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CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma
- Seong-Su Han†1,
- Van S Tompkins†2,
- Dong-Ju Son†5,
- Sangwoo Han3,
- Hwakyung Yun6,
- Natalie L Kamberos1,
- Casey L Dehoedt2,
- Chunyan Gu2,
- Carol Holman2,
- Guido Tricot4,
- Fenghuang Zhan4 and
- Siegfried Janz2Email author
DOI: 10.1186/s40164-015-0005-2
© Han et al.; licensee BioMed Central. 2015
Received: 7 March 2015
Accepted: 10 March 2015
Published: 27 March 2015
Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM).
We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c-Myc) mice, or in double-transgenic IL6MYC mice. qPCR measurements and analysis of clinical BL and MM datasets were employed to validate candidate NF-κB/STAT3 target genes.
qPCR demonstrated that IL6- and/or MYC-dependent neoplasms in mice invariably contain elevated mRNA levels of the NF-κB target genes, Cdkn1a and Fancd2. Clinical studies on human CDKN1A, which encodes the cell cycle inhibitor and tumor suppressor p21, revealed that high p21 message predicts poor therapy response and survival in BL patients. Similarly, up-regulation of FANCD2, which encodes a key member of the Fanconi anemia and breast cancer pathway of DNA repair, was associated with poor outcome of patients with MM, particularly those with high-risk disease.
Our findings suggest that CDKN1A and FANCD2 are potential oncotargets in BL and MM, respectively. Additionally, the IL-6- and/or MYC-driven mouse models of human BL and MM used in this study may lend themselves to the biological validation of CDKN1A and FANCD2 as molecular targets for new approaches to cancer therapy and prevention.
p21 tumor suppressor Fanconi anemia and breast cancer DNA damage repair Genetically engineered mouse models of human cancer Molecularly targeted cancer therapyBackground
Comparative histopathologic, genomic and biological analyses of malignant tumor counterparts in humans and mice afford a powerful approach to improve our understanding of evolutionarily conserved signaling networks that underlie oncogenesis and are thus of great significance for public health. An important objective of cross-species analysis of neoplastic development is the discovery of concordantly deregulated genes that play an important role in tumor development and progression, response to therapy, acquisition of drug resistance, and clinical outcome. Protein-encoding genes that are overexpressed in cancer cells and potentially inhibitable by small compounds are of particular interest to that end, because they are actionable in terms of molecularly targeted drug development. Here, we take advantage of MYC- [1], IL6- [2] and IL6MYC-transgenic (Tg) mice [3,4] that recapitulate important features of human Burkitt lymphoma (BL) or multiple myeloma (MM) to uncover up-regulated candidate cancer genes that might have been overlooked in other studies. We show that MYC and/or IL-6-driven B cell and plasma cell tumors of mice exhibit constitutive NF-κB activity that leads to overexpression of NF-κB target genes such as Cdkn1a and Fancd2. These genes encode the well-established tumor suppressor, p21, and a key member of the Fanconi anemia/breast cancer DNA damage repair pathway, respectively. Interrogation of a well-annotated clinical dataset (n = 351) suggested that FANCD2 is a MM gene. Likewise, in vitro studies on tumor cell lines and clinical outcome results indicated that CDKN1A may be a BL oncogene. Although additional work is warranted before the utility of CDKN1A and FANCD2 as molecular targets for drug development can be fully evaluated, our study underlines the value of comparative oncogenomic and molecular genetic research on human-mouse cancer counterparts for developing new approaches to cancer therapy and prevention.
Constitutive NF-κB and STAT3 activity in IL-6 and/or MYC-driven B cell and plasma cell tumors in mice
Up-regulation of Cdkn1a and Fancd2 in mouse tumor cells
CDKN1A is a candidate oncogene in human Burkitt lymphoma (BL)
Induction of CDKN1A in the course of a drug-induced stress response in BL cells
The availability of representative tumor cell lines afforded an opportunity to examine the cancer cell-autonomous properties of p21 in human BL in greater depth. We selected 5 independent cell lines, 3 of which are infected with Epstein Barr virus (EBV) and thus express the virus-encoded oncoprotein LMP1: Daudi, Raji and Jiyoye. Two cell lines, DG75 and Ramos, do not harbor EBV (Figure 4B, bottom). Mouse Hal2G1 tumor cells, which carry the mCD40-LMP1 and iMycEμ transgenes [13], were included for comparison. EBV+ BL cells contained increased CDKN1A mRNA compared to EBV− BL cells (Figure 4B, top), whereas TP53 message (Figure 4B, center) and p53 DNA-binding activity (Figure 4C) were consistently low irrespective of EBV/LMP1 status. Next we measured CDKN1A expression under conditions of drug-induced stress imposed by treatment of cells with the cancer-inhibiting agent, piperlongumine (PL). In agreement with our previous finding that PL kills human BL and mouse BL-like cells by virtue of a mechanism that includes inhibition of NF-κB [13,16], we found that PL kills 3 of 3 BL lines with similar efficacy (Figure 4D, top). PL-dependent induction of both CDKN1A (Figure 4D, center) and p53 DNA binding activity (Figure 4D, bottom) was more robust in EBV− DG75 cells than in EBV+ Daudi and Raji cells, but a larger study is warranted to decide whether this is truly associated with EBV/LMP1 status or caused by coincidence. Be this as it may, the results described above implicate the activation of the p53/p21 pathway in the PL-dependent stress response in BL cells.
FANCD2 is a candidate multiple myeloma (MM) gene
FANCD2 is associated with high-risk myeloma
Keeping in mind that the prognosis of myeloma depends in large measure on tumor genetics [17] and that risk stratification models of myeloma rely on genetic features, such as changes in gene expression according to the 70-gene model [18], to assign newly diagnosed cases to standard-risk groups (median OS >10 years) and high-risk groups (2–3 years) [19], we analyzed whether FANCD2High status might be associated with high-risk disease as defined by the 70-gene signature [18]. Forty-six of 351 myeloma patients (13%) carried this signature (Figure 5C), with most of them falling into four subgroups of myeloma: proliferation (PR, n = 20), MAF/MAFB (MF, n = 12), MMSET (MS, n = 9) and hyper-diploid (HY, n = 4). In all four subgroups, mean FANCD2 levels were elevated in high-risk relative to standard-risk disease, but statistical significance was only reached in one subgroup, PR (p = 0.0043, Mann–Whitney test (Figure 5D, left). When all 46 high-risk cases were pooled and the mean FANCD2 expression level of that pool was compared to all 305 standard-risk cases, the up-regulation of FANCD2 in high-risk myeloma was highly significant (p = 0.004; Figure 5D, right). This result suggested that FANCD2 is a bona fide high-risk myeloma gene as defined by the 70-gene model.
The main finding of this study is the implication of FANCD2 and CDKN1A in high-risk MM and BL, respectively. CDKN1A was first identified as an inhibitor of cell cycle progression and tumor development that is up regulated by wild-type p53 [20,21]. Nowadays CDKN1A is more broadly considered as a regulator of fundamental cell-fate decisions, such as proliferation, differentiation and senescence [22]. With respect to oncogenesis, the tumor suppressor function of CDKN1A is well established, yet there is also growing evidence for oncogenic properties of CDKN1A-encoded p21. For instance, p21 is overexpressed in mouse fibroblasts undergoing transformation induced by ionizing radiation [23]. The underlying mechanism is not known but likely includes protection from apoptosis, which is emerging as key for p21's oncogenic functions [24]. In line with that, cytoplasmic p21, the accumulation of which is stimulated by AKT- or IKKβ-dependent pathways, suppresses programmed cell death [25]. Furthermore, NF-κB-dependent up-regulation of p21 inhibits apoptosis in cells damaged by doxorubicin [26] or UV irradiation [27]. Importantly, tumor development studies in laboratory mice have demonstrated that deletion of Cdkn1a inhibits lymphoma in Trp53-deficient [28], Atm-deficient [29] and normal mice [30], rather than promoting lymphoma as one might expect from the loss of a tumor suppressor gene. In further agreement with p21's survival-enhancing activity, lymphomas arising in Cdkn1a-deficient mice demonstrate a high rate of apoptosis [31]. In human cancers, overexpression of CDKN1A is frequently seen in carcinoma (prostate, cervix, breast, ovary, skin), brain tumor (glioma) and hematological malignancy [25]. With regard to the latter, strong experimental evidence indicates that p21's pro-survival function plays an important role in the natural history of human leukemia [32]. These findings support the result of this study suggesting that p21 promotes BL by functioning as an oncogene in the mature B-cell lineage.
The observed overexpression of Fancd2 and Xrcc6 in myeloma-like plasma cell tumors from IL6MYC mice established an interesting parallel to human MM, in which the Fanconi anemia/breast cancer (FA/BRCA) DNA damage repair pathway has been identified as an important effector mechanism of myeloma cell responses to replicative stress induced by DNA alkylating agents, such as the widely used myeloma drug melphalan [33]. FA/BRCA has also been implicated in the acquisition of drug including bortezomib resistance by myeloma cells [34]. FANCD2 is a key player in the FA/BRCA pathway and XRCC6 is a facilitator of DNA double-strand break repair. Both repair proteins are subject to regulation by NF-κB (e.g., p50/RelB dimers) [33,35,36] and both intersect functionally with p21. The latter is illustrated by reports that p21 can activate FA-BRCA-dependent [37] and XRCC6-dependent [38] DNA repair, although this has not yet been demonstrated for myeloma. In this study, we provided clinical evidence for a role of FANCD2 in myeloma. Unlike XRCC6 expression, which was not associated with survival in the Total Therapy 2 (TT2) myeloma dataset used here (n = 351), the message levels of FANCD2 were significantly correlated with event-free and overall survival of patients with myeloma. Moreover, overexpression of FANCD2 appeared to be a feature of high-risk myeloma, a subset of the disease for which new therapeutic approaches are urgently needed. Patients with high-risk myeloma have extremely poor outcomes; as such, they define an unmet medical need. The median overall survival for patients with standard-risk myeloma is >10 years years, yet that for patients with high-risk disease is 2–3 years, despite the application of aggressive, risk-adapted therapies including tandem autologous stem-cell transplantation (ASCT) and new myeloma drugs [19]. The results presented here support the view that FANCD2 may be a bone fide high-risk myeloma gene that is worthy for consideration as molecular target for new, targeted therapies of patients with MM.
Starting with the observation that IL-6 and/or MYC-driven B cell and plasma cell tumors in BALB/c mice exhibit constitutive NF-κB/STAT3 activity that leads to up-regulation of NF-κB target genes, we found that two genes of this sort, CDKN1A and FANCD2, are important for human BL and human MM, respectively. It is possible that these genes drive neoplastic development in the mature B-cell lineage, but this has not been demonstrated here. Additional functional and mechanistic studies are warranted before it can be decided whether CDKN1A and FANCD2 provide viable molecular targets for new therapeutic approaches to BL and MM. MYC-driven BL-like tumors and IL6MYC-driven MM-like tumors in laboratory mice may lend themselves as experimental model systems to that end.
Transgenic mice, human BL cell lines, and normal B-lymphocytes
The generation and tumor phenotypes of single-transgenic MYC [1] or IL6 [2] mice and double-transgenic IL6MYC mice [3,4] have been previously reported. All transgenes were on the genetic background of BALB/c (C). Breeding, maintenance and handling of mice was conducted according to IACUC guidelines and approved under University of Iowa ACURF study protocol 1301010. Human Burkitt lymphoma (BL) cell lines, purchased from ATCC (Manassas, VA), were maintained in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum, in a humidified 5% CO2 incubator at 37°C. Human B cells were isolated from peripheral blood of healthy individuals as previously described [16]. Normal B220+ B cells were fractionated from the spleen of inbred C mice, using MACS® CD45R magnetic beads columns from Miltenyi Biotec (Auburn, CA).
Quantitative reverse-transcription PCR (qPCR)
Reverse transcription, performed on 1 μg of TRIzol (Sigma-Aldrich, St. Louis, MO)-extracted total RNA, was followed by cDNA synthesis using the AMV reverse transcriptase kit (Roche, Indianapolis, IN). qPCR was performed with the help of TaqMan Universal PCR Master Mix (Applied Biosystems, Carlsbad, CA), using primers and 6-carboxyfluorescein (6-FAM) / Black Hole (BHQ)-labelled probes to specific target genes (IDT, Coralville, IA). Sequences of probes are available upon request. The Applied Biosystems 7900 HT device was used for amplification and detection of PCR product. ABI SDS v 2.3 software (Applied Biosystems, Carlsbad, CA) was employed for analyzing results. The Ct value for each gene was normalized to the internal reference control, HPRT1 for human genes or Hprt for mouse genes, and represented as fold gene expression change relative to gene expression in normal human or mouse B cells or, in case of drug studies, to vehicle-treated cells.
Cell proliferation
Proliferation was determined using the Cell Titer 96® MTS/PMS assay (Promega, Madison, WI). Briefly, 1 x 105 cells in 100 μl growth media were plated into 96-well plates (Costar, Cambridge, MA). After 20 hours, 20 μl of MTS/PMS solution was added per well. Four hours later, the absorbance at 490 nm was measured using a Multiskan Spectrum plate reader (Thermo Scientific, Hudson, NH).
Preparation of nuclear and cytosolic extracts
Cells (1 × 107) were lysed with 400 μl of buffer A (10 mM KCl, 0.2 mM EDTA, 1.5 mM MgCl2, 0.5 mM DTT, and 0.2 mM PMSF) at 4°C for 10 minutes. Lysate was centrifuged for 5 minutes at 14,000 g and supernatants were collected as cytosolic extracts. Pellet was re-suspended in 100 μl ice-cold buffer C (20 mM HEPES [pH 7.9], 420 mM NaCl, 1.5 mM MgCl2, 20% [v/v] glycerol, 0.2 mM EDTA, 0.5 mM DTT, and 0.2 mM PMSF), incubated at 4°C for 20 minutes and centrifuged for 6 minutes at 14,000 g. Supernatant was collected as nuclear extract (NE). Protein concentration of NE was determined using a BCA kit (Bio-Rad, Richmond, CA).
Electrophoretic mobility shift assays (EMSA)
EMSA was carried out in 25 μl of binding buffer (10 mM Tris [pH 7.5], 100 mM NaCl, 1 mM DTT, 1 mM EDTA, 4% [w/v] glycerol, 0.1 mg/ml sonicated salmon sperm DNA), using 10 μg of NE. Oligonucleotides containing consensus NF-κB (Promega, Madison, WI), MYC/MAX or p53 DNA recognition and binding sites (Santa Cruz Biotechnology, Santa Cruz, CA) were end-labeled to a specific activity of 105 CPM, using γ-[32P]-ATP and T4-polynucleotide kinase followed by purification on a Nick column (GE Healthcare, Piscataway, NJ). Reaction mixtures were incubated at room temperature for 20 minutes and resolved on 6% non-denaturing polyacrylamide gels. Gels were dried and subjected to autoradiography. For super-shift assays, 2 μg antibody was added (20 min, ambient temperature) after the reaction with radiolabeled oligonucleotide had been completed. Antibodies to p50 (sc-114X), p65 (sc-109X), c-Rel (sc-70X), p52 (sc-298X), RelB (sc-48366X) or Myc (sc-764X) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).
Microarray-based gene expression profiling (GEP)
GEP using the Affymetrix U133Plus 2.0 microarray (Santa Clara, CA) were performed as previously described [39]. Microarray data and outcome data on the 351 patients included in this study are available in the NIH Gene Expression Omnibus (GEO) under accession number GSE2658. Microarray data on the 44 individuals with MGUS and 22 samples of normal plasma cells (NPC) included here are available at GSE5900. Plasma-cell isolation, total RNA extraction, cRNA synthesis, and hybridization to microarrays were performed as described previously [18]. Statistical analysis of microarray data took advantage of the GCOS1.1 software (Affymetrix, Santa Clara, CA) and involved log-rank tests for univariate association with disease-related survival.
Burkitt lymphoma
Epstein Barr virus
Event-free survival
Electrophoretic mobility shift assay
Multiple myeloma
Overall survival
This work was supported in part by NIH Training Grant T32-HL07734 and National Natural Science Foundation of China (NNSFC) Grant 81250110552 (both to VT); by a Hyundai Hope on Wheels Research Scholar Grant (to NLK); by NCI R01CA152105, Leukemia & Lymphoma Society Translational Research Program Awards 6246–11 and 6094–12, and NNSFC Award 81228016 (all to F.Z.); by institutional start-up funds from the Department of Internal Medicine, CCOM, UI (to FZ and GT); by a P50 CA97274 UI/MC Lymphoma SPORE Career Development Award and NCI R01CA151354 (both to SJ); and by NCI Core Grant P30CA086862 in support of The University of Iowa Holden Comprehensive Cancer Center.
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Reaching all modalities for student learning can be tricky in an online environment, where student engagement is difficult to measure and extrinsic motivation harder to instill. Choosing appropriate course tools goes a long way toward providing enough varied activities to match multiple learning styles, and maximize the chance that your students have mastered the material.
A major component of face-to-face classes that needs translation to the online environment is the social and interpersonal element, which some learning theories argue is crucial to learning. If a subset of students learn better collaboratively, how might their interactions be approximated in the online environment?
One common answer is to use discussion boards in Webcourses. This becomes particularly valuable when students are required to make discussion postings, since otherwise there may be little activity. Likewise, some instructors require students not only to make initial posts, but also to comment on the posts by other students as well. To guarantee substantive postings, it may be advisable to grade each post and response, though this might require additional work by the instructor.
Also available are tools for live chat, a "who's online" notification, and email within Webcourses. If student to student communication is woven tightly enough into a curriculum, one or more of these tools may be worthwhile pursuing.
Face to Face Activities |
Online Equivalent |
PowerPoint lecture | Modules of just text/images that convey information; PowerPoint presentation for download; PowerPoint presentatiosn with instructor's audio "narrating" a lecture (use free software AuthorPoint to compress this resulting video file) |
Interactive lecture; question-driven interactions with students | Modules that call for synchronous use of the Chat tool; online office hours using Chat or third-party chat tools such as Skype |
Discussion-based seminars | Forums and discussion boards online (consider carefully whether the instructor should himself/herself post to the forum) |
Student response "clickers" | Online quiz, or survey via third party such as SurveyMonkey.com |
Student groups | Electronic groups within Webcourses; the "Who's Online" tool; chat rooms; third-party wikis for group projects or class notes |
Role-play | Blogs generated by students, done in role-play fashion |
Reflective writing | Blogs written by students |
Library research | Google; social bookmarking tools online |
Homework from the textbook | Practice at the publisher's website |
Community-building and learning names | Avatar-based interaction, such as Second Life; Facebook groups |
Organization Tools
Calendar: Enter important events and deadlines, and allow Students to enter their own events.
Search: Search for content in the course.
Syllabus: Provide course requirements, objectives, and policies.
Communication Tools
Announcements: Post important information in a central location.
Chat: Chat with other users in the course in real time, or use the Whiteboard to display images.
Discussions: Post and respond to messages on specific topics.
Mail: Send messages to other users.
Student Learning Activities
Assessments: Create quizzes, self tests, and surveys.
Assignments: Create assignments for Students to submit online. Students can work independently or in groups.
Goals: Create goals that list the qualitative and quantitative performance expected in your course.
Content Tools
Learning Modules: Organize and present content and activities to Students.
Local Content: Allow Students to easily access large files from a portable medium, such as CD-ROM, instead of downloading the files from the Learning System.
Media Library: Create a glossary or image collection.
Web Links: Create links to Internet resources.
Student Tools
My Files: Allow Students to store their own files.
My Grades: Allow Students to check their grades.
My Progress: Allow Students to track their own progress.
Notes: Allow Students to take notes.
Continue to the next section: Assessments
Kevin Haran
College of Arts and Humanities
My goal in teaching studio art is to give students a college-level experience in creating a body of work that they would not have made on their own. This work will represent an awareness of traditional and contemporary issues in art. I challenge art students while offering encouragement as they pursue their educa...
Jane Waterman
College of Sciences
Science is like a big jigsaw puzzle, and each research project is like a piece of that puzzle. To get this message across to my students, at all the levels I teach, I try to bring science alive to my classes, show them that science is always a work in progress and that it is exciting. I think it is important to in...
Patricia Angley
College of Arts and Humanities
Interaction with my
students motivates me to find different and innovative classroom techniques,
methods, and challenges to keep them engaged with their learning. I try to
listen to them, hear what they know and don't know so that we can make meaning
together as we read and interpret diverse and difficult text...


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Radian Studio
How to Buy
Radian Users
- Defense
- Intelligence
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- Federal, State and Local
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- Land Administration
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- Highways
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Easy to Play
Magic is Just a Click Away
Endless Power - Effortlessly
Radian delivers effortless access to a world of spatial data - your world - within an integrated system that features point and click ease to hundreds of functions. Data that powers decisions, wealth creation and success in today's world is spatial data and Radian delivers the seamless capability to manage and understand that data,
Fast Opens
Data in a Radian project is fast. Really fast. No need to wait minutes for a large table, image or drawing to display. Radian opens 100 GB images instantly and allows you to pan and zoom effortlessly with zero delay. Likewise with very large vector datasets such as drawings or maps where Radian opens the project instantly and will render a huge drawing in seconds when other systems take minutes. As you zoom in Radian will render scenes instantly.
Fast Saves
No need to risk safe workflow by hesitating to save a project because you know it will take a long time. You can open a 100 GB project, make extensive changes and then save the project instantly as well. The project is already saved before your finger comes up off the click of the mouse.
Radian Intelligence for Easy Connections
Radian applies a treasure trove of knowledge, experience and street-smart savvy when connecting to hundreds of different database servers, web data sources, file databases and file formats. With a point and a click the data you want is accessed and available to you because Radian knows the tricky details involved in so many different sources. You can see that in action when you connect to a web-based image server. Radian automatically loads the URL with all the baffling details that might take you hours of tinkering or days of searching web forums to figure out on your own. Several different file formats use the same three-letter extension? No problem, as Radian can tell them apart and will automatically use the right dataport to connect./p>
Automatic Projections
Radian knows basically all projections everywhere. Automatic support for thousands and thousands of different coordinate systems, all of EPSG and a seeming infinity of others has all your needs covered. Radian also uses parallel processing to re-project data on the fly, even read-only data, to show data in different projections together at the same time. Automatically. No need to alter the source data. The image nearby shows terrain elevation data in Latitude / Longitude overlaid on a Bing image server display in pseudo-Mercator. Radian does it all for you. Automatically.
Raw Speed Makes it Easy
Fast is easy and slow is hard. Just say no to slow. Radian automatically uses every CPU and every CPU core in your system for CPU parallelism and if you have a GPU will automatically apply GPU acceleration to run massively parallel computations using thousands of GPU cores. Radian always runs parallel for maximum possible speed.
No Need to Learn Parallel Programming
Run parallel code without learning anything about how to code parallel algorithms. Radian SQL automatically applies CPU parallelism everywhere, using every CPU core you have in every statement, every operator and every function. Radian also revolutionizes the use of massively parallel GPU acceleration by automatically parallelizing SQL both for CPU parallelism and GPU paralleism. GPU acceleration works everywhere in Radian SQL where worthwhile work arises: in the SELECT list, in WHERE, in EXECUTE, ...everywhere. You don't have to learn programming environments like CUDA. Use the same SQL you already know and Radian automatically parallelizes it to use GPGPU. If you don't have a GPU Radian automatically falls back to CPU parallelism with no need to edit code or change any SQL. It's all automatic.
Automatic, Dynamic Previews - See before you Do
See what a point-and-click template or an expression will do before you commit the change. Visual previews throughout Radian - tables, images, drawings, maps - prevent errors and wasted workflow. The images above show how a point and click Buffers template is previewed in
blue preview color in a map. As we change buffer settings in the transform dialog the preview in the map automatically changes. Besides avoiding errors, that makes it easy to pick exactly the right buffer setting for what we want to do. The Best Documentation
Radian provides lavishly illustrated documentation that explains the entire system with hundreds of step-by-step, illustrated examples. Screenshots and diagrams make it easy to understand and apply sophisticated concepts.
Radian Writes SQL for You
You know those "Hello, World" moments when you really would like to see how it's done in a new system, to learn how to cut through infrastructure and do what you want? Radian makes that easy for you by automatically writing SQL to show you how it's done.
Want to see how a point-and-click template works? Click the Edit Query button and Radian launches a command window loaded with the SQL the template executes so you can see what functions are being used. It's a live query, so you can customize the SQL as you like or copy and paste into new queries.
virtuoso Spatial Functions
Radian provides every tool you need to blend, transform, analyze and manipulate the world's most complex spatial data in a flash. Radian's sophisticated parallelized spatial operators, like topology and spatial overlays, work with mixed objects, pathological geometry and do not require special data cleaning or simplification before use. Hundreds of specialized Radian functions are waiting for you patiently on the shelf, tucked unobtrusively out of the way but bristling with power, ready to work for you when your SQL calls them into play.
Scripting Built In
Every Radian installation includes Google's multi-threaded V8 engine so the world's finest JavaScript is always at your fingertips. Radian also automatically provides programming in C#, JScript, JScript.NET, VB.NET and VBScript that are part of Radian's Microsoft environment, with IronPython and IronRuby automatically added to Radian menus when installed. Radian also supports F#, PerlScript and PythonScript when installed.
See Everything - All the Web Sources
The world's spatial data - your spatial data - hangs out in a host of database servers, file databases, web server sources and file formats. Radian connects to them all, including multiple sources at the same time. Better still Radian connects automatically to a vast range of web servers that provide data and images on the fly. Petabytes of data - at your beck and call. Radian connects to geocoding servers for geocoding addresses. Radian connects to image servers to provide street maps and satellite imagery, like Bing, Google, Here, NearMaps, OpenStreet Maps, WikiMapia, MapQuest and Yandex. Radian connects to hundreds of thousands of servers using protocols like ESRI ArcGIS REST, ECWP, OSM, TMS, WFS, WMS and WMTS. Join Radian and see the world.
Formatting On the Fly
Radian can format and style images and drawings on the fly, even from read-only web servers like Bing and Google. Combine and manipulate channels, apply hill shading and automatically calculate statistics and intervals to apply palettes to images. Apply thematic formatting to drawings all without changing the data.
Includes Everything
Install one package and you have it all at your fingertips. No need to buy expensive extras or to struggle to integrate separate products. Radian includes everything, right out of the box. All the extras are already built-in. Launch Radian and you can do it all right away.
No Puzzles
Radian was built from the ground up by a single, professional team as a totally seamless and superlatively complete package that saves you time and money. No need to figure out a jigsaw puzzle of quirky packages and no need to spend days playing software developer. Total Radian integration and legendary Manifold quality set you free to focus on your business.
Feel at Home
Radian speaks your language. Create and share user-editable localization files. Download samples for French, German, Spanish, English and Portuguese.
"So how fast is this reprojection? It's hard not to use rude words here. Disruptively fast! ...Radian's speed-up over Manifold 8 for this task is 16x." - User post on beta forum.
"... when I said "Radian is much faster than PostgresSQL with uncomplicated SQL." I was thinking about the time I spend trying to get PostgresSQL server working rather than how fast queries work. When I succeed I find [simple queries] work similarly fast if key field indexes are set up in both... For dweebs like me having to run a database server on your home computer is daunting so a program that has its own database functionality internal and local is much faster in terms of real effort time." - Forum post
"If PGAdmin or Spatialite had just what RS has in it now in terms of GUI, it would be transformational. Simply stated, RS offers something that doesn't exist in the GIS field (or better yet, spatial analytics field - or maybe data mining field)." - User post on beta forum.
Buy Now via the Online Store
Buy Manifold products on the Online Store. The store is open 24 hours / seven days a week / every day of the year. Orders are processed immediately with serial number email sent out in seconds. Use Manifold products today!


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Serve consumers the best tasting, healthiest, and most sustainable beef on the market.
Provide customers with complete transparency from pasture to plate.
Work with ranchers to produce animals of the highest quality, raised in the healthiest manner and minimize the impact bringing them to market.
With ranches in Uruguay, we produce the highest quality grass fed beef in the world. We believe in grass fed beef. The world's demand for protein is growing, and the environmental and human health costs of feedlot beef, factory chicken, vast monocrops like soy and commercial fishing are proving to be unsustainable. We are USDA certified, USDA-process verified, and we meet all USDA "Natural", "Grass Fed", and "Free Range" Protocols.


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National Barbecue Association award-winning sauces are glazed on slow-smoked Texas beef brisket, pulled pork, and St. Louis ribs
Views of the Susquehanna River and its mountainous backdrop accompany made-from-scratch pastas, burgers, and 10 different kinds of wings
From the merchant: Authentic Lebanese kitchen/lounge Traditional and fresh dishes; falafel, Shawarma, Kabobs. Eclectic Entertainment. BYOB
A popular spring-summer series featuring jazz, soul, and tribute bands, performed amid the rolling hills of this Hershey-area winery
Bar with sports-themed dining rooms, more than 80 flat-screen TVs, and pub food, such as wings with more than 40 award-winning sauces
An old-fashioned family restaurant serving up breakfast greats as well as fried seafood galore
Enjoy a delicious pizza, tasty sub, gooey calzone, and more with unbeatable prices and a friendly face
This barbecue joint boasts both a brick and mortar locale and a food truck, each serving smoked meats, pork buns, and comforting sides
Casual italian-american restaurant features pizza, hot and cold subs, stromboli, burgers, cheese steaks, wings, and salads
Handmade pizzas made from fresh ingredients to bring a slice of New York to the Smithsburg area
Gourmet steaks and fresh seafood such as crab cakes, striped sea bass, and lobster bisque


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*1. Built-in memory capacity after formatting.
EXILIM and BEST SHOT are registered trademarks of CASIO COMPUTER CO., LTD. YouTube™ is a registered trademark of YouTube™, LLC. Any other company or product names are registered trademarks or trademarks of those companies.
*2. Compatible with Eye-Fi Card, an SD memory card-type wireless LAN. *3. When using Panasonic Pro High Speed 1GB SD Memory Card. *4. Range is affected by optical zoom. *5. May differ according to camera settings. *6. F7.5 is the aperture when an ND filter is being used. *7. SOS: Standard Output Sensitivity. REI: Recommended Exposure Index. *8. Image size 2048 x 1536 pixels. *9. Auto Mode, standard brightness monitor setting. Specs are subject to change w/o notice


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Though Aditya Chopra is one of the most popular filmmakers, he is a very private person. Adi likes to stay away from the limelight and so you'll never see him at events or in photographs. In fact, none of us know how he talks or behaves. However, Ranveer Singh just gave us an insight into his life. The actor was at the You and Me song launch where he mimicked his Befikre director and we have to say it was hilarious.
When Ranveer was asked what was so different about Befikre that Aditya Chopra decided to direct a film after eight years? The actor wanted to give Adi's point of view and so, he got into Adi's shoes. Ranveer said, "He (Adi) is never going to meet you to answer this question on his own, so I will be his mouthpiece. Should I imitate him and answer? (Everyone says yes and Ranveer starts acting like Adi). The thing is, I started writing this film thinking that someone else will direct it. But at some point I thought to myself, yaar nahi, main hi ye direct kar sakta hu. So that is a little sneak peak into the man you have never met." Check out Ranveer mimicking Aditya Chopra in the video right here:
Adi has returned to direction after nearly 8 years. He last directed Shah Rukh Khan and Anushka Sharma in Rab Ne Bana Di Jodi (2008). Now, Ranveer Singh and Vaani Kapoor have got the opportunity to work with him in Befikre. ALSO READ – Did Ranveer Singh just FRIEND ZONE Deepika Padukone? watch video
For the uninitiated, Befikre celebrates the Parisian way of life. Dharam (Ranveer) meets Shyra (Vaani) and a romantic journey begins. The movie has been shot in Paris and it is currently, one of the most exciting films of the year. It releases on December 9, which is also Adi's daughter – Adira's first birthday. ALSO READ – Ranveer Singh promises a BEFIKRE episode of Koffee with Karan with Ranbir Kapoor – watch video


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What's going on?
Marking Places
Marking Places is our creative project funded by the Big Lottery Awards For All fund. We are working with the community to create some commemorative markers for heritage sites in Burgess Park. Our Winter/Spring workshops will take place at Waterside Care Home.
Community Green
The Mayor Of London's Get Moving programme encouraged fresh approaches to physical, mental and creative activity for older Londoners. Art in the Park's Community Green gardening and food project, in partnership with Southwark Council and based in Burgess Park community garden, was one of only 16 projects in London to receive funding. Under the Community Green banner, and thanks to a small grant from Notting Hill Housing, we also ran Intergenerational Summer Workshops for people to design, decorate and plant containers for their balconies and gardens.
Place to Remember
Place to Remember was our heritage project funded by the Heritage Lottery Fund exploring the social and architectural history of four local buildings in Walworth and Camberwell. We were delighted to have so many local people and organisations involved, and that ASC gallery was able to host our final exhibition.
Garden Planters with Rose Court Care Home
We have been working in the garden with residents of Anchor's Rose Court Care Home and members of Age Concern Lewisham and Southwark's Yalding Road Healthy Living Centre, thanks to a small grant from United St Saviour's.
Pottery Classes – for Children and Adults
We run classes for adults and children at the studio. Come and have some fun with clay! Enjoy clay painting and wheel throwing, ceramics and ceramic painting. We are now offering kiln firings and other services to ceramicists without their own kiln of studio. Firings start from £40 – please get in touch with Nam Tran for more details for classes and firings.
Thank you to The Bigger Picture!
The Bigger Picture at EDT Film Club has funded the purchase of a pottery wheel for the use of local people in Southwark and Lambeth. To have a second wheel has allowed us to work with twice the number of people at each session and events. Thank you all at the Bigger Picture EDT Film Club!
Courses and Workshops
We have many new art courses and workshops running throughout the year. Life drawing, wood carving, mosaics, pewter and more. See here for more details. Some concessions are available.
Want to work with Art in the Park?
Art in the Park is a charity devoted to enriching Londoners' lives and environment through the visual arts. We run art, performance-based and heritage projects, education and training workshops and are involved in community, studio and public art projects. Our well-resourced studios and training space are located in the centre of Burgess Park, London and run by a team of experienced and talented artists.
Become a member
Find out more about who we are and what we're up to by becoming a member of Art in the Park. Members can expect regular updates on events and workshops. There will be two meetings each year for members to share experiences and views on how Art in the Park should develop and grow.
Make a donation
Team Building with Art in the Park
All successful companies need innovation, creativity, and ingenuity. Art in the Park has organised creative team-building days for many different work-teams over the years. These sessions are tailor-made for the group and we are flexible as to content and size of team.
Paint Machines
Designed and built by Art in the Park artist William Hudson, each one of our three paint machines offer a unique and interactive approach to the creation of art. And everyone leaves with their own unique piece of artwork, or two… or three…!
Hire the Paint Machines for your own event!


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SimHQ have posted a review of TOCA/DTM Race Driver 3:
My impression is that it doesn't matter how many cars and races you shoehorn onto the DVD and on your harddrive when the overall driving experience is dull and unconvincing. RD3 really feels unfinished and unloved by its creators. Why else would you throw in such a lot of cars and tracks, yet totally neglect to create a somewhat realistic, or at least overall engaging racing-experience? Why else would you neglect to enhance in-car views and add pitstops? I just never feel like I'm participating in races, I'm just playing another game here. Before parting, let us just remind ourselves that whereas serious, hard-core sims don't sell that well, Codemasters have been able to sell enough copies of their racing games to actually continue producing those games, and following them up with sequels and new releases, so clearly there is a market.You can read the full review here and don't forget to view our game profile.


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Would you like to save as your currency permanently or for this visit only?
We have been going to this hotel for over 25yrs & just love it it is so central for everything,touring shopping golf & walking so close to the historic town of Stirling. New decor slightly on the dark side in dining room.
The hotel was in a really good location, with superb grounds to enjoy. The leisure club was excellent and the staff were very helpful.
A beautiful place and surroundings.Would definetly recommend to other friends and family to stay here. Only concern was, that the air con was not working correctly
Beautiful location and friendly staff. Only one small lift. Expect to wait.
leisure facilities were put in a famoly room with small double bed, decor needs some updating
The situation of the hotel. The helpfulness of the staff The food was not particularly impressive.
They were very accommodating and let us change rooms to get away from the wedding noise. Lots of weddings - and accompanying loud music!
used the full use of the hotel ,the swimming pool etc was first class no
Friendly relaxing atmosphere
Excellent situation , with magnificent view.
pleasant surroundings, helpful staff no
Very relaxing No bar
quality of food; peaceful; excellent room; beautiful grounds
good location and grounds no one at reception and failed to respond to room service.Apparently issues with the phones
location , fantastic building
I liked the setting and peaceful atmosphere of the hotel. I did not like the room we were allocated, advertised as graciously comfortable. It was more suitable as a single room. Also had a few 'do's and don'ts which were a bit unacceptable.
excellent service and helpful staff
Everything was first class - the come and go easy policy is so homely. The staff have time for you, and want to give you of the best in a totally unobtrusive way. The silence is palpable, and for anyone wanting to relax, it is simply perfect. The facilities are so good, they cannot be described - only experienced; if you want peace and quiet, along with good food. Nothing, except that the tap dripped!
The food was good in quantity and quality. The reception was non-existent, even after using the designated bell and the designated emergency phone no. The reason for this was that the responsible member of staff was at a meeting. Unacceptable.The immediate surroundings of the hotel wewre well maintained - the grass ahd been cut. Outwith that the grounds were poorly maintained. The scrap metal was something outwith the realms of sculpture. The decor was past its sell by date and the hotel needed some investment. Small niggly things, like a leaking noisy tap, were unacceptable.
The service was first class nothing was a bother to the staf I would liked to have been able to visit a bar for drinks where I could purchase draught beer
This is an excellent example of a country hotel. It is set in a large estate, so guests can enjoy a long entrance drive to the building! The interior and furnishings reflect a lost era, one we can only experience here and similar establishments. Our room was reasonably sized although lacking the massive bath experienced in an earlier visit. The hotel has a 5 course dinner available. The food is excellent. However, the price at £50 per head is steep. When coffee is an extra at £4, it appears that the proprietors are being greedy. As there is nowhere else nearby, especially considering that long entrance drive, what can you expect from a monopoly?
Pleasant atmosphere; comfortable room; friendly helpful staff. No tea or coffee facilities in the room. Room (and bed) clearly intended for a single occupant (only one bed light).
Peaceful surroundings. Very friendly & helpful staff even though two of my 3three days the hotel was busy with functions I got a good meal in the bar area and quick service. Compared to the rates I usually have to pay in Stirling this was value for money. It may not be in the centre of town but its very easy to get in by public transport if you want a night out and a taxi is not going to break the bank!! Why do hotels have to use "fussy" taps for bath/shower? S.M.C. are no exception and the one in room 214 took all of my strength (I am 6' and 15st) to alter the heat setting. Not great for a family!!
Very helpful friendly staff. The breakfast menu was excellent. I thought there was going to be a problem when we arrived - 6 rooms had been reserved instead of 3. I appreciate that there was a wedding reception but the bar service at 11pm was slow.
Clearly very handy if attending a conference at the Management Centre, but actually this would still be a great place to stay even if just visiting Stirling or the area for leisure. Food and service all brilliant. a clear commitment to green issues – more than lip service. Not really any bad points. The hot water for a bath in the evening was not quite as warm as I would have liked, though the shower in the morning was a very decent temperature. It could b that I needed to run the hot tap for longer, but that would have run counter to the environmentally friendly ethos of the place.
The hotel is good for people using the management centre or the university, it is not a leisure hotel. the rooms are basic but fine. Some areas such as the bathroom would benefit from refurbishment / upgrading. Customer service could be improved.
All staff very friendly, hotel very clean, rooms cleaned every day to high standard,good choice at breakfast Only fault was that the double beds were very small so did not have very much room to move ,so did not sleep very well
was at a wedding ideal the hairdryer in room did not work I didn't have one with me
Staff professional/friendly and location setting is great.
Friendly, helpful staff. Brilliant location with stunning views of countryside and Wallace Monument. First Class!
On the University of Stirling campus, so ideal for meetings with University management and faculty
Peaceful room, Friendly staff, Excellent breakfast.
Preis in Ordnung No Internet access in the room, no smoking rooms.
Comfortable and relaxed. Parking was a bit tough.
Very often a long wait to be served at the bar as it was one of the waiters who kept coming through from the restaurant to serve drinks.
everything was just fine.
location room was small. generally looked a bit tired
Location, price. Car park needs better signing, and information on how to get the barrier moved.
The food was good in the bar. The lobby is a little shabby as are some of the corridors but for the money I paid this is not unreasonable
Receptionist extremely helpful Very small room, was under the impression that there would be a bath. Evening meal very disappointing; ordered roast which was supposed to come with roast potatoes and was only told there were none left after it had arrived. Gravy very lumpy and meat very chewy. Only one large towel in room.
The Golden Lion is perfectly located 5 minutes from the train, and at the heart of Stirling. There was dozens of pubs, restaurants and shops to keep you entertained, the room and bathrooms were clean, and the staff were lovely and had no problems holding my bag until check-in time. I was even able to squeak into a top-floor room with an amazing view over Stirling and of the surrounding hill-side - spectacular! While the exterior and main floor are exquisite and inviting, the hotel rooms left a lot to be desired. The beds were comfortable enough, the bathroom was functional, however it is out-dated and has an off-colour that doesn't come out from years of use. Luckily it was big and spacious - a great break to stretch your legs after a busy day.
Location Trying to find the way up a one way street
The longe bar and playing chess but not the very expensive drinks and it cried out for a log/ burnes fire as not overly warm Not impressed at all. room was cold due to single glazing even with the heating on. the resturant menu is very limited in choice, we saw a some guests eating out, as we did. there was no hotel info in the room?? Breakfast was a little disorganised and felt rushed. we arrived around 8.30 and it is served until 10am. the waitress removed my partners plate before I had finished then hovered as I was on my last mouthful and removed the plate as I was still eating, very poor indeed.
the location is great and the hotel is interesting because it is an old school.
swimming pool was clean with helfully staff the breakfast. mine breakfast was cold on all three days and the servise was slow you lucky to get your drink after you finish you breakfast with cold toast also it not cooked to order like it says on the breakfast menu.
Lovely breakfast and bed was very comfortable. Generally very dated, and a bit tired. Only paid £79 so not too expensive wouldn't pay more.
The comfort of the hotel, its faclities and the staff made this a most enjoyable stay. Unfortunately, my wife was unable to have a spa treatment due to the majority of staff being away on training
The location and friendly staff. The rain!!!!!!!!!!!!!!!
Nice big room Choice at breakfast was poor compared to similarly priced hotels I have stayed at eg no potato scones, hash browns, no apparent veggie option
Tired room needed decorating
Freindly staff - nice atmosphere Room could have been a little larger - also unable to open window wide enough to get fresh air.
Was working so only used the bed and then only for 4 hours No
on the whole, a well run and clean hotel, staff pleasant and location of hotel excellent if you plan to visit surrounding areas.
Staff were welcoming. Process for booking in and out was quick. Everything asked for was provided. On entering the room it was slightly cold. However after an hour it did warm up.
Desk staff were helpful in finding a restaurant. The breakfast offered a variety of options. I wish there had been a separate sheet on the bed instead of just a duvet. I understand that this is typical of most UK and European hotels.
We found the staff very pleasant and helpful. The room was clean and comfortable. The breakfast arrangements were roomy and the food was good.
Nice hotel could have been better Room smelling of smoke complained and nothing was done about it
Staff were brilliant, I had to stay extra night due to snow, staff had road closures all printed off for guests. Room clean, I put comfort down to good as I found the bed a bit hard but this may suit other people. breakfast included, great. as above, bed a little hard.
the location was great for the park and ride in to stirling. the eating inn next door was excellent too.
Lock on room did not work, staff acted quickly to solve problem Lock did not work, however we were moved to another room
convenience Walls between rooms were paper thin
Excellent staff. I'd like the choice to have a cooked breakfast.
The location at the foot of the Ochil hills was superb and handy for Stirling city centre. They need to pipe music into the bar area to break the silence.
Very attractive place to stay. Clean and comfortable.
The venison was out of this world - fantastic! The staff were also fun and friendly - had a super time in the bar! No hair dryers was unusual, however, must be common here as there isn't one at the Holiday Inn either!
Right from the hard working lovely staff to the shower, the whole castle was lovely. The room was in keeping with the surroundings and was very please to see a clean bathroom. The evening meal was well worth the money and would certainly go back again. The floor board were a bit squeaky but that cant be helped so was aware when walking over the floor.
The food was very well presented and very tasty There was no mirror in the bedroom area and not quite enough light at the bathroom mirror
The room was very nice and the bed very comfortable. The food in the resturant was excellent. N/A
The staff, food, comfort, position - in the city but on the edge of countryside It was a bit too hot, traffic noise (i'm a light sleeper!)
Good, no-nonsense food; special offers on Mon-Weds regarding pricing of wine, comfortable room. Good location for walk into Stirling to see castle etc. City-centre location means ambient noise from road and early-morning bin lorry activity
Friendly efficient staff, relaxed atmosphere, cleanliness, wonderful food N/A
The size of the room was decent and the bathroom very clean and a good size also. The bed was not very comfy.
We had a lovely break and would definately come back No complaints at all
comfortable and welcoming, very enjoyable
the very efficient and friendly staff. the high quality of the rooms and the personal attention given to us.
Delightful hotel, central to town centre with attractive weekend rates.
All the staff were quite efficient and friendly. The room had everything I needed. Very nice breakfast and everything was when and where I needed it. Great location, too, and a charming house to stay in.
the location to the town centre the road leading upto the hotel, was strange to locate due to the road lay out.
I don't like typical breakfast (beans, eggs etc...) no choices in morning menu
myself and my daughter had a very pleasant stay lovely breakfast helpful staff pleasant room would definately stay again
We both enjoyed our stay at the hotel. The staff were very friendly and pleasant. We had a great 5 day break
The cleanliness, the proximity to the city center and the railway station, the good breakfast.
staff very friendly at all times. Food good. Great central location yet quiet
Friendly staff The most important thing and the reason I stay in a Hotel is for a comfortable bed. Th bed in room 3 was the most uncomfotable bed I have slept in. Also I would like my own key when out late
From the minute we arrived the staff made us feel welcome, the customer service was outstanding
The rooms were excellent - large, clean and comfortable. The staff were superb - very accomodating and helpful. We will definitely be visiting Stirling again and will stay at The Terraces Hotel.
Helpfulness of staff
The staff were all extremely friendly and helpful. The hotel could do with a bit of modernisation.
staff were helpful and friendly breakfast was great overall very pleasant stay room was lovely
dining room exceptional and the menu excellent. room a bit small but nicely decorated and fresh. external looked a bit tired.
the view
Good breakfast. Morning paper. Room was quiet. The window curtain is practically tranparent and this led to light pollution from outside
lovely room, good breakfast
friendly staff
Exellent Value for Money Breakfast Site Seing Castle Monuments and also met Friends for a birthday Party
The breakfast was cooked well, no grease, and a full English available with the choice of buffet providing cereals, fruit juices, fruit and toast etc. The beds were clean and comfortable. Yes unfortunately we were placed in a room which must have been a 'smoking' room before the law was enforced. Therefore the room smelf strongly of stale tobacco smoke and it was necessary to sleep with the window wide open all night. Also the shower did not run with hot water, only luke warm to cold, therefore had to have a bath and use the shower lower to rinse hair when washed in the bath, whih left us cold!
I stayed at the hotel due to the snow and the service was very good and the food was delicious and fairly priced. The bed wasnt very comfortable
The room was clean and comfortable. The staff were friendly and polite.
very good value slow service in the dining room
It suited our purpose close to family. will probably come again. Your contradicting yourselves. Don't like... complaint... is the same. So whats the answer. We had two for such a short stay. your sandwiches were poorly constructed and appeared frozen, and no staff covering our bar area, sitting waiting for service...
Convienent for staying in Bridge of Allan The room needs renovation. THe ceiling has water stain. One of the knobs on the bathtub is gone! Internet connection is very poor - cannot connect to the internet!
The food at the hotel was of a very good standard and very reasonably priced and the staff were pleasent and helpful. The price of the room was competative but this was reflected in its condition. The condition of the decor in the room was in a word "tatty", the double room was small but warm and the bathroom was of a good size with everything working as it should.
Friendly (Hungarian) receptionist. Central location. The hotel had character though was a little tatty. The bar menu described the dishes in detail, however my experience was that the description did not fully match the food served. The bar was run by a foreign (Polish?) girl with little command of English and no grace. Not a nice experience.
All staff were helpful and friendly. Good meal in the restaurant.
The breakfast was excellent. Everything else was very good. Only the Christmas promotion decorations up in July.
The hotel was perfectly situated. The staff were extremely friendly and made our stay very happy. The place could do with a lick of paint. It was obvious there had been signs of damp. Looking out the window, the side gardens needed atttention and there was a dead bird directly underneath the window, which obviously had been there for some time.
Very nice rooms little hard to find
was amazed was top class for price paid .we WILL be back thanks n/a
The welcome was excellent. Bed was comfy and I realy got to relax after a stressfull day of meetings. Would definatly visit again and recomend to others.
Alistair and Alieen were just lovely, Made us feel very welcome and had made up a handy list for taxi numbers, restaurants ect. The room was lovely and warm for us coming in and was beautifully decorated. My partner and I will be using them again.
The owner is very friendly and helpful. There is a pub within easy walking distance, and the room was warm, clean and a good size. It is a fair way out of town, but not a problem if you have a car.


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UFC light heavyweight champion Daniel Cormier underwent surgery on Monday and says he is on the "recovery" already.
Cormier was forced out of a planned meeting with Jon Jones this month for the title. Officials placed Ovince Saint Preux in a bout with Jones for the interim belt in his absence.


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The Last Voyage of Columbus
Book cover, paperback edition.
Author | Martin Dugard |
Language | English |
Genre | Biography |
Publisher | Little, Brown & Company |
Publication date
June 1, 2005 |
Media type | Novel |
Pages | 304 |
The Last Voyage of Columbus: Being the Epic Tale of the Great Captain's Fourth Expedition, Including Accounts of Sword fight, Mutiny, Shipwreck, Gold, War, Hurricane and Discovery (also referred to as The Last Voyage of Columbus,) is a non-fiction book, authored by Martin Dugard and published in 2005 by Little, Brown and Company.[1] The plot is a lifelong account of explorer Christopher Columbus and his founding of what is now often referred to as the New World. The book received positive reviews by critics.
The books topic focuses on Christopher Columbus, who was one of the first European founders of the Americas. The book tells the story of his life, as well as the problems he faced with his journeys. Columbus had seduced some of the most powerful woman in Europe to pay the expenses of his trip.[2] The book follows Columbus' departure from Spain prior to his first voyage before sunrise on August 3, 1492. After three days of sailing on the Pinta, the rudder became loose, unable to cope with the strength of the seas, Columbus and his fleet stayed for a month on the Canary Islands. After repairing the ship, the fleet resumed sailing, despite pleas from fellow crew members for Columbus to turn back, which he ignored. On October 11, 1492, after seeing a distant light, it was later confirmed this was the area which would soon be marked as the New World, claiming the land to for the Spanish sovereigns, as well as claiming numerous other islands for Spain. In reward for this, Columbus was given ten thousand Spanish maravedis and 1/10 of all Royal profits.[2]
Ben Cosgrove of The San Francisco Chronicle comments "Dugard's book breathes life into that futile, unquenchable, 500-year-old dream. There's adventure for you."[3] Ben Sisario of The New York Times noted about that book that "In a rich, fluent account, Dugard offers both a gripping naval adventure and a revealing history of the competitive mercantile politics of the turn of the 16th century, and portrays Columbus as a star-crossed striver eager to legitimize his quest."[4] James Neal Webb of Book Page comments "The Last Voyage of Columbus, a new book by Martin Dugard, is of the latter variety, and in it we find a figure who, while familiar, is more human and thus more interesting than the Christopher Columbus we know from history textbook."[5]
- ^ The Last Voyage of Columbus: Being the Epic Tale of the Great Captain's Fourth Expedition, Including Accounts of Swordfight, Mutiny, Shipwreck, Gold, War, Hurricane and Discovery. Google Book Search. Retrieved 2008-01-28.
- ^ a b "The Last Voyage of Columbus. THE VOYAGE THE WHOLE WORLD REMEMBERS". Hachette Book Group USA. Retrieved 2008-01-28.[dead link]
- ^ Cosgrove, Ben. "Sailing to the New World, for fourth and final time". San Francisco Chronicle. Retrieved 2008-01-27.
- ^ Sisario, Ben (July 31, 2005). "Nonfiction Chronicle". The New York Times. Retrieved 2008-01-27.
- ^ Webb, Neal James. "Sailing with Columbus. REVIEW BY JAMES NEAL WEBB". Book Page. Retrieved 2008-01-28.


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Fan of 2 Teams
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Manchester City
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OMIDO updated their profile
OMIDO wrote in WC Qualifying Asia Chat
Thank you, I know we deserve automatic qualification because of our looks but our football skills are amongst the best in Asia. ehem ehem 6-0 speaks for itself ...
On OMIDOs wall
Hay dude tnx for add me but how can i add u..........?
im loyal with my team and u r fan of the biggest rival of my team so i only add u
as a cool rival.......
True, thx
Bummer result in the second round! Gutted!!
LOL, thx, Not sure the Red's agree!!!!!!
The only, more like.
Congratulating roma fans?!! just after a 3 point win? they played a rubbish juve, but played the rubbish juve side very well. well done to roma!
Fantastic profile pic!
I am not going to give you "He was lucky blah blah etc etc."
But to be honest, he played during a time when the second best in his position was Wes Brown!!! H...
Wow well done leeds playing like a true premier league side
Has he fallen ill? no news of him being unwell in the english media! can u update please
Great post andy!!
Del Piero still plays his heart for Juve every match. a true legend
Strongly agree with u mate
What's happening to juve? time for a new manager!
Zidane!!!!!!!!!!!!! for the headbutt.
All i can say is Gary Neville, unlike his brother a true gentleman in my opinion, belongs to the same group of crap footballers whose footballing skills aren't ...
Sorted, cheers
Can someone please tell me how much the footytube jersey is valued so that i can adjust my paypal payment accordingly and hopefully get one if still in stock?
This is a genuine football poll on the Guardian website: (and quite rightly so 86.8% of football fans across the country believe that yes he fits such descripti...


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Keb' Mo' Peace...Back By Popular Demand
Price: | $7.19 |
List Price: |
You Save: | $0.80 (10% Off) |
Currently Out of Stock:
We'll get more as soon as possible
on most orders of $50+
Brand New
CD Details
- Released: September 21, 2004
- Originally Released: 2004
- Label: Sony
Entertainment Reviews:
Living Blues - pp.46-8
"With PEACE...BACK BY POPULAR DEMAND, a collection of songs about peace and social justice, Keb' Mo' puts his music where his politics are....Keb's plea for peace is hard to miss."Tracks:
- $0.99 on iTunes1.For What It's Worth
- $0.99 on iTunes2.Wake Up Everybody
- $0.99 on iTunes3.People Got To Be Free
- $0.99 on iTunes4.Talk
- $0.99 on iTunes5.What's Happening Brother
- $0.99 on iTunes6.The Times They Are A-Changin'
- $0.99 on iTunes7.Get Together
- $0.99 on iTunes8.Someday We'll All Be Free
- $0.99 on iTunes9.(What's So Funny 'Bout) Peace, Love And Understanding
- $0.99 on iTunes10.Imagine
Product Description:
Personnel: Keb' Mo' (vocals, acoustic guitar, electric guitar, slide guitar, mandolin); Keb' Mo'; Paul Jackson, Jr. (guitar, acoustic guitar, electric guitar); James Harrah (electric guitar); Mark Cargill (violin, fiddle); Susan Chatman (violin); Karen Elaine Bakunin (viola); Miguel Martinez (cello); Lon Price (saxophone); Mindi Abair (soprano saxophone, alto saxophone); Nick Lane (trombone); Greg Phillinganes (piano, organ); Reggie McBride (bass instrument); Stephen Ferrone, Steve Ferrone (drums); Alex Brown, Maxi Anderson, Phillip Ingram, Wil Wheaton (background vocals); Jeff Paris (mandolin, piano, electric piano, Fender Rhodes piano, keyboards, synthesizer); Harvey Mason, Sr. (drums); Paulinho Da Costa (percussion).
Audio Mixers: Keb' Mo'; Mark Johnson .
Recording information: Conway Studios, Hollywood, CA; The Village Recorders, West Los Angeles, CA.
Photographer: V'ronique Vial.
What began as a few protest songs recorded by Keb' Mo' in response to the war in Iraq turned into 2004's PEACE?BACK BY POPULAR DEMAND, a 10-pack of tunes about hope and freedom. Amazingly completing this project in a month's time, Keb' Mo' managed to rustle up an interesting array of (mostly) covers.
With his rich vocals and laid-back phrasing, the Los Angeles native shines on a bubbly reading of Donny Hathaway's "Someday We'll All Be Free," takes a crackling walk through McFadden and Whitehead's "Wake Up Everybody," and strips Dylan's "The Times They Are A-Changin'" down to an acoustic piano duet. Unusual arrangements abound, whether it's the vocals fed through an echo chamber that defines Mo's version of Marvin Gaye's "What's Happening Brother" or the country-blues romp through Nick Lowe's "(What's So Funny 'Bout) Peace, Love and Understanding" that's rendered with a healthy smattering of mandolin and fiddle. The one original here is "Talk," an inquisition to the President of the United States, goosed along by the guitarist's distinctive dobro work. If music can help change the world, then PEACE is a good start.
Music Lovers' Ratings & Reviews:
Customer Rating:
Based on 29 ratings.
Based on 29 ratings.
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Proof that the Devil doesn't have all the good music
At the time of his death, on February 24 at the age of 60, Christian freak-folk luminary Larry Norman was working on an album with guests including Modest Mouse's Isaac Brock and the Pixies' Frank Black, the latter of whom said, upon Norman's passing, "Larry was my door into the music business and the most Christ-like person I ever met." If you read that quote and find yourself re-assesing what kind of a band the Pixies really were, you might want to have a click at the video above: whatever your notions of Christian rock, Norman doesn't fit it. In his prime, he looked like an Allman Brother, sang with voice as piercingly nasal as Axl Rose's, made birdcalls and nonsense words a part of his signature style, and wrote songs that compared Jesus to a UFO. (Before "Come on, Pilgrim" was the name of a Pixies EP, it was one of Norman's catchphrases.) Far closer to Roky Erikson than to politely pious souls like Amy Grant, Norman was among the first to complete a circle that reconnected rock and roll's sanctified, unruly spirit -- which had emerged, in part, from black spirituals and the rhythm-and-blues they spawned in the 1940s and '50s -- with the strain of psychedelic Christianity that emerged in California in the early 1970s. According to Josh Frank's oral history of the Pixies, Fool the World, Norman figured prominently in Frank Black's musical coming-of-age, which for Black transpired in a specific context: the death of the hippie dream. "A lot of people who were older, coming out of the '60s, '70s, hedonistic lifestyles, sexually promiscuous or involved in a lot of drugs," Black says in Fool the World, "people that had destroyed their lives, they came out of it clinging onto Jesus Christ." He continued:
Southern California Pentecostal culture, it's fire and brimstone but it's more like, success, like, "God wants you to be successful!" I probably discovered Larry Norman when I was 13 because my family had taken up this religious experience, whatever you want to call it. I was going along with it, as my whole family was. I think when you're 13 or 14 you're open to a lot of stuff, and if people say, "Hey, Jesus!" you don't go, "Ooh, I'm cynical!" You just kind of go, "Yeah, Jesus, cool!" Larry Norman is a real oddball guy. He's not like what people would think of him. "Ooh, a Christian, what's that going to be about?" He's totally his own thing.
Larry Norman was born in Texas in 1948, moved with his family to San Francisco a few years later, and performed publicly before the age of 10, often accompanying his father on Christian missions to prisons and hospitals. His band People! recorded two albums for Capitol in the mid-'60s, and performed on bills with the Doors, the Who, and Hendrix. His 1969 solo album Upon This Rock is often mentioned as the first Christian rock album, although Norman bore little resemblance to the genre that followed him. As an outspoken opponent of racism and poverty, he clashed often with conservatives and his music was banned from Christian retailers. In a career spanning 40 years, he released scores of albums and performed to stadium-sized crowds. Norman knew he was near the end on February 23 when he wrote an emotional farewell letter to his fans. "We are not sure of the date when I will die," he wrote, noting that he hoped "to be buried in a simple pine box with some flowers inside." Although he hoped to "push back the darkness with my bravest effort," he was resigned to meet his maker. "I feel like a prize in a box of cracker jacks with God's hand reaching down to pick me up," he said.


text:
- Home
- Business Opportunities
No. of Franchise Outlets: 04
Investment: Rs. 5lac - Rs. 10lac
Saran Education Pvt. Ltd. - a business model for you to start in education sector!
MASOOM KIDS by SARAN EDUCATION PVT LTD, a unique with innovative PRE- SCHOOL in India. We at Masoom kids believe that "EVERY CHILD IS UNIQUE" we are passion to transform education in new shape and explore for each child a sound base of experiences, a strong sense of self-esteem, and an excitement and curiosity for learning for better and RESPONSIBLE CHILD.
At MASOOMKIDS Preschool we integrate the community into our classrooms. Our students go out and explore the community. We also have community members come into the classroom and share with the children and staff
We EXPLORE-EXIBITE-EDUCATE tots not only for education but a RESPONSIBLE CHILD.
We at MASOOM KIDS is to deliver high quality of education programs that equip our students with a solid foundation in integrated curriculum with technological savvy, methods, materials, and interactions needed to create the environment that leads to enriched learning opportunities for every child.
A range of early childhood settings preschools and integrated centres use the framework to design play-based programs that encourage children's:
- Communication
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- Area Required: 1500-3000 sq ft
- Investment: Rs. 5lac - Rs. 10lac
- Franchise/Brand Fee: Rs. 150000
- Royalty/Commission: 8%
Our system specifically designed for the children to enhance the level of understanding:
- A strong sense of identity
- Connections with their world
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- Effective life skill based learning and leading with mix of various types of activities skills and modules are exhibited.
- We have a solid commitment to providing high quality care and education for young children.
Interested in above franchise model? Connect now to know more & become franchisee!
Thanks & Regards
MASOOM KIDS Team


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The AMD Radeon R9 290X might run a bit hot and loud for some people, so what happens if we lower the target GPU temperature?
If you recall the AMD Radeon R9 290X in quiet mode has a target GPU temperature of 95C and a maximum fan speed of 40%. We wanted to see what would happen if we lowered the target GPU temperature while gaming, so we used Alt + Tab and went into CCC to lower the target temperature.
We dropped the target temperature down to just 65C to see what would happen and that was the only setting that we changed in AMD OverDrive. The temperature was at 94C in the game, but was gradually dropping (86C in the shot above) when we were tabbed out of the game.
Here is a shot of what happened when we applied the new Target GPU temperature in the middle of a game title. Notice the core clock speed immediately throttled back as did the voltages, but the fan speed ramped up to nearly 70 percent. The maximum fan speed was set to 40%, but it appears that doesn't really matter as the GPU temperature target takes priority. Maybe once the GPU temperature reaches 65C, the fan will spin down to something quieter as this was topping 70dB on our sound meter.
After a few minutes the Radeon R9 290X was playing Battlefield 3 at just 64C, but notice the core clock was stilling running around 727 MHz, which is much lower than it would be with a GPU temperature target of 95C. Notice that fan speed settled down and was running at 46 percent, so much for a maximum of 40 percent right? So, we successfully lowered the operating temperature down to 65C, but the fan needed to spin faster and the card got louder and ran slower. Not sure that is exactly what we were going after, but let's take a look at what happened to the game performance.
Radeon R9 290X | Radeon R9 290X | Percent Difference | |
Temperature Target | 95C | 65C | |
Bioshock Infinite | |||
2560×1600 | 82.12 | 68.96 | -16.0% |
1920×1080 | 131.62 | 109.57 | -16.8% |
Tomb Raider | |||
2560×1600 | 79.4 | 64.9 | -18.3% |
1920×1080 | 137.9 | 111.6 | -19.1% |
Hitman Absolution | |||
2560×1600 | 34.3 | 30.4 | -11.4% |
1920×1080 | 54.5 | 46.6 | -14.5% |
3DMark Fire Strike | 9,727 | 9,092 | -6.5% |
As you can see our real world game performance dropped on average 16% and our 3DMark score dropped by nearly 7% by lowering the GPU Target Temperature 30C. We like being able to adjust the temperature of the card, but you'll be giving up performance and increasing the fan noise. Not too sure how many people are buying a $549 video card and would be looking to do something like this. Of course you can do this at any temperature setting between 50 to 95C, so the warmer you go you'll see less of a performance hit. WE picked 65C as many of the AMD Radeon R9 280X video card that we recently reviewed were running below 70C at full gaming load.


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Wrensilva announces a smaller and lighter take on the record console-- the Loft, a console built out of N. American walnut able to stream records directly to Sonos speaker systems.
The Loft features modern internals inside retro stylings, with an OA2 precision Gimbal tonearm and Ortofon 2m Red cartridge paired with a 300W per channel Bang & Olufsen ICEpower classD amplifier. The turntable is fully decoupled belt-driven, while wifi connectivity allows one to push whatever vinyl is being played to a whole-home Sonos system.


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Hey, I just got a new Sony HDR-UX1 for Christmas and it's an awesome camera. The only problem is, I have no idea if there is any way to transfer the video onto my powerbook. Any suggestions?
firewire through iMovie, and if you shoot in HD, iMovie should be able to capture the HD, which is pretty cool! Congrats on a sweet new camera!
According to CamcorderInfo.com's review... It's still a challenge at the point. Quoting from http://www.camcorderinfo.com/content/Sony-HDR-UX1-Camcorder-Review.htm ---- Editing (1.0) Heres the tricky part. So far, there is one and only one way to view AVCHD footage on anything but the camcorder: Sonys in-the-box editing software (a chorus of groans rises from the audience). Yes, we know that in-the-box software is usually rudimentary at best, and malfunctioning at worst. Included in the bundle is an ACVHD player, a media import program, and the latest version of Picture Motion Browser. In this case, we found the whole process extremely frustrating. A PC in our office that has never given us any trouble was completely unable to read the disc after installing the software. Our Macs were rendered entirely useless, as the software can only be installed on Windows machines. Finally, another PC in the office was able to pull the footage, but by that point, we were pretty frustrated with the whole process. DVD footage is often a hassle, but nothing prepared us for this little battle. Heres another problem. Though a number of software manufacturers have signed on for AVCHD, including Adobe, Avid, InterVideo, Nero, and Ulead, not single one of them has a product on the market to read it, nor have they given a date when said software will be released. Even Sony Vegas cant play AVCHD yet (though Vegas 7 is due out soon). Without a workflow solution in place, even a mediocre one, AVCHD is a format trapped in its own media. This review would have been out a whole week earlier if we hadn't run into these problems, and think about the number of resources we have on hand. What is the poor average consumer to do if they owned an HDR-UX1 right now? We have no doubt that solutions are in the works from any number of sources, but we are writing in the present. The present says: "wait on it."
Pretty much what Moof1904 said. You've got a camera that has almost zero editing support out yet. Lethal


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Donaji & the Magical Poncho
This is the story of a fearless girl and her encounter with the wicked cold wind god
4.29 / 5.00 3,948 ViewsEdit: *Daily second, Weekly 5th, Review Crew Pick, added to the zelda collection, and front page! Thanks a ton NG I am speechless : >*
Ten years before Majora's Mask, which might explain why the characters are younger than in the game : >
There were a lot of starts and stops for this flash, but I am glad it if finally finished. Special thanks to the voice actors for being so patient through this. Also to the folks on the Skype Superlab, Budj, Joey, Tami, Teejay, Gustavos, and Anna for testing and helping me with the animation flow over countless hours. : P
I had this idea about a year ago and sent the script to a different animator. However before she got started, she dropped out of the project because of school, so I ended up animating the entirety of it.
The flash is a double narrative, featuring two different stories, that share a same meaning. Since a lot of people are not familiar with Majora's Mask, or have it fresh in their heads, I knew it might have people that wouldn't understand it or be familiar with the characters, such as the young boy "Kafei." So I equipped it with a moral at the end to make it interesting for non- zelda fans as well, hopefully.
Special thanks to Seraphim for the great looking loading screen art. Hopefully people can contact him if they need commissions done, he was great to work with.
I hope you enjoy the bitter sweet parable of A Keaton's Tale
Mmmm I wanna see more.
This was very good and you guys deserve frontpage!
Don't stop the work and make a sequel!
Thanks for your review : >
When tales of the forest are told, you normally expect an owl to tell it, but a nine tale fox works just as well particuliarly when speaking of tales.
this is a really great story you managed to create a story out of something that was not even mentioned in zelda / just a great job.


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Doctor insights on:
Food Poisoning Facts For Kids
How would I know if my child has food poisoning vs. Stomach flu?
Very tough: Unless you know the suspected food and are able to test it, or there is an outbreak with an epidemiological analysis it may be very hard to determine the source of self-limited nausea, vomiting, diarrhea. On the other hand if your child has fever, other symptoms outside the GI tract, they probably have a viral illness, although not necessarily influenza. ...Read more
Poisoning (Definition)
Toxic ingestion (also called "poisoning") is a condition in which a person has eaten or drank a substance that causes ill symptoms or damage to his body. Taking an overdose of a medicine, taking any dose of a poison, drinking too much vodka, or accidentally drinking antifreeze . . . are all ...Read more
How to get food poisoning?
Food Poisoning: Food poisoning can be caused by bacteria (E.coli, Listeria monocytogenes, Shigells, Staphylococcus Aureus, C. botulinum, Clostridium perfingens, V. cholerae, C. jenui.), viruses ((Norovirus, Rotovirus and Hepatitis A)& toxins in food Ciguatera in tropical fish that have eaten toxic plankton, Shellfish fed on toxic algae, Scromboid in poorly refrigerated dark meat fish,Puffer fish. Some mushrooms > ...Read more
How to cure food poisoning?
Treatment: Treatment of Food poisoning may include oral or intravenous replacement of fluids/ electrolytes. Antibiotics may be needed for bacterial infections. Hospitalization is sometimes necessary. ...Read more
How does food poisoning spread?
By what you eat: Food poisoning doesn't spread from person to person. Rather, bacteria or virus is eaten which causes a reaction in your body. Everyone who eats the same food has similar reaction i.e. Nausea, vomiting, diarrhea , abdominal pain, etc. ...Read more
See 1 more doctor answer
How can I treat food poisoning?
Symptomatically: For the most part. Although some causes of foodborne gastroenteritis should not be treated with anti-diarrheal meds despite diarrhea because shigella and e. Coli o157 can be made worse. Remember some foodborne diseases are not specifically gastrointestinal such as botulism and amnestied shellfish poisoning and scombroid fish poisoning. ...Read more
See 1 more doctor answer
How is food poisoning diagnosed?
Clinically: It is usually a clinical diagnosis based on the presentation. Sometimes we will get stool studies depending on the clinical circumstances. ...Read more
How do you treat food poisoning?
Fluids, maybe meds: Supportive care, fluids, brat diet (bananas, rice, applesauce, tea), maybe meds. Not always antibiotics; be careful using antidiarrheals-can retain the germ. Probiotics can be helpful. Contact md if prolonged, fever, bleeding, can't keep things down or in. ...Read more
See 2 more doctor answers
What could cause food poisoning?
Food poisoning: Food poisoning can be caused by bacteria, viruses and toxins in food. ...Read more
See 1 more doctor answer
What to do about food poisoning?
FOOD POISONING: Avoid uncooked food and tapwater.Well cooked kills bacteria and spores.Take extra precautions while traveling to underdeveloped regions in the world. ...Read more
How can you fight food poisoning?
Be cautious : Of where st what you eat. When you eat out make sure your trust the food preparation and staff hygiene. Avoid ordering raw or under cooked foods. At home wash your produce well. Don't use the same cutting boards for meats as you do veggies. Wash your cutlery well. Cook your food thoroughly. ...Read more
Food Poisoning (Definition)
Food poisoning, also known as foodborne illness, is an illness coming from food contaminated by bacteria, viruses, parasites, toxins, or other substances. Anyone can be at risk, but pregnant women, older adults, and people with chronic ...Read more
Nutrition (Definition)
Nutrition is the synergistic combination of nutrients found in food and water that allows the human body to perform all essential ...Read more
- Talk to a doctor live online for free
- Facts on food poisoning
- Interesting facts about food poisoning
- Junk food facts for kids
- Ask a doctor a question free online
- Fun facts for kids about food
- Food poisoning
- Facts on chickenpox for kids
- Oesophagus facts for kids
- Talk to a pediatrician online


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Tommy Hilfiger Men's Classic Crew Neck Tees 4-Pack - White
Out of stock. This product has SOLD OUT!
Tommy Hilfiger Men's Classic Crew Neck Tees 4-Pack - White
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Available in men's sizes - check size chart for correct fit!
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- Tommy Hilfiger apparel
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- Style: Classic Crew Neck Tee
- Colour: White
- Pack contents: 4 t-shirts
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- Materials: 100% cotton
- Machine washable
- Country of origin: Sri Lanka