bluuebunny/crossref_metadata_2025 huggingface dataset:
Grain-Size Control on the Rare Earth Elements Distribution in the Late Diagenesis of Cretaceous Shales from the Southern Apennines (Italy)
Authors: Cavalcante Francesco , Belviso Claudia , Piccarreta Giuseppe , Fiore Saverio
Published: February 2014

Different grain-size fractions of samples collected from shales were investigated to determine the role of late diagenetic grade and mineralogy on the rare earth elements (REE) distribution. The samples were collected from Upper Cretaceous varicoloured shales of the Sicilide Unit near the Corleto Perticara villages, Southern Apennines (Italy). The mineralogical and chemical composition of the sample’s five fractions (>63, 32–63, 2–32, 0.1–2, and <0.1 µm) was studied. The data indicate that certain accessory minerals are more important than clay minerals in controlling the REE distribution. In particular, zircon controls the distribution of earth elements in the 0.1–2 µm fraction and is an efficient mechanism in determining the concentration and distribution of REEs in the studied shales.
Investigation of Serum Oxidized Low-Density Lipoprotein IgG Levels in Patients with Angiographically Defined Coronary Artery Disease
Authors: Moohebati Mohsen , Kabirirad Vahid , Ghayour-Mobarhan Majid , Esmaily Habibollah , Tavallaie Shima , Akhavan Rezayat Amir , Pourghadamyari Hossein , Sahebkar Amirhossein
Published: February 2014

It has been suggested that antioxidized low-density lipoprotein (anti-oxLDL) antibodies play a role in the pathogenesis of atherosclerosis. The aim of this study was to measure serum ox-LDL IgG levels in 31 patients with angiographically defined coronary artery disease (CAD) (≥50% stenosis in at least one major coronary artery; CAD+group) and compare these levels with those of 32 subjects with <50% coronary stenosis (CAD−group) and 24 healthy age- and sex-matched controls using ELISA. We did not find any significant difference between CAD+, CAD−, and control groups in regard to oxLDL IgG levels (P=0.83). Serum oxLDL IgG levels did not differ between 1VD (one vessel disease), 2VD (2 vessels disease), and 3VD (3 vessels disease) subgroups of CAD+patients (P=0.20). Serum anti-oxLDL titers were only significantly correlated with LDL-C in the CAD+group (P<0.05) and waist and hip circumference (P<0.05andP<0.01, resp.) in the CAD−group. In stepwise regression analysis, none of the conventional cardiovascular risk factors was associated with serum ox-LDL IgG levels. The present results suggest that serum levels of ox-LDL IgG are neither associated with the presence and severity of CAD nor with the conventional cardiovascular risk factors.
Alcohol and Other Drug Use during Pregnancy among Women Attending Midwife Obstetric Units in the Cape Metropole, South Africa
Authors: Petersen Williams Petal , Jordaan Esmé , Mathews Catherine , Lombard Carl , Parry Charles D. H.
Published: February 2014

Little is known about the nature and extent of alcohol and other drug (AOD) use among pregnant women in Cape Town, South Africa, despite the very high levels of AOD use in this part of the country. A cross-sectional survey was conducted among pregnant women attending 11 Midwife Obstetric Units (MOUs) in greater Cape Town. A two-stage cluster survey design was used. In total, 5231 pregnant women were screened to assess self-reported prevalence estimates. Of these, 684 (13.1%) were intentionally subsampled and completed an interviewer-administered questionnaire and provided a urine sample for biological screening. Urinalyses showed that 8.8% (95% CI: 6.7–10.9) of the subsample tested positive for at least one illicit drug. This is higher than the self-reported prevalence (3.6%). In addition, 19.6% (95% CI: 16.3–22.8) of the sub-sample tested positive for alcohol which is lower than the self-reported prevalence (36.9%). There are high levels of substance use among pregnant women attending public sector antenatal clinics. There is a need for routine screening for AOD use and appropriate responses depending on the women’s level of risk.
Automatic Recognition of Seismic Intensity Based on RS and GIS: A Case Study in Wenchuan Ms8.0 Earthquake of China
Authors: Zhang Qiuwen , Zhang Yan , Yang Xiaohong , Su Bin
Published: February 2014

In recent years, earthquakes have frequently occurred all over the world, which caused huge casualties and economic losses. It is very necessary and urgent to obtain the seismic intensity map timely so as to master the distribution of the disaster and provide supports for quick earthquake relief. Compared with traditional methods of drawing seismic intensity map, which require many investigations in the field of earthquake area or are too dependent on the empirical formulas, spatial information technologies such as Remote Sensing (RS) and Geographical Information System (GIS) can provide fast and economical way to automatically recognize the seismic intensity. With the integrated application of RS and GIS, this paper proposes a RS/GIS-based approach for automatic recognition of seismic intensity, in which RS is used to retrieve and extract the information on damages caused by earthquake, and GIS is applied to manage and display the data of seismic intensity. The case study in Wenchuan Ms8.0 earthquake in China shows that the information on seismic intensity can be automatically extracted from remotely sensed images as quickly as possible after earthquake occurrence, and the Digital Intensity Model (DIM) can be used to visually query and display the distribution of seismic intensity.
Semiphysiological versus Empirical Modelling of the Population Pharmacokinetics of Free and Total Cefazolin during Pregnancy
Authors: van Hasselt J. G. Coen , Allegaert Karel , van Calsteren Kristel , Beijnen Jos H. , Schellens Jan H. M. , Huitema Alwin D. R.
Published: February 2014

This work describes a first population pharmacokinetic (PK) model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL) into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL) were 0.119 L/min (RSE 58%) and 0.142 L/min (RSE 44%) for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences.
Kinetic Spectrophotometric Determination of Gemifloxacin Mesylate and Moxifloxacin Hydrochloride in Pharmaceutical Preparations Using 4-Chloro-7-nitrobenzo-2-oxa-1,3-diazole
Authors: Abdel Wahed Mohammed G. , El Sheikh Ragaa , Gouda Ayman A. , Abou Taleb Sayed
Published: February 2014

Simple, sensitive, and accurate kinetic spectrophotometric method was proposed for the determination of gemifloxacin mesylate (GMF) and moxifloxacin hydrochloride (MOX) in pure forms and pharmaceutical preparations (tablets). The method is based on coupling the studied drugs with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) in the presence of alkaline borate buffer. Spectrophotometric measurement was achieved by recording the absorbance at 466 and 464 nm for GMF and MOX, respectively, after a fixed time of 20 and 15 min on a water bath adjusted at 70 ± 5°C for both drugs. The different experimental parameters affecting the development and stability of the color were carefully studied and optimized. The absorbance-concentration plots were linear over the ranges 0.5–8.0 and 2.0–12 μg mL−1for GMF and MOX, respectively. The limit of detection of the kinetic method was about 0.12 (2.47 × 10−7 M) and 0.36 (8.22 × 10−7 M) μg mL−1for GMF and MOX, respectively. The proposed methods have been applied and validated successfully with percentage relative standard deviation (RSD% ≤ 0.52) as precision and percentage relative error (RE% ≤ 1.33) as accuracy. The robustness of the proposed method was examined with recovery values that were 97.5–100.5 ± 1.3–1.9%. Statistical comparison of the results with the reference spectrophotometric methods shows excellent agreement and indicates no significant difference in accuracy or precision.
Chemical Feature-Based Molecular Modeling of Urotensin-II Receptor Antagonists: Generation of Predictive Pharmacophore Model for Early Drug Discovery
Authors: Pandey Anubhuti , Paliwal Sarvesh Kumar , Paliwal Shailendra Kumar
Published: February 2014

For a series of 35 piperazino-phthalimide and piperazino-isoindolinone based urotensin-II receptor (UT) antagonists, a thoroughly validated 3D pharmacophore model has been developed, consisting of four chemical features: one hydrogen bond acceptor lipid (HBA_L), one hydrophobe (HY), and two ring aromatic (RA). Multiple validation techniques like CatScramble, test set prediction, and mapping analysis of advanced known antagonists have been employed to check the predictive power and robustness of the developed model. The results demonstrate that the best model, Hypo 1, shows a correlation (r) of 0.902, a root mean square deviation (RMSD) of 0.886, and the cost difference of 39.69 bits. The model obtained is highly predictive with good correlation values for both internal (r2=0.707) as well as external (r2=0.614) test set compounds. Moreover, the pharmacophore model has been used as a 3D query for virtual screening which served to detect prospective new lead compounds which can be further optimized as UT antagonists with potential for treatment of cardiovascular diseases.
Embryotoxic and Teratogenic Effects of Norfloxacin in Pregnant Female Albino Rats
Authors: Aboubakr Mohamed , Elbadawy Mohamed , Soliman Ahmed , El-Hewaity Mohamed
Published: February 2014

This study was designed to investigate the possible developmental teratogenicity of norfloxacin in rats. Forty pregnant female rats were divided into four equal groups. Group A received norfloxacin in a dose of 500 mg/kg·b·wt/day orally from 6th to 15th day of gestation. Groups B and C received 1000 and 2000 mg/kg·b·wt/day orally for the same period, respectively; Group D behaved as control and received 0.5 mL distilled water orally for the same period. The dams were killed on 20th day of gestation and their fetuses were subjected to morphological, visceral, and skeletal examinations. Norfloxacin significantly decreased the number of viable fetuses, increased the number of resorbed fetuses, and induced retardation in growth of viable fetuses; some visceral and skeletal defects in these fetuses were seen and these effects were dose dependant. Conclusively, norfloxacin caused some fetal defects and abnormalities, so it is advisable to avoid using this drug during pregnancy.
A 26-Year-Old Retained Demised Abdominal Pregnancy Presenting with Umbilical Fistula
Authors: Daniel Nnadi , Bashir Bello , Ibrahim Ango , Swati Singh
Published: February 2014

This is a report on a 72-year-old postmenopausal woman who presented with passage of fetal bones through an umbilical fistula. She was diagnosed as a case of demised abdominal pregnancy, which had been retained for 26 years. She subsequently had exploratory laparotomy, evacuation of the abdominal pregnancy, hysterectomy, and bowel resection. The patient’s condition remained unstable throughout the postoperative period and she died from septicemia on the eleventh day.
Synthesis and Characterization of Silver and Gold Nanoparticles Using Aqueous Extract of Seaweed,Turbinaria conoides,and Their Antimicrofouling Activity
Authors: Vijayan Sri Ramkumar , Santhiyagu Prakash , Singamuthu Muthukkumarasamy , Kumari Ahila Natarajan , Jayaraman Ravindran , Ethiraj Kannapiran
Published: February 2014

Silver and gold nanoparticles were synthesized using an aqueous extract of the seaweedTurbinaria conoidesand their antibiofilm activity against marine biofilm forming bacteria is reported here. The UV-Vis spectra showed the characteristics SPR absorption band for Ag NPs at 421 and for Au NPs at 538 nm. Further, the synthesized nanoparticles were characterized using FT-IR, XRD, FESEM, EDX, and HRTEM analysis. Spherical and triangular nanostructures of the Ag and Au nanoparticles were observed between the size ranges of 2–17 nm and 2–19 nm, respectively. The synthesized Ag NPs are efficient in controlling the bacterial biofilm formation; however, Au NPs did not show any remarkable antibiofilm activity. The maximum zone of inhibition was recorded againstE. coli(17.6±0.42 mm), followed bySalmonellasp.,S. liquefaciens, andA. hydrophila. The macrotube dilution method inferred the MIC (20–40 µL mL−1) and MBC (40–60 µL mL−1) of Ag NPs. The CLSM images clearly showed the weak adherence and disintegrating biofilm formation of marine biofilm bacterial strains treated with Ag NPs. TheArtemiacytotoxicity assay recorded the LC50value of88.914±5.04 µL mL−1. Thus the present study proved the efficiency of Ag NPs as a potent antimicrofouling agent and became the future perspective for the possible usage in the biofouling related issues in the aquaculture installations and other marine systems.
Corrosion Inhibition of Carbon Steel in 0.5 M H2SO4by Phtalocyanine Blue
Authors: Valle-Quitana J. C. , Dominguez-Patiño G. F. , Gonzalez-Rodriguez J. G.
Published: February 2014

Phthalocyanine blue dye has been investigated as a carbon steel corrosion inhibitor in 0.5 M sulfuric acid by using polarization curves, electrochemical impedance spectroscopy, and gravimetric tests. Dye concentrations included 0, 100, 200, 400, 600, 800, and 1000 ppm, whereas testing temperatures were 25, 40, and 60°C. Results indicated that phtalocyanine blue is a good corrosion inhibitor with its efficiency increasing with the concentration up to 40°C, but it increases at 60°C. Inhibitor improves the passive film properties and it forms an adherent, compact, protective film, acting, therefore, as an anodic-type inhibitor. At 25 and 40°C the corrosion process was under charge transfer, whereas at 60°C the adsorption/desorption of some species from the metal surface controlled the corrosion process.
Combination-Combination Synchronization of Four Nonlinear Complex Chaotic Systems
Authors: Zhou Xiaobing , Xiong Lianglin , Cai Xiaomei
Published: February 2014

This paper investigates the combination-combination synchronization of four nonlinear complex chaotic systems. Based on the Lyapunov stability theory, corresponding controllers to achieve combination-combination synchronization among four different nonlinear complex chaotic systems are derived. The special cases, such as combination synchronization and projective synchronization, are studied as well. Numerical simulations are given to illustrate the theoretical analysis.
Influence of Electrode Placement on Signal Quality for Ambulatory Pregnancy Monitoring
Authors: Rooijakkers M. J. , Song S. , Rabotti C. , Oei S. G. , Bergmans J. W. M. , Cantatore E. , Mischi M.
Published: February 2014

Noninvasive fetal health monitoring during pregnancy has become increasingly important in order to prevent complications, such as fetal hypoxia and preterm labor. With recent advances in signal processing technology using abdominal electrocardiogram (ECG) recordings, ambulatory fetal monitoring throughout pregnancy is now an important step closer to becoming feasible. The large number of electrodes required in current noise-robust solutions, however, leads to high power consumption and reduced patient comfort. In this paper, requirements for reliable fetal monitoring using a minimal number of electrodes are determined based on simulations and measurement results. To this end, a dipole-based model is proposed to simulate different electrode positions based on standard recordings. Results show a significant influence of bipolar lead orientation on maternal and fetal ECG measurement quality, as well as a significant influence of interelectrode distance for all signals of interest.
The Role of PinX1 in Growth Control of Breast Cancer Cells and Its Potential Molecular Mechanism by mRNA and lncRNA Expression Profiles Screening
Authors: Shi Rong , Zhou Jue-Yu , Zhou Hui , Zhao Zhen , Liang Sang-Hua , Zheng Wen-Ling , Ma Wen-Li
Published: February 2014

As a major tumor suppressor gene, the role of PinX1 in breast cancer and its molecular mechanism remain unclear. In this study, overexpression of PinX1 was generated in 3 breast cancer cell lines, and knockdown of PinX1 was performed in a nontumorigenic breast cell line. The regulation of PinX1 on cell proliferation and cell cycle was observed. A microarray-based lncRNA and mRNA expression profile screening was also performed. We found a lower growth rate, G0/G1 phase arrest, and S phase inhibition in the PinX1 overexpressed breast cancer cells, while a higher growth rate, decreased G0/G1 phase, and increased S phase rate in the PinX1 knocked-down nontumorigenic breast cell. A total of 977 mRNAs and 631 lncRNAs were identified as differentially expressed transcripts between PinX1 overexpressed and control MCF-7 cells. Further analysis identified the involvement of these mRNAs in 52 cancer related pathways and various other biological processes. 11 enhancer-like lncRNAs and 25 lincRNAs with their adjacent mRNA pairs were identified as coregulated transcripts. Our results confirmed the role of PinX1 as a major tumor suppressor gene in breast cancer cell lines and provided information for further research on the molecular mechanisms of PinX1 in tumorigenesis.
A Replication Study for the Association of rs726252 in PAPPA2 with Developmental Dysplasia of the Hip in Chinese Han Population
Authors: Shi Dongquan , Sun Wei , Xu Xingquan , Hao Zheng , Dai Jin , Xu Zhihong , Chen Dongyang , Teng Huajian , Jiang Qing
Published: February 2014

Developmental dysplasia of the hip (DDH) is a common developmental hip disorder, which ranges from mild acetabulum malformation to irreducible hip dislocation. A previous study suggested a significant association of pregnancy-associated plasma protein-A2 (PAPPA2) with DDH susceptibility in Chinese Han population. But with the consideration of the sample size, the association was still debatable. To confirm the association of the reported single nucleotide polymorphism (SNP) in PAPPA2, rs726252 with DDH, we conducted a case-control study in a larger number of subjects. We genotyped rs726252 in 697 DDH subjects and 707 control subjects by TaqMan assay. The association between this SNP and DDH was evaluated statistically. No significant difference was found in any comparison of genotype distribution nor allele frequency between cases and controls. Our replication study indicated that the association between rs726252 and DDH in Chinese Han population was debatable. The association between PAPPA2 and DDH should be evaluated by additional studies.
Imaging and Cognitive Reserve Studies Predict Dementia in Presymptomatic Alzheimer's Disease Subjects
Authors: Ferrari Camilla , Nacmias Benedetta , Bagnoli Silvia , Piaceri Irene , Lombardi Gemma , Pradella Silvia , Tedde Andrea , Sorbi Sandro
Published: February 2014

There is strong evidence that Alzheimer's disease (AD) pathology starts decades before clinical onset. Cognitive reserve (CR) and brain reserve can be a good predictive model for AD development. Neuroimaging can help in describing cerebral reserves, as well as in detecting AD brain pathology before the onset of clinical dementia. Education and occupation act as proxies for CR and are associated with a lower risk of AD and delayed onset of symptoms. The apolipoprotein E (ApoE)-ε4 allele is a strong risk factor for AD and is associated with lower hippocampal volume even in normal aging. A fluorodeoxyglucose positron emission tomography study of brain metabolism shows different metabolic phenotypes among subjects with different educational levels and ApoE genotypes. More highly educated subjects reach a clinical level when the cerebral areas involved in coping with network disruption are seriously impaired, and the AD-ε4 carriers show more global metabolic brain impairment compared with non-ε4 carriers. Thus, CR can counteract a genetically unfavorable background, suggesting a possible preventive strategy. AD research findings have already produced results, since recent epidemiological studies report a decreasing incidence of AD in the last years.
Prevalence of Metabolic Syndrome and Its Relationship with Physical Activity in Suburban Beijing, China
Authors: Zhang Wei-Hong , Xue Peng , Yao Meng-Ying , Chang Hai-Min , Wu Yan , Zhang Lei
Published: February 2014

Background: The present study aimed to estimate the up-to-date prevalence of metabolic syndrome and its relationship with physical activity among suburban adults in Beijing, China. Methods: A cross-sectional survey in a representative sample of 19,003 suburban adults aged 18-76 years was carried out in 2007-2008. Data was collected via questionnaires and blood pressure, anthropometric, and laboratory measurements. Results: Of the residents aged 18-76 years in suburban Beijing, 25.9% (27.3% in men and 25.1% in women), 21.3% (19.4% in men and 22.9% in women), and 25.3% (24.2% in men and 26.1% in women) had 1 component, 2 components, and 3 or more components of metabolic syndrome, respectively. The age-standardized prevalence of metabolic syndrome and its components, including abdominal obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure, and elevated fasting plasma glucose, decreased across categories with increasing physical activity. After adjusting for age, sex, education level, smoking, and alcohol consumption, residents were more likely to have metabolic syndrome across categories with decreasing physical activity; a similar relationship also applied to components of metabolic syndrome. Conclusion: A high prevalence of metabolic syndrome and its components is commonly present in suburban Beijing. Increasing physical activity can reduce the relative risk of metabolic syndrome and it components.
Biochemical Indicators of Dental Caries in Saliva: An in vivo Study
Authors: Hegde M.N. , Hegde N.D. , Ashok A. , Shetty S.
Published: February 2014

This study evaluated the superoxide dismutase (SOD) activity, copper and zinc levels in saliva of caries-active and caries-free individuals. Eighty healthy adults were divided according to WHO criteria: caries-free (DMFT = 0) and caries-active (DMFT >10). Saliva collected was estimated for SOD activity as well as copper and zinc levels using the atomic nitro blue tetrazolium chloride reduction method and absorption spectrophotometry, respectively. The Student t test was applied. In conclusion, SOD activity as well as copper and zinc levels increased in the caries-active group and showed statistically significant results.
Changes in Voice Quality after Speech-Language Therapy Intervention in Older Children with Cerebral Palsy
Authors: Miller Nick , Pennington Lindsay , Robson Sheila , Roelant Ella , Steen Nick , Lombardo Eftychia
Published: February 2014

Objective: We examined whether perceived voice quality is altered in a group of children with cerebral palsy (CP) following an intervention focusing on respiration and phonation, and whether possible improvements might be associated with increased intelligibility levels. Methods: Sixteen individuals with CP and dysarthria (9 girls, mean age 14 years, SD = 2; 9 with spastic type CP, 2 dyskinetic, 4 mixed, 1 Worster-Drought syndrome) completed intelligibility assessments on separate days twice before intervention, at termination of treatment and at 6-week follow-up using 50 words from the Children's Speech Intelligibility Measure lists, and describing cartoon strips. Experienced speech-language pathologists rated voice quality employing GRBAS scales. Results: There was no clear evidence that change in voice quality pre-post intervention was large compared with change in the pre-intervention or post-intervention periods. Asthenia demonstrated largest improvement (effect size of 0.4). Intelligibility correlated weakly with Grade, Breathiness and Asthenia, but not with Roughness or Strain. A deterioration of 1 unit on the Grade and Asthenia scales was associated with an approximately 11% decrease in intelligibility. Conclusion: Perceived changes in voice quality were small compared to changes in intelligibility. Further investigations must examine other variables potentially associated with intelligibility gain to better understand the links between the respiratory-phonatory intervention and improved intelligibility.
New and Evolving Rare Diseases Research Programs at the National Institutes of Health
Authors: Groft S.C. , Rubinstein Y.R.
Published: February 2014

Research emphasis on rare diseases and orphan products remains a major focus of the research Institutes and Centers of National Institutes of Health (NIH). NIH provides more than USD 31 billion annually in biomedical research and research support. This research is the basis of many of the health advances in rare and common diseases. Numerous efforts and a major emphasis by the public and private sector initiatives have resulted in an increase of interventions and diagnostics for rare diseases. Newer translational research programs provide a more systematic and coordinated approach to rare diseases research and orphan products development. The approach that is offered requires extensive public-private partnerships with the pharmaceutical industry, contract research organizations, philanthropic foundations, medical and scientific advisory boards, patient advocacy groups, the academic research community, research and regulatory scientists, government funding agencies, and the public. Each program is unique and requires lengthy planning and collaborative efforts to reach programmatic goals.
EUROPLAN: A Project to Support the Development of National Plans on Rare Diseases in Europe
Authors: Taruscio D. , Gentile A.E. , De Santis M. , Ferrelli R.M. , Posada de la Paz M. , Hens M. , Huizer J. , Fregonese L. , Stefanov R. , Bottarelli V. , Weinman A. , Le Cam Y. , Gavhed D. , Mincarone P. , Bushby K. , Frazzica R.G. , Donati C. , Vittozzi L. , Jessop E.
Published: February 2014

Background/Aims: National Plans for Rare Diseases (RDs) are the common denominator of current public health policy concerns on RDs across the EU. With the aim of a better distribution of the available resources, they conjugate the European objective that aims at ensuring that patients with RDs have access to high-quality care - including diagnostics, treatment and rehabilitation - with the national priorities of selecting specific measures for adoption and implementation. Methods: The European Project for Rare Diseases National Plans Development (EUROPLAN, www.europlanproject.eu) is cofunded by the EU Commission (DG-SANCO) and is coordinated by the Italian National Center for Rare Diseases of the Istituto Superiore di Sanità (ISS). The EUROPLAN goal is to promote the implementation of National Plans or Strategies to tackle RDs and share relevant experiences within countries, linking national efforts, through a common strategy at a European level. In order to fulfill these objectives, EUROPLAN involved health authorities, clinicians, scientists, the European Organisation for Rare Diseases (EURORDIS), and many other patient groups as associated and collaborating partners from several European countries. Results: The project was launched in 2008 and foresaw 2 implementation phases: phase 1 (2008-2011) to build the consensus definition of operational tools (recommendations and indicators), and the ongoing phase 2 (2012-2015), mainly aimed at capacity building with the proactive involvement of multilevel stakeholders. EUROPLAN is facilitating and accelerating the implementation of National Plans in almost all EU and several non-EU Countries. Conclusions: EUROPLAN is a European and an international process more than a project, and it could be defined as a ‘litmus test' demonstrating how the collaboration between institutions and patients' associations can accelerate the process of awareness and development of policies and actions.
The Current Situation and Needs of Rare Disease Registries in Europe
Authors: Taruscio D. , Gainotti S. , Mollo E. , Vittozzi L. , Bianchi F. , Ensini M. , Posada M.
Published: February 2014

Background: Registries are considered key instruments for developing rare disease (RD) clinical research, enhancing patient care and health planning, and improving social, economic and quality-of-life outcomes. Indeed, it is usually the case that no single institution, and in many cases no single country, has sufficient data to provide results that can be applied broadly to clinical and translational research. However, the fragmentation and heterogeneity of the registries, which are often the result of spontaneous initiatives, limit the general applicability of their observations. Methods: An inquiry has been carried out by the EPIRARE, a European Union (EU)-funded project (‘Building Consensus and Synergies for the EU Registration of Rare Disease Patients') aiming at paving the way to the creation of a European Platform for RD Registries, by means of an on-line questionnaire among European RD registries on their main activities and needs, the way they deal with methodological, technical and regulatory issues and the way they find resources to carry on their activities. Results: In spite of the heterogeneity of the European registries, some elements of relevance for an action to improve the situation of patient registries in the EU are apparent. The needs more frequently indicated by registry holders were financial support, motivation of data providers, data quality assessment, improvement of communication and visibility, and extension of collaborations. Moreover, the registry holders were in favor of a common EU platform providing services for RD registries. Conclusion: It appears that the current situation of the European registries provides the transition towards a more uniform, higher quality and better coordinated approach.
A Model for the European Platform for Rare Disease Registries
Authors: Vittozzi L. , Gainotti S. , Mollo E. , Donati C. , Taruscio D.
Published: February 2014

Background: The current situation of rare disease (RD) registries is rather heterogeneous, and new ways to support the registration of RD patients are being sought in the European Union (EU) and the US. The project ‘Building Consensus and Synergies for the EU Registration of RD Patients', funded by the EU, aimed to define a model platform for EU RD registries. Methods: A number of surveys and extensive consultations among registry stakeholders have been carried out to study how the platform can best fulfill their needs. Results: This web-based, multidisease and multipurpose platform is intended to provide a number of functions: a metadata and data repository function supporting the planning of research studies and the production of predefined outputs for the funding organizations and the public, provision of tools and resources of use to registries, promotion of registration and networking among patients and professionals. Conclusion: Its main impact is expected to be on data and procedures standardization, on the establishment of new registries, on the sustainability of the smaller ones, and on the registration of those RDs for which a dedicated registry is not sustainable, e.g. ultra-rare diseases or diseases for which there is no special research, clinical or economic interest. It will also impact on the production of sounder information on RD and RD-dedicated health systems, by promoting registry data comparability and quality.
EU Pancreas: An Integrated European Platform for Pancreas Cancer Research - from Basic Science to Clinical and Public Health Interventions for a Rare Disease
Authors: Milne R. , La Vecchia C. , Van Steen K. , Hahn S. , Buchholz M. , Costello E. , Esposito I. , Hoheisel J.D. , Lange B. , Lopez-Bigas N. , Michalski C.W. , Real F.X. , Brand A. , Malats N. ,   on behalf of the COST Action BM1204 participants
Published: February 2014

Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way ‘from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.
Efferent Inhibitory Effect Observed in Otoacoustic Emissions and Auditory Brainstem Response in the Neonatal Population
Authors: de Araújo Lucas Rodrigues Priscila , Pereira Lauris José Roberto , Schochat Eliane
Published: February 2014

Objective: To characterize the inhibitory effect (IE) in the otoacoustic emission (OAE) and auditory brainstem response (ABR) in newborns at high and low risk for hearing loss. Design: Cross-sectional study. Patients and Methods: Seventy-nine newborns at low risk for hearing loss and 46 at high risk underwent transient evoked OAE (TEOAE), distortion product OAE (DPOAE) and ABR testing with or without the presence of contralateral white noise presented at a level of 60 dB SPL. Results: For both low- and high-risk newborns, there were no significant differences in IE between the left and right ears. There was a statistically significant difference in the right-ear IE between the low- and high-risk group for DPOAE and ABR testing. There was also greater agreement of the efferent system evaluation outcomes between TEOAE and ABR. Conclusions: ABR testing detected IE in a greater number of newborns in the low-risk, as compared to the high-risk group.
Effects of Jak2 Type 1 Inhibitors NVP-BSK805 and NVP-BVB808 on Jak2 Mutation-Positive and Bcr-Abl-Positive Cell Lines
Authors: Ringel Frauke , Kaeda Jaspal , Schwarz Michaela , Oberender Christian , Grille Peggy , Dörken Bernd , Marque Fanny , Manley Paul W. , Radimerski Thomas , le Coutre Philipp
Published: February 2014

Janus kinases are critical components of signaling pathways that regulate hematopoiesis. Mutations of the non-receptor tyrosine kinase JAK2 are found in many BCR-ABL-negative myeloproliferative neoplasms. Preclinical results support that JAK2 inhibitors could show efficacy in treating chronic myeloproliferative neoplasms. JAK2 has also been postulated to play a role in BCR-ABL signal transduction. Therefore, inhibitors of JAK2 kinases are turning into therapeutic strategies for treatment of chronic myelogenous leukemia (CML). In this study, the effects of two novel JAK2 inhibitors, NVP-BSK805 and NVP-BVB808, have been investigated in cell lines expressing either BCR-ABL or mutant JAK2. Possible synergies between NVP-BSK805/NVP-BVB808 and the kinase inhibitors imatinib and nilotinib were assessed. Proliferation and apoptosis tests with both substances showed response in the following cell lines: CHRF-288-11, SET-2 and UKE-1. All BCR-ABL-positive cell lines showed some reduction in proliferation, but with half-maximal growth-inhibitory values >1 µM. Combination of the JAK2 inhibitors with imatinib and nilotinib showed no significant additive or synergistic effects, although all BCR-ABL-positive cell lines responded well to both CML therapeutic agents. Interestingly, it seemed that the combination of imatinib with NVP-BSK805 had a protective effect on the cells. Combination treatment with nilotinib did not show this effect.
Exploring Clinician Confidence in the Management of Adolescent Menstrual and Reproductive Health Problems
Authors: Neylon Orla M. , Grover Sonia R. , Zacharin Margaret
Published: February 2014

Purpose: A high incidence of menstrual problems is reported in adolescent girls, with significant attendant morbidity. The majority are likely to be seen and managed by doctors other than specialist gynaecologists. This study aimed to survey the practice of doctors other than gynaecologists, to establish their chosen therapeutic options and confidence levels and to explore knowledge, using clinically challenging scenarios. Methods: A questionnaire designed to fulfil the above aims was distributed to a wide range of clinicians across paediatric disciplines and primary care. Results: The questionnaire was returned by 306 clinicians. General practitioners and paediatric endocrinologists were more confident in management and were more likely to self-manage patients (p < 0.01). The oral contraceptive pill was the most frequently chosen first-line therapy by all clinicians, followed by transdermal oestrogen/progesterone, etonorgestrel implant, progesterone-only pills, levonorgestrel-intrauterine system and depot medroxyprogesterone acetate injections. General, community and subspecialist paediatricians were more likely to choose suboptimal management strategies for each of five clinical scenarios. Conclusions: Low confidence levels, suboptimal therapy choices and high referral rates are common among general paediatricians, community paediatricians and subspecialists for adolescents with menstrual and reproductive health concerns. Targeted education for these clinician groups, towards optimizing management for these patients, would enhance care.
Physiological Estrogen Replacement Therapy for Puberty Induction in Girls: A Clinical Observational Study
Authors: Ankarberg-Lindgren Carina , Kriström Berit , Norjavaara Ensio
Published: February 2014

Background/Aim: The goal of estrogen replacement therapy (ERT) in girls with hypogonadism is to achieve the endocrine milieu similar to natural puberty, where transdermal administration is the most physiological route. The aim of the study was to evaluate guidelines for the induction of puberty with transdermal estradiol (E2) patches in a large outpatient setting. Methods: In a retrospective study, serum E2 levels from 18 clinics were analyzed at the Göteborg Pediatric Growth Research Center laboratory, as part of the initiation of ERT in girls with hypogonadism. Exclusion criteria were pubertas tarda and pubertal arrest. Eighty-eight observations (50 with Turner syndrome, TS) were included. Serum E2 levels were determined by extraction + radioimmunoassay (detection limit 4 pmol/l) and analyzed in relation to the dose of Evorel® (25 µg/24 h, containing 1.60 mg estradiol hemihydrate; Janssen-Cilag Pharmaceutica N.V., Beerse, Belgium). Results: There was a linear relationship between serum E2 and the weight-based dose, with r = 0.56, p < 0.0001 for all observations and r = 0.59, p < 0.0001 for the TS study group. Linear regression analysis for doses of 0.05-0.07 µg/kg resulted in serum levels of 17-23 pmol/l (TS 17-24 pmol/l) and doses of 0.08-0.12 µg/kg in 26-39 pmol/l (TS 27-39 pmol/l). Conclusions: For the initiation of ERT with nocturnally administered E2 patches, we recommend reduced starting doses of 0.05-0.07 µg/kg, with the goal of mimicking E2 levels during gonadarche. In older girls, when breast development is of high priority, the starting dose can still be 0.08-0.12 µg/kg.
Guanine Nucleotide-Binding Protein α Subunit Hypofunction in Children with Short Stature and Disproportionate Shortening of the 4th and 5th Metacarpals
Authors: Inta Ioana Monica , Choukair Daniela , Bender Sebastian , Kneppo Carolin , Knauer-Fischer Sabine , Meyenburg Kahina , Ivandic Boris , Pfister Stefan M. , Bettendorf Markus
Published: February 2014

Background:GNAS encodes the α subunit of the stimulatory G protein (Gsα). Maternal inherited Gsα mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. Aims: Here we investigated the Gsα pathway in short patients with distinct shortening of the 4th and 5th metacarpals. Methods: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsα protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. Results: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsα activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. Conclusions: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsα protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsα dysfunction.
Epidemiology, Presentation and Long-Term Evolution of Graves' Disease in Children, Adolescents and Young Adults with Turner Syndrome
Authors: Valenzise Mariella , Aversa Tommaso , Corrias Andrea , Mazzanti Laura , Cappa Marco , Ubertini Graziamaria , Scarano Emanuela , Mussa Alessandro , Messina Maria Francesca , De Luca Filippo , Wasniewska Malgorzata
Published: February 2014

Background: Epidemiological studies on the association between Turner syndrome (TS) and Graves' disease (GD) are sparse and no studies are available on the clinical course of GD in TS. Objectives: To retrospectively investigate the GD prevalence in children and young adults with TS and to compare the GD course in patients with or without TS who were followed up for 4.1 ± 0.6 and 4.5 ± 3.7 years, respectively. Design: The prevalence of GD in 408 TS patients was evaluated; presentation and evolution of GD under therapy were evaluated both in 7 patients with TS (group A) and in 89 patients without TS (group B). Results: (a) The prevalence of GD in TS patients was 1.7%; (b) GD in TS was not associated with a specific karyotype; (c) with respect to group B patients, those of group A exhibited at presentation more advanced age, a lower fT4 level and more frequent association with other autoimmune diseases, and (d) the clinical course under methimazole therapy was not different in the two groups. Conclusions: The prevalence of GD in children and young adults with TS is 1.7% and in TS patients, GD presents later and its clinical course is not different than in those without TS.
Purified Human Breast Milk MUC1 and MUC4 Inhibit Human Immunodeficiency Virus
Authors: Mthembu Yolanda , Lotz Zoe , Tyler Marilyn , de Beer Corena , Rodrigues Jeronimo , Schoeman Leann , Mall Anwar Suleman
Published: February 2014

Background: The HIV-AIDS pandemic is prevalent in sub-Saharan Africa. Breastfeeding is a risk factor, with transmission from mother to child being as high as 40%. Objectives: To determine the antiviral activity of crude breast milk and its purified mucins MUC1 and MUC4 against HIV-1 in patients who were HIV positive compared to those who were not. Methods: Twenty-one human milk samples were taken from both groups. Breast milk mucins were purified by density-gradient ultracentrifugation in caesium chloride and analyzed by SDS-PAGE, Western blotting and amino acid content. The inhibition of the virus by crude milk and purified mucin was assayed by an in vitro HIV-1 p24 assay. Results: SDS-PAGE for purified mucin showed several high-molecular-weight bands for the HIV-negative group and prominently stained single bands on the stacking gel with faintly periodic acid Schiff-positive glycoprotein bands observed in some cases in the running gel for the HIV-positive mucins. Western blot analysis identified the mucins in both groups to be MUC1 and MUC4. Both mucins showed more intensity on Western blotting for the HIV-positive group. There was no difference in the content of serine, threonine and proline of purified mucins for both groups. HIV-1 was not inhibited by crude breast milk from normal (13/14 samples) and infected individuals (19/19 samples). Fifteen of 20 and 16/18 samples of purified mucin from the uninfected and HIV-positive groups, respectively, inhibited the virus. Conclusions: Crude breast milk does not inhibit HIV-1, whilst purified mucins do in an in vitro assay.
Allitridin Reduces IKr Current by Disrupting the Trafficking of Human Ether-à-Go-Go-Related Gene Channels
Authors: Li Guoliang , Cheng Gong , Wu Jine , Ma Shuting , Zhang Aifeng , Han Wenqi , Sun Chaofeng
Published: February 2014

Objectives: To investigate the effects of allitridin on human ether-à-go-go-related gene (hERG) channels. Methods: We used whole-cell patch clamping and laser confocal scanning microscopy to evaluate the effects of allitridin on hERG currents and the membrane expression of the hERG protein expressed in HEK 293 cells. Results: The amplitude of IKr showed a concentration-dependent decrease with increasing allitridin concentration. Additionally, alterations in the gating properties of hERG channels were also confirmed. Allitridin does not alter the voltage- and time-dependent activation of hERG channels, the gating properties of hERG channel inactivation over time or the recovery from inactivation, but allitridin does cause alterations in the steady-state inactivation and the deactivation of hERG channels. We further evaluated the influence of allitridin on membrane expression of the hERG protein. Images of allitridin-treated cells showed a reduction in hERG protein on the membrane and retention in the cytoplasm. Conclusions: To the best of our knowledge this is the first study to show that allitridin reduces the IKr current by impairing the trafficking of hERG channels. The results may demonstrate that allitridin could be a promising candidate for the prevention and treatment of arrhythmia-related diseases.