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By: Tracey Manailescu
What is Instagram?
"Instagram is an online mobile photo-sharing, video-sharing and social networking service that enables its users to take pictures and videos, apply digital filters to them, and share them on a variety of social networking services, such as Facebook, Twitter, Tumblr and Flickr." Wikipedia
How to create an account: It's easy. Really. Download the Instagram app on your phone. Enter your email and choose a password. When you have signed up for your Instagram account, edit your profile and add your company name, a photo of you or your company logo, and your url. You can also add a small blurb about you and your company. Find people to follow and get followers right away by clicking on the button to add your Facebook friends that have Instagram accounts. They should follow you back.
Do you have a personal and a professional Instagram account, or do you lump it into one? I just have one. There are so many debates about this but I try to keep it related to my world which consists of weddings, conferences, travel, eye candy and some random family & pet photos. It sounds a bit eclectic, but that kind of fits my personality.
How often should you be updating your Instagram? Update it when you have something interesting & wedding/design worthy to share. Over posting is going to turn people off. (Unfortunately, there isn't an option to hide someone's posts yet like on Facebook, but you can block someone from seeing your posts. Go to their account, it'll still show that they are following you, but they won't be able to see your posts. Go to that person's page. Click on the button in the top right corner, beside their username. "Block User" button in RED will come up, click on it, and they will no longer see your photos or get notifications from you.
What photos should you share on your Instagram? Show your followers work that you have done, shows photos of couples & their weddings that you have worked with/on, shares a glimpse into your wedding company & you (and your team) on site visits, planning meetings with vendors, cake tastings, catering tastings, share what inspires you, what you are capable of, share when you attend conferences and courses, share your magazine ads or wedding show booth, show your office, desk, files, any badges you have received for getting in publications, any products that you offer, etc. Consider this a free way of advertising yourself to potential clients. This being said your followers should be able to see a little bit of you in your posts, too.
Contests can get you get more clients, likes and comments on your Instagram Hold contests for your local followers or potential clients. Who doesn't like free stuff, right? Some ideas are to add a wedding related photo and have followers guess what the photo is, where it is, have followers provide captions for your post, etc. for a prize. (A prize could be movie passes, a gift card for a date night to a local restaurant, etc.) Have a contest for couples to share their engagement photos with you to win one of your services
Example: #Lovebirds, share your engagement photo with us to win a 2 hour Consultation with ****** Prize valued at $200. Add photo and tag #WPICwearengaged When you like or comment on peoples posts, they are much more likely to reciprocate.
What is the deal with #Hashtags? Hashtags are key words. When you add a hashtag that is relevant to your Instagram post and someone is searching for something specific, your photo and account will "pop up". This is a chance for those people who checked you out to "follow" you (this translates into increasing your followers). Examples: #romance #GTAweddingplanner #WPICcertified #weddingcake etc. Try to not over use the #'s though. It is recommended to use 1-3 #hashtags with each post.
Add video: Share some exiting moments or highlights of a wedding or event, or a "how-to" segment in a short video, so your followers can feel more connected to you. Click here to see Instagram's tips about adding videos.
Some Instagram Statistics:
Instagram launched in 2010 and currently has 7.3 million daily users worldwide
Most posts happen on a Thursday, but Sunday is the most effective
Instagram is available in 10 languages
55% of users are women, 45% are men according to Social Times
34% of users are aged 25-44 according to Social Times
Some Groovy Apps for iphone and Androids:
If you want to add some "awesome-sauce" to your photos, why not try some of these apps to increase the look and feel of your photos? (Some are free and some are a small fee.)
Aviary for touch ups, frames, stickers, etc. (Free)
PhotoWonder lets you edit, makes you skinnier, removes acne, add makeup, add cool effects, make collages, and change colour saturation. (Free)
A Beautiful Mess has some filters to change your photos up, but the best part are the fun borders, text options and hand-drawn doodle overlays. (Cost is .99 cents)
Snapseed red eye filters, saturation, cropping, and anytime you want photos to pop. (Free)
Overgram So many great fonts to add text to your photos (Free)
Facetune corrects small facial imperfections like wrinkles, whitening your teeth, get rid of blemishes, enhance your eyes and lips. (Cost $2.99)
Bubbleframe Create photo bubbles with your photos (Cost $1.99)
FuzelPro lets you create animated collages. What? Yup. Click on the examples from their site to be amazed! (Cost $1.99)
8mm A whole bunch of cool effects for shooting vintage videos, and lets you add dust, scratches, flickering frames, light leaks and more vintage effects to your films. (Cost $1.99)
Share some of your favourite apps in the comments section with us!


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Relizon Wins $30MM in New Health Care Business
Wednesday, March 03, 2004
Press release from the issuing companyDAYTON, Ohio, March 2, 2004 -- The Relizon Company, a leading North American supplier of business process solutions for document management, billing and relationship marketing, today announced that it has recently won over $30 million in new multi-year document management contracts from the health care sector. The new wins represent both leading health care networks, such as CHRISTUS Health, University Hospital Health System and Mariner Post-Acute Network, as well as individual providers such as Scott and White Hospital in Temple, Texas. Relizon is now a preferred supplier of two of the nation's top health care purchasing organizations (GPOs) and stands as the fastest growing brand in the health care document management market. On the heels of these recent wins, Relizon is today also announcing the formation of a strategic health care business group responsible for better serving the unique requirements of current and potential health care provider companies. Relizon's rapidly growing and maturing health care business is the result of providing solutions that solve specific business issues faced by hospitals and other institutions. As a leader in document management, Relizon applies its deep knowledge and operational experience to design and deliver solutions, executed with unparalleled service to member organizations. Relizon's approach is national in scope, yet meets regional needs, enabling the company to easily support the supply chain management objectives of the GPO, as well as the unique service needs of its members. A typical example of how Relizon is helping health care customers meet the unique challenges of that sector is Memorial Hospital of Gulfport, Mississippi. Memorial is a rapidly growing acute care facility with 420 beds, three urgent care clinics, and offsite behavioral health, rehabilitation and physical medicine. Most recently, Relizon has helped Gulfport Memorial prepare more than 672 different types of patient chart documents for online access. "That's where Relizon is really helping us out -- getting all of our forms ready to be scanned in for electronic archival," said Dick Roesner, distribution manager of Memorial Hospital. Relizon also helps Gulfport manage more than 600 administrative documents. "Now with everything bundled under Relizon, we've got a handle on what we need, when we need it, and in what quantities," Roesner added. "It's made my life as a distribution manager a lot easier." With more than 40 manufacturing and distribution facilities and 4,500 employees strategically located across the U.S. and Canada, Relizon provides health care clients with a national network that delivers solutions regionally, for faster turnaround and stronger customer service. "We've found that Relizon's document management capabilities align perfectly with the needs of health care institutions for a strong national player that can deliver exceptional service to individual hospitals across the country," said Timothy Schriner, president of Relizon's U.S. Business Communications Group. "With dozens of manufacturing and distribution sites across the U.S., we are less than 3 hours away from nearly all of our GPO member hospitals." "We believe the time is ripe to leverage the expertise we've gained from years of serving health care clients and create a more dedicated focus on this sector," he added. "Our strategic health care group will ensure that customers benefit from our strong health care domain experience and our portfolio of best practices to transform their document management processes."
Industry News
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subset: commoncrawl


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Pathology Research International
Volume 2012, Article ID 913523, 10 pages
The Role of Molecular Pathology in the Diagnosis of Cutaneous Lymphomas
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 7.103 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA
Received 1 August 2012; Accepted 18 October 2012
Academic Editor: Gary Tse
Copyright © 2012 Philipp W. Raess and Adam Bagg. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Primary cutaneous lymphomas can be difficult to be distinguished from reactive mimics, even when integrating histologic, immunophenotypic, and clinical findings. Molecular studies, especially PCR-based antigen receptor gene rearrangement (ARGR) analysis, are frequently useful ancillary studies in the evaluation of cutaneous lymphoproliferations. The biologic basis of ARGR studies is discussed, as well as a comparison of various current protocols. The pitfalls and limitations of ARGR analysis are also highlighted. Recent advances in the understanding of the molecular pathogenesis of various cutaneous lymphomas are discussed. Some of these nascent discoveries may lead to the development of diagnostically useful molecular assays.
1. Introduction
Cutaneous lymphoproliferations remain a challenging area to both dermatopathologists and hematopathologists despite concerted research efforts and recent diagnostic advances. The molecular pathogenesis of systemic lymphomas has been rigorously studied for some time, whereas cutaneous lymphomas were initially not given the same focus. However, over the last 5–10 years, cutaneous lymphomas have been the subject of intensive investigation at the genetic level [1]. Together with the standardization of diagnostic approaches and clinical classification, molecular analysis is likely to assume an increasing role in the evaluation of cutaneous lymphomas and their mimics. Indeed, molecular testing is already incorporated into recommendations for diagnosis and staging of cutaneous T-cell lymphoma (CTCL) [1–3]. The purpose of this paper is twofold: (1) to discuss the role and limitations of antigen receptor gene rearrangement studies and (2) to summarize recent developments in our understanding of the molecular pathogenesis of cutaneous lymphomas.
2. Antigen Receptor Gene Rearrangements
2.1. Generation of Immunological Diversity
An understanding of the diagnostic utility of evaluating immunoglobulin and T-cell receptor gene (collectively referred to hereafter as antigen receptor genes (ARGs)) rearrangements is predicated upon an understanding of their normal biology. ARG structure and the processes through which they are rearranged are responsible for the ability of the adaptive immune system to identify a vast array of antigens. ARGs are composed of multiple variable (V), diversity (D), and joining (J) regions, followed by a constant (C) region. Several antigen receptor genes (IGK@, IGL@, TRG@, and TRD@) do not contain D regions.
In the IGH@ gene, for example, the process of recombination begins with the alteration of tertiary gene structure to place a single D segment and a single J segment in close physical proximity, followed by the creation of a double-stranded DNA break and the rejoining of these D and J segments by recombination activating gene (RAG) proteins with the excision of intervening DNA (Figure 1). Terminal deoxynucleotidyl transferase (TdT) adds (and subtracts) several random nucleotides to the recombination site, thus increasing ARG diversity. Following D-J recombination, a similar process joins a V segment with the recombined D-J segment (followed by TdT action); D-J recombination always occurs before V-DJ recombination. The order of recombination of different ARGs is also typically hierarchical. In developing B cells, the IGH@ gene undergoes recombination followed by the IGK@ gene and, failing successful IGK@ rearrangement, the IGL@ gene. In developing T cells, the sequence of events is usually recombination at TRD@, then TRG@, TRB@, and finally TRA@. The sequence of these events has implications for detecting ARG rearrangements (ARGRs) in lymphoid neoplasms; the IGH@ and TRG@ loci are the most frequently evaluated in ARGR assays, since these are expected to be rearranged in the majority of B-cell and T-cell neoplasms, respectively.
ARGR and the random insertion (and deletion) of nucleotides by TdT are largely responsible for generating the tremendous diversity required for a functional adaptive immune system. These two processes (recombinatorial and junctional diversity, respectively, at all seven different ARG loci) each leads to approximately 106 different combinations, yielding the potential for as many as 1012 different ARGRs. The rearranged ARGs contain both framework regions (FRs), which correspond to structurally important portions of immunoglobulin protein and are conserved between genes, and complementarity determining regions (CDRs), which are variable between genes and largely determine antigen specificity. While two of the CDRs (1 and 2) are encoded in the germline of different V segments, CDR3 is generated by both recombinatorial and junctional diversity and represents the most heterogeneous region of the ARG and ultimately the immunoglobulin (Figure 1(a)) or T-cell receptor (Figure 1(b)) protein. The uniqueness of each rearranged ARG can be exploited as a molecular fingerprint used to determine if a lymphoproliferation is clonal or not. If all or many lymphocytes within a sample are an expansion from a single transformed lymphocyte (in other words, a lymphoid neoplasm), this population will share the same ARGR and is considered clonal. A polyclonal population, conversely, contains many lymphocytes, each with different ARGRs, as seen in reactive lymphoproliferations. Assays that determine the clonality of a lymphoid infiltrate examine the number of different ARGRs present, typically by differentiating ARGRs on the basis of size (or length). In the context of polymerase chain reaction (PCR) assays, these size differences are predominantly a consequence of the effects of TdT.
2.2. Immunoglobulin and T-Cell Receptor Gene Rearrangement Analysis
Southern blot analysis of ARGR is no longer employed clinically due to laborious technical requirements including the use of radioactivity, high input DNA requirements (10–20 g), inability to be performed on formalin-fixed paraffin-embedded (FFPE) tissue (with the latter two issues especially constraining in skin biopsies), and relatively limited sensitivity (5–10%) [5, 6]. PCR-based techniques have supplanted Southern blot analysis [7, 8]; they require less input DNA, can be performed on FFPE tissue, and have a more rapid turnaround time.
PCR-based strategies take advantage of the variability in ARGR size, which is primarily due to the variability in the size of CDR3 (in IGH@, e.g.) that in turn is largely the result of the actions of TdT (junctional diversity). PCR primers are directed against conserved FRs in the V and J regions; for CDR3 amplification, these are FR3 and FR4. Since long introns separate individual V regions from one another, only 5′ primers that anneal in the V region most proximal to the recombination site (namely, the one involved in the actual rearrangement) will create an amplicon that is sufficiently short to amplify efficiently. The same concept applies to 3′ primers and J regions. Amplicons are then separated based on their length in base pairs, typically via capillary electrophoresis. A sample is considered clonal if ARGs of only one size are detected (Figure 2(a)) and polyclonal if a Gaussian distribution of ARG sizes is detected (Figure 2(b)). Some cases may display ARGR patterns that are not straightforward to interpret; these are discussed in more detail later. Multiple algorithms have been proposed to determine whether a peak is significantly elevated above background [9, 10]. Some of these involve calculating the ratio of peak height to neighboring peaks or the expected Gaussian distribution. Uniformity has not been achieved in the application of methods for determining the presence of a "true" peak. Some groups, in particular the BIOMED consortium (see below), eschew the application of seemingly arbitrary numerical values to determine what makes a dominant peak monoclonal. We recommend a qualitative assessment of any peaks, in the context of a thorough understanding of assay limitations based on individual PCR protocols and both histologic and immunophenotypic features of the specimen, to determine whether a peak is meaningful.
Although simple in concept, the first generation of ARGR PCR assays initially posed several technical challenges since multiple differing approaches were described. The use of multiple target loci and genes, heterogeneous primer sets, different platforms for analysis of PCR products, and variation in sample types, amongst many other variables, made comparison between studies difficult. This technological heterogeneity led to challenges in determining optimal diagnostic approaches. In 2003, a multinational effort by the BIOMED consortium described standardized primer sets and methodology for the detection of clonal ARGRs [11]. This landmark study has served as a reference point for subsequent investigations into PCR-based assessment of clonality and as a guide for the development of clinical assays. The original description of the BIOMED-2 primer sets includes 107 primers in 18 multiplexed PCR reactions that interrogate both immunoglobulin (IGH@ VH-JH, IGH@ DH-JH, IGK@, and IGL@) and T-cell receptor gene rearrangements (TRB@, TRG@, and TRD@). Multiple updates in 2007 detailed assay refinements and performance in numerous neoplastic and reactive samples (summarized in [12]), albeit with a conspicuous paucity of cutaneous specimens.
2.3. Performance of BIOMED-2 in Cutaneous Samples and Comparison with Other PCR-Based Assays
Following refinement of the BIOMED-2 protocol, the reported sensitivity of this assay was 99% for both B- and T-cell neoplasms [12]. The specificity of this protocol was reported to be 75% in a large set of histologically reactive lesions, with an additional 15% of samples representing "probably polyclonal" lesions [13]. However, the vast majority of specimens tested in these studies consisted of fresh/frozen nodal tissue. The performance of the BIOMED-2 protocol in more common FFPE samples and underrepresented tissues became a focus of future work. Multiple groups have investigated the performance of the BIOMED-2 protocol in cutaneous FFPE samples, with reported sensitivities ranging from 77% to 94% for T-cell neoplasms [14–16] and 85% for B-cell neoplasms [17]. The lower sensitivity of these studies is likely due to decreased DNA quality in FFPE tissue.
Although the BIOMED-2 protocol performs relatively well in FFPE cutaneous samples, adoption of this approach is far from universal. Multiple authors have proposed alternative PCR protocols and demonstrated their equivalency by direct comparison to the BIOMED-2 protocol in both fresh/frozen and FFPE cutaneous samples [14, 15, 18]. In a recent College of American Pathologists survey [19], approximately equal proportions of responding laboratories used the commercially available BIOMED-2 primer set versus other commercial or laboratory-developed assays for IGH@ rearrangements. For TRG@ analysis, a fewer laboratories (49 versus 66) used BIOMED-2 primer sets versus other assays, in particular laboratory-developed tests. The low rate of adoption of BIOMED-2 protocol may reflect its cost, increased complexity, or equivalent performance within certain sample types that are prevalent in an individual laboratory's case load.
ARGR studies, regardless of the protocol employed, are often of increased importance when the histologic and/or clinical appearance of a cutaneous lymphoid lesion has features that preclude clearly distinguishing a benign process from a lymphoma. In cutaneous specimens, analysis of T-cell receptor gene rearrangements (TCRGRs) is more commonly performed than that of immunoglobulin genes. This is partly because primary cutaneous T-cell neoplasms are more common than primary cutaneous B-cell neoplasms, but also because of the sometimes-overlapping histological features of CTCL and benign inflammatory dermatoses. In addition, T cells do not have an easily measurable immunophenotypic marker of clonality akin to immunoglobulin light-chain restriction in mature B-cell neoplasms. Finally, identifying a clonal ARGR is included in recommended algorithms for diagnosing mycosis fungoides (MF) [1, 3].
TCRGR testing has been most thoroughly investigated in differentiating MF from reactive inflammatory dermatoses. Early work demonstrated clonality by TCRGR in 76% of cases with initial suspicion of CTCL, but was limited by a small sample size () [20]. Others have reported similar sensitivity (78%) and specificity (74%) in large series of CTCL and benign inflammatory dermatoses [21]. TCRGR testing has also been shown to be useful in differentiating specific subtypes of CTCL from their reactive histologic mimics. For example, granulomatous MF is included in the differential diagnosis of granuloma annulare and cutaneous sarcoidosis. In one series, clonal TCRGRs were identified in 13/14 (94%) cases of granulomatous MF and only 2/50 (4%) cases of granuloma annulare and sarcoidosis [16]. Concordantly, other authors have detected clonal TCRGR in only 4/29 (14%) of cutaneous granulomatous infiltrates [22].
ARGR testing, however, is not a panacea for histologically challenging cutaneous lymphoid infiltrates. Cutaneous lymphoid hyperplasia (CLH), also known as pseudolymphoma, is a brisk lymphoid infiltrate that is difficult to differentiate from a cutaneous lymphoma on clinical, histological, and immunophenotypic grounds [23]. Clonal ARGRs have been reported in 4%–61% of cases in several series of CLH; this wide range is likely due in part to differing histologic definitions of CLH, small sample sizes, and nonuniform PCR strategies [24–26]. Nonetheless, the preponderance of evidence indicates that ARGR testing is frequently a useful diagnostic test in the evaluation of cutaneous lymphoid infiltrates.
2.4. Pitfall and Limitations of ARGR Studies
PCR-based ARGR assays are susceptible to numerous biologic and technical factors that can complicate or confound analysis. In many instances, ARGR generates results that are either clearly clonal or polyclonal. However, ARGR assays may generate a pattern of peaks that is neither clonal nor polyclonal, a finding termed oligoclonality (Figure 3). Oligoclonal ARGR studies may represent the greatest interpretive challenges for both individual assay interpretation and integration of ARGR results into a meaningful diagnosis; importantly, this is not a failure of the assay per se, but rather a reflection of biology as a result of a limited antigen receptor repertoire found in some reactive processes.
Clonal heterogeneity within a lesion may also cause difficulty in interpreting ARGR studies. Conventional wisdom suggests that a maximum of two peaks (corresponding to biallelic rearrangement in a single clone) may be found in a single clonal process. However, clonal heterogeneity within a bona fide neoplasm can lead to increased numbers of peaks. This phenomenon is well documented in CTCL [27, 28].
False negative gene rearrangement PCR results are not uncommon and can result from various circumstances that result in poorly annealing PCR primers. Because of the large numbers of individual V-, D-, and J-segments in ARGs, it is not practical to include primers which are specific for every single segment. Rather, family-specific primers are used so that, for example, 6 or 7 IGH@ V primers are used instead of ~45 individual V primers. However, several lymphomas have been demonstrated to have a nonrandom utilization of gene segments, so rational design of primer sets can optimize detection rates [29, 30].
Somatic hypermutation is a common cause of false negative IGH@ rearrangement studies found in B cells that originate from or have transited through the germinal center. As a naïve B cell interacts with antigen in the germinal center, point mutations are introduced by the enzyme activation-induced deoxycytidine deaminase (AID), primarily into CDR3. Should these mutations occur in an FR (typically FR3), PCR primers may not anneal effectively. This could result in an inefficient or ineffective PCR reaction and a false negative result.
False positive gene rearrangement studies also pose challenges during diagnosis. If the ARG from an individual cell is preferentially amplified in a background that does not contain many other lymphoid cells (and hence limited ARGs), a "clonal" rearrangement may result. However, a repeat analysis will typically reveal the presence of a differently sized rearrangement; the inability to reproduce the detection of an identical monoclonal rearrangement is what defines pseudoclonality [31]. False positive results occur due to preferential PCR amplification of an individual amplicon within a limited pool of polyclonal ARGs. This concept was elegantly demonstrated by using laser capture microdissection of 10-10,000 lymphocytes from reactive and clonal processes [32]. Pseudoclonality was demonstrated when fewer than 2,000 lymphoid cells captured from a cutaneous biopsy of a reactive dermatitis were amplified via TRG@ PCR. In contrast, when more than 2,000 cells of the same lymphoproliferation were analyzed, TRG@ PCR was polyclonal. Increased complexity of assay design (multiple tubes and/or fluorophores) has also been shown to decrease the specificity of TCRGR through a similar principle [33]. Division of a pool of ARGRs into multiple separately analyzed PCRs can result in a pseudoclonal spike being considered positive when compared to an artificially decreased polyclonal background. For these reasons, it is recommended that all PCR analyses are performed in duplicate and only those peaks that are reproducible in independent analyses can be considered to reflect definitive evidence of clonality.
Clonal T-cell receptor rearrangements can be detected in B-cell neoplasms, and vice versa [34]. Clonal rearrangements of both T-cell receptor and immunoglobulin receptor genes have also been identified within the same neoplasm. These do not represent "true" false positives, but it is important to remember that ARGR should not be used to determine lineage.
2.5. Strategies and Recommendations to Improve Performance of PCR-Based Assays in Cutaneous Lymphoma
Despite its limitations, data gleaned from ARGR testing provide critical information in differentiating reactive from neoplastic lymphoproliferative cutaneous infiltrates. It is important to appreciate that such analyses are not perfect arbiters of neoplastic versus reactive lymphoproliferations, and that occasionally intermediate results actually reflect the inherent heterogeneity of the normal immune response. Nevertheless, a number of testing strategies have been proposed to increase the accuracy of ARGR PCR.
Performing ARGR testing from multiple cutaneous sites and concurrent blood testing can be extremely useful, since the documentation of an identical clone in two or more sites increases the likelihood that it is indeed reflective of a bona fide neoplasm [28, 35, 36]. We recommend this strategy when multiple lesions are present and amenable to biopsy. Note that this should not substitute for performing the same PCR in duplicate on an individual site; this step remains critical in excluding pseudoclonality.
Not all cutaneous lymphoid infiltrates are ideal candidates for ARGR testing. Algorithms which tailor ARGR testing to the clinically determined pretest probability of CTCL have been advocated as a rational approach to this conundrum [21]. This approach provides the benefit of integrating clinical information with testing strategy and has been demonstrated to increase the positive and negative predictive value in a large series ( samples) of reactive and neoplastic lymphoid infiltrates. When the pretest probability of CTCL is moderately low, for example, a positive ARGR test increases the positive predictive value from 41% to 80%. The authors propose a diagnostic algorithm that maximizes sensitivity when pre-test probability is moderately low and maximizes specificity when pre-test probability is moderately high. Furthermore, the authors recommend against TCRGR testing in cases with very low or very high pre-test probability of MF.
3. Molecular Pathogenesis of Cutaneous Lymphomas
The dissection of the molecular pathways involved in the development of cutaneous lymphomas has not proceeded at the same pace as it has in noncutaneous lymphomas. There may be a number of explanations for this, not the least of which is the typically small size of the lesions and challenges in accruing sufficient amounts of material to study. Nevertheless, a number of recent discoveries have been made that may aid the development of better diagnostic tools, refinement of prognostication, and targeted therapy. What follows is not intended to be a comprehensive review of all types of cutaneous lymphomas. The focus here is on those specific subtypes where molecular analysis might currently have practical applications.
4. T-Cell Neoplasms
4.1. Mycosis Fungoides
Several gene expression (mRNA) profiling studies have been performed in MF and have been correlated with patient outcomes. Additionally, mRNA expression studies also suggest potential therapeutic targets in MF lymphomagenesis. Early work in this arena implicated genes involved in the NF-B signaling pathway in the pathogenesis of MF, confirming in vitro studies [37, 38]. Multiple gene expression studies in MF followed; an interesting caveat of many of these studies is the heterogeneity of the tissue analyzed. Cutaneous biopsies rarely, if ever, contain a homogeneous population of neoplastic cells. The choice of control also markedly affects analysis; is normal skin the most appropriate control, or a reactive lymphoid infiltrate? In order to control for these variables, a meta-analysis of publicly available mRNA expression databases was performed from tumor-stage MF, isolated reactive T-cell subsets, normal skin, and skin with reactive inflammatory infiltrates [39]. Several hundred gene products were differentially expressed in tumor stage MF, including multiple gene products involved in the NF-B signaling pathway. Continued investigation of clues provided by gene expression data may potentially lead to a greater understanding of lymphomagenesis and rational development of targeted therapeutics.
In addition to mRNA gene expression data, microRNA (miRNA) expression profiling has also identified numerous targets that are differentially expressed in MF versus reactive inflammatory dermatoses [40, 41]. A panel of five miRNAs identified through expression profiling has recently been shown to potentially differentiate reactive lymphoid infiltrates from neoplastic lesions in CTCL (primarily MF) [40]. While the majority of these studies have utilized array-based platforms, another approach is to use deep sequencing to analyze miRNA expression in peripheral blood lymphocytes in Sézary syndrome [42]. This may be advantageous in minimizing hybridization and other technical artifacts, but its utility in tissue-based samples with admixed reactive and neoplastic cells has yet to be demonstrated.
Comparative genomic hybridization, an array-based technology that identifies small chromosomal losses and gains at higher resolution than conventional cytogenetics, has also been applied to MF [43]. Multiple recurrent (>35% of samples) chromosomal abnormalities were identified (including gains on 7q, 7p, and 1q, losses on 5q, 9p, and 13q) that correlate well with mRNA expression data from these regions. Three chromosomal alterations were associated with decreased survival by univariate analysis in a relatively small data set of only 24 cases (9p21 loss, 8q24.3 gain, and 1q21-22 gain). A subsequent study used an approach with a much higher resolution and confirmed copy number alterations in samples of tumor-stage MF at some of the same loci as previously reported [44]. These alterations involve known protooncogenes and tumor suppressor genes (8q24.21 (MYC) gain, 9p21.3 (CDKN2A, CDKN2B, and TMAP) loss, and 10q26qter (MGMT, EBF3) loss) and also demonstrated prognostic differences. However, multivariate analysis did not demonstrate significant differences in prognosis. Whether these are primary or secondary genetic events is unknown. Nonetheless, the pathways involved may still be useful for the identification of efficacious targeted therapeutics.
4.2. Primary Cutaneous Anaplastic Large Cell Lymphoma
Primary cutaneous anaplastic large cell lymphoma (PCALCL) has recently been the focus of several interesting, and potentially confusing, studies describing translocations involving 6p25, which are seen in 20–26% of cases [45, 46]. These translocations were first described in a series of peripheral T-cell lymphomas (PTCLs), including some PCALCLs [47], and initially the gene on 6p25 most commonly involved in PCALCL was presumed to be the nearby IRF4 oncogene. However, subsequent analysis revealed that a slight majority of these 6p25.3 rearrangements in ALCL (both primary cutaneous and ALK-negative systemic) involve DUSP22 [48], while fewer (~30%) do indeed involve IRF4. DUSP22 is a dual-specificity phosphatase that inhibits T-cell antigen receptor signaling and has been shown to have a tumor suppressor function in ALK-positive ALCL [49]. The translocation partner for DUSP22 is the common fragile site FRA7H on 7q32.3 in almost one-half of these cases and remains unknown in the other described cases.
Array CGH has also been performed in CALCL in numerous studies; however, no recurrent chromosomal gains or losses have been consistently identified across studies [50–53].
5. B-Cell Neoplasms
5.1. Primary Cutaneous Follicle Centre Lymphoma
Primary cutaneous follicle centre lymphoma (PCFCL) is a well-defined clinical entity that is surrounded by some controversy at the molecular level. Nodal follicular lymphoma, one of the most common lymphoma subtypes, has been thoroughly investigated and is characterized by the t(14;18)(q32;21) translocation involving the IGH@ and BCL2 genes in ~85-90% of cases. The prevalence of this translocation in PCFCL, however, has been the subject of much debate. Disparate results regarding the presence of t(14;18)(q32;21) have been reported and appear to be related, at least in part, to the analytic technique employed. Studies that have used PCR-based approaches have demonstrated the presence of the t(14;18)(q32;21) in 0 to 41% of cases, whereas studies using FISH report a prevalence of 0–51% [54–56]. Multiple variables complicate interpretation of these disparate results, including differing PCR strategies, potential inclusion of secondary cutaneous follicular lymphoma samples, and geographic variability. A direct comparison of PCR- and FISH-based approaches demonstrated the t(14;18)(q32;21) translocation in 11/27 cases by FISH and in 0/27 cases by PCR [56]. BCL2 expression by immunohistochemistry was noted in 10/27 cases (in cases both with the translocation and those without), in concordance with other published results [55]. The presence of BCL2 overexpression supports the role of the t(14;18)(q32;21) translocation in the pathogenesis and also implies other molecular mechanisms of BCL2 upregulation in translocation-negative cases, similar to what has been documented in nodal cases. Translocations involving the IGH@ and BCL6 genes (t(3;14)(q27;q32)) are also noted in a small fraction of PCFCL, again paralleling what is noted in nodal follicular lymphoma. Although better understanding of the pathogenesis of PCFCL will be gained through continued investigation into the underlying molecular biology, it is important to note that the prognosis of these patients is generally excellent whether or not a translocation is identified.
5.2. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
When first described, primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) was differentiated from other primary cutaneous large B-cell lymphomas because of its later age of onset, frequent dissemination to noncutaneous sites, and worse prognosis, in addition to high frequency of primary lesions on the lower extremities. Further support for PCDLBCL, LT as a separate clinicopathologic entity was provided by CGH and gene expression data that demonstrated unique patterns distinct from other histologically similar PCBCLs [57–59]. The prevalence of chromosomal rearrangements involving 3q27 (BCL6), 8q24 (MYC), and 14q32 (IGH@) loci was found to be much higher in PCLDBCL, LT (11/14 cases) versus other PCBCL (0/15) [60]. Further work supported the concept that there are different patterns of chromosomal alterations between PCFCL, which can also display large cell morphology, and PCDLBCL, LT, identifying the loss of 9p21.3/CDKN2A through deletion in ~75% cases of PCDLBCL, LT [61]. This has been confirmed in other studies [62] and portends an adverse prognosis [63].
Point mutations in MYD88 can be found in approximately two-thirds of PCDLBCL, LT cases, while none was identified in the cases of PCFCL and primary-cutaneous marginal zone lymphoma [64]. Although these findings emanate from a relatively small series that needs to be confirmed by larger studies, the specificity of this mutation in PCDLBCL, LT may provide a useful diagnostic molecular marker of this subtype of primary cutaneous B-cell lymphoma. However, MYD88 mutations also occur in noncutaneous DLBCL, so it may be less useful in distinguishing PCDLBCL, LT from secondary cutaneous DLBCL [65].
5.3. Primary Cutaneous Marginal Zone Lymphoma
Genetically, primary cutaneous marginal zone lymphoma (PCMZL) differs from extranodal marginal zone lymphomas (mucosa associated lymphoid tissue/MALT lymphomas) arising in noncutaneous sites. The most frequent recurrent chromosomal abnormality in PCMZL is t(3;14)(p14.1;q32), although it occurs in only up to 10% of reported cases and is not specific to this site as it also occurs in ocular and thyroid extranodal MZL [66]. This translocation is thought to lead to the overexpression of FOXP1 by IGH@ enhancer elements. Other recurrent translocations in PCMZLs include t(14;18)(q32;q21) and t(11;18)(q21;q21), both affecting MALT1; however, these translocations are present in less than 15% of cases [60, 67, 68].
6. Conclusion
ARGR analysis is a useful assay to help characterize cutaneous lymphoproliferations. However, it is just one tool in the diagnostic armamentarium that we have at our disposal and needs, as always, to be integrated with the clinical picture, histology, and immunophenotype to make cogent diagnoses. It is not a perfect test and does not always provide results that definitively distinguish neoplastic from reactive lymphoid infiltrates. However, rather than viewing this as a failure of the assay (which, of course, is not flawless), it is important to appreciate that this may merely be reflective of the underlying biology and heterogeneity of the infiltrates themselves. Positive and negative predictive values are improved when these assays are used judiciously and appropriately. Finally, as the molecular pathways underlying specific subtypes of cutaneous lymphomas are dissected, we anticipate the development of novel assays that will be used in routine clinical practice to facilitate diagnosis and direct therapy.
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text: JACKSON — Bradley Arant Boult Cummings, LLP has formed a new privacy and information security team that will focus on representing clients on the most pressing privacy and data security issues. Partners Paige M. Boshell and Amy S. Leopard will serve as co-chairs. The team brings together a cross-disciplinary group of the firm's attorneys who currently help clients minimize the ...Read More »


text:
SCOTTSDALE, Ariz. -- The College Swimming Coaches Association of America (CSCAA) recently released its 2007 Winter/Spring Academic All-America Teams and both of Washington and Lee's programs were ranked second in Division III and combined to take the overall crown with the nation's highest grade-point average (GPA).
W&L's swimming programs combined to boast the best GPA in the nation with a 3.626. The men ranked second in the nation with a GPA of 3.62, while the women totaled a 3.63 GPA to also finish second in the nation.
Individually, seniors Tim McGlaston (Attleboro, Mass./Attleboro) and Alex Sweet (Louisville, Ky./Kentucky Country Day), and juniors Paul Crook (Nashville, Tenn./Montgomery Bell) and Brett Tatman (Marietta, Ga./George Walton) were named Academic All-Americans after posting a GPA over 3.5 during winter term and competing at the 2007 NCAA Championships.
At NCAA's, McGlaston and Sweet earned First Team All-America honors as members of the second-place finishing 200 free relay and the sixth-place finishing 400 free relay. Sweet, Tatman and Crook took the bronze in the 800 free relay to garner First Team All-America accolades for their finish.
Additionally, Sweet registered a sixth-place finish in the 100 free in a school-record time of 45.24 to earn an additional First Team All-America citation. He earned Honorable Mention All-America status with a 14th-place in the 200 free and as a member of the 400 medley relay team that finished in 15th place. McGlaston and Sweet also finished 12th and 13th, respectively, in the 50 free en route to earning Honorable Mention All-America honors
The men's team finished eighth overall at NCAA's last season to equal their best-ever finish and were also the only team to finish in the Top 10 at NCAA's and Top 10 GPA. The W&L women concluded the 2006-07 campaign with a 7-9 overall record and will return all but one swimmer to their roster in 2007-08.


text:
Stolen, but Not Lost
A Key Discovery
*Excerpted with permission of Janet Tombow
When Uncle Rich answered my call, I said, "I am obsessed with finding Norma (mother). Do you know anything else that might help me get in contact with her?"
Quickly he responded, "I found her sister, Phyllis, listed in the Cleveland telephone book. She still lives in the same house she did for all of her life. I called her and she wants to talk with you." I never asked him why he didn't call me with this information sooner. I guess he didn't call waiting to see if I truly wanted to find her. Or else sooner would have rushed the timing of my preparation. I needed to go through all of these steps to be ready for the contact with my birth mother.
"Does she know if Norma is alive?" I eagerly asked.
"Norma is alive and living in Florida" Uncle Rich answered and reiterated, "and your Aunt's eager to talk with you." So, he gave me her telephone number before I hung up.
I was still eager to make the connection to Norma, so I didn't hesitate to make the call to my "Aunt Phyl", as I remembered she was called. I didn't remember anything about what my Aunt looked like, how close our relationship had been, or when I had seen her last. But my first priority was to find out how to contact my birth Mother, and this was finally the right connection I needed to be able to finally reach her.
When Aunt Phyl answered the call, she seemed very happy to hear from me. I explained who I was and that I "…wanted to reach my mother, Norma Wallace."
She asked, "Why do you want to talk with her?"
For a moment I wanted to say that I'd prefer discussing that with my mother. But I was afraid to offend this direct link to finding my Mother. So, I went through the logic of, "…wanting to ask her forgiveness for judging her all my life and explain why I haven't been in touch before this."
She surprised me by saying, "I'll have to call her to see if she will talk with you, because there has been so much hurt over this, you know!"
I thought to myself, "You're darned right there has been hurt over this!" But instead of verbalizing that, I said, "Please see if she will talk with me", and gave her my telephone number.
It wasn't more than 15 minutes later and the telephone rang. I thought it would be my birth mother, so with some trepidation, I answered, "Hello?"
To my disappointment, it was Aunt Phyl again. She called me back with the update, "I spoke with Norma and she wants to talk with you…" Now I was getting hopeful, but then she added, "…but she wants you to call her because she's afraid you'll hang up on her if she calls you."
That didn't sound like a problem, so I said, "I will call her." Then, she gave me my birth Mother's telephone number in Clearwater, Florida. (By the way, William Wallace in Clearwater, Florida was on one of the lists Sally had given me; I just hadn't reached that point in the call lists yet! I concluded that the contact was not supposed to be made via a "cold call"!)
Aunt Phyl wanted to talk a few minutes more, while I was eager to make that next call! But I was polite and took the time to converse with her briefly. Aunt Phyl told me a few interesting things that I didn't realize had occurred. She asked, "Do you remember playing with Rusty (her son and my cousin)?" But I didn't have that memory either. Then, she mentioned she had letters from me, as she used to correspond with me when I was a little girl. Surprised, I questioned, "You have letters that I wrote??"
She added, "Yes, and from your stepmother too!"
I told her, "I don't remember writing those letters. But my stepmother used to write out the words for me when I was little, and I copied them into letters to people. So maybe that is what happened." This was another memory of which I had no recollection, nor did I want to dwell on it. When I copied those letters, I remember getting verbally and physically abused if I made any mistakes. Not a happy memory!
I didn't know I wrote letters or received any from relatives for all of those years I had been apart from my birth Mother. I thought no one wanted anything to do with me. So, hearing about these letters was a big surprise.
She added, "I saved them. I hope you'll come to see me and I'll show them to you."
Now, my Aunt Phyl AND my Uncle Rich wanted me to come see them. But I could only focus on the goal of talking with my birth mother. So, I promised to visit in the future, but couldn't promise when. We ended the conversation at that point.
Contacting the "Right" Norma Wallace…
Now I had the right phone number for the RIGHT Norma Wallace…but my first thought was, "Okay, what do I do now?"


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PetSmart, Inc. to Host First Quarter 2013 Earnings Conference Call
PetSmart, Inc. to Host First Quarter 2013 Earnings Conference Call
PHOENIX--(BUSINESS WIRE)-- On Wednesday, May 22, 2013 at 4:30 p.m. (EDT) PetSmart, Inc. (NASDAQ: PETM) will host a conference call announcing its results for the first quarter 2013. The earnings release will be distributed the same day, after the close of the market.
To listen to the live call, dial:
Within the United States and Canada: (866) 814-1933
Internationally: (703) 639-1365
Conference ID #: 1613971
Listen at www.petm.com
A replay of the conference call will be available through June 22, 2013 11:59 p.m. EDT.
To access the replay dial:
Within the United States and Canada: (888) 266-2081
Internationally: (703) 925-2533
Conference ID #: 1613971
The announcement will be archived at www.petm.com.
About PetSmart
PetSmart, Inc. (NAS: PETM) is the largest specialty pet retailer of services and solutions for the lifetime needs of pets. The company employs approximately 52,000 associates and operates more than 1,278 pet stores in the United States, Canada and Puerto Rico, over 196 in-store PetSmart® PetsHotel® dog and cat boarding facilities, and is a leading online provider of pet supplies and pet care information (http://www.petsmart.com). PetSmart provides a broad range of competitively priced pet food and pet products; and offers dog training, pet grooming, pet boarding, PetSmart Doggie Day CampSM day care services and pet adoption services. Through its in-store pet adoption partnership with PetSmart Charities®, PetSmart has helped save the lives of more than 5 million pets since 1994. PetSmart Charities, Inc. and PetSmart Charities of Canada, Inc. ("PetSmart Charities") are independent, nonprofit organizations that save the lives of homeless pets and reduce shelter intake through spay/neuter efforts. In 2012, nearly 450,000 dogs and cats found homes through the organization's adoption centers in all PetSmart stores and by sponsoring community adoption events. PetSmart Charities is the leader in granting money to help pets in need, with more than $28 million given in 2012 throughout North America.
PetSmart, Inc.
Investor Relations, 623-587-2025
KEYWORDS: United States North America Arizona
The article PetSmart, Inc. to Host First Quarter 2013 Earnings Conference Call originally appeared on Fool.com.Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.
Copyright © 1995 - 2013 The Motley Fool, LLC. All rights reserved. The Motley Fool has a disclosure policy.


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Tuesday, 4 April 2017
Delft C - Coat of Arms
Like any city should have Delft has got a weapon. In 1816, as a result of the Napoleon era, the coat of arms of Delft was registered as:
"Of silver loaded with a picket of saber. The weapon is covered with a crown with 5 florets, all made of gold, and is held by the second climbing lions of throat."
Note: Wavy lines are often applied on the pole, in plans, the crown has three leaves and 2x3 pearls and the lions are looking at you.
The coat of arms is older than the one shown above. To illustrate that have a look at the glass stained window in the city of Edam:
I was there recently in Edam, and saw this window. The bar in the middle symbolizes the "Oude Delft". The "Oude Delft" (Old Delft) is the oldest canal in Delft and is probably dug around 1100.
8 comments:
Thank you for sharing, Han...really love learning more about Delft.ReplyDelete
Hugs and blessings...CatReplies
Ugly red lions aren't they? But I told you I have something with heraldy.Delete
Thank you for looking at these mean beasts,
The story bahind each coat of arms is so interesting...thanks for sharing this one. hugs abbyReplyDeleteReplies
Yes it certainly isn't the beauty of the weapon itself, but old stories are worth telling, aren't they?Delete
Love learning the history, thank you.ReplyDeleteReplies
That's the beauty of living in an old town, behind everything is a story somewhere.Delete
The first Canal 1100?ReplyDelete
It is old.
Where in Edam is this window?
Mona LisaReplies
City Hall in Edam, Mona Lisa. They have a lot of weapons of cities in the Netherlands there. It's very pretty. But then again I love stained glass windows.Delete


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Although we don't believe in timing the market or panicking over market movements, we do like to keep an eye on big changes -- just in case they're material to our investing thesis.
Expect to see a flat start to the stock market today, as the Dow Jones Industrial Average (DJINDICES:^DJI) is set to fall by an insignificant 2 points at the opening bell. With Cyber Monday kicking off, online retailers like eBay should benefit from more shopping moving to the Internet. Yet, traditional retailers including Wal-Mart (NYSE:WMT) and Best Buy (NYSE:BBY) will also be in focus after sales results from the industry's biggest weekend failed to impress.
However, the box office was a real bright spot over the Thanksgiving holiday. Lions Gate's (NYSE:LGF-A) Hunger Games: Catching Fire raked in more than $100 million in its second weekend, bringing the movie's worldwide total to $573 million. And that record result came despite a huge opening from Disney's (NYSE:DIS) Frozen, which wasn't a Pixar creation, but had a very Pixar-like performance: It grossed a hot $66.7 million in its debut.
Lions Gate can be confident that it has a multi-year franchise on its hands, and that Catching Fire will beat the original Hunger Games' impressive haul. As for Disney, it's good to see that its in-house animation studio can succeed, given that Pixar, for the first time in eight years, won't be releasing a movie next year .
Unfortunately, the good news didn't spread to traditional retailers this past weekend. Total spending actually ticked lower over the Black Friday crush, according to the National Retail Federation. Sales did spike on Thanksgiving Day as stores opened earlier than ever, but companies just managed to pull revenue ahead from other days. And moving sales into the holiday itself also promises to hurt profits. Wal-Mart estimates that it will pay an additional $70 million to workers that came in on Thanksgiving .
Shoppers spent an estimated $407 over the holiday weekend, on average, down from $423 last year. That dip suggests that discounting is playing a major role in holiday shopping this year. Investors saw this coming, as Best Buy warned in early November that it planned to match other retailers in being "more promotional" this year. Still, discounting threatens to crimp gross margins for Best Buy, as well as most other retailers in the fourth quarter.
Fool contributor Demitrios Kalogeropoulos owns shares of Walt Disney. The Motley Fool recommends eBay and Walt Disney. The Motley Fool owns shares of eBay and Walt Disney. Try any of our Foolish newsletter services free for 30 days. We Fools may not all hold the same opinions, but we all believe that considering a diverse range of insights makes us better investors. The Motley Fool has a disclosure policy.