypertrophy (12.6–14 mm; ≤2 segments) appreciated by CMR but not echo. No subjects had late gadolinium enhancement. During median 35-month follow-up, 2 subjects developed overt hypertrophic cardiomyopathy, including 1 with mild LVH by CMR at baseline.

Conclusions—

Echo is unlikely to miss substantial LVH; however, CMR identified mild hypertrophy in ≈10% of mutation carriers with normal echo wall thickness. CMR may be a useful adjunct in hypertrophic cardiomyopathy family screening, particularly in higher risk situations, or if echocardiographic images are suboptimal or suggest borderline LVH.
Residual Ischemia After Revascularization in Multivessel Coronary Artery Disease
Authors: Arnold Jayanth R. , Karamitsos Theodoros D. , van Gaal William J. , Testa Luca , Francis Jane M. , Bhamra-Ariza Paul , Ali Ali , Selvanayagam Joseph B. , Westaby Steve , Sayeed Rana , Jerosch-Herold Michael , Neubauer Stefan , Banning Adrian P.
Published: May 2013

Background—

Revascularization strategies for multivessel coronary artery disease include percutaneous coronary intervention and coronary artery bypass grafting. In this study, we compared the completeness of revascularization as assessed by coronary angiography and by quantitative serial perfusion imaging using cardiovascular magnetic resonance.

Methods and Results—

Patients with multivessel coronary disease were recruited into a randomized trial of treatment with either coronary artery bypass grafting or percutaneous coronary intervention. Angiographic disease burden was determined by the Bypass Angioplasty Revascularization Investigation (BARI) myocardial jeopardy index. Cardiovascular magnetic resonance first-pass perfusion imaging was performed before and 5 to 6 months after revascularization. Using model-independent deconvolution, hyperemic myocardial blood flow was evaluated, and ischemic burden was quantified. Sixty-seven patients completed follow-up (33 coronary artery bypass grafting and 34 percutaneous coronary intervention). The myocardial jeopardy index was 80.7±15.2% at baseline and 6.9±11.3% after revascularization (
P
<0.0001), with revascularization deemed complete in 62.7% of patients. Relative to cardiovascular magnetic resonance, angiographic assessment overestimated disease burden at baseline (80.7±15.2% versus 49.9±29.2% [
P
<0.0001]), but underestimated it postprocedure (6.9±11.3% versus 28.1±33.4% [
P
<0.0001]). Fewer patients achieved complete revascularization based on functional criteria than on angiographic assessment (38.8% versus 62.7%;
P
=0.015). After revascularization, hyperemic myocardial blood flow was significantly higher in segments supplied by arterial bypass grafts than those supplied by venous grafts (2.04±0.82 mL/min per gram versus 1.89±0.81 mL/min per gram, respectively;
P
=0.04).

Conclusions—

Angiographic assessment may overestimate disease burden before revascularization, and underestimate residual ischemia after revascularization. Functional data demonstrate that a significant burden of ischemia remains even after angiographically defined successful revascularization.

Clinical Trial Registration—

URL:
http://www.controlled-trials.com
. Unique identifier:ISRCTN25699844.
Serum Proprotein Convertase Subtilisin/Kexin Type 9 and Cell Surface Low-Density Lipoprotein Receptor
Authors: Tavori Hagai , Fan Daping , Blakemore John L. , Yancey Patricia G. , Ding Lei , Linton MacRae F. , Fazio Sergio
Published: May 2013

Background—

Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates low-density lipoprotein (LDL) receptor (LDLR) degradation, thus influencing serum cholesterol levels. However, dysfunctional LDLR causes hypercholesterolemia without affecting PCSK9 clearance from the circulation.

Methods and Results—

To study the reciprocal effects of PCSK9 and LDLR and the resultant effects on serum cholesterol, we produced transgenic mice expressing human (h) PCSK9. Although hPCSK9 was expressed mainly in the kidney, LDLR degradation was more evident in the liver. Adrenal LDLR levels were not affected, likely because of the impaired PCSK9 retention in this tissue. In addition, hPCSK9 expression increased hepatic secretion of apolipoprotein B–containing lipoproteins in an LDLR-independent fashion. Expression of hPCSK9 raised serum murine PCSK9 levels by 4.3-fold in wild-type mice and not at all in LDLR
−/−
mice, in which murine PCSK9 levels were already 10-fold higher than in wild-type mice. In addition, LDLR
+/−
mice had a 2.7-fold elevation in murine PCSK9 levels and no elevation in cholesterol levels. Conversely, acute expression of human LDLR in transgenic mice caused a 70% decrease in serum murine PCSK9 levels. Turnover studies using physiological levels of hPCSK9 showed rapid clearance in wild-type mice (half-life, 5.2 minutes), faster clearance in human LDLR transgenics (2.9 minutes), and much slower clearance in LDLR
−/−
recipients (50.5 minutes). Supportive results were obtained with an in vitro system. Finally, up to 30% of serum hPCSK9 was associated with LDL regardless of LDLR expression.

Conclusions—

Our results support a scenario in which LDLR represents the main route of elimination of PCSK9 and a reciprocal regulation between these 2 proteins controls serum PCSK9 levels, hepatic LDLR expression, and serum LDL levels.
Nighttime Blood Pressure and New-Onset Left Ventricular Hypertrophy
Authors: Cuspidi Cesare , Facchetti Rita , Bombelli Michele , Sala Carla , Negri Francesca , Grassi Guido , Mancia Giuseppe
Published: May 2013

The relationship between circadian blood pressure (BP) variations and the extent of subclinical cardiac organ damage is still debated. In a general population, we investigated the association of night-to-day BP fall, as well as nocturnal BP level (mean and lowest values), with left ventricular (LV) hypertrophy and the value of both BP parameters in predicting new-onset LV hypertrophy. Office BP, 24-hour ambulatory BP values, and laboratory investigations were assessed on entry in 1682 subjects (50.2% men; mean age, 50.2±13.7 years) of the Pressioni Arteriose Monitorate E Loro Associazioni. Echocardiographic LV mass was measured at the initial evaluation and 10 years later. Multiple regression analyses, including daytime systolic BP (SBP), age, sex, and body mass index, showed that the lowest SBP level and the extent of nocturnal SBP decline were independently related to baseline LV mass. After adjustment for several confounders, both mean nocturnal SBP (relative risk for each 10-mm Hg increase in SBP, 1.15; 95% confidence interval, 1.01–1.23;
P
<0.0001) and the lowest SBP level (relative risk for each 10-mm Hg increase in SBP, 1.10; 95% confidence interval, 1.02–1.19;
P
=0.01) were independent predictors of new-onset LV hypertrophy. This was not the case for the magnitude of nighttime SBP fall (hazard ratio for each 10% decrease in SBP, 0.91; 95% confidence interval, 0.80–1.04;
P
=0.18). In a general population, nighttime BP level rather than the nocturnal BP decline may be regarded as a reliable parameter for predicting the development of LV hypertrophy in subjects with normal LV mass. This finding may have important implications for optimizing cardiovascular prevention in the general population.
Top–Down Modulation from Inferior Frontal Junction to FEFs and Intraparietal Sulcus during Short-term Memory for Visual Features
Authors: Sneve Markus H. , Magnussen Svein , Alnæs Dag , Endestad Tor , D'Esposito Mark
Published: May 2013

Visual STM of simple features is achieved through interactions between retinotopic visual cortex and a set of frontal and parietal regions. In the present fMRI study, we investigated effective connectivity between central nodes in this network during the different task epochs of a modified delayed orientation discrimination task. Our univariate analyses demonstrate that the inferior frontal junction (IFJ) is preferentially involved in memory encoding, whereas activity in the putative FEFs and anterior intraparietal sulcus (aIPS) remains elevated throughout periods of memory maintenance. We have earlier reported, using the same task, that areas in visual cortex sustain information about task-relevant stimulus properties during delay intervals [Sneve, M. H., Alnæs, D., Endestad, T., Greenlee, M. W., & Magnussen, S. Visual short-term memory: Activity supporting encoding and maintenance in retinotopic visual cortex. Neuroimage, 63, 166–178, 2012]. To elucidate the temporal dynamics of the IFJ-FEF-aIPS-visual cortex network during memory operations, we estimated Granger causality effects between these regions with fMRI data representing memory encoding/maintenance as well as during memory retrieval. We also investigated a set of control conditions involving active processing of stimuli not associated with a memory task and passive viewing. In line with the developing understanding of IFJ as a region critical for control processes with a possible initiating role in visual STM operations, we observed influence from IFJ to FEF and aIPS during memory encoding. Furthermore, FEF predicted activity in a set of higher-order visual areas during memory retrieval, a finding consistent with its suggested role in top–down biasing of sensory cortex.
T'ain't What You Say, It's the Way That You Say It—Left Insula and Inferior Frontal Cortex Work in Interaction with Superior Temporal Regions to Control the Performance of Vocal Impersonations
Authors: McGettigan Carolyn , Eisner Frank , Agnew Zarinah K. , Manly Tom , Wisbey Duncan , Scott Sophie K.
Published: May 2013

Historically, the study of human identity perception has focused on faces, but the voice is also central to our expressions and experiences of identity [Belin, P., Fecteau, S., & Bedard, C. Thinking the voice: Neural correlates of voice perception. Trends in Cognitive Sciences, 8, 129–135, 2004]. Our voices are highly flexible and dynamic; talkers speak differently, depending on their health, emotional state, and the social setting, as well as extrinsic factors such as background noise. However, to date, there have been no studies of the neural correlates of identity modulation in speech production. In the current fMRI experiment, we measured the neural activity supporting controlled voice change in adult participants performing spoken impressions. We reveal that deliberate modulation of vocal identity recruits the left anterior insula and inferior frontal gyrus, supporting the planning of novel articulations. Bilateral sites in posterior superior temporal/inferior parietal cortex and a region in right middle/anterior STS showed greater responses during the emulation of specific vocal identities than for impressions of generic accents. Using functional connectivity analyses, we describe roles for these three sites in their interactions with the brain regions supporting speech planning and production. Our findings mark a significant step toward understanding the neural control of vocal identity, with wider implications for the cognitive control of voluntary motor acts.
Taxonomic revision of the Afrotropical species of the tribe Eudorylini (Diptera, Pipunculidae)
Authors: FÖLDVÁRI MIHÁLY
Published: May 2013

This paper revises the Afrotropical species of the tribe Eudorylini. The four genera (Claraeola, Clistoabdominalis, Dasydorylas, Eudorylas) present in the Afrotropical Region comprise 77 species (4, 4, 8 and 61 species respectively), 15 of them are new to science: Clistoabdominalis namibiensis, Dasydorylas bodocsi, D. okongoensis, Eudorylas angolae, E. barracloughi, E. brandbergensis, E. femoralis, E. gabela, E. hirsutus, E. lobus, E. pectinatus, E. pilulus, E. protumidus, E. rooibergensis and E. skorpionensis. Six new species name combinations are published: Claraeola hadrosoma, Clistoabdominalis crassus, Dasydorylas africanus, D. evanidus, D. minymerus and D. turneri.Type material for all available species was studied and species are (re)described in detail. Drawings of male and female terminalia are presented and an identification key to the males (only males were available in the majority of the species) is provided as well as individual species diagnoses for an easier species recognition.Eight new synonymies are proposed: Dorilas (Eudorylas) dorsalis and Dorilas (Eudorylas) apiculatus toDasydorylas evanidus, Pipunculus (Eudorylas) fractus to Eudorylas amitinus, Dorilas (Eudorylas) pusillus to Eudorylas diversus, Dorilas (Eudorylas) modicus to Eudorylas encerus, Dorilas (Eudorylas) megacanthus to Eudorylas garambensis and Dorilas (Eudorylas) quadratus and Pipunculus (Eudorylas) eremnoptera to Pipunculus mutillatus.A discussion on earlier methodology of species description within this group, in particular that of D. E. Hardy’s works, is given.
Revision of Thai Dissomphalus Ashmead, 1893 (Hymenoptera, Bethylidae), with description of twenty four new species
Authors: MUGRABI DANIELE F. , AZEVEDO CELSO O.
Published: May 2013

The Thai Dissomphalus classification is reviewed, and 29 species are recognized. Previously described species, D. browni Terayama, D. chiangmaiensis Terayama, and D. thaianus Terayama had their known distribution and taxonomic variations broadened. Dissomphalus wusheanus Terayama is newly recorded from Thailand. Twenty-four new species, D. epitus Mugrabi & Azevedo, sp. nov., D. verus Mugrabi & Azevedo, sp. nov., D. prilus Mugrabi & Azevedo, sp. nov.,D. daneus Mugrabi & Azevedo, sp. nov., D. gabrus Mugrabi & Azevedo, sp. nov., D. gionus Mugrabi & Azevedo, sp. nov., D. cherrus Mugrabi & Azevedo, sp. nov., D. julius Mugrabi & Azevedo, sp. nov., D. davus Mugrabi & Azevedo, sp. nov., D. zethus Mugrabi & Azevedo, sp. nov., D. hetus Mugrabi & Azevedo, sp. nov., D. joelus Mugrabi & Azevedo, sp. nov., D. nandus Mugrabi & Azevedo, sp. nov., D. jubus Mugrabi & Azevedo, sp. nov., D. kelsus Mugrabi & Azevedo, sp. nov., D. turinus Mugrabi & Azevedo, sp. nov., D. paulus Mugrabi & Azevedo, sp. nov., D. barbus Mugrabi & Azevedo, sp. nov., D. robus Mugrabi & Azevedo, sp. nov., D. geanus Mugrabi & Azevedo, sp. nov., D. magnetus Mugrabi & Azevedo, sp. nov., D. lidinus Mugrabi & Azevedo, sp. nov., D. mugrus Mugrabi & Azevedo, sp. nov. and D. ferrerus Mugrabi & Azevedo, sp. nov., are described and illustrated. A key to the males of Dissomphalus from the Oriental region is provided.
A Highly Configurable Vortex Initialization Method for Tropical Cyclones
Authors: Rappin Eric D. , Nolan David S. , Majumdar Sharanya J.
Published: May 2013

A highly configurable vortex initialization methodology has been constructed in order to permit manipulation of the initial vortex structure in numerical models of tropical cyclones. By using distinct specifications of the flow in the boundary layer and free atmosphere, an array of parameters is available to modify the structure. A nonlinear similarity model that solves the steady-state, height-dependent equations for a neutrally stratified, axisymmetric vortex is solved for the boundary layer flow. Above the boundary layer, a steady-state, moist-neutral, hydrostatic and gradient wind balanced model is used to generate the angular momentum distribution in the free atmosphere. In addition, an unbalanced mass-conserving secondary circulation is generated through the assumption of conservation of mass and angular momentum above the boundary layer. Numerical simulations are conducted using a full-physics mesoscale model to explore the sensitivity of the vortex evolution to different prescriptions of the initial vortex. Dynamical adjustment is found to be dominant in the early evolution of the simulations, thereby masking any sensitivity to initial changes in the secondary circulation and boundary layer structure. The adjustment time can be significantly reduced by arbitrarily enhancing the moisture in the eyewall region.
Time Course of Urothelial Changes in Rats and Mice Orally Administered Arsenite
Authors: Arnold Lora L. , Suzuki Shugo , Yokohira Masanao , Kakiuchi-Kiyota Satoko , Pennington Karen L. , Cohen Samuel M.
Published: May 2013

Inorganic arsenic (arsenite and arsenate) at high exposures is a known human carcinogen, inducing tumors of the urinary bladder, skin, and lungs. In two experiments, we examined the urothelial proliferative effects of treatment with 173 ppm sodium arsenite (100 ppm arsenic) in the drinking water for 6 and 24 hr, and 3, 7, and 14 days in female F344 rats and 43.3 ppm sodium arsenite (25 ppm arsenic) in female C57BL/6 wild-type and arsenic (+3 oxidation state) methyltransferase knockout (As3mt KO) mice that are unable to methylate arsenicals. In the rat and both mouse genotypes, scanning electron microscopy showed cytotoxic urothelial changes as early as 6 hr after the start of arsenic exposure. The severity of AsIII-induced cytotoxic urothelial changes increased over time in the rat and in the As3mt KO mouse. Light microscopy showed an increase in urothelial hyperplasia in the rat. No significant increases in bromodeoxyuridine-labeling index were observed. The data support the hypothesis that the sequence of events in the mode of action for urothelial effects of orally administered inorganic arsenic in the rat and mouse involves superficial cytotoxicity with consequent regenerative increased cell proliferation similar to the findings associated with the administration of dimethylarsinic acid (DMAV) in rats.
Modification and characterization of bentonite with quaternary ammonium and phosphonium salts and its use in polypropylene nanocomposites
Authors: Seyidoglu Tijen , Yilmazer Ulku
Published: May 2013

Montmorillonite-rich local bentonite was modified with four different quaternary alkyl salts: hexadecyltrimethylammonium bromide ((HMA)(Br)), tetra(kis)decylammonium bromide ((TKA)(Br)), tetrabutylammonium tetrafluoroborate ((TBA)(BF4)), and tetrabutylphosphonium tetrafluoroborate ((TBP)(BF4)) to produce organoclays. The organoclays produced were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis (TGA), and x-ray diffraction (XRD). The XRD results indicate that the d-spacing of the organoclays increased as a consequence of the exchange of Na+ ions in the clay galleries with the cation of the surfactants with long alkyl tails. The d-spacing of the bentonite increased from 1.2 nm to 1.78 nm, 2.56 nm, 1.48 nm, and 1.64 nm after modification with HMA, TKA, TBA, and TBP cations, respectively. TGA analysis of the organoclays showed that the decomposition temperatures of the organoclays were higher than the melt processing temperature of polypropylene (PP), permitting the use of these organoclays in melt processing of PP. Ternary composites of PP/PP-grafted maleic anhydride/organoclays were prepared using a twin screw extruder followed by injection molding for characterization. Transmission electron microscopy analysis of the composites showed intercalated structures as well as microcomposite formations. Mechanical properties of pure PP were improved through ternary composite formation.