bluuebunny/crossref_metadata_2025 huggingface dataset:
TrkAIII Promotes Microtubule Nucleation and Assembly at the Centrosome in SH-SY5Y Neuroblastoma Cells, Contributing to an Undifferentiated Anaplastic Phenotype
Authors: Farina Antonietta R. , Di Ianni Natalia , Cappabianca Lucia , Ruggeri Pierdomenico , Ragone Marzia , Ianni Giulia , Gulino Alberto , Mackay Andrew R.
Published: June 2013

The alternative TrkAIII splice variant is expressed by advanced stage human neuroblastomas (NBs) and exhibits oncogenic activity in NB models. In the present study, employing stable transfected cell lines and assays of indirect immunofluorescence, immunoprecipitation, Western blotting, microtubule regrowth, tubulin kinase, and tubulin polymerisation, we report that TrkAIII bindsα-tubulin and promotes MT nucleation and assembly at the centrosome. This effect depends upon spontaneous TrkAIII activity, TrkAIII localisation to the centrosome and pericentrosomal area, and the capacity of TrkAIII to bind, phosphorylate, and polymerise tubulin. We propose that this novel role for TrkAIII contributes to MT involvement in the promotion and maintenance of an undifferentiated anaplastic NB cell morphology by restricting and augmenting MT nucleation and assembly at the centrosomal MTOC.
Neural Pathways Conveying Novisual Information to the Visual Cortex
Authors: Qin Wen , Yu Chunshui
Published: June 2013

The visual cortex has been traditionally considered as a stimulus-driven, unimodal system with a hierarchical organization. However, recent animal and human studies have shown that the visual cortex responds to non-visual stimuli, especially in individuals with visual deprivation congenitally, indicating the supramodal nature of the functional representation in the visual cortex. To understand the neural substrates of the cross-modal processing of the non-visual signals in the visual cortex, we firstly showed the supramodal nature of the visual cortex. We then reviewed how the nonvisual signals reach the visual cortex. Moreover, we discussed if these non-visual pathways are reshaped by early visual deprivation. Finally, the open question about the nature (stimulus-driven or top-down) of non-visual signals is also discussed.
Therapeutic Effects of the Superoxide Dismutase Mimetic Compound Me2DO2A on Experimental Articular Pain in Rats
Authors: Di Cesare Mannelli Lorenzo , Bani Daniele , Bencini Andrea , Brandi Maria Luisa , Calosi Laura , Cantore Miriam , Carossino Anna Maria , Ghelardini Carla , Valtancoli Barbara , Failli Paola
Published: June 2013

Superoxide anion () is overproduced in joint inflammation, rheumatoid arthritis, and osteoarthritis. Increased production leads to tissue damage, articular degeneration, and pain. In these conditions, the physiological defense against , superoxide dismutases (SOD) are decreased. The complex MnL4 is a potent SOD mimetic, and in this study it was tested in inflammatory and osteoarticular rat pain models.In vivoprotocols were approved by the animal Ethical Committee of the University of Florence. Pain was measured by paw pressure and hind limb weight bearing alterations tests. MnL4 (15 mg kg−1) acutely administered, significantly reduced pain induced by carrageenan, complete Freund’s adjuvant (CFA), and sodium monoiodoacetate (MIA). In CFA and MIA protocols, it ameliorated the alteration of postural equilibrium. When administered by osmotic pump in the MIA osteoarthritis, MnL4 reduced pain, articular derangement, plasma TNF alpha levels, and protein carbonylation. The scaffold ring was ineffective. MnL4 (10−7 M) prevented the lipid peroxidation of isolated human chondrocytes when was produced by RAW 264.7. MnL4 behaves as a potent pain reliever in acute inflammatory and chronic articular pain, being its efficacy related to antioxidant property. Therefore MnL4 appears as a novel protective compound potentially suitable for the treatment of joint diseases.
Desmoplastic Small Round Cell Tumor of Stomach
Authors: Abu-Zaid Ahmed , Azzam Ayman , AlNajjar Asma , Al-Hussaini Hussa , Amin Tarek
Published: June 2013

Desmoplastic small round cell tumor (DSRCT) is an extremely uncommon, highly aggressive, and malignant mesenchymal neoplasm of undetermined histogenesis. Less than 200 case reports have been documented in literature so far. Herein, we report a 26-year-old otherwise healthy female patient who presented with a 1-month history of epigastric pain. On physical examination, a palpable, slightly mobile, and tender epigastric mass was detected. All laboratory tests were normal. A chest, abdominal, and pelvic contrast-enhanced computed tomography (CT) scans showed a 3.8 × 7.2 × 8.7 cm ill-defined mass, involving gastric fundus and extending into gastric cardia and lower gastroesophageal junction. It was associated with multiple enlarged gastrohepatic lymph nodes; the largest measured 1.2 cm. There was no evidence of ascites or retroperitoneal or mesenteric lymphatic metastases. Patient underwent total gastrectomy with D2 lymphadenectomy, splenectomy, and antecolic Roux-en-Y esophagojejunal anastomosis. Histopathological examination revealed coexpression of mesenchymal, epithelial, and neural markers. The characteristic chromosomal translocation (t(11; 22)(p13; q12)) was demonstrated on fluorescence in situ hybridization (FISH) technique. Diagnosis of DSRCT of stomach was confirmed. Patient received no postoperative radiotherapy or chemotherapy. A postoperative 3-month followup failed to show any recurrence. In addition, a literature review on DSRCT is included.
Low Mismatch Key Agreement Based on Wavelet-Transform Trend and Fuzzy Vault in Body Area Network
Authors: Wu Yang , Sun Yongmei , Zhan Lei , Ji Yuefeng
Published: June 2013

Body area network (BAN) is an emerging branch of wireless sensor networks for personalized applications in many fields, such as health monitoring. The services in BAN usually have a high requirement on security, especially for the medical diagnosis, which involves private information. With limitations of power and computation capabilities, one of the main challenges to ensure security in BAN is how to generate or distribute a shared key between nodes for lightweight symmetric cryptography. The current research almost exploits the randomness and distinctiveness (characteristics) of physiological signals to solve the key generation problem. However, it needs the help of additional hardware support and has the constraint on positions deployment, to acquire vital signals, which will bring the high cost and hardness to implementation of real system. To avoid the above problems, this paper presents a novel key generation scheme and a key distribution protocol, both of which are only based on wireless modules equipped on sensors. By exploiting the high correlation of received signal strength index (RSSI) between peer-to-peer communications, our scheme can provide a shared symmetric cryptographic key under the presence of an eavesdropper. We conduct experiments on the real Telosb nodes, and the results demonstrate that our proposed methods have a good performance on security.
Recruiting for Epigenetic Research: Facilitating the Informed Consent Process
Authors: Jallo Nancy , Lyon Debra E. , Kinser Patricia Anne , Kelly Debra Lynch , Menzies Victoria , Jackson-Cook Colleen
Published: June 2013

Because the effects of epigenetic (gene-environment interaction) changes have been associated with numerous adverse health states, the study of epigenetic measures provides exciting research opportunities for biobehavioral scientists. However, recruitment for studies focusing on any aspect of genetics poses challenges. Multiple factors, including lack of knowledge regarding a research study, have been identified as barriers to recruitment. Strengthening the informed consent process through extended discussion has been found to be effective in recruiting for research studies in general, yet there is a paucity of information that focused on such a recruitment strategy for epigenetic studies. In this paper, we share our experiences with strategies to strengthen the informed consent process as well as provide samples of materials developed to heighten potential participants’ understanding of epigenetics, in 4 epigenetic research studies with women from diverse backgrounds experiencing a range of health issues. The combined enrollment success rate for epigenetic studies using the process was 89% with participants representing a diverse population. We posit that carefully developed recruitment scripts provided a foundation for improving potential participants’ understanding of the research project. Easy to understand illustrations of the epigenetic process provided a basis for active engagement and encouraged individual questions.
Pregnancy after Acute Coronary Syndrome: A Proposal for Patients’ Management and a Literature Review
Authors: Janion-Sadowska Agnieszka , Sadowski Marcin , Kurzawski Jacek , Zandecki Łukasz , Janion Marianna
Published: June 2013

Coronary artery disease complicates only 0.01% of all pregnancies. For this reason, more exhaustive data on the management of such cases is lacking. Even guidelines on management of cardiovascular disease in pregnant women are scarce focusing mainly on acute myocardial infarction. This is a complex issue involving thorough evaluation of cardiovascular status in each pregnant woman, assessment of risk for developing coronary complications, and close cooperation with obstetric teams. Safety data on typical cardiac drugs such as statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or novel antiplatelet drugs are also scarce and their effect on the developing human fetus is not well understood. We present a review on the management of such patients.
Penile Calciphylaxis in End Stage Renal Disease
Authors: Barbera Vincenzo , Di Lullo Luca , Gorini Antonio , Otranto Giovanni , Floccari Fulvio , Malaguti Moreno , Santoboni Alberto
Published: June 2013

Calciphylaxis, better described as “Calcific uremic arteriolopathy” (CUA), involves about 1–4% of hemodialysis patients all around the world with high mortality rates. We describe a rare clinical case of CUA in peritoneal dialysis patient associated with urological disease. Penile calciphylaxis represents rare clinical complication, and an early diagnosis and multidisciplinary approach are requested. Pathogenesis is still unclear, and therapeutic approaches need more long-term clinical trials to test their efficacy and safety.
Chemical Composition and Anti-Inflammatory Effect of Ethanolic Extract of Brazilian Green Propolis on Activated J774A.1 Macrophages
Authors: Szliszka Ewelina , Kucharska Alicja Z. , Sokół-Łętowska Anna , Mertas Anna , Czuba Zenon P. , Król Wojciech
Published: June 2013

The aim of this study was to investigate the chemical composition and anti-inflammatory effect of ethanolic extract of Brazilian green propolis (EEP-B) on LPS + IFN-γor PMA stimulated J774A.1 macrophages. The identification and quantification of phenolic compounds in green propolis extract were performed using HPLC-DAD and UPLC-Q-TOF-MS methods. The cell viability was evaluated by MTT and LDH assays. The radical scavenging ability was determined using DPPH•and ABTS•+. ROS and RNS generation was analyzed by chemiluminescence. NO concentration was detected by the Griess reaction. The release of various cytokines by activated J774A.1 cells was measured in the culture supernatants using a multiplex bead array system based on xMAP technology. Artepillin C, kaempferide, and their derivatives were the main phenolics found in green propolis. At the tested concentrations, the EEP-B did not decrease the cell viability and did not cause the cytotoxicity. EEP-B exerted strong antioxidant activity and significantly inhibited the production of ROS, RNS, NO, cytokine IL-1α, IL-1β, IL-4, IL-6, IL-12p40, IL-13, TNF-α, G-CSF, GM-CSF, MCP-1, MIP-1α, MIP-1β, and RANTES in stimulated J774A.1 macrophages. Our findings provide new insights for understanding the anti-inflammatory mechanism of action of Brazilian green propolis extract and support its application in complementary and alternative medicine.
Do Renal Cysts Affect the Success of Extracorporeal Shockwave Lithotripsy? A Retrospective Comparative Study
Authors: Gücük Adnan , Öztürk Ufuk , Üyetürk Uğur , Kemahlı Eray , Akın Güven , İmamoğlu M. Abdurrahim , Metin Ahmet
Published: June 2013

The aim of this study was to assess the effect of simple renal cysts on extracorporeal shockwave lithotripsy (SWL) in patients with calyceal renal calculi. Patients with simple renal cysts >35 mm and ipsilateral renal calculi <20 mm that were treated with SWL constituted group 1 (cyst + calculi). The control group included patients aged >40 years that had renal calculi <20 mm and no cysts that were treated with SWL. The 2 groups were compared according to age, gender, body mass index, calculi size, localization, and density, the calculi fragmentation rate, and the percentage of stone-free patients. Mean cyst size in group 1 was44.04±9.08 mm. Mean age in group 1 was61.4±10.2years versus56.9±8.2years in the control group; the difference was significant (P=0.045). There were not any other significant differences between the 2 groups, except for the stone-free rate (P>0.05), which was 33.3% in group 1 and 68.2% in the control group (P=0.017). The presence of renal cysts in a patient with calculi requires that an individualized treatment plan be devised, so as to provide the patient with the most effective treatment.
Retrospective Review of Pectoralis Major Ruptures in Rodeo Steer Wrestlers
Authors: Lau Breda H. F. , Butterwick Dale J. , Lafave Mark R. , Mohtadi Nicholas G.
Published: June 2013

Background. Pectoralis major tendon ruptures have been reported in the literature as occupational injuries, accidental injuries, and sporting activities. Few cases have been reported with respect to rodeo activities.Purpose. To describe a series of PM tendon ruptures in professional steer wrestlers.Study Design. Case series, level of evidence, 4.Methods. A retrospective analysis of PM ruptures in a steer wrestling cohort was performed. Injury data between 1992 and 2008 were reviewed using medical records from the University of Calgary Sport Medicine Center.Results. Nine cases of pectoralis major ruptures in professional steer wrestlers were identified. Injuries occurred during the throwing phase of the steer or while breaking a fall. All athletes reported unexpected or abnormal behavior of the steer that contributed to the mechanism of injury. Seven cases were surgically repaired, while two cases opted for nonsurgical intervention. Eight cases reported successful return to competition following the injury.Conclusion. Steer wrestlers represent a unique cohort of PM rupture case studies. Steer wrestling is a demanding sport that involves throwing maneuvers that may predispose the muscle to rupture. All cases demonstrated good functional outcomes regardless of surgical or non-surgical treatment.
HER2 and Breast Cancer Stem Cells: More than Meets the Eye
Authors: Korkaya Hasan , Wicha Max S.
Published: June 2013

The development of HER2 targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggest that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (CSC) population. A new study suggests that the regulation of BCSCs by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population, and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these HER2-negative tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biologic explanation for retrospective analysis of clinical trials, which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population. Cancer Res; 73(12); 3489–93. ©2013 AACR.
Putative Predictive Biomarkers of Survival in Patients with Metastatic Pancreatic Adenocarcinoma Treated with Gemcitabine and Ganitumab, an IGF1R Inhibitor
Authors: McCaffery Ian , Tudor Yanyan , Deng Hongjie , Tang Rui , Suzuki Samuel , Badola Sunita , Kindler Hedy L. , Fuchs Charles S. , Loh Elwyn , Patterson Scott D. , Chen Li , Gansert Jennifer L.
Published: June 2013

Purpose: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma.

Experimental Design: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated.

Results: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28–0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF-1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09–0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09–0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11–0.73), and in patients with lower IGFBP-2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07–0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS.

Conclusions: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma. Clin Cancer Res; 19(15); 4282–9. ©2013 AACR.
Exposure–Response Relationships of the Efficacy and Safety of Ipilimumab in Patients with Advanced Melanoma
Authors: Feng Yan , Roy Amit , Masson Eric , Chen Tai-Tsang , Humphrey Rachel , Weber Jeffrey S.
Published: June 2013

Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure–response relationships for measures of efficacy and safety in patients with advanced melanoma.

Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady–state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional–hazards model.

Results: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively.

Conclusions: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. Clin Cancer Res; 19(14); 3977–86. ©2013 AACR.
Targeting Treatment-Resistant Breast Cancer Stem Cells with FKBPL and Its Peptide Derivative, AD-01, via the CD44 Pathway
Authors: McClements Lana , Yakkundi Anita , Papaspyropoulos Angelos , Harrison Hannah , Ablett Matthew P. , Jithesh Puthen V. , McKeen Hayley D. , Bennett Rachel , Donley Christopher , Kissenpfennig Adrien , McIntosh Stuart , McCarthy Helen O. , O'Neill Eric , Clarke Robert B. , Robson Tracy
Published: June 2013

Purpose: FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC).

Experimental Design: Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment ± other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti–stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence.

Results: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESA+/CD44+/CD24− or aldehyde dehydrogenase (ALDH)+ cell subpopulations in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self-renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01–mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy-induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling.

Conclusions: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial. Clin Cancer Res; 19(14); 3881–93. ©2013 AACR.
Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner
Authors: Cerezo Michaël , Tichet Mélanie , Abbe Patricia , Ohanna Mickaël , Lehraiki Abdelali , Rouaud Florian , Allegra Maryline , Giacchero Damien , Bahadoran Philippe , Bertolotto Corine , Tartare-Deckert Sophie , Ballotti Robert , Rocchi Stéphane
Published: June 2013

Metformin was reported to inhibit the proliferation of many cancer cells, including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of antiproliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial–mesenchymal transition such as Slug, Snail, SPARC, fibronectin, and N-cadherin and with inhibition of MMP-2 and MMP-9 activation. Furthermore, our data indicate that this process is dependent on activation of AMPK and tumor suppressor protein p53. Finally, we showed that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment. Mol Cancer Ther; 12(8); 1605–15. ©2013 AACR.
Ischemia Modified Albumin and Plasma Oxidative Stress Markers in Alzheimer's Disease
Authors: Can Murat , Varlibas Figen , Guven Berrak , Akhan Ozkan , Yuksel Gulbun Asuman
Published: June 2013

Objectives: The objective of this study was to determine ischemia modified albumin (IMA) and oxidant status in Alzheimer's disease (AD). Therefore, we evaluated the IMA and oxidant status by measuring serum uric acid, albumin and gamma-glutamyltransferase (GGT) in AD. Methods: The plasma albumin, uric acid, GGT and IMA levels were measured by spectrophotometric methods in 32 AD patients and 32 healthy controls. The Mini Mental Status Examination and Clinical Dementia Rating Scale were used to evaluate the cognitive functions of AD patients. Results: AD patients had significantly higher IMA levels as compared to those of the controls respectively. Uric acid concentrations were significantly decreased and GGT values were significantly increased in AD when compared with control group. Albumin levels of the patients were also compared and no significant difference was detected. Conclusion: Oxidative stress and IMA levels rise in AD. However, large prospective studies are required to understand the mechanisms leading to increased IMA levels during AD, whether preceded or not by AD.
Phenotypic Evaluation of Severely Damaged Ocular Surface after Reconstruction by Cultured Limbal Epithelial Cell Transplantation
Authors: Sharma Shweta , Tandon Radhika , Mohanty Sujata , Kashyap Seema , Vanathi Murugesan
Published: June 2013

Objective: To report the clinical outcome of autologous cultured limbal epithelial cell transplantation (CLECT) followed by deep anterior lamellar keratoplasty (DALK) in paediatric eyes and to correlate the clinical outcome with the phenotype of rejuvenated corneal epithelium. Methods: Four patients with total limbal stem cell deficiency (LSCD) underwent autologous CLECT. Cultivated cell sheets were transplanted onto the damaged ocular surface followed by DALK surgery. Excised corneal buttons were subjected to histopathological analysis. Data recorded included age, sex, laterality, nature of injury, follow-up period, severity of stem cell deficiency, visual acuity, Schirmer's test and impression cytology. Results: At a mean follow-up period of 19.5 ± 7.4 (range 9-26) months after CLECT, all 4 eyes showed epithelialized and clinically stabilized ocular surface. Manual DALK was performed in all 4 eyes, with a mean follow-up of 9.75 ± 4.5 (range 5-15) months. All eyes exhibited smooth and clear corneal epithelium with improved visual acuity. Excised corneal buttons demonstrated organized corneal epithelial morphology and showed expression of cornea-specific CK3/12 marker. Conclusion: Restoration of severely damaged ocular surface following chemical injury by using 2-stage meticulous approaches offers a new modality for the treatment of severe LSCD. Transplantation of cultivated autologous limbal epithelial cell sheet followed by DALK surgery can efficiently restore the corneal phenotype with improved vision.
Development of a Quality of Life Scale for Vitiligo
Authors: Şenol Aslı , Yücelten Ayşe Deniz , Ay Pınar
Published: June 2013

Background: No vitiligo-specific quality of life scale exists. Objective: To develop a reliable and valid quality of life scale for vitiligo patients. Methods: The content was derived from in-depth interviews with vitiligo patients. The internal consistency, test-retest reliability and validity of the scale, VLQI (Vitiligo Life Quality Index), were evaluated. Results: Internal consistency was high with 30 patients and then with 183 patients (Cronbach's α 0.92 and 0.91). Test-retest scores were correlated (r = 0.86, p < 0.001). There was no difference between the test and retest scores (p > 0.05). VLQI was correlated with DLQI (Dermatology Life Quality Index) (r = 0.77, p < 0.001) and with the perceived severity by the patients (r = 0.57, p < 0.001). There was a significant relationship between the VLQI and the extent of the disease (p = 0.015). Factor analysis revealed six subscales. Conclusion: The VLQI is a valid and reliable instrument assessing quality of life of vitiligo patients.
Oncological Outcome of Primary versus Secondary Muscle-Invasive Bladder Cancer Is Comparable after Radical Cystectomy
Authors: Aziz A. , Gierth M. , Fritsche H.M. , May M. , Otto W. , Denzinger S. , Wieland W.F. , Merseburger A. , Riedmiller H. , Kocot A. , Burger M.
Published: June 2013

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. Objective: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. Materials and Methods: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. Results: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. Conclusion: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC.
Initial Presentation of Brucella Endocarditis in a Previously Healthy Eighteen-Year-Old Young Man
Authors: Chowdhury Mohammed Andaleeb , El Abbassi Wael , Najeeb Ahmed , Mansoor Anoop
Published: June 2013

Brucellosis is a reported endemic in the Middle East, Arabian Peninsula, South Asia, and Central and South America, with a high fatality rate of 80%. We present a case report of Brucella endocarditis in a young 18-year-old male who developed aortic and mitral vegetation, subaortic abscess and mitral leaflet perforation. He was started on antibiotics but his cardiac status rapidly deteriorated and eventually needed a double valve replacement. We would like to share our experience and the challenges we faced in managing this case, which is uncommon, especially in young adults.
The Importance of Disease Prevalence in Assessing the Diagnostic Value of a Test: Endoscopic Markers in Celiac Disease
Authors: Pellegrino Salvatore , Furfaro Federica , Tortora Andrea , Naso Pietro , D'Agate Cinzia , Spina Massimo , Belluardo Nunzio , Bertone Aldina , Passanisi Guido , Malandrino Sebastiana , Familiari Luigi , Villanacci Vincenzo , Puzzo Lidia , Tuccari Giovanni , Sciacca Agata , Vieni Giuseppe , Costa Stefano , Currò Giovanni , Magazzù Giuseppe , Sferlazzas Concetta , Bassotti Gabrio
Published: June 2013

Background/Aims: We evaluated the diagnostic variability and reproducibility of endoscopic signs in two populations with a different pretest likelihood of celiac disease (CD). Methods: We recruited 289 CD patients (both adults and children) in a multicenter prospective study. Group 1 (high risk) included 111 patients referred for positive serology. Group 2 (low risk) included 178 unselected patients. Mosaic pattern, reduction/loss of Kerckring's folds, scalloping of the valvulae conniventes and a nodular pattern were the endoscopic findings looked for in the duodenum. Results: In group 1, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of endoscopic findings were 100, 84.6, 94.2 and 100% in adults, and 86.8, 9.1, 82.1 and 12.5% in children. In group 2, the sensitivity, specificity, PPV and NPV of endoscopic findings were 33.3, 91.4, 7.7 and 98.5% in adults, and noncalculable, 78.3, 0.0 and 100% in children. Comparing group 1 and group 2, there was a statistically significant difference in sensitivity and PPV in adults, and in specificity, PPV and NPV in children. Concerning the reproducibility of endoscopic findings, a wide variability of κ values was found. Conclusion: Endoscopic signs have low reproducibility for CD, and their diagnostic value in selecting patients for multiple intestinal biopsies is unacceptable, especially in populations with low disease prevalence.
Time between First and Second Transurethral Resection of Bladder Tumors in Patients with High-Grade T1 Tumors: Is It a Risk Factor for Residual Tumor Detection?
Authors: Süer Evren , Özcan Cihat , Baltacı Sümer , Gülpınar Ömer , Burgu Berk , Haliloğlu Ahmet , Bedük Yaşar
Published: June 2013

Purpose: We evaluated the risk factors for residual tumor detection after transurethral resection of bladder tumors (TURBT) in patients with newly diagnosed high-grade T1 transitional cell carcinoma of the bladder. Patients and Methods: Overall 132 patients underwent TURBT for primary bladder tumors and were diagnosed as high-grade T1 bladder cancer. Patients with incomplete resections were excluded from the study. Clinical and pathologic characteristics of the patients were compared and multivariate analysis was performed to determine independent prognostic factors. Results: Residual tumor was demonstrated in 57 (43.1%) of the patients. The residual tumor rate was significantly lower in patients with solitary tumors, tumors <3 cm in diameter, muscle presence in the initial TURBT pathologic sample and treated by an expert surgeon. In patients with solitary bladder tumors, tumors at the dome and posterior wall of the bladder exhibited higher rates of residual tumor (p < 0.0001). The time elapsed between first and second TURBT was significantly shorter in patients without residual tumor compared to patients with residual tumor at second TURBT (32.6 ± 9.1 vs. 39.3 ± 10.9 days, respectively, p = 0.001). Multivariate analysis demonstrated that time elapsed between first and second TURBT is the most important parameter for residual tumor detection. Conclusion: Our study revealed that multiple tumors, tumors >3 cm in size, absence of detrusor muscle in the initial TURBT specimen, TURBT performed by trainees and finally, as a new finding, prolonged interval between first and second TURBT are independent predictors for residual tumor detection in patients with high-grade T1 tumors.
Off-Pump versus On-Pump Coronary Artery Bypass Grafting in Octogenarians: Comparison of Short-Term Outcomes and Long-Term Survival
Authors: Lee Daniel C. , Ramirez Sergio A. , Bacchetta Matthew , Borer Jeffrey S. , Ko Wilson
Published: June 2013

Off-pump coronary artery bypass (OPCAB) has gained increasing acceptance with potential benefits for high-risk elderly patients. We report a surgeon's operative outcomes in octogenarians with an OPCAB program. Retrospective, intention-to-treat analysis of 97 consecutive octogenarians who underwent coronary bypass by a single surgeon between 1997 and 2001 before and after initiation of a multi-vessel OPCAB program was performed. OPCAB was attempted in all octogenarians. The OPCAB cohort had higher serum creatinine (OPCAB vs. pre-OPCAB: 1.30 ± 0.79 mg/dl vs. 1.08 ± 0.27, p = 0.04) and ejection fractions (52 ± 14% vs. 45 ± 11%, p = 0.02) than the pre-OPCAB cohort. The OPCAB group was more likely to require urgent/emergency surgery (63 vs. 40%, p = 0.04) and to have chronic renal insufficiency (18 vs. 3%, p = 0.05). After programmatic change to OPCAB, significant postoperative improvements were observed in the length of hospital stay (17 ± 19 vs. 8 ± 4 days, p < 0.01), duration of inotropic requirement (47 ± 70 vs. 18 ± 39 h, p < 0.04), duration of ventilator support (51 ± 54 vs. 16 ± 27 h, p < 0.01) and incidence of tracheostomy (16 vs. 3%, p < 0.02). In-hospital mortalities (3.2 vs. 2.7%), strokes (3 per group) and 5-year survival did not differ significantly (57 vs. 67%, p = 0.50, NS). Despite some higher preoperative risks, the OPCAB program demonstrated clinical benefits in octogenarians but no advantage in hospital-mortality or long-term survival.
Fertility-Sparing Surgery for Young Women with Early-Stage Epithelial Ovarian Cancer
Authors: Nam Joo-Hyun , Park Jeong-Yeol
Published: June 2013

Background/Aims: To discuss the latest findings on oncologic and reproductive outcomes of fertility-sparing surgery in epithelial ovarian cancer (EOC) and to suggest proper indications for this treatment. Methods: A search of Medline database was performed for articles dealing with fertility-sparing surgery for EOC published in the English literature between January 1, 1969, and October 1, 2012. Results: To date, 918 patients with EOC underwent fertility-sparing surgery; 109 (11.9%) had disease recurrence and 48 (5.2%) died of disease. Retrospective studies suggest that fertility-sparing surgery may be safely performed in young women with a strong desire to preserve fertility and with nonclear cell histology, FIGO stage IA, IC and grade 1-2 disease or clear cell histology and FIGO stage IA disease. To date, 177 patients have succeeded in achieving 242 pregnancies, resulting in 214 term (88%) and 1 preterm (0.4%) births. Miscarriage rate was about 10% (25/242) and ectopic pregnancy rate was 0.8% (2/242) after fertility-sparing surgery. No congenital anomaly has been reported. Conclusions: Although randomized controlled trials have yet to be performed, many studies have suggested that fertility-sparing surgery is safe, with promising reproductive outcomes. Cautious selection of patients is important because of 5.2% mortality and 11% recurrence after this surgery.
Pharmacokinetics and Pharmacodynamics of Orally Administered Clonidine: A Model-Based Approach
Authors: Klein R.H. , Alvarez-Jimenez R. , Sukhai R.N. , Oostdijk W. , Bakker B. , Reeser H.M. , Ballieux B.E.P.B. , Hu P. , Klaassen E.S. , Freijer J. , Burggraaf J. , Cohen A.F. , Wit J.M.
Published: June 2013

Background/Aims: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. Methods: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. Results: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 ± 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 ± 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. Conclusion: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects.
Hypoxia Induces Mesenchymal Gene Expression in Renal Tubular Epithelial Cells: An in vitro Model of Kidney Transplant Fibrosis
Authors: Zell Stephanie , Schmitt Roland , Witting Sandra , Kreipe Hans H. , Hussein Kais , Becker Jan U.
Published: June 2013

Background: The development of interstitial fibrosis and tubular atrophy is a common complication after kidney transplantation and is associated with reduced long-term outcome. The hallmark of tubulointerstitial fibrosis is an increase in extracellular matrix resulting from exaggerated activation of fibroblasts/myofibroblasts, and tubular atrophy is characterized by a decrease in tubular diameter and loss of function. Atrophic epithelial cells may undergo epithelial-to-mesenchymal transition (EMT) with potential differentiation into interstitial fibroblasts. One potential driver of EMT in developing interstitial fibrosis and tubular atrophy is chronic hypoxia. Methods: The expression of 46 EMT-related genes was analyzed in an in vitro hypoxia model in renal proximal tubular epithelial cells (RPTEC). Furthermore, the expression of 342 microRNAs (miR) was evaluated in hypoxic culture conditions. Results: Hypoxic RPTEC expressed markers of a more mesenchymal phenotype and showed an increased expression of matrix metalloproteinase-2 (MMP2). MMP2 expression in RPTEC correlated inversely with a decreased expression of miR-124, which was found to have a putative binding site for the MMP2 transcript. Overexpression of miR-124 inhibited MMP2 protein translation. Hypoxia was associated with increased migration/proliferation of RPTEC which was reversed by miR-124. Conclusions: These results indicate that hypoxia promotes a mesenchymal and migratory phenotype in renal epithelial cells, which is associated with increased MMP2 expression. Hypoxia-dependent MMP2 expression is regulated via a reduced transcription of miR-124. Overexpression of miR-124 antagonizes hypoxia-induced cell migration. Further research is needed to elucidate the functional role of miR-124 and MMP2 in the development of fibrosis in renal transplant degeneration.
Impairment of Static Vestibular Function Is Limited in Patients with Sudden Sensorineural Hearing Loss with Vertigo
Authors: Kim Chang-Hee , Na Bo Ra , Park Hong Ju , Shin Jung Eun
Published: June 2013

Sudden sensorineural hearing loss with vertigo (SSNHL_V) and vestibular neuritis (VN) are common neuro-otologic disorders that cause acute spontaneous vertigo. The SSNHL_V and VN lesion sites are thought to be within the labyrinth and the vestibular nerve, respectively. Neurolabyrinthitis of a viral origin is the most commonly accepted etiology of SSNHL_V, and neural degeneration due to viral infection (predominantly in the superior vestibular nerve) is thought to be responsible for the pathophysiology of VN. The objective of this study was to compare the static vestibular imbalance between SSNHL_V and VN patients during the acute stage of the disease. We compared the results of spontaneous nystagmus (SN), subjective visual vertical (SVV), and canal paresis (CP) between SSNHL_V and VN patients within 10 days from the onset of vertigo. Significant SN was observed in 58% of SSNHL_V and 90% of VN patients (p < 0.001), and abnormal SVV was observed in 10% of SSNHL_V and 78% of VN patients (p < 0.001). However, CP values were not significantly different between the 2 groups (50.8 ± 19.7% in SSNHL_V and 57.1 ± 18.9% in VN). In conclusion, significant SN and abnormal SVV are less frequently encountered in SSNHL_V than in VN even though the caloric test did not reveal significant differences at the acute stage.
The effect of monthly ibandronate on bone mineral density and bone turnover markers in patients with haemophilia A and B and increased risk for fracture
Authors: Vyzantiadis Timoleon-Achilleas , Charizopoulou Maria , Adamidou Fotini , Karras Spyridon , Goulis Dimitrios , Karagiannis Asterios , Garipidou Vasilia , Vakalopoulou Sofia , Anagnostis Panagiotis
Published: June 2013

Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, no study has so far evaluated the effects of anti-osteoporotic therapy on BMD in haemophilia. The primary endpoint of this prospective study was to estimate the effect of 12-month therapy of oral ibandronate 150 mg/ month on BMD in patients with haemophilia A and B. Secondary endpoint was its effect on turnover markers (BTM) of bone resorption [serum C-terminal telopeptide of type 1 collagen (sCTX), tartrate-resistant acid phosphatase band 5b] and bone formation (osteocalcin and bone-specific alkaline phosphatase. Ten adult patients with T-score < −2.5 SD or Z-score < −2 and/or increased risk of fracture according to FRAX model were included. All received 1,000 mg/day calcium carbonate with 800 IU/d cholecalciferol. Males with haemophilia A (n=7) or B (n=3) (mean age 43.5 ± 13.5 years) were studied. Ibandronate resulted in an increase in lumbar BMD (from 0.886 ± 0.169 to 0.927 ± 0.176 g/cm2, 4.7%, p=0.004). No change in BMD of total hip (from 0.717 ± 0.128 to 0.729 ± 0.153 g/cm2, p=0.963) or femoral neck (0.741 ± 0.135 to 0.761 ± 0.146 g/cm2, p=0.952) was noticed. Ibandronate led to a decrease in sCTX (from 0.520 ± 0.243 to 0.347 ± 0.230 ng/ml, −29.9%, p=0.042). No change was observed in other BTM. Ibandronate was generally well-tolerated. In conclusion, ibandronate significantly improved BMD in lumbar spine and reduced bone resorption in adults with haemophilia at increased risk of fracture. Its effect on hip BMD and bone formation markers was not significant.
Increased expression of cell adhesion molecule receptors on monocyte subsets in ischaemic heart failure
Authors: Wrigley Benjamin , Tapp Luke , Shantsila Eduard , Gregory Lip
Published: June 2013

The objective of this study was to evaluate the expression of cell adhesion molecule (CAM) receptors (integrins) on monocyte subsets in heart failure (HF) and examine their prognostic implication. Increased levels of soluble CAMs have been observed in patients with HF, but the precise mechanism of monocyte adhesion to the vascular endothelium remains unknown. Patients with acute HF (AHF, n=51) were compared to those with stable HF (SHF, n=42) and stable coronary artery disease (CAD, n=44) without HF. Expression of integrins-receptors to intercellular adhesion molecule-1 (ICAM-1R) and vascular CAM-1 (VCAM-1R) on monocyte subsets was assessed by flow cytometry. Monocyte subsets were defined as CD14++CD16–CCR2+ (‘classical’, Mon1), CD14++CD16+CCR2+ (‘intermediate’, Mon2), and CD14+CD16++CCR2– (‘non-classical’, Mon3). Compared to patients with SHF, those with AHF had significantly higher expression of ICAM-1R on Mon2 (p=0.01). Compared to those with stable CAD, patients with SHF had a significantly higher expression of ICAM-1R on Mon2 (p=0.025). Compared to SHF, patients with AHF had a similar expression of VCAM-1R on both Mon1 and Mon3 but significantly higher expression on Mon2 (p=0.019). There were no significant differences between SHF and CAD in monocyte expression of VCAM-1R. In multivariate Cox regression analysis, VCAM-1R expression on Mon2 was associated with adverse clinical outcome (death or rehospitalisation) in AHF [HR 1.07 (1.01–1.14), p=0.029]. In conclusion, HF is associated with increased monocyte expression of integrins-receptors to both ICAM-1 and VCAM-1, being particularly linked to Mon2 subset. Expression of VCAM-1R on Mon2 may have prognostic value in patients with AHF.
Pathophysiological role of neutrophils in acute myocardial infarction
Authors: Carbone Federico , Nencioni Alessio , Mach François , Vuilleumier Nicolas , Montecucco Fabrizio
Published: June 2013

The pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix-degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical models with pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post-ischaemic outcomes.