bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Effects of Exposures to Environmental Factors: The Polish Mother and Child Cohort Study
Authors: Polanska Kinga , Hanke Wojciech , Sobala Wojciech , Trzcinka-Ochocka Malgorzata , Ligocka Danuta , Brzeznicki Slawomir , Strugala-Stawik Halina , Magnus Per
Published: September 2013

This paper estimates the effects of exposure to environmental factors, including lead, mercury, environmental tobacco smoke (ETS), and polycyclic aromatic hydrocarbons (PAH), on child psychomotor development. The study population consists of mother-child pairs in the Polish Mother and Child Cohort Study. Prenatal and postnatal exposure to environmental factors was determined from biomarker measurements as follows: for lead exposure—cord blood lead level, for mercury—maternal hair mercury level, for ETS—cotinine level in saliva and urine, and for PAH—1-hydroxypyrene (1-HP) in urine. At the age of 12 (406 subjects) and 24 months (198 subjects) children were assessed using Bayley Scales of Infant and Toddler Development. There were no statistically significant effects of prenatal exposure to mercury or 1-HP on child psychomotor development. After adjusting for potential confounders, adverse effects of prenatal exposure to ETS on motor development (β= −2.6;P=0.02) and postnatal exposure to ETS on cognitive (β= −0.2;P=0.05) and motor functions (β= −0.5;P=0.01) were found. The adverse effect of prenatal lead exposure on cognitive score was of borderline significance (β= −6.2;P=0.06). The study underscores the importance of policies and public health interventions that aim to reduce prenatal and postnatal exposure to lead and ETS.
Chronic Urticaria: Indian Context—Challenges and Treatment Options
Authors: Khan Sujoy , Maitra Anirban , Hissaria Pravin , Roy Sitesh , Padukudru Anand Mahesh , Nag Nalin , Singh Harpal
Published: September 2013

Urticaria is a common condition that occurs in both children and adults. Most cases have no specific allergic trigger and the aetiology of urticaria remains idiopathic and occasionally spontaneous in nature. Inappropriate advice such as avoidance of foods (milk, egg, prawn, and brinjal) is common place in certain sections of India mostly by nonspecialists that should not be routinely recommended. It is important to look for physical urticarias such as pressure urticaria in chronic cases, which may be present either alone or in combination with other causes. Autoimmune causes for chronic urticaria have been found to play an important role in a significant proportion of patients. Long-acting nonsedating antihistamines at higher than the standard doses is safe and effective. Quality of life is affected adversely in patients with chronic symptomatic urticaria and some may require multidisciplinary management.
Inverse Coefficient Problem of the Parabolic Equation with Periodic Boundary and Integral Overdetermination Conditions
Authors: Kanca Fatma
Published: September 2013

This paper investigates the inverse problem of finding a time-dependent diffusion coefficient in a parabolic equation with the periodic boundary and integral overdetermination conditions. Under some assumption on the data, the existence, uniqueness, and continuous dependence on the data of the solution are shown by using the generalized Fourier method. The accuracy and computational efficiency of the proposed method are verified with the help of the numerical examples.
Peripheral and Spinal Mechanisms of Acupoint Sensitization Phenomenon
Authors: Rong Pei-Jing , Li Shaoyuan , Ben Hui , Li Liang , Yu Ling-Ling , Cui Chang-Xiang , Li Xia , Zhu Bing
Published: September 2013

This study was carried out on adult female Sprague-Dawley rats to observe the position, size, and sensitivity change of inflammatory reactions on body surfaces induced by colorectal import of inflammatory irritant mustard oil. Colorectal distension (CRD) was adopted as a visceral noxious stimulus to record the activities of spinal dorsal horn wide-dynamic range (WDR) neurons activities at spinal segments L1–L3. The study also observed the activations of WDR neurons by electro-acupuncture (EA) on acupoints of Zusanli-Shangjuxu before and after different intensities of CRD stimulation and the dose-response relationship between stimulus and response. The results show that in the case of visceral inflammation, the number of exudation points of neurogenic reaction on body surfaces increased along with the severity of visceral inflammation (Li et al. 2006). The area of peripheral receptive fields of WDR neurons also enlarged along with the intensity of visceral inflammatory response. The activation effect of EA on WDR neurons was positively correlated with the severity of visceral inflammation. Therefore, we concluded that the function of acupoints can be sensitized by visceral noxious stimuli. When the function of internal organs was damaged, the number of reaction points on body surfaces, the size of acupoints’ receptive fields, and the sensitivity of acupoints changed accordingly.
Analysis of Face Stability during Excavation of Double‐O‐Tube Shield Tunnel
Authors: Yang Yuyou , Zhou Qinghong , Li Hongan , Huang Xuegang , Tu Xiaoming
Published: September 2013

This paper focuses on the face stability analysis of Double‐O‐Tube shield tunnel. This kind of analysis is significant to ensure the safety of workers and reduce the influence on the surrounding environment. The key point of the stability analysis is to determine the supporting pressure applied to the face by the shield. A collapse failure will occur when the supporting pressure is not sufficient to prevent the movement of the soil mass towards the tunnel. A three‐dimensional collapse failure mechanism was presented in this paper. Based on the mechanism of a single circular shield tunnel, the mechanism of Double‐O‐Tube shield tunnel was established by using the fact that both of the mechanisms are symmetrical. Then by means of the kinematic theorem of limit analysis, the numerical results were obtained, and a design chart was provided. The finite difference software FLAC3D was applied to investigate the face failure mechanism of DOT shield tunnel established in this paper; the critical supporting pressures of the collapse failure mechanism in different strata (sand and silt) were calculated. Through comparative analysis, the theoretical values were very close to the numerical values. This shows that the face failure mechanism of DOT shield tunnel is reasonable, and it can be applied to the sand and silt strata.
Onyx Embolization of Ruptured Intracranial Aneurysm Associated with Behçet's Disease
Authors: Kurdi Maher , Baeesa Saleh , Bin-Mahfoodh Mohammed , Kurdi Khalil
Published: September 2013

Introduction. Intracranial aneurysms associated with Behçet's disease (BD) are a rare occurrence. They are fragile, thin-walled pseudoaneurysms, which have high tendency to rupture and present a therapeutic challenge.Case Presentation. We report a 26-year-old male with BD presented with subarachnoid hemorrhage due to ruptured middle cerebral artery aneurysm. Additionally, two unruptured aneurysms were identified. He underwent endovascular embolization using Onyx with successful obliteration of the ruptured aneurysm. Medical therapy resulted in regression of one and resolution of the other aneurysms.Conclusion. We describe the first report of the application of Onyx for obliteration of ruptured cerebral aneurysm in BD as a feasible and safe therapeutic option for patients who are not candidates for other techniques.
MicroRNA-429 Modulates Hepatocellular Carcinoma Prognosis and Tumorigenesis
Authors: Huang Xiao-Ying , Yao Jin-Guang , Huang Hong-Dong , Wang Chao , Ma Yun , Xia Qiang , Long Xi-Dai
Published: September 2013

MicroRNA-429 (miR-429) may modify the development and progression of cancers; however, the role of this microRNA in the hepatocellular carcinoma (HCC) has not been well elaborated. Here, we tested miR-429 expression in 138 pathology-diagnosed HCC cases and SMMC-7721 cells. We found that miR-429 was upregulated in HCC tumor tissues and that the high expression of miR-429 was significantly correlated with larger tumor size (odd ratio (OR), 2.70; 95% confidence interval (CI), 1.28–5.56) and higher aflatoxin B1-DNA adducts (OR = 3.13, 95% CI = 1.47–6.67). Furthermore, this microRNA overexpression modified the recurrence-free survival and overall survival of HCC patients. Functionally, miR-429 overexpression progressed tumor cells proliferation and inhibited cell apoptosis. These results indicate for the first time that miR-429 may modify HCC prognosis and tumorigenesis and may be a potential tumor therapeutic target.
Optimization of Extraction Parameters by Using Response Surface Methodology, Purification, and Identification of Anthocyanin Pigments in Melastoma malabathricum Fruit
Authors: Anuar Nordiyanah , Mohd Adnan Ahmad Faris , Saat Naziz , Aziz Norkasmani , Mat Taha Rosna
Published: September 2013

Anthocyanins not just have various benefits in food industry but also have been used as natural colourants in cosmetic, coating products and as potential natural photosensitizers in solar cell. Thus, the main purpose of this study was to obtain information on the maximum yield of anthocyanin that can be recovered from Melastoma malabathricum fruit. Factors such as extraction temperature, extraction time, and solid to liquid ratio were identified to be significantly affecting anthocyanin extraction efficiency. By using three‐level three‐factor Box‐Behnken design, the optimized conditions for anthocyanin extraction by acidified methanol (R2 = 0.972) were temperature of 60°C, time of 86.82 min, and 0.5 : 35 (g/mL) solid to liquid ratio while the optimum extraction conditions by acidified ethanol (R2 = 0.954) were temperature of 60°C, time of 120 min, and 0.5 : 23.06 (g/mL) solid to liquid ratio. The crude anthocyanin extract was further purified by using Amberlite XAD‐7 and Sephadex LH‐20 column chromatography. Identification of anthocyanins revealed the presence of cyanidin dihexoside, cyanidin hexoside, and delphinidin hexoside as the main anthocyanins in M. malabathricum fruit.
Differentially Methylated Loci Distinguish Ovarian Carcinoma Histological Types: Evaluation of a DNA Methylation Assay in FFPE Tissue
Authors: Kelemen Linda E. , Köbel Martin , Chan Angela , Taghaddos Soreh , Dinu Irina
Published: September 2013

Epigenomic markers can identify tumor subtypes, but few platforms can accommodate formalin-fixed paraffin-embedded (FFPE) tumor tissue. We tested different amounts of bisulfite-converted (bs) DNA from six FFPE ovarian carcinomas (OC) of serous, endometrioid, and clear cell histologies and two HapMap constitutional genomes to evaluate the performance of the GoldenGate methylation assay. Methylation status at each 1,505 CpG site was expressed asβ-values. Comparing 400 ng versus 250 ng bsDNA, reproducibility of the assay ranged from Spearmanr2=0.41to 0.90, indicating thatβ-values obtained with a lower DNA amount did not always correlate well with the higher amount. Average methylation for the six samples was higher using 250 ng (β-value = 0.45,SD=0.29) than with 400 ng (β-value = 0.36,SD=0.32). Reproducibility between duplicate HapMap samples (r2=0.76to 0.92) was also variable. Using 400 ng input bsDNA,THBS2andERGwere differentially methylated across all histologic types and between endometrioid and clear cell types at <0.1% false discovery rate. Methylation did not always correlate with gene expression (r2=-0.70to 0.15). We found that lower bsDNA overestimates methylation, and, using higher bsDNA amounts, we confirmed a previous report of higher methylation ofTHBS2in clear cell OC, which could provide new insight into biological pathways that distinguish OC histological types.
A Topology Visualization Early Warning Distribution Algorithm for Large‐Scale Network Security Incidents
Authors: He Hui , Fan Guotao , Ye Jianwei , Zhang Weizhe
Published: September 2013

It is of great significance to research the early warning system for large‐scale network security incidents. It can improve the network system’s emergency response capabilities, alleviate the cyber attacks’ damage, and strengthen the system’s counterattack ability. A comprehensive early warning system is presented in this paper, which combines active measurement and anomaly detection. The key visualization algorithm and technology of the system are mainly discussed. The large‐scale network system’s plane visualization is realized based on the divide and conquer thought. First, the topology of the large‐scale network is divided into some small‐scale networks by the MLkP/CR algorithm. Second, the sub graph plane visualization algorithm is applied to each small‐scale network. Finally, the small‐scale networks’ topologies are combined into a topology based on the automatic distribution algorithm of force analysis. As the algorithm transforms the large‐scale network topology plane visualization problem into a series of small‐scale network topology plane visualization and distribution problems, it has higher parallelism and is able to handle the display of ultra‐large‐scale network topology.
Functions, Cooperation, and Interplays of the Vegetative Growth Signaling Pathway in theAspergilli
Authors: Pusztahelyi Tünde , Pócsi István
Published: September 2013

Knowledge on the functions, cooperation, and interplays of the signaling and regulatory pathways of filamentous fungi is crucial when their industrial performance is improved or when new-type antifungals are developed. Many research groups aim at a deeper understanding of vegetative growth signaling because this cascade also influences other important physiological processes including asexual and sexual developments, autolysis and apoptotic cell death as well as the production of a wide array of important secondary metabolites. This review also focuses on how this signaling pathway is interconnected with other signaling cascades setting up a robust but delicately regulated signaling network in theAspergilli.
First Evidence of Increased Plasma Serotonin Levels in Tako-Tsubo Cardiomyopathy
Authors: Rouzaud Laborde C. , Delmas C. , Mialet-Perez J. , Pizzinat N. , Biendel-Picquet C. , Boudou N. , Dumonteil N. , Spreux-Varoquaux O. , Carrié D. , Galinier M. , Parini A. , Lairez O.
Published: September 2013

Background. There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS).Methods and Results. Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9±4.6,P=0.02versus control;5.7±5.6,P=0.001versus control; and1±0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P=0.33).Conclusion. This finding suggests that serotonin could participate to the pathophysiology of TTC.
A Clinical Review of the Association of Thyroid Stimulating Hormone and Cognitive Impairment
Authors: Annerbo Sylvia , Lökk Johan
Published: September 2013

Clinical and subclinical hypothyroidism as well as overt hyperthyroidism in middle-aged and elderly adults are both associated with decreased cognitive functioning as memory, reaction time, and visuospatial organization. Subclinical hyperthyroidism (SH) or low serum concentrations of TSH concentrations have been associated with dementia in previous epidemiological studies, but the association in the elderly has not been established. There is little or no consensus regarding how thyroid function is associated with cognitive performance in the elderly. In this focused review, we have performed an examination between eleven studies from the last five years examining the association between thyroid function and cognitive performance in elderly people, a group who is overrepresented among individuals with minor abnormalities in serum TSH and thyroid hormone concentration. Six of the studies showed a consistent finding of an association between SH with cognitive impairment or dementia. In general, taking into account the largest and most powerfully designed studies, there is a strong body of evidence supporting the association between SH and cognitive impairment. The scarce number of publications on these topics indicates the need of more research especially regarding longitudinal and interventional studies thus hopefully enabling confirmation or rejection of causality between TSH abnormalities and dementia.
Voltammetry Study of an Anti-HIV Compound by means of a Thin Organic Membrane
Authors: Nassi Achille , Ebelle Thiery Christophe , Dika Manga Joseph M. , Mabou Leuna Jules-Blaise , Donkeng Dazie Joel , Ngameni Emmanuel
Published: September 2013

Cyclic and square wave voltammetries have been used to study electrochemical behaviour of an anti-HIV agent (Guttiferone A) at the liquid-liquid interface. The thin organic membrane is formed by an organic solvent containing redox probe. Guttiferone A, a benzophenone (BP) with appropriate electrolyte. It is demonstrated that BP possesses three reduction systems due to the redox transformation of the three tautomeric forms that lead to the migration of proton between the hydroxyl group in position 4 and the carbonyl group in positions 2 and 10. The transfer of proton from the aqueous solution to the organic phase is crucial for the redox transformation of BP into the organic membrane. The voltammograms obtained are strongly influenced by the pH of the aqueous phase. The electrochemical mechanism consists of 2e−/2H+exchange to form the separate redox compound BPH2.
Photoinitiated Polymerization of 2-Hydroxyethyl Methacrylate by Riboflavin/Triethanolamine in Aqueous Solution: A Kinetic Study
Authors: Ahmad Iqbal , Iqbal Kefi , Sheraz Muhammad Ali , Ahmed Sofia , Mirza Tania , Kazi Sadia Hafeez , Aminuddin Mohammad
Published: September 2013

The polymerization of 1–3 M 2-hydroxyethyl methacrylate (HEMA) initiated by riboflavin/triethanolamine system has been studied in the pH range 6.0–9.0. An approximate measure of the kinetics of the reaction during the initial stages (~5% HEMA conversion) has been made to avoid the effect of any variations in the volume of the medium. The concentration of HEMA in polymerized solutions has been determined by a UV spectrophotometric method at 208 nm with a precision of ±3%. The initial rate of polymerization of HEMA follows apparent first-order kinetics and the rates increase with pH. This may be due to the presence of a labile proton on the hydroxyl group of HEMA. The second-order rate constants for the interaction of triethanolamine and HEMA lie in the range of 2.36 to  M−1 s−1 at pH 6.0–9.0 suggesting an increased activity with pH. An increase in the viscosity of HEMA solutions from 1 M to 3 M leads to a decrease in the rate of polymerization probably as a result of the decrease in the reactivity of the flavin triplet state. The effect of pH and viscosity of the medium on the rate of reaction has been evaluated.
Urokinase Plasminogen Activator System–Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapy
Authors: Zhang Yilin , Kenny Hilary A. , Swindell Elden P. , Mitra Anirban K. , Hankins Patrick L. , Ahn Richard W. , Gwin Katja , Mazar Andrew P. , O'Halloran Thomas V. , Lengyel Ernst
Published: September 2013

The urokinase system is overexpressed in epithelial ovarian cancer cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in ovarian cancer, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide–loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA-targeted nanobins were internalized by ovarian cancer cells, whereas both inductively coupled plasma optical mass spectrometry (ICP-MS) and fluorescence-activated cell sorting (FACS) analyses confirmed more than four-fold higher uptake of targeted nanobins when compared with untargeted nanobins. In a coculture assay, the targeted nanobins showed efficient uptake in ovarian cancer cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either downregulating uPA receptor expression in the ovarian cancer cells using short-hairpin RNA (shRNA) or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% vs. 27%; P < 0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared with untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, aldehyde dehydrogenase-1A1 (ALDH1A1), expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA-targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy using protease receptors. Mol Cancer Ther; 12(12); 2628–39. ©2013 AACR.
Parathyroidectomy Reduces Intradialytic Hypotension in Hemodialysis Patients with Secondary Hyperparathyroidism
Authors: Shih Chia-Jen , Tarng Der-Cherng , Yang Wu-Chang , Yang Chih-Yu
Published: September 2013

Background: Secondary hyperparathyroidism is associated with vascular calcification and arterial stiffness in patients with end-stage renal disease. The aim of this study was to analyze the frequency of intradialytic hypotension (IDH) and cardiovascular function before and after parathyroidectomy (PTX) in maintenance hemodialysis patients. Methods: We compared predialytic and intradialytic blood pressure, left and right ventricular ejection fraction (LVEF and RVEF), and cardiothoracic ratio 1 month before PTX, and 6 and 12 months after PTX. IDH was defined as a decrease in systolic blood pressure ≥ 20 mmHg or a decrease in mean arterial pressure ≥ 10 mmHg. Results: At the time of PTX, the mean age of the patients was 57.4 ± 12.0 years, and the mean dialysis vintage was 12.2 ± 5.8 years. At baseline, 6 months, and 12 months after PTX, the average numbers of sessions disturbed by IDH during 13 dialysis sessions (1 month) were 6.4, 3.9 (p < 0.016 vs. baseline), and 4.0 sessions (p < 0.037 vs. baseline, p = 0.801 vs. 6 months), respectively. LVEF and RVEF were improved significantly after PTX. Furthermore, volume status was also improved, as evidenced by the significantly greater ultrafiltration volume and reduced cardiothoracic ratio. Conclusions: Hemodialysis patients with severe secondary hyperparathyroidism are more likely to achieve normotensive and euvolemic status after PTX, probably through improved heart function and reduced IDH episodes.
Unusual Images of Mass-Forming Intrahepatic Cholangiocarcinoma
Authors: Takakura Kazuki , Kajihara Mikio , Iwasaki Tetsuyoshi , Ide Daisuke , Miyazaki Tamihiro , Arai Yoshinori , Saruta Masayuki , Arihiro Seiji , Matsuoka Mika , Koido Shigeo , Ito Ryusuke , Matsumoto Michinori , Gocho Takeshi , Wakiyama Shigeki , Yanaga Katsuhiko , Tajiri Hisao
Published: September 2013

We experienced a case of mass-forming intrahepatic cholangiocarcinoma which could not been diagnosed accurately without pathologic findings. A 78-year-old Japanese woman with no particular symptoms was admitted for changes in liver function tests. Ultrasonography revealed a solid liver tumor. When there are no typical imaging features, no pathognomonic clinical findings and no obvious risk factors for any specific hepatic tumor, it may be difficult to make an accurate diagnosis before surgical resection. The lesion was resected on the basis of a high degree of suspicion for malignancy and submitted for pathologic evaluation. Microscopically, the neoplasm was a moderately differentiated adenocarcinoma with abundant fibrous stroma, consistent with a mass-forming cholangiocarcinoma. This case exemplifies the importance of considering the various tumorous and non-tumorous diseases in the differential diagnosis of a liver mass with atypical features, especially when malignancy cannot be excluded.
Five Hemoglobin Variants in a Double Heterozygote for α- and β-Globin Chain Defects
Authors: Singha Kritsada , Fucharoen Goonnapa , Fucharoen Supan
Published: September 2013

Genetic interactions of different defective globin chains could render laboratory diagnostics in a routine setting difficult. We report a hitherto undescribed condition of double heterozygosity for hemoglobin (Hb) Q-Thailand with α+-thalassemia and Hb Tak found in 2 adult Thai individuals. Both patients were healthy and had no pertinent past medical history. A complete blood count revealed slight elevations of Hb and HCT values with low MCV and MCH. Interestingly, Hb analysis demonstrated, in addition to Hb A, A2, and F, as many as 5 Hb variants including Hb Tak (αA2βTak2), Q-Thailand (αQT2βA2), QA2 (αQT2δ2), QF (αQT2γ2), and a novel variant, Hb QTak (αQT2βTak2). Hematological findings of these unusual cases were compared with those of pure heterozygotes for Hb Q-Thailand and Hb Tak found in our series. Hb analysis using combined HPLC and capillary electrophoresis did help in the initial recognition and in making presumptive diagnoses, but definite diagnoses of these cases with complex α- and β-hemoglobinopathies could only be obtained after DNA analysis.
Electronic Cigarettes: A Short Review
Authors: Bertholon J.F. , Becquemin M.H. , Annesi-Maesano I. , Dautzenberg B.
Published: September 2013

Marketed since 2004 as an alternative to nicotine delivery and advertised as a valid means to smoking cessation, the electronic (e)-cigarette has been the subject of much controversy but very little experimental study. This review provides a brief summary of the current knowledge of this product. Propylene glycol and glycerol, the main ingredients of the fluid that is vaporized, have proved to be harmless in the fog machines of the entertainment industry. However, in the case of the e-cigarette fluid, the composition is not properly labeled: additives like nicotine and flavors vary between and within brands and contamination with various chemicals has been detected. The short-term toxicity seems low, but the long-term toxicity is unknown. The usefulness of the e-cigarette in smoking cessation has still to be clinically established.
Functional Neuroimaging of Breastfeeding Analgesia by Multichannel Near-Infrared Spectroscopy
Authors: Bembich Stefano , Davanzo Riccardo , Brovedani Pierpaolo , Clarici Andrea , Massaccesi Stefano , Demarini Sergio
Published: September 2013

Background: Newborns perceive pain, and several non-pharmacologic analgesic methods have been used during painful procedures. Activation of the neonatal somatosensory cortex, in association with a painful procedure without analgesia, has been demonstrated by two-channel near-infrared spectroscopy (NIRS). Objectives: To evaluate both cortical and behavioural responses of healthy term newborns to a painful procedure during two non-pharmacologic analgesic interventions, i.e. glucose solution and breastfeeding. Methods: The effects of glucose and breastfeeding on pain-associated neonatal cortical activity were studied in two groups (n = 30) by multichannel NIRS during a heel prick. Cortical activation was identified by variations in oxygenated haemoglobin. Neonatal pain expression was assessed by a validated scale. Results: No significant variations in cortical activity emerged using glucose solution, whereas breastfed newborns showed widespread cortical activation. Breastfed neonates showed significantly less behavioural pain expression. Conclusions: Glucose is associated with no significant cortical activation and may interfere with pain-associated response at the cortical level. Conversely, breastfeeding analgesia is associated with generalized cortical activation and may act by multisensory stimulation, possibly overwhelming pain perception.
Ischemic Stroke in Patients with Solid Gynecologic Tract Tumors and Coagulopathy
Authors: Tadokoro Yasuhiro , Sakaguchi Manabu , Yagita Yoshiki , Furukado Shigetaka , Okazaki Shuhei , Fujinaka Toshiyuki , Kimura Tadashi , Yoshimine Toshiki , Mochizuki Hideki , Kitagawa Kazuo
Published: September 2013

Aim: Patients with gynecological neoplasms often suffer ischemic stroke. This study aimed to clarify the underlying mechanisms of ischemic stroke in patients with gynecological tract tumors. Methods: We retrospectively reviewed 6 patients with gynecologic tumors and hypercoagulability who were being treated for acute ischemic stroke between 2006 and 2012. Diffusion-weighted magnetic resonance imaging (DW-MRI), cardiovascular risk factors including plasma D-dimer levels, and histologic examination of the patients' solid tumors were performed. All 6 patients underwent transesophageal echocardiography (TEE) for nonbacterial thrombotic endocarditis (NBTE) and paradoxical embolism. Results: All 6 patients showed elevated plasma D-dimer levels. In 1 patient, paradoxical embolism was diagnosed. In the remaining 5 patients, DW-MRI scans showed numerous lesions in multiple vascular territories, and in 4 of these 5 patients, TEE demonstrated vegetations on the mitral valve, leading to the diagnosis of NBTE. Interestingly, 2 of these 4 patients had benign uterine tumors, whereas the other 2 had ovarian cancer. Conclusions: NBTE was the main etiology for ischemic stroke in patients with gynecologic tract tumors and coagulopathy. Both malignant and benign tumors of the gynecologic tract can cause NBTE.
Culture of Mouse Amniotic Fluid-Derived Cells on Irradiated STO Feeders Results in the Generation of Primitive Endoderm Cell Lines Capable of Self-Renewal in vitro
Authors: Babic Aleksandar M. , Jang Sunyoung , Nicolov Eugenia , Voicu Horatiu , Luckey Chance J.
Published: September 2013

The cells present in amniotic fluid (AF) are currently used for prenatal diagnosis of fetal anomalies but are also a potential source of cells for cell therapy. To better characterize putative progenitor cell populations present in AF, we used culture conditions that support self-renewal to determine if these promoted the generation of stable cell lines from AF-derived cells (AFC). Cells isolated from E11.5 mouse were cultured on irradiated STO fibroblast feeder layers in human embryonic germ cell derivation conditions. The cultures grew multicellular epithelial colonies that could be repropagated from single cells. Reverse transcription semiquantitative polymerase chain reaction of established cell lines revealed that they belonged to the extraembryonic endoderm (ExEn) expressing high levels of Gata6, Gata4, Sox17, Foxa2 and Sox7 mRNA. Hierarchical clustering based on the whole transcriptome expression profile of the AFC lines (AFCL) shows significant correlation between transcription profiles of AFCL and blastocyst-derived XEN, an ExEn cell line. In vitro differentiation of AFCL results in the generation of cells expressing albumin and α-fetoprotein (AFP), while intramuscular injection of AFCL into immunodeficient mice produced AFP-positive tumors with primitive endodermal appearance. Hence, E11.5 mouse AF contains cells that efficiently produce XEN lines. These AF-derived XEN lines do not spontaneously differentiate into embryonic-type cells but are phenotypically stable and have the capacity for extensive expansion. The lack of requirement for reprogramming factors to turn AF-derived progenitor cells into stable cell lines capable of massive expansion together with the known ability of ExEn to contribute to embryonic tissue suggests that this cell type may be a candidate for banking for cell therapies.
Larotaxel with Cisplatin in the First-Line Treatment of Locally Advanced/Metastatic Urothelial Tract or Bladder Cancer: A Randomized, Active-Controlled, Phase III Trial (CILAB)
Authors: Sternberg Cora N. , Skoneczna Iwona A. , Castellano Daniel , Theodore Christine , Blais Normand , Voog Eric , Bellmunt Joaquim , Peters Frank , Le-Guennec Solenn , Cerbone Linda , Risse Marie-Laure , Machiels Jean-Pascal
Published: September 2013

Background: This open-label, randomized phase III trial evaluated larotaxel/cisplatin versus gemcitabine/cisplatin as first-line treatment for locally advanced (T4b) or metastatic urothelial tract or bladder cancer. Methods: Patients were randomized to larotaxel 50 mg/m2 with cisplatin 75 mg/m2 every 3 weeks (larotaxel/cisplatin) or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 70 mg/m2 on day 1 every 4 weeks (gemcitabine/cisplatin). The primary endpoint was overall survival (OS). Results: The trial was prematurely closed following the sponsor's decision to stop clinical development of larotaxel (n = 337 randomized). The larotaxel dose was reduced to 40 mg/m2 and cisplatin to 60 mg/m2 following a data monitoring committee safety review of the first 97 patients. At the time of analysis, the median OS was 13.7 months [95% confidence interval (CI) 11.2-17.1] with larotaxel/cisplatin and 14.3 months (95% CI 10.5 to not reached) with gemcitabine/cisplatin [hazard ratio (HR) 1.21; 95% CI 0.83-1.76; p = 0.33]. The median progression-free survival (PFS) was 5.6 months (95% CI 4.1-6.2) with larotaxel/cisplatin and 7.6 months (95% CI 6.6-9.1) with gemcitabine/cisplatin (HR 1.67; 95% CI 1.24-2.25). More myelosuppression was observed with gemcitabine/cisplatin. Conclusion: There was no difference in OS. Although the trial was closed prematurely, PFS appeared worse with larotaxel/cisplatin, suggesting that larotaxel/cisplatin does not improve outcomes versus cisplatin/gemcitabine.
Efficient Delivery of siRNA by Atelocollagen in a Murine Laser-Induced Choroidal Neovascularization Model
Authors: Ito Yuya , Nozaki Miho , Sugitani Kazuhiko , Ashikari Masayuki , Hirano Yoshio , Ogura Yuichiro
Published: September 2013

Purpose: Previous studies have shown that small interfering RNAs (siRNAs) could suppress angiogenesis via stimulation of toll-like receptor-3 (TLR3). The purpose of this study was to determine the efficacy of atelocollagen to deliver siRNA without TLR3 stimulation in the laser-induced choroidal neovascularization (CNV) model. Methods: CNV was induced by laser injury in C57BL/6J mice and volumes were measured 7 days later. Nontargeted siRNA, 21-nucleotide (nt) siRNA-Luc (Luciferase) and 21-nt siRNA-Vegfa were injected into the vitreous following injury. Atelocollagen was incubated with naked 21-nt siRNAs before injection. To block TLR3 endosomal activity, chloroquine was injected intravitreously after laser injury. Results: The mean CNV volumes were significantly smaller in the naked siRNA-Luc, naked siRNA-Vegfa, or siRNA-Vegfa/atelocollagen complex compared with PBS, atelocollagen or siRNA-Luc/atelocollagen complex-injected mice (p < 0.05). Conclusion: These findings demonstrate that atelocollagen may deliver siRNA without nonspecific TLR3 stimulation in the murine laser-CNV model.
Diabetes Mellitus in Neonates and Infants: Genetic Heterogeneity, Clinical Approach to Diagnosis, and Therapeutic Options
Authors: Rubio-Cabezas Oscar , Ellard Sian
Published: September 2013

Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
Toll-Like Receptor 9 Is Required for Chronic Stress-Induced Immune Suppression
Authors: Li Hui , Zhao Jing , Chen Michael , Tan Yang , Yang Xiaohua , Caudle Yi , Yin Deling
Published: September 2013

Objectives: Mental and physical stress can suppress the immune system in both humans and animals. The mechanism by which stress affects immune responses, however, remains poorly defined. Toll-like receptors (TLRs) play a key role in modulating immune responses and cell survival. The mechanisms by which TLRs modulate chronic stress are largely unexplored. Methods: Six- to 8-week-old male mice were subjected to chronic 12-hour daily physical restraint stress. Apoptotic cells were determined by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. We examined cytokine levels by enzyme-linked immunosorbent Assay (ELISA). The expression of CYP11A1 was determined by quantitative real-time RT-PCR. Results: TLR9-deficient mice were resistant to chronic stress-induced lymphocyte apoptosis. In addition, in TLR9 knockout (KO) mice, chronic stress-induced upregulation of corticosterone levels was significantly decreased. Notably, lymphocytes from both TLR9 KO and wild-type mice were similarly sensitive to corticosteroid-induced cell apoptosis. Moreover, TLR9 deficiency blocked the chronic stress-induced imbalance in T helper (Th) 1 and Th2 cytokine levels. Conclusion: Taken together, our findings reveal that TLR9 plays an essential role in chronic stress-induced immune suppression.
Insulin Resistance and Cardiovascular Risk Factors in 3- to 5-Year-Old Overweight or Obese Children
Authors: Bocca Gianni , Ongering Eva C. , Stolk Ronald P. , Sauer Pieter J.J.
Published: September 2013

Background/Aims: The increasing rate of overweight and obesity is alarming. The complications of overweight and obesity at a young age are largely unknown. We aimed to assess the prevalence of insulin resistance (IR) and cardiovascular risk factors among overweight and obese children aged 3-5 years. Methods: The study population consisted of 75 children (29 overweight, 46 obese). We performed anthropometry and bioelectrical impedance analysis as an indicator of body composition. IR was determined by the updated Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR). Cardiovascular risk factors were defined by the presence of increased serum triglycerides, blood pressure, and HOMA2-IR and by a decreased serum HDL cholesterol. Results: An elevated HOMA2-IR was found in 7.7% of the children. HOMA2-IR was correlated with body mass index (r = 0.63), waist circumference (r = 0.62) and percentage body fat (r = 0.58) (all p < 0.001). Cardiovascular risk factors were present in 6.9% (triglycerides) to 74.3% (hypertension) of the children. Conclusion: IR and cardiovascular risk factors are already evident in many 3- to 5-year-old overweight and obese children. IR is strongly related to body composition.
Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in LMNA
Authors: Thong Kah Mean , Xu Yaoxian , Cook Jackie , Takou Anna , Wagner Bart , Kawar Bisher , Ong Albert C.M.
Published: September 2013

Background and Aim: Focal segmental glomerulosclerosis (FSGS) is a common cause of idiopathic nephrotic syndrome in adults (35%). A number of genetic and familial forms of FSGS have been recognized. Here, we report a large pedigree with a pathogenic mutation in LMNA (R349W) in which four members were found to have biopsy-proven FSGS. The LMNA gene codes for lamins A and C, major components of the nuclear lamina which function in nuclear architecture, integrity and the regulation of gene expression. Methods: Pedigree screening and mutation analysis of LMNA gene in all family members. Renal biopsies were performed in proteinuric patients. A molecular 3D model of the familial LMNA mutation was constructed. Results: There were a total of 16 affected members from four generations, 12 of whom were found to carry the germline LMNA mutation. All affected adults had clinical features of familial partial lipodystrophy (FPLD) of the non-Dunnigan variety. Four patients within the same generation presented with a variable degree of renal impairment and proteinuria. Renal biopsies from all four revealed FSGS. The familial mutation is a missense change (R349W) in exon 6 of LMNA (c.1045C>T). Conclusions: We report a genetic link between LMNA and biopsy-proven FSGS in a large pedigree with FPLD. This unexpected association extends the disease spectrum of LMNA to the kidney and suggests that the physiological role of LMNA could be relevant to the maintenance of glomerular structure and function.
The Inside-Out Amyloid Hypothesis and Synapse Pathology in Alzheimer's Disease
Authors: Gouras Gunnar K. , Willén Katarina , Faideau Mathilde
Published: September 2013

Cumulative evidence in brains and cultured neurons of Alzheimer's disease (AD) transgenic mouse models, as well as in human postmortem AD brains, highlights that age-related increases in β-amyloid peptide (Aβ), particularly in endosomes near synapses, are involved in early synapse dysfunction. Our immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive Aβ aggregation and pathology, particularly within dystrophic neurites and synapses. These studies confirm that neuritic/synaptic Aβ accumulation is the nidus of plaque formation. Aβ-dependent synapse pathology in AD models is modulated by synaptic activity and is plaque independent. The amyloid precursor protein (APP) is normally transported down neurites and appears to be preferentially processed to Aβ at synapses. Synapses are sites of early Aβ accumulation and aberrant tau phosphorylation in AD, which alter the synaptic composition at early stages of the disease. Elucidating the normal role of APP, and potentially of Aβ, at synapses should provide important insights into the mechanism(s) of Aβ-induced synapse dysfunction in AD and how to therapeutically mitigate these dysfunctions.
Linkage of Type 2 Diabetes on Chromosome 9p24 in Mexican Americans: Additional Evidence from the Veterans Administration Genetic Epidemiology Study (VAGES)
Authors: Farook Vidya S. , Coletta Dawn K. , Puppala Sobha , Schneider Jennifer , Chittoor Geetha , Hu Shirley L. , Winnier Deidre A. , Norton Luke , Dyer Thomas D. , Arya Rector , Cole Shelley A. , Carless Melanie , Göring Harald H. , Almasy Laura , Mahaney Michael C. , Comuzzie Anthony G. , Curran Joanne E. , Blangero John , Duggirala Ravindranath , Lehman Donna M. , Jenkinson Christopher P. , DeFronzo Ralph A.
Published: September 2013

Objective: Type 2 diabetes (T2DM) is a complex metabolic disease and is more prevalent in certain ethnic groups such as the Mexican Americans. The goal of our study was to perform a genome-wide linkage (GWL) analysis to localize T2DM susceptibility loci in Mexican Americans. Methods: We used the phenotypic and genotypic data from 1,122 Mexican-American individuals (307 families) who participated in the Veterans Administration Genetic Epidemiology Study (VAGES). GWL analysis was performed using the variance components approach. Data from 2 additional Mexican-American family studies, the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), were combined with the VAGES data to test for improved linkage evidence. Results: After adjusting for covariate effects, T2DM was found to be under significant genetic influences (h2 = 0.62, p = 2.7 × 10-6). The strongest evidence for linkage of T2DM occurred between markers D9S1871 and D9S2169 on chromosome 9p24.2-p24.1 (LOD = 1.8). Given that we previously reported suggestive evidence for linkage of T2DM at this region also in SAFDGS, we found the significant and increased linkage evidence (LOD = 4.3, empirical p = 1.0 × 10-5, genome-wide p = 1.6 × 10-3) for T2DM at the same chromosomal region, when we performed a GWL analysis of the VAGES data combined with the SAFHS and SAFDGS data. Conclusion: Significant T2DM linkage evidence was found on chromosome 9p24 in Mexican Americans. Importantly, the chromosomal region of interest in this study overlaps with several recent genome-wide association studies involving T2DM-related traits. Given its overlap with such findings and our own initial T2DM association findings in the 9p24 chromosomal region, high throughput sequencing of the linked chromosomal region could identify the potential causal T2DM genes.
High Evolutionary Dynamism in 5S rDNA of Fish: State of the Art
Authors: Rebordinos L. , Cross I. , Merlo A.
Published: September 2013

The 5S ribosomal DNA (rDNA) consists of one transcriptional unit of about 120 base pairs, which is separated from the next unit by a non-transcribed spacer (NTS). The coding sequence and the NTS together form a repeat unit which can be found in hundreds to thousands of copies tandemly repeated in the genomes. The NTS regions seem to be subject to rapid evolution. The first general model of evolution of these multigene families was referred to as divergent evolution, based on studies using hemoglobin and myoglobin as model systems. Later studies showed that nucleotide sequences of different multigene family members are more closely related within species than between species. This observation led to a new model of multigene family evolution, termed concerted evolution. Another model of evolution, named the birth-and-death model, has been found to be more suitable to explain the long-term evolution of these multigene families. According to this model, new genes originate by successive duplications, and these new genes are either maintained for a long time or are lost, or else degenerate into pseudogenes. In this review we describe different sources of variability in the 5S rDNA genes observed in several distinct fish species. This variability is mainly referred to NTSs and includes the presence of other multigene families (mainly LINEs, SINEs, non-LTR retrotransposons, and U snRNA families). Different types of microsatellites have also been found to contribute to the increase of variability in this region. Our recent results suggest that horizontal transfer contributes to the increase of diversity in the NTSs of some species. Variability in the 5S rDNA coding region affecting the stability of the structure, but without effects on the function of the 5S rRNA, is also described. Retrotransposons seem to be responsible for the high dynamism of 5S rDNA, while microsatellites acting as recombination hot spots could stabilize a wide variety of unusual DNA structures, affecting DNA replication and enhancing or decreasing promoter activity in gene expression. The relationship between the high variability found at molecular level and the low variability found at chromosomal level is also discussed.