bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Adult Male Circumcision on Premature Ejaculation: Results from a Prospective Study in China
Authors: Gao Jingjing , Xu Chuan , Zhang Jingjing , Liang Chaozhao , Su Puyu , Peng Zhen , Shi Kai , Tang Dongdong , Gao Pan , Lu Zhaoxiang , Liu Jishuang , Xia Lei , Yang Jiajia , Hao Zongyao , Zhou Jun , Zhang Xiansheng
Published: January 2015

The purpose of this study is to investigate the effects of adult male circumcision on premature ejaculation (PE). Therefore, between December 2009 and March 2014, a total of 575 circumcised men and 623 uncircumcised men (control group) were evaluated. Detailed evaluations (including circumcision and control groups) on PE were conducted before circumcision and at the 3-, 6-, 9-, and 12-month follow-up visits after circumcision. Self-estimated intravaginal ejaculatory latency time (IELT), Patient-Reported Outcome measures, and 5-item version of the International Index of Erectile Function were used to measure the ejaculatory and erectile function for all subjects. The results showed that, during the one-year follow-up, men after circumcision experienced higher IELT and better scores of control over ejaculation, satisfaction with sexual intercourse, and severity of PE than men before circumcision (P<0.001for all). Similarly, when compared with the control group, the circumcised men reported significantly improved IELT, control over ejaculation, and satisfaction with sexual intercourse (P<0.001for all). These findings suggested that circumcision might have positive effects on IELT, ejaculatory control, sexual satisfaction, and PE severity. In addition, circumcision was significantly associated with the development of PE.
Modulation and Predictors of Periprosthetic Bone Mineral Density following Total Knee Arthroplasty
Authors: Mau-Moeller Anett , Behrens Martin , Felser Sabine , Bruhn Sven , Mittelmeier Wolfram , Bader Rainer , Skripitz Ralf
Published: January 2015

Total knee arthroplasty (TKA) leads to a loss of periprosthetic bone mineral density (BMD). Great importance is attached to the prevention of periprosthetic bone loss with a view to ensuring a long service life of the prosthesis. In order to provide appropriate recommendations for preventive movement therapy measures to combat peri-implant bone loss, it is necessary to know the predictors of periprosthetic BMD. The aim of this study was (1) to determine the change of periprosthetic BMD of the femur and tibia and (2) to analyse the effects of different predictors on periprosthetic BMD. Twenty-three patients with primary TKA were evaluated 10 days and 3 months postoperatively. The data analysis comprised (1) the change in periprosthetic BMD from pretest to posttest and (2) the correlations between BMD and the variables isometric maximum voluntary force, lean mass, physical activity (step count), and BMI using multiple linear regression and structural equation modelling (SEM). BMD of the distal femur was significantly reduced by 19.7% (P = 0.008) 3 months after surgery, while no changes were found in BMD of the tibia. The results of SEM demonstrate that 55% of the BMD variance was explained by the model (χ2=0.002;df=1;P=0.96;χ2/df=0.002;RMSEA<0.01;TLI=1.5;CFI=1.0). A significant direct effect was only evidenced by the variable lean mass (β=0.38;b=0.15;SE=0.07;C.R.=2.0;P=0.046). It can be assumed that a large muscle mass with accompanying distribution of high mechanical load in the bones can contribute to local changes of periprosthetic BMD. Concrete recommendations for preventing peri-implant bone loss therefore include exercises which have the aim of maintaining or building up muscle mass.
OSAS Surgery and Postoperative Discomfort: Phase I Surgery versus Phase II Surgery
Authors: Gasparini Giulio , Torroni Andrea , Di Nardo Francesco , Pelo Sandro , Foresta Enrico , Boniello Roberto , Romandini Mario , Cervelli Daniele , Azzuni Camillo , Marianetti Tito Matteo
Published: January 2015

Introduction. This study aims to investigate the reasons that discourage the patients affected by OSAS to undergo orthognathic surgery and compares the postoperative discomfort of phase I (soft tissue surgery) and phase II (orthognathic surgery) procedures for treatment of OSAS.Material and Methods. A pool of 46 patients affected by OSAS was divided into two groups: “surgery patients” who accepted surgical treatments of their condition and “no surgery patients” who refused surgical procedures. The “surgery patients” group was further subdivided into two arms: patients who accepted phase I procedures (IP) and those who accepted phase II (IIP). To better understand the motivations behind the refusal of II phase procedures, we asked the patients belonging to both the IP group and “no surgery” group to indicate the main reason that influenced their decision to avoid II phase procedures. We also monitored and compared five parameters of postoperative discomfort: pain, painkiller assumption, length of hospitalization, foreign body sensation, and diet assumption following IP and IIP procedures.Results. The main reason to avoid IIP procedures was the concern of a more severe postoperative discomfort. Comparison of the postoperative discomfort following IP versus IIP procedures showed that the former scored worse in 4 out of 5 parameters analyzed.Conclusion. IIP procedures produce less postoperative discomfort. IIP procedures, namely, orthognathic surgery, should be the first choice intervention in patients affected by OSAS and dentoskeletal malformation.
Diabetes-Resistant NOR Mice Are More Severely Affected by Streptozotocin Compared to the Diabetes-Prone NOD Mice: Correlations with Liver and Kidney GLUT2 Expressions
Authors: Kahraman S. , Aydin C. , Elpek G. O. , Dirice E. , Sanlioglu A. D.
Published: January 2015

Nonobese Diabetic (NOD) mice are susceptible strains for Type 1 diabetes development, and Nonobese Diabetes-Resistant (NOR) mice are defined as suitable controls for NOD mice in non-MHC-related research. Diabetes is often accelerated in NOD mice via Streptozotocin (STZ). STZ is taken inside cells via GLUT2 transmembrane carrier proteins, the major glucose transporter isoforms in pancreatic beta cells, liver, kidneys, and the small intestine. We observed severe adverse effects in NOR mice treated with STZ compared to NOD mice that were made diabetic with a similar dose. We suggested that the underlying mechanism could be differential GLUT2 expressions in pancreatic beta cells, yet immunofluorescent and immunohistochemical studies revealed similar GLUT2 expression levels. We also detected GLUT2 expression profiles in NOD and NOR hepatic and renal tissues by western blot analysis and observed considerably higher GLUT2 expression levels in liver and kidney tissues of NOR mice. Although beta cell GLUT2 expression levels are frequently evaluated as a marker predicting STZ sensitivity in animal models, we report here very different diabetic responses to STZ in two different animal strains, in spite of similar initial GLUT2 expressions in beta cells. Furthermore, use of NOR mice in STZ-mediated experimental diabetes settings should be considered accordingly.
Relapse of Multiple Myeloma Presenting as Extramedullary Plasmacytomas in Multiple Organs
Authors: Köse Murat , Buraniqi Ersida , Akpinar Timur Selçuk , Kayacan Seyit Mehmet , Tükek Tufan
Published: January 2015

Multiple myeloma is a neoplastic plasma cell disorder. It is characterized by collections of abnormal plasma cells accumulating in the bone marrow, where they interfere with the production of normal blood cells. It usually presents as a multisystemic involvement, whose symptoms and signs vary greatly. Some patients have slowly progressive disease while others have aggressive clinical behavior by extramedullary involvement. In addition to renal failure, anemia, hypercalcemia, lytic bone lesions, and immunodeficiency, it also affects multiple organ system, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, lymph nodes, and bone. To raise awareness of the variable presentations of this disease, we report a 53-year-old male patient, with multiple myeloma in his first remission who relapsed with extramedullary plasmacytomas (EMPs) involving multiple organs, such as pancreas, adrenal glands, kidney, skin, lung, liver, spleen, and lymph nodes.
Toxicity Evaluation of Pũrṇa Cantirotaya Centũram, a Siddha Medicine in Wistar Rats
Authors: Chitra B. , Ramaswamy R. S. , Suba V.
Published: January 2015

Pũrṇa Cantirotaya Centũram (PCC), a herbometallic formulation of Siddha medicine, consists of mercury, sulphur, and gold, processed with red cotton flower and plantain stem pith juices. To evaluate its safety, acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively. In acute study, PCC was administered orally at 5, 50, 300, and 2000 mg/kg body weight. Animals were observed for toxic signs for 14 days. Gross pathology was performed at the end of the study. In repeated dose toxicity study, PCC was administered at 2.5, 25, and 50 mg/kg body weight daily for 28 days. Satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of PCC. In acute toxicity study, no treatment related death or toxic signs were observed. It revealed that the LD50 cut-off value of PCC is between 2000 and 5000 mg/kg body weight. The repeated dose study did not show evidence of any treatment related changes in all observations up to the high dose level, when compared with the control. Histopathological examination revealed no abnormalities except mild hyperplasia of stomach in high dose group. This study provides scientific validation for the safety of PCC.
Key Proteins of Activating Cell Death Can Be Predicted through a Kainic Acid-Induced Excitotoxic Stress
Authors: Tsai Hsiu-Ling , Chang Sue-Joan
Published: January 2015

Epilepsy is a major neurological disorder characterized by spontaneous seizures accompanied by neurophysiological changes. Repeated seizures can damage the brain as neuronal death occurs. A better understanding of the mechanisms of brain cell death could facilitate the discovery of novel treatments for neurological disorders such as epilepsy. In this study, a model of kainic acid- (KA-) induced neuronal death was established to investigate the early protein markers associated with apoptotic cell death due to excitotoxic damage in the rat cortex. The results indicated that KA induces both apoptotic and necrotic cell death in the cortex. Incubation with high concentrations (5 and 500 μM, >75%) and low concentrations (0.5 pM: 95% and 50 nM: 8%) of KA for 180 min led to necrotic and apoptotic cell death, respectively. Moreover, proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry demonstrated that antiapoptotic proteins, including heat shock protein 70, 3-mercaptopyruvate sulfurtransferase, tubulin-B-5, and pyruvate dehydrogenase E1 component subunit beta, were significantly higher in apoptosis than in necrosis induced by KA. Our findings provide direct evidence that several proteins are associated with apoptotic and necrotic cell death in excitotoxicity model. The results indicate that these proteins can be apoptotic biomarkers from the early stages of cell death.
New Representations of Spherical Indicatricies of Bertrand Curves in Minkowski 3-Space
Authors: Aydemir İsmail , Yerlikaya Fırat
Published: January 2015

We obtained a new representation for timelike Bertrand
curves and their Bertrand mate in 3-dimensional Minkowski space. By using
this representation, we expressed new representations of spherical indicatricies
of Bertrand curves and computed their curvatures and torsions. Furthermore
in case the indicatricies of a Bertrand curve are slant helices, we investigated
some new characteristic features of these curves.
Visible‐Light Photocatalytic Activity of N‐Doped TiO2 Nanotube Arrays on Acephate Degradation
Authors: Zhang Xinlei , Zhou Juan , Gu Yufen , Fan Ding
Published: January 2015

Highly ordered nitrogen‐doped titanium dioxide (N‐doped TiO2) nanotube arrays were prepared by anodic oxidation method and then annealed in a N2 atmosphere to obtain N‐doped TiO2 nanotube arrays. The samples were characterized with scanning electron microscope (SEM), X‐ray powder diffraction (XRD), X‐ray photoelectron spectrum (XPS), and UV‐visible spectrophotometry (UV‐vis) spectrum. Degradation of the insecticide acephate under the visible light was used as a model to examine the visible‐light photocatalytic activity of N‐doped TiO2 nanotube arrays. The results show that N type doping has no notable effects on the morphology and structure of TiO2 nanotube arrays. After N type doping, the N replaces a small amount of O in TiO2, forming an N–Ti–O structure. This shifts the optical absorption edge and enhances absorption of the visible light. N‐doped TiO2 nanotube arrays subjected to annealing at 500°C in N2 atmosphere show the strongest photocatalytic activity and reach a degradation rate of 84% within 2 h.
Combined Liposuction and Excision of Lipomas: Long-Term Evaluation of a Large Sample of Patients
Authors: Copeland-Halperin Libby R. , Pimpinella Vincenza , Copeland Michelle
Published: January 2015

Background. Lipomas are benign tumors of mature fat cells. They can be removed by liposuction, yet this technique is seldom employed because of concerns that removal may be incomplete and recurrence may be more frequent than after conventional excision. Objectives. We assessed the short- and long-term clinical outcomes and recurrence of combined liposuction and limited surgical excision of subcutaneous lipomas. Methods. From 2003 to 2012, 25 patients with 48 lipomas were treated with liposuction followed by direct excision through the same incision to remove residual lipomatous tissue. Initial postoperative follow-up ranged from 1 week to 3 months, and long-term outcomes, complications, and recurrence were surveyed 1 to 10 years postoperatively. Results. Lipomas on the head, neck, trunk, and extremities ranged from 1 to 15 cm in diameter. Early postoperative hematoma and seromas were managed by aspiration. Among 23 survey respondents (92%), patients were uniformly pleased with the cosmetic results; none reported recurrent lipoma. Conclusions. The combination of liposuction and excision is a safe alternative for lipoma removal; malignancy and recurrence are uncommon. Liposuction performed through a small incision provides satisfactory aesthetic results in most cases. Once reduced in size, residual lipomatous and capsular tissue can be removed without expanding the incision. These favorable outcomes support wider application of this technique in appropriate cases.
Long-Term Consequences of Hepatitis C Viral Clearance on the CD4 (+) T Cell Lymphocyte Course in HIV/HCV Coinfected Patients
Authors: Dazley J. , Sison R. , Slim J.
Published: January 2015

The long-term impact of pegylated-interferon plus ribavirin treatment outcome on CD4 T cell course in patients coinfected with human immunodeficiency virus and hepatitis C virus is largely unclear in the literature. The aim of this study was to investigate the impact of HCV-RNA clearance by standard anti-HCV therapy on long-term CD4 cells recovery in HIV/HCV patients on successful combined antiretroviral therapy. We retrospectively enrolled HIV/HCV-coinfected patients on HIV medications and treated for hepatitis C. CD4 + T cell counts were registered at baseline and after hepatitis C therapy. Multiple linear regression analysis was performed to identify independent predictors of CD4 + T cell change following the anti-HCV treatment outcome. Of the 116 patients enrolled, 54 (46.6%) reached a sustained virological response. During a follow-up of 24 months, the SVR group showed a mean annual increase in CD4 + T cell from baseline of 84 cells/ll at 1 year and of a further 38 cells/ll within the second year (P=0.01, 0.001, resp.). An insignificant mean increase of 77 cells/ll occurred in the non-SVR group within month 24 (P=0.06). Variables associated with greater CD4 gains were higher nadir, lower preinterferon CD4 counts, and lower body mass index (BMI).
A Comprehensive Review on Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future Challenges
Authors: Phadatare Suvarna P. , Momin Munira , Nighojkar Premanand , Askarkar Sonali , Singh Kamalinder K.
Published: January 2015

Dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS) is a common disorder of the tear film caused by decreased tear production or increased evaporation and manifests with a wide variety of signs and symptoms. The present review from interpretation of the literature gives detailed information on the prevalence, definition, causes, diagnostic tests, and medical management of dry eye disease. A number of systems contribute to the physiological integrity of the ocular surface and disruption of system may or may not produce symptoms. Therefore accurate diagnosis of dry eyes with no or minimal disruption of physiological function is necessary. The paper also discusses different colloidal drug delivery systems and current challenges in the development of topical ophthalmic drug delivery systems for treatment of KCS. Due to the wide prevalence and number of factors involved, newer, more sensitive diagnostic techniques and novel therapeutic agents have been developed to provide ocular delivery systems with high therapeutic efficacy. The aim of this review is to provide awareness among the patients, health care professionals, and researchers about diagnosis and treatment of KCS and recent developments and future challenges in management of dry eye disease.
Searching for Neutrinoless Double-Beta Decay of130Te with CUORE
Authors: Artusa D. R. , Avignone F. T. , Azzolini O. , Balata M. , Banks T. I. , Bari G. , Beeman J. , Bellini F. , Bersani A. , Biassoni M. , Brofferio C. , Bucci C. , Cai X. Z. , Camacho A. , Canonica L. , Cao X. G. , Capelli S. , Carbone L. , Cardani L. , Carrettoni M. , Casali N. , Chiesa D. , Chott N. , Clemenza M. , Copello S. , Cosmelli C. , Cremonesi O. , Creswick R. J. , Dafinei I. , Dally A. , Datskov V. , De Biasi A. , Deninno M. M. , Di Domizio S. , di Vacri M. L. , Ejzak L. , Fang D. Q. , Farach H. A. , Faverzani M. , Fernandes G. , Ferri E. , Ferroni F. , Fiorini E. , Franceschi M. A. , Freedman S. J. , Fujikawa B. K. , Giachero A. , Gironi L. , Giuliani A. , Goett J. , Gorla P. , Gotti C. , Gutierrez T. D. , Haller E. E. , Han K. , Heeger K. M. , Hennings-Yeomans R. , Huang H. Z. , Kadel R. , Kazkaz K. , Keppel G. , Kolomensky Yu. G. , Li Y. L. , Ligi C. , Liu X. , Ma Y. G. , Maiano C. , Maino M. , Martinez M. , Maruyama R. H. , Mei Y. , Moggi N. , Morganti S. , Napolitano T. , Nisi S. , Nones C. , Norman E. B. , Nucciotti A. , O’Donnell T. , Orio F. , Orlandi D. , Ouellet J. L. , Pallavicini M. , Palmieri V. , Pattavina L. , Pavan M. , Pedretti M. , Pessina G. , Pettinacci V. , Piperno G. , Pira C. , Pirro S. , Previtali E. , Rampazzo V. , Rosenfeld C. , Rusconi C. , Sala E. , Sangiorgio S. , Scielzo N. D. , Sisti M. , Smith A. R. , Taffarello L. , Tenconi M. , Terranova F. , Tian W. D. , Tomei C. , Trentalange S. , Ventura G. , Vignati M. , Wang B. S. , Wang H. W. , Wielgus L. , Wilson J. , Winslow L. A. , Wise T. , Woodcraft A. , Zanotti L. , Zarra C. , Zhu B. X. , Zucchelli S.
Published: January 2015

Neutrinoless double-beta (0νββ) decay is a hypothesized lepton-number-violating process that offers the only known means of asserting the possible Majorana nature of neutrino mass. The Cryogenic Underground Observatory for Rare Events (CUORE) is an upcoming experiment designed to search for 0νββdecay of130Te using an array of 988 TeO2crystal bolometers operated at 10 mK. The detector will contain 206 kg of130Te and have an average energy resolution of 5 keV; the projected 0νββdecay half-life sensitivity after five years of livetime is 1.6 × 1026 y at 1σ(9.5 × 1025 y at the 90% confidence level), which corresponds to an upper limit on the effective Majorana mass in the range 40–100 meV (50–130 meV). In this paper, we review the experimental techniques used in CUORE as well as its current status and anticipated physics reach.
Cutaneous and Gastrointestinal Symptoms in Two Patients with Systemic Mastocytosis Successfully Treated with Omalizumab
Authors: Lieberoth Sofie , Thomsen Simon Francis
Published: January 2015

The pathogenesis of mastocytosis is not well defined and thus treatment remains challenging and remains on a palliative basis. We present two cases (a 48-year-old woman and a 57-year-old man) with indolent systemic mastocytosis in whom omalizumab (anti-IgE) reduced gastrointestinal and cutaneous symptoms significantly. This observation provides additional insight into the effects of omalizumab on systemic mastocytosis.
Enhanced Light Trapping in Thin Film Solar Cells Using a Plasmonic Fishnet Structure
Authors: Seal Sayan , Budhraja Vinay , Ji Liming , Varadan Vasundara V.
Published: January 2015

Incorporating plasmonic structures into the back spacer layer of thin film solar cells (TFSCs) is an efficient way to improve their performance. The fishnet structure is used to enhance light trapping. Unlike other previously suggested discrete plasmonic particles, the fishnet is an electrically connected wire mesh that does not result in light field localization, which leads to high absorption losses. The design was verified experimentally. A silver fishnet structure was fabricated using electron beam lithography (EBL) and thermal evaporation. The final fabricated structure optically resembles a TFSC. The results predicted by numerical simulations were reproduced experimentally on a fabricated sample. We show that light absorption in the a-Si absorber layer is enhanced by a factor of 10.6 at the design wavelength of 690 nm due to the presence of the fishnet structure. Furthermore, the total absorption over all wavelengths was increased by a factor of 3.2. The short-circuit current of the TFSC was increased by 30% as a result of including the fishnet.
Imaging Atherosclerosis with Hybrid Positron Emission Tomography/Magnetic Resonance Imaging
Authors: Ripa Rasmus Sejersten , Kjær Andreas
Published: January 2015

Noninvasive imaging of atherosclerosis could potentially move patient management towards individualized triage, treatment, and followup. The newly introduced combined positron emission tomography (PET) and magnetic resonance imaging (MRI) system could emerge as a key player in this context. Both PET and MRI have previously been used for imaging plaque morphology and function: however, the combination of the two methods may offer new synergistic opportunities. Here, we will give a short summary of current relevant clinical applications of PET and MRI in the setting of atherosclerosis. Additionally, our initial experiences with simultaneous PET/MRI for atherosclerosis imaging are presented. Finally, future potential vascular applications exploiting the unique combination of PET and MRI will be discussed.
Toxicity and Loss of Mitochondrial Membrane Potential Induced by Alkyl Gallates in Trypanosoma cruzi
Authors: Andréo Rogério , Regasini Luís Octávio , Petrônio Maicon Segalla , Chiari-Andréo Bruna Galdorfini , Tansini Aline , Silva Dulce Helena Siqueira , Cicarelli Regina Maria Barretto
Published: January 2015

American trypanosomiasis or Chagas disease is a debilitating disease representing an important social problem that affects, approximately, 10 million people in the world. The main aggravating factor of this situation is the lack of an effective drug to treat the different stages of this disease. In this context, the search for trypanocidal substances isolated from plants, synthetic or semi synthetic molecules, is an important strategy. Here, the trypanocidal potential of gallates was assayed in epimastigotes forms of T. cruzi and also, the interference of these substances on the mitochondrial membrane potential of the parasites was assessed, allowing the study of the mechanism of action of the gallates in the T. cruzi organisms. Regarding the preliminary structure-activity relationships, the side chain length of gallates plays crucial role for activity. Nonyl, decyl, undecyl, and dodecyl gallates showed potent antitrypanosomal effect (IC50 from 1.46 to 2.90 μM) in contrast with benznidazole (IC50 = 34.0 μM). Heptyl gallate showed a strong synergistic activity with benznidazole, reducing by 105-fold the IC50 of benznidazole. Loss of mitochondrial membrane potential induced by these esters was revealed. Tetradecyl gallate induced a loss of 53% of the mitochondrial membrane potential, at IC50 value.
Sex Hormones in Allergic Conjunctivitis: Altered Levels of Circulating Androgens and Estrogens in Children and Adolescents with Vernal Keratoconjunctivitis
Authors: Sacchetti Marta , Lambiase Alessandro , Moretti Costanzo , Mantelli Flavio , Bonini Stefano
Published: January 2015

Purpose.Vernal keratoconjunctivitis (VKC) is a chronic allergic disease mainly affecting boys in prepubertal age and usually recovering after puberty. To evaluate a possible role of sex hormones in VKC, serum levels of sex hormones in children and adolescents with VKC were assessed.Methods.12 prepubertal and 7 early pubertal boys with active VKC and 6 male patients with VKC in remission phase at late pubertal age and 48 healthy age and sex-matched subjects were included. Serum concentration of estrone, 17 beta-estradiol, dehydroepiandrosterone-sulfate, total testosterone and free testosterone, dihydrotestosterone (DHT), cortisol, delta-4-androstenedione, follicle-stimulating hormone, luteinizing hormone, and sex-hormones binding globuline (SHBG) were evaluated.Results.Serum levels of Estrone were significantly increased in all groups of patients with VKC when compared to healthy controls (P<0.001). Prepubertal and early pubertal VKC showed a significant decrease in DHT (P=0.007andP=0.028, resp.) and SHBG (P=0.01andP=0.002, resp.) when compared to controls and serum levels of SHBG were increased in late pubertal VKC in remission phase (P=0.007).Conclusions and Relevance.VKC patients have different circulating sex hormone levels in different phases of the disease and when compared to nonallergic subjects. These findings suggest a role played by sex hormones in the pathogenesis and/or activity of VKC.
Fatal Retroperitoneal Bleeding Caused by Neurofibromatosis: A Case Report and Review of the Literature
Authors: Moerbeek Patrick R. , van Buijtenen Jesse M. , van den Heuvel Baukje , Hoksbergen Arjan W. J.
Published: January 2015

A young female was brought into the emergency department with pulseless electrical activity (PEA) after local resection of neurofibromateous lesions. Chest ultrasonography was normal. Abdominal ultrasonography was not performed. After successful resuscitation a total body CT-scan was performed to rule out potential bleeding sources. However, haemodynamic instability reoccurred and the scan had to be aborted at the thoracoabdominal level. No thoracic abnormalities were found. Resuscitation was reinitiated and abdominal ultrasonography was performed, showing a large amount of abdominal fluid. A progressive fall in haemoglobin was noted. Emergency laparotomy was performed, revealing a large retroperitoneal haematoma. Despite ligation and packing, bleeding continued. Postoperative angiography showed active bleeding from a branch of the left internal iliac artery, which could be successfully coiled. Unfortunately, the patient died five days later due to irreversible brain damage. Revision of an MRI scan made one year earlier showed a 10 cm large retroperitoneal neurofibromatous lesion exactly at the location of the current bleeding. This case shows that patients with neurofibromatosis might develop spontaneous life-threatening bleeding from retroperitoneal located lesions. Furthermore, it points out the necessity of focused assessment with ultrasonography of the abdomen in all patients with PEA of unknown origin.
miR340 Suppresses the Stem-like Cell Function of Glioma-Initiating Cells by Targeting Tissue Plasminogen Activator
Authors: Yamashita Daisuke , Kondo Toru , Ohue Shiro , Takahashi Hisaaki , Ishikawa Madoka , Matoba Ryo , Suehiro Satoshi , Kohno Shohei , Harada Hironobu , Tanaka Junya , Ohnishi Takanori
Published: January 2015

Glioma-initiating cells (GIC) have stem-like cell properties thought to be sufficient for recurrence, progression, and drug resistance in glioblastomas. In the present study, we defined miRNA (miR)-340 as a differentially expressed miRNA in human GICs that inhibit GIC-mediated tumorigenesis. Furthermore, we defined tissue plasminogen activator (PLAT) as a critical direct target of miR340 for inhibition. Among miRNAs screened, we found that miR340 expression was decreased in all human GICs and in human glioblastoma tissues, compared with human neural stem cells and normal brain tissues. miR340 overexpression in GICs suppressed their proliferative, invasive, and migratory properties in vitro, triggering cell senescence in vitro and inhibiting GIC-induced tumorigenesis in mouse brains. shRNA-mediated silencing of PLAT in GICs phenocopied the effects of miR340 overexpression in vitro and in vivo, suggesting a potential role for tissue factor in stem-like cell function. Taken together, our results identified miR340 as a tumor suppressor that functions in GIC to enforce PLAT blockade and ablate their stem-like functions. Cancer Res; 75(6); 1123–33. ©2015 AACR.
No Association between Adherence to a Healthy Nordic Food Index and Colorectal Cancer: Results from a Swedish Cohort Study
Authors: Roswall Nina , Li Yingjun , Kyrø Cecilie , Sandin Sven , Löf Marie , Adami Hans-Olov , Weiderpass Elisabete
Published: January 2015

Background: Recently, the Nordic diet has gained interest, and a healthy Nordic food index has been developed, which has been found inversely related to colorectal cancer among Danish women. This single finding, however, requires replication in other cohorts.

Methods: We conducted a prospective study in the Women's Lifestyle and Health cohort, including 45,222 women, recruited in 1991–92, and followed up ever since through Swedish registries. Participants were classified according to the Nordic food index (consisting of whole grain bread, oatmeal, apples/pears, cabbages, root vegetables, and fish/shellfish), and the association between adherence and colorectal cancer was assessed using the Cox proportional hazards models.

Results: In the fully adjusted models, we found no association, neither with the continuous index score [incidence rate ratio (IRR), 1.04; 95% confidence interval (CI), 0.95–1.12, per 1-point increment] nor in the categorical analyses (IRR, 1.09; 95% CI, 0.78–1.52 for highest vs. lowest adherers).

Conclusion: The present study does, thus, not support a previous finding of an inverse association between a healthy Nordic food index and colorectal cancer.

Impact: This article adds new evidence to the field of the Nordic diet in disease prevention. Cancer Epidemiol Biomarkers Prev; 24(4); 755–7. ©2015 AACR.
An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma
Authors: von Tresckow Bastian , Morschhauser Franck , Ribrag Vincent , Topp Max S. , Chien Caly , Seetharam Shobha , Aquino Regina , Kotoulek Sonja , de Boer Carla J. , Engert Andreas
Published: January 2015

Purpose: This phase I/II study investigated JNJ-40346527, a selective inhibitor of the colony-stimulating factor-1 receptor (CSF-1R) tyrosine kinase as treatment for relapsed or refractory classical Hodgkin lymphoma (cHL).

Experimental Design: Patients ≥18 years with histopathologically confirmed initial diagnosis of cHL that had relapsed or was refractory after ≥1 appropriate therapies were assigned to sequential cohorts of oral daily doses of JNJ-40346527 (150, 300, 450, 600 mg every day, and 150 mg twice a day). For the dose-escalation phase, the primary endpoint was to establish the recommended phase II dose. Secondary endpoints included safety, pharmacokinetics, and pharmacodynamics.

Results: Twenty-one patients [(150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3) every day, and 150 mg twice a day: 7] were enrolled, 10 men, median age 40 (range, 19–75) years, median number of prior systemic therapies 6 (range, 3–14). No dose-limiting toxicities were observed; maximum-tolerated dose was not established. Best overall response was complete remission in 1 patient (duration, +352 days) and stable disease in 11 patients: (duration, 1.5–8 months). Median number of cycles: 4 (range, 1–16). Most common (≥20% patients) possibly drug-related adverse events (per investigator assessment) were nausea (n = 6), headache, and pyrexia (n = 5 each). JNJ-40346527 exposure increased in near dose-proportional manner over a dose range of 150 to 450 mg every day, but plateaued at 600 mg every day. Target engagement was confirmed (>80% inhibition of CSF-1R phosphorylation, 4 hours after dosing).

Conclusions: JNJ-40346527, a selective inhibitor of CSF-1R was well tolerated, and preliminary antitumor results suggested limited activity in monotherapy for the treatment of cHL. Clin Cancer Res; 21(8); 1843–50. ©2015 AACR.
Intratumor Molecular and Phenotypic Diversity in Hepatocellular Carcinoma
Authors: Nault Jean-Charles , Villanueva Augusto
Published: January 2015

Hepatocellular carcinoma is a highly heterogeneous disease both at the molecular and clinical levels. Intratumor morphologic and genetic heterogeneity adds a new level of complexity in our understanding of liver carcinogenesis, and it is likely an important determinant of primary and secondary resistance to targeted therapies. Clin Cancer Res; 21(8); 1786–8. ©2015 AACR.

See related article by Friemel et al., p. 1951
STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade
Authors: Triplett Todd A. , Tucker Christopher G. , Triplett Kendra C. , Alderman Zefora , Sun Lihong , Ling Leona E. , Akporiaye Emmanuel T. , Weinberg Andrew D.
Published: January 2015

In preclinical tumor models, αOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining αOX40 antibodies with an inhibitor of the TGFβ receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/αOX40 dual therapy resulted in an increase in proliferating granzyme B+ CD8 T cells, which produced higher levels of IFNγ, compared with treatment with either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Because others have published that STAT3 signaling is detrimental to T-cell function within the tumor microenvironment, we explored whether deletion of STAT3 in OX40-expressing cells would affect this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling, most likely in the T cells of tumor-bearing mice. Cancer Immunol Res; 3(5); 526–35. ©2015 AACR.
Children's Toothbrushing Frequency: The Influence of Parents' Rationale for Brushing, Habits and Family Routines
Authors: Trubey Rob J. , Moore Simon C. , Chestnutt Ivor G.
Published: January 2015

Objectives: To assess the relationship between parental and family factors and children's toothbrushing frequency at different times of day. Methods: A cross-sectional questionnaire survey of predominantly low-socio-economic status parents of children aged 3-6 years (n = 296) in South Wales, UK. Data were collected on the child's weekly toothbrushing frequency (morning and evening), the parents' rationale for brushing their child's teeth in the morning and evening, the strength of a parent's habit for brushing a child's teeth in the morning and evening, and the extent to which the family's daily routines were stable from day to day. Socio-demographic details were also collected. Results: Reported weekly brushing frequency was significantly (p < 0.001) higher in the morning (mean ± SD: 6.57 ± 1.37) than the evening (mean ± SD: 5.99 ± 2.15). Parents had significantly (p < 0.001) more interest in the cosmetic benefits of toothbrushing in the morning compared to the evening. Multivariate analysis showed that an increasing focus on the cosmetic benefits of toothbrushing was associated with significantly (p < 0.05) less weekly brushing in the evening. The extent to which brushing a child's teeth was ‘habitual' was significantly (p < 0.001) associated with weekly toothbrushing frequency at both times of day. Conclusions: Parents' rationale for brushing their children's teeth can vary at both an individual level and at different times of day. Understanding these variations is important in designing interventions to improve brushing frequency for at-risk children. The results also demonstrate habituation as being an important factor in understanding toothbrushing frequency. Further research is required to understand the mechanisms involved in habit formation and maintenance with children's oral hygiene behaviour.
Insulin Receptor and the Kidney: Nephrocalcinosis in Patients with Recessive INSR Mutations
Authors: Simpkin Arabella , Cochran Elaine , Cameron Fergus , Dattani Mehul , de Bock Martin , Dunger David B. , Forsander Gun , Guran Tulay , Harris Julie , Isaac Iona , Hussain Khalid , Kleta Robert , Peters Catherine , Tasic Velibor , Williams Rachel , Yap Kok Peng Fabian , O''Rahilly Stephan , Gorden Philipp , Semple Robert K. , Bockenhauer Detlef
Published: January 2015

Background/Aims: Donohue and Rabson-Mendenhall syndrome are rare autosomal recessive disorders caused by mutations in the insulin receptor gene, INSR. Phenotypic features include extreme insulin resistance, linear growth retardation, paucity of fat and muscle, and soft tissue overgrowth. The insulin receptor is also expressed in the kidney, where animal data suggest it plays a role in glomerular function and blood pressure (BP) regulation, yet such a role in the human kidney is untested. Patients with biallelic INSR mutations provide a rare opportunity to ascertain its role in man. Methods: Retrospective review of patients with INSR mutations. Data for BP, renal imaging, plasma creatinine and electrolyte levels, as well as urine protein, albumin and calcium excretion were sought from the treating clinicians. Results: From 33 patients with INSR mutations, data were available for 17 patients. Plasma creatinine was low (mean ± SD: 25 ± 9 μmol/l) and mean plasma electrolyte concentrations were within the normal range (n = 13). Systolic BP ranged between the 18th and 91st percentile for age, sex, height and weight (n = 9; mean ± SD: 49 ± 24). Twenty-four-hour urinary calcium data were available from 10 patients and revealed hypercalciuria in all (mean ± SD: 0.32 ± 0.17 mmol/kg/day; normal <0.1). Nephrocalcinosis was present in all patients (n = 17). Urinary albumin excretion (n = 7) ranged from 4.3-122.5 μg/min (mean ± SD: 32.4 ± 41.0 μg/min; normal <20). Conclusions: INSR dysfunction is associated with hypercalciuria and nephrocalcinosis. No other consistent abnormality of renal function was noted. Normotension and stable glomerular function with only moderate proteinuria is in contrast to genetically modified mice who have elevated BP and progressive diabetic nephropathy.
Symptoms in Plasma Cell Vulvitis: First Observational Cohort Study on Type, Frequency and Severity
Authors: Virgili Annarosa , Corazza Monica , Minghetti Sara , Borghi Alessandro
Published: January 2015

Background: Studies assessing symptoms of plasma cell vulvitis (PCV) are lacking. Objectives: To assess the prevalence and severity of PCV-related symptoms and identify possible associations between patient characteristics, clinical features of PCV and treatments administered before a definitive diagnosis. Methods: Thirty-six patients affected with PCV were included. Data were collected by direct interview and clinical examination. Results: Thirty patients (83.3%) complained of symptoms: burning was the most frequent (80.6%) while dyspareunia was the severest. Of the symptomatic patients, 73.3% experienced severe symptoms. Severity of symptoms was not associated with age at onset and duration of PCV. Almost 70% of the patients had previously undergone treatments. Conclusions: Symptoms in PCV are frequent and more than often severe. Neither age at onset nor duration of the disease nor the extent of vulvar involvement were associated with symptom severity. Both the delay in diagnosis and the inappropriate previous treatments seem to indicate frequent misdiagnosis.
Safety and Effectiveness of a 2009 H1N1 Vaccine in Chronic Kidney Disease Children
Authors: Donmez Osman , Akaci Okan , Albayrak Nurhan , Altas Ayse
Published: January 2015

Background/Aims: Influenza vaccination is the most effective method for preventing influenza infection and its complications. The risk groups are children with chronic kidney diseases (CKDs) such as children on peritoneal dialysis (PD) and hemodialysis (HD), predialysis CKD (pCKD) and renal transplant (RTx) patients and immunosuppressed children. The aim of the present study was to assess the safety and immunogenicity of a single administration of a monovalent inactivated pandemic (H1N1) 2009 vaccine in children with CKD. Methods: Patients were given a single intramuscular injection of 0.5 ml of monovalent inactivated vaccine. Results: Totally, there were 25 pediatric patients with a diagnosis of CKD (16 PD, 2 HD, 3 pCKD and 4 RTx). Seroconversion was observed in 15 of the 16 patients with PD. Seroconversion occurred in all patients undergoing pCKD and HD. However, 3 of the RTx patients were seronegative. Conclusion: This study demonstrated a high level of immunogenicity and safety of an (H1N1) 2009 influenza vaccine in children with CKD.
Limitations of Standard Immunosuppressive Treatment in ANCA-Associated Vasculitis and Lupus Nephritis
Authors: Tesar Vladimir , Hruskova Zdenka
Published: January 2015

Introduction of the standard immunosuppressive treatment has dramatically changed the outcome of patients with both ANCA-associated vasculitis and lupus nephritis, transforming them from incurable diseases with very high short-term mortality to chronic debilitating diseases with much lower short-term, but still relatively high long-term, morbidity/mortality. Long-term morbidity with damage accumulating partly due to the adverse events of the available treatment (namely gonadal toxicity, malignancy, bone disease, cataracts, diabetes, and thromboembolic and cardiovascular disease) has become a major concern. Although cyclophosphamide-based regimens have been partly replaced by newer agents in both ANCA-associated vasculitis and lupus nephritis (namely rituximab or mycophenolate, respectively) their short-term and medium-term adverse events may not be significantly less frequent and we can only hope that new treatments will translate into better long-term outcomes including better long-term safety.
Rituximab in the Treatment of Anti-Neutrophil Cytoplasm Antibody-Associated Vasculitis
Authors: Jones Rachel B.
Published: January 2015

The introduction of cyclophosphamide and high-dose glucocorticoids for anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) has allowed a reduction in 1-year mortality from 80% to 10-20%. AAV is now a chronic disease, and greater emphasis has turned to improving treatment-related toxicity, reducing relapses and providing alternative treatments for refractory disease. Rituximab, an anti-CD20 B cell-depleting therapy, has been used for over a decade in patients with AAV. Rituximab offers a significant advance in the treatment of these diseases. It has an established role for remission induction and is now being investigated as a remission maintenance agent. For remission induction, randomised trials have reported similar remission rates with rituximab and cyclophosphamide, and rituximab is now an approved alternative to cyclophosphamide in severe AAV. In clinical practice, rituximab is increasingly used for refractory and relapsing disease. Further remission induction data with rituximab for life-threatening renal and pulmonary disease may be provided by the ongoing PEXIVAS trial (NCT00987389). With standard therapies, 50% of patients with newly diagnosed AAV relapse by 5 years. Relapses are higher still in patients with known relapsing disease. For remission maintenance, treatment trials are comparing repeat rituximab dosing to azathioprine. The MAINRITSAN trial (NCT00748644) included mainly newly diagnosed AAV patients following cyclophosphamide induction therapy. The RITAZAREM trial (NCT01697267) is randomising patients with relapsing disease after rituximab induction therapy. Preliminary results with rituximab maintenance therapy are encouraging, although the optimal dosing regimen and duration has yet to be defined. Other areas for further investigation include remission maintenance therapy requirement after rituximab induction in newly diagnosed AAV, and the role of rituximab in eosinophilic granulomatosis with polyangiitis where no randomised data exists.
Lupus Nephritis: From Pathogenesis to Targets for Biologic Treatment
Authors: Liu Yujuan , Anders Hans-Joachim
Published: January 2015

Background/Aims: Lupus nephritis is an organ manifestation of systemic autoimmunity. Current treatment algorithms are still based on unselective immunosuppressive drugs. There is hope that highly selective biological drugs could be as or even more effective but less toxic. A profound understanding of the pathogenesis of lupus nephritis is necessary to identify the optimal molecular targets. Methods: PubMed and www.clincialtrials.gov were searched using ‘lupus nephritis' as the key word. Results: The pathogenesis of lupus nephritis is based (1) on the mechanisms that lead to loss of tolerance against nuclear autoantigens, i.e. systemic lupus, and then (2) on the mechanisms of immune complex-induced intrarenal inflammation. Systemic lupus develops when genetic variants allow autoimmunization against nuclear autoantigens, e.g. by impairing lymphocyte depletion via apoptosis, opsonization, and rapid phagocytic clearance. This allows endogenous nucleic acids to directly activate Toll-like receptors on dendritic cells or B cells, a process that drives IFN-α-driven immunity, antigen presentation, and the activation of autoreactive lymphocyte subsets. Activation of B cells and their maturation to plasma cells promotes autoantibody production and subsequent immune complex glomerulonephritis. Complement and numerous proinflammatory cytokines drive the inflammatory process that can cause kidney injury, scarring, and chronic kidney disease. Conclusion: Systemic lupus is more a variable syndrome than a single disorder based on heterogeneous genetic variants and complex aberrant immune alterations. This makes it less likely that a single specific biological drug will be as efficient as currently used unselective immunosuppressive drugs. Autoantibody production and intrarenal immune complex formation are the hallmark of lupus nephritis. However, kidney injury and scarring also result from local amplification of tissue inflammation. Therefore, a combination of unselective immunosuppressive and biological drugs that block immune cell recruitment or proinflammatory cytokines may be promising to improve disease outcomes in lupus nephritis.