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WWU Vikings
Vikings earn No. 3 seed at West Regionals
The Western Washington University volleyball team earned the No. 3 seed at the West Regional of the 2014 NCAA Division II National Championships, which takes place on Nov. 20-22 at host and No. 1 seed Northwest Nazarene.
The Vikings, 21-6, face No. 6 seed Cal State San Bernardino (21-6) in an opening-round match at 11 a.m. Thursday, Nov. 20. The winner advances to the second round against either No. 2 seed Alaska Anchorage (21-5) or No. 7 seed Sonoma State (20-6) at 4 p.m. Friday, Nov. 21.
All matches will be videostreamed on Stretch Internet.
In the two other first-round matches, No. 5 seed BYU Hawaii (21-5) faces No. 4 seed Central Washington (19-7) and No. 1 seed Northwest Nazarene (24-2) plays No. 8 seed Dixie State (20-8).
It is the eighth trip to the NCAA nationals for WWU, all of them during the 15-year tenure of Flick. The Vikings earned an at-large regional berth after finishing third in the Great Northwest Athletic Conference with a 14-4 record. The 20-win season is their third straight and 10th during Flick's tenure.
WWU will be making a third straight regional appearance, the first time it has done that since a similar run from 2001 to 2003. The Vikings reached the national championship match in 2007, the only time they have advanced past the first two rounds.
WWU, ranked No. 15 in this week's American Volleyball Coaches Association/NCAA II Top 25 Poll, has won its last four matches. Earlier the Vikings had a seven-match winning streak, the longest in the GNAC this season.
The Vikings lost in five sets to CSUSB at the Central Washington Wildcats Classic on Sept. 16. The Coyotes have won six regional titles, two straight from 2003 to 2004 and four straight from 2008 to 2011. CSUSB, which holds a 10-2 series advantage over WWU, is ranked No. 22 nationally.
BYU Hawaii, the Pacific West Conference champion, has won the last two regional crowns, reaching the national title match in 2013. Northwest Nazarene captured the GNAC title and Sonoma State took the California Collegiate Athletic Association crown.
WWU libero Samantha Hutchinson is the NCAA II national statistical leader in digs per set average at 7.23 and is second in total digs at 745. She was a first-team American Volleyball Coaches Association All-American last year and a two-time GNAC Defensive Player of the Year. She ranked second nationally in digs per set last year as a junior and fifth as a sophomore.
Hutchinson ranks second among WWU leaders in career digs with 2,416 (6.62 avg. per set), trailing only Courtney Schneider (2004-07) at 2,695.
WWU middle blocker Kayla Erickson ranks 11th among school career leaders in kills with 1,011. She is second all-time in both WWU and GNAC history in career attack percentage at .340.
Erickson, the 2013 GNAC Player of the Year and a second-team Daktronics All-American, tops WWU in kills (354, 3.44 avg.), attack percentage (.307) and blocks (101, 0.98). She has posted double-figure kills in 23 matches this fall.
Erickson ranks fourth among GNAC leaders in attack percentage, fifth in kills and eighth in blocks.
Setter Kristina Tribley leads the GNAC in assists per set at 11.02 (915) and opposite-side hitter Jennica McPherson is third in service aces at 0.32 (28).
Outside hitter Rachel Roeder is averaging 3.11 kills per set (314), outside hitter Kelsey Moore 2.98 kills (292), and middle blocker Joellee Buckner (R-Fr., Colville) 0.77 blocks (77).
Flick is averaging 21.1 victories per year and her win total and 79.1 winning percentage are both program bests. She ranks No. 8 nationally in win percentage among DII coaches and has been named GNAC Coach of the Year eight times.
Last week, WWU swept a road trip to Alaska, winning in three sets at Alaska Fairbanks and prevailing in five sets at Alaska Anchorage, to earn GNAC Team of the Week honors. Moore had a career-high 23 kills in the UAA victory and was named GNAC Offense Player of the Week.
CSUSB ranks fifth nationally in blocks per set at 2.53. Brenna McIntosh is third nationally in blocks per set at 1.37, and Tori May is second in attack percentage at .412.


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Product Category
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- Contact Person:Mr. Max Qing
- Job Title:General Manager
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Hitek Industry Co., Ltd is one of the leading professional manufacturers and suppliers in HVACR, Sanitary Wares, Brass Wares, Pipes and Pipe Fittings fields. Based in Hongkong, Hitek Industry Co., Ltd invested five companies in Zhejiang, Jiangsu, Guangdong and Henan to produce and supply various Sanitary Wares, Pipes and Pipe Fittings during past 18 years. Our mission is "One-stop Supply, Satisfying Customers".
Hitek Industry & Trading Co., Ltd is global company committed to experienced global staffs, world class quality, fast on time delivery, advanced modern production line, excellent service and competitive price.
Hitek Industry Co., Ltd's management team includes experienced engineers, researchers and workers who understand well the needs of the mechanical systems and marketing of the pipes and pipe fittings fields. We always devote ourselves to the development of new products and offer top service to our customers and to create new value.
Hitek Industry & Trading Co., Ltd offers the following quality products:
- General HVACR Products
- Refrigeration Components and Air Conditioner Spare Parts
- Sanitary Wares and Brass Wares
- Copper Tube and Copper Fittings
- Brass Tube and Brass Fitting
- Insulation Pipe, Foam and Insulation Sheet
- Aluminum Tube, Aluminum Sheet and Plate
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The products we supplied are under ISO 9000, ISO 14000 management systems and with CE, UL, CCC, TUV, UPC, NSF, WHI, Kite Mark approval.
In order to have sufficient variation for our customer, we set up our mainland office in Suzhou(half hour from Shanghai by train) to collect and organize all goods we produced.
Our commitment is to deliver superior quality products and excellent service. At Hitek Industry & Trading Co., Ltd, we hope we can work closely with you and do our best to offer you,build and nourish longterm business relationship.
Contact Person:

subset: commoncrawl


text:
Bible Verse of The Day on "Anger": It is Written,
This you know, my beloved brethren. But let everyone be quick to hear, slow to speak and slow to anger; for the anger of man does not achieve the righteousness of God. James 1:19-20
Feel free to leave your prayer requests in the comment section. Have a blessed day!


text:
The J-TAC (Stephenville, Tex.), Vol. 1, No. 12, Ed. 1 Tuesday, May 4, 1920
Description: Weekly student newspaper from John Tarleton Agricultural College in Stephenville, Texas that includes local, state and campus news along with advertising.
Date: May 4, 1920
Item Type: Refine your search to only Newspaper
Partner: Tarleton State University


text:
Get yourself ready for the most exhilarating work out for mind, body & soul. Open your mind and step into a room full of UV light, where the music is flowing and the energy is out of this world.
The doors open from 7:00pm so before you hop onto your yoga mats go all out with neon!!!! White and fluorescent clothing is suggested to enhance the theme... glow sticks and UV body paint will be provided to really get you in the mood... get ready to GLOW!
At 8pm we begin a juicy Vinyasa Flow session with DJ and black lights. The class starts gently with a normal flow and builds with the music to a workout that can only be described as Euphoric, and ending with a well deserved extended Savasana. Leave feeling elated, floating on the highest cloud... and the best bit? No hangover the next day, the result instead is a newly toned body and a clear mind!
Investment £20 - CLICK HERE to book.


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Boron Cement
Production of boron modified active belite cement produced with colemanite addition to clinker raw material was developed under the scope of the collaboration made with Turkish Cement Manufacturer Organization, a patent certificate was obtained for the cement and TSE standard coded TS 13353 was issued.
Properties of the concrete produced with boron modified active belite cement was evaluated under the scope of the project carried out with DSİ-Technical Research and Quality Control Department Head and the project report was published as "BOREN Publication No:". Coatings of a concrete highway of 3600 meters and a water channel was built by using boron cement were performed. Performance of the highway was monitored by Directorate General for Highways and the concrete performance of the water channel was monitored by General Directorate of State Hydraulic Works. Our efforts for application of the product in commercial production and public investments are continued.
Sodium Boron Hydride
Pilot production and synthesis of sodium boron hydride was achieved under the project with title "Sodium Boron Hydride Synthesis and Pilot Production" commenced by TÜBİTAK-MAM Chemical Institute and our Institute in year 2004, however, there has not been any result obtained from the works carried out for commercial production of this product yet. In addition, the effort put by Eti Mine Works General Directorate for establishing a production plant by tendering has remained inconclusive.
Trimethyl Borate
Synthesis of trimethyl borate was achieved under the scope of the project carried out by Istanbul technical University with support of the Institute and the patent certificate for production technology of the product was obtained. Same product can be produced as a side product during the production of sodium boron hydride.
Battery Fuel
Production of two direct sodium boron hydride fuel battery (DSBH-YP) of 100 Watt and 1 kWatt under the projects carried out under the collaboration of the Institute and TÜBİTAK-MAM Energy Institute, and PEM type fuel battery of 4 kWatt to be used in vehicle application was achieved.
Studies for adaptation of this product to different applications will be carried out at "BORON TÜBİTAK-MAM Boron and Hydrogen Technologies Centre", which was founded under the structure of TÜBİTAK-MAM Energy Institute.
Boron Doped Ceramic
While boron is used in the glazing application of ceramic, studies were carried out for using boron in the structure of the ceramic with the collaboration of Ceramic Research Centre (SAM) and it was found that boron provides an improvement in the durability of ceramic, a decrease in the production temperature and an increase in the production rate.
Flame Resistive Wooden Plate
Preliminary research and trial production of usage of boron chemicals as flame retardant under the framework of the collaboration between the Institute and Kastamonu Tree Industry. According to B1 and B2 flammability test, the samples were identified to meet the requirements of the class B2, and close to meet the requirements of the class B1.
Boron Nitride Coatings
Cubic boron nitride coating was developed from hexagonal boron nitride source by using PVD Magnetron Sputtering Production technology. In addition to characterization of the coatings made with a device produced by a national company, positive results were obtained from performance measurements of different applications and particularly cutting tools and moulds.


text:
Your Funeral
I refuse to write another,
Song, poem, book, essay,
About you.
I refuse to burn you,
Etch you,
Scratch you,
Into the skin of my mind,
The clean slate that was my innocence,
My purity, my consciousness, my memories,
So that you will continue to live,
To thrive, to eat off of the love,
You took you took for granted.
But I am not sad, I am not giving you
The satisfaction to say that I am
Depressed, miserable,
Colored different shades of blue,
Because it was you,
Who locked me out,
When I had no one.
I had no one, but you.
You are dead to me.


text:
My very first experience of authentic ramen goes back to 2013 when I made my first trip to Hong Kong. Now, before you go "machaan… Ramen is Japanese da. What food blogger you are?", the origins of ramen aren't quite clear with historical records stating that it was the Chinese who created the noodle ( known as lamian) and the dish perfected by the Japanese in the early 20th century; among other theories, none of which are relevant to my love for this wonderful dish.
While we witness the end of summer, and all the mango inspired food festivals and beers, Fatty Bao welcomes the monsoon with their ramen festival. Aptly title 'Raining Ramen', the festival showcases soulful ramen bowls from across south East Asia. I was invited to experience what the team had to offer. That afternoon, I didn't have any reinforcements who could order different bowls and I could get a taste of almost everything on the menu. Requesting for smaller portions so that I could try more than just one bowl, I started off with the Spicy Crab Gyoza & Miso Butter Ramen. This bowl of ramen was so wonderfully balanced with flavours of the smoked tomato shining through without overpowering the otherwise delicate flavour of the crab and the sinful miso butter. The team had done a fabulous job of having delicate and robust flavours in one dish. This particular bowl of ramen makes it to the list of 'food that hits your soul'. The ramen was accompanied by a pleasing Thai-inspired mocktail called Bora Bora, a mixture of passion fruit, coconut water and green apple. Put together, these two were ideal companions for a cloudy monsoon afternoon of reading and 'me time'.
The second ramen bowl I ordered was intense and in-your-face. The Braised Lamb Tantamen Ramen offered a very meaty slow-cooked lamb bone broth that would bring joy to the heart of only a staunch non-vegetarian. Served with curly noodles, peanuts and chilli, this bowl was Trooper by Iron Maiden compared to last bowl which was a Nocturne by Chopin. While there was nothing wrong with any of the flavours, this one is recommended only to the hard core non veg lover… you know the kind that enjoys bone marrow… definitely not the 'leg piece chicken biryani' eater. This bowl was paired with a far more sober mocktail of watermelon, basil and chamomile tea called the Melon Sipper.
Dessert was another delightful affair. Not a part of the ramen food festival menu, I ordered the Lemon Tart. This was a very pretty dish comprising of lemon mousse, pistachio crumble, mint meringue, raspberry sorbet and an almond sable. Perfectly balanced out without being too citrusy or too sweet, the dessert was just what the doctor ordered (or the waiter recommended) to mute the very intense flavours of the lamb broth from earlier.
The festival offers a range of ramen bowls from pork to duck breast to even green tea. The festival runs till the 20th of July, across all Fatty Bao restaurants in India. The price starts at INR 395++ for the vegetarian options and INR 425++ for the non-vegetarian options.
PS – I made the mistake of writing this post late at night, and am craving for some ramen right now. I'll have to make do with fruit ( Bah!)


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Looking forward to participating in Capricon later this week (February 14-17) at the Westin North Shore in Wheeling, IL … [Read More...]
I'm so glad you found my home on the Internet. Perhaps you've stopped by to learn more about The Apothecary's Curse, a 2017 Bram Stoker Award finalist and recipient of the 2017 Best Adult Fantasy/SF at Killer Nashville.
The Apothecary's Curse is an alchemist's brew of historical fantasy and medical thriller as a physician and an apothecary race against time to recover the ancient book that made them immortal centuries ago.
"Anne Rice meets Michael Crichton in this fever dream of a fantasy. Richly textured, terrifying, and somehow timely. . .Will keep readers up well past their bedtime. Highly recommended!" –Jay Bonansinga, New York Times–bestselling author of The Walking Dead: Search and Destroy and Self Storage.
I will have a major announcement in the next weeks about a new Apothecary's Curse book, so sign up for my mailing list to stay up to date.
I'm gratified that my 2010 book on the hit show House, M.D. continues to please readers, and almost monthly, I'm stopped or receive an email from someone who's read and loved it!!
I am available for public appearances (I love doing them!!), talks, panels and workshops, readings and signings. So contact me for more information.
Right now, I'm working on yet another project, which takes place in, but is apart from Gaelan's story (it takes place 300 years before he was born!), but is very much a part of the TAC-Verse.
So look around, leave a comment–and please sign up for the mailing list.
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Happy December! Win a Copy of The Apothecary's Curse
Enter now to win a copy of The Apothecary's Curse. What's it about? Let me tell you a bit... Between magic and science, … [Read More...]
Comic-Con Interview: Arvind Ethan David on 'Darkness Visibile,' 'Dirk Gently' and More
Arvind Ethan David (The Infidel) is executive producer of the Netflix/BBC America hit series Dirk Gently Holistic … [Read More...]
Barbara's Blog
Will You be at Capricon this Weekend? Find me and Say Hi!!
Looking forward to participating in Capricon later this week (February 14-17) at the Westin North Shore in Wheeling, IL … [Read More...]
Novel Writing: The Revision Process Part 1
Most of you know that bit of excellent writing advice, the rule about letting a draft sit and marinate for a time before … [Read More...]
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About Barbara
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Series Award
my LF
About Henriette Ebbesen
Henriette Sabroe Ebbesen, born April 5th 1994, is currently residing in Copenhagen, Denmark, where she works as a fine art photographer alongside studying medicine at University of Copenhagen. Ebbesen has always been interested in the painting media, but her passion for fine art photography started recently in 2015, when she came to Georgia Southern University, GA, USA on a Rotary Scholarship to study art from 2015-2016. Ebbesen is interested in reflections and uses reflective surfaces to decompose space and objects within the picture frame in order to create surreal effects in her photographs. Ebbesen's photographs have been exhibited both in the USA and Europe, and she has been featured and published by magazines like Blink Magazine, Kaltblut Magazine, Musée Magazine, and Vogue Italy. Ebbesen has also won several awards and honorable mentions in different photography competitions, including two of Life Framer's monthly competitions. Ebbesen's portfolio is currently featured on Photo Vogue Italia with whom she recently exhibited in Milan, November 2017 during "Photo Vogue Festival", a photo festival organized by Vogue Italy.
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Danubian trails, drinking virgin blood with a straw, heads above the trees, final? show in WienWednesday, January 21st, 2009
Well there's already dozens of tales to tell from the XLt/Stencil Nation tour on the Danubian trails, but we are a bit pressed for time as we prepare for our show in Vienna.
> 22.01 Wien, AT – Zeitvertreib @ 7pm with SN vs. XLt after party (spec. guest Dieter Puntigam)
As soon as we landed in [...]


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Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10–competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10–competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24hiCD27+ B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10–dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.
B cells are generally considered to positively regulate immune responses by producing antigen-specific antibody and helping to induce optimal CD4+ T-cell activation.1 However, B cells and specific B-cell subsets can also negatively regulate immune responses in mice.2⇓⇓⇓–6 The absence or loss of these regulatory B cells exacerbates disease symptoms in contact hypersensitivity, experimental autoimmune encephalomyelitis, chronic colitis, collagen-induced arthritis, and lupus-like models of autoimmunity.7⇓⇓⇓⇓⇓⇓⇓–15 In many of these cases, B cells regulate inflammation, asthma, and T cell–mediated autoimmunity through the production of interleukin-10 (IL-10).8⇓–10,12⇓⇓⇓–16 Both human and mouse IL-10 exhibit numerous pleiotrophic activities in vitro and in vivo, including suppression of both Th1 and Th2 polarization and inhibition of antigen presentation and proinflammatory cytokine production by dendritic cells, monocytes, and macrophages.17
In mice, a subset of IL-10–competent regulatory B cells can be functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of in vitro stimulation with lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and ionomycin, with monensin included in the cultures to block IL-10 secretion.12,13 These IL-10–competent B cells have been labeled as B10 cells to identify them as the predominant, if not exclusive, source of B-cell IL-10 production and to distinguish them from other regulatory B-cell subsets that may also exist.5 For example, inducible IL-12–producing B cells regulate intestinal inflammation.18 B10 cells are found within the spleens of naive wild-type mice at frequencies of 1% to 3%, where they predominantly represent a subset of the phenotypically unique CD1dhiCD5+CD19hi B-cell subpopulation that shares overlapping cell surface markers with multiple phenotypically defined B-cell subsets.11⇓⇓–14,19,20 Additional B cells within the CD1dhiCD5+ B-cell subpopulation acquire the ability to function like B10 cells during 48 hours of in vitro stimulation with LPS or agonistic CD40 monoclonal antibody (mAb).5 These B10 progenitor (B10pro) cells are then able to express cytoplasmic IL-10 after stimulation with PMA, ionomycin, and monensin for 5 hours.21 B10 cells also require diverse B-cell antigen receptors for their development,21 and their regulatory functions are Ag-restricted in vivo.12,13 Spleen B10-cell numbers increase significantly in diabetes- and lupus-prone mice,14,21 and the adoptive transfer of antigen-primed CD1dhiCD5+ B cells reduces inflammation during contact hypersensitivity and autoimmune disease.12,13,22
The identification and characterization of an IL-10–producing B-cell subset in mice raise the issue of whether B cells with these functional properties exist in humans. Studies of B-cell IL-10 production in humans have yielded diverse results that are currently difficult to unify into a coherent model.23⇓⇓⇓⇓–28 It is also unknown whether human B10 cells share overlapping physiologic triggers with mouse B10 cells that lead to IL-10 production and their expansion in vitro.12,13,21 Therefore, the purpose of the current study was to enumerate and characterize the IL-10 competent B10 and B10pro cell subsets in humans.
Heparinized blood was obtained from healthy donors (age, 14-73 years) or from patients. Patients with rheumatoid arthritis met the American College of Rheumatology 1987 revised classification criteria.29 Patients with systemic lupus erythematosus satisfied the 1982 classification criteria.30 Patients with primary Sjögren syndrome fulfilled the American-European consensus group criteria.31 Patients with autoimmune vesiculobullous skin disease, including bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris, and dermatitis herpetiformis, had typical clinical and histologic findings, with diagnostic findings on direct immunofluorescence of perilesional skin or oral mucosa.32,33 Patients with multiple sclerosis fulfilled the 2005 McDonald criteria for relapsing remitting or primary progressive multiple sclerosis34 or secondary progressive multiple sclerosis as defined using the Lublin and Reingold criteria.35 Tissues were obtained anonymously from persons without identifiable hematologic disorders, with the purified B cells immediately cryopreserved (> 90% cell viability). Cryopreserved cord blood samples were obtained from the Duke University Stem Cell Laboratory and the Carolinas Cord Blood Bank.
Blood mononuclear cells were isolated by centrifugation over a discontinuous Lymphoprep (Axis-Shield PoC As) gradient. Cell numbers were quantified by hemocytometer, with relative lymphocyte percentages among viable cells (based on scatter properties) determined by flow cytometry. In some experiments, B cells were enriched using RosetteSep (StemCell Technologies) following the manufacturer's protocols. CD19-mAb-coated microbeads (Miltenyi Biotec) were used to purify blood B cells by positive selection following the manufacturer's instructions. When necessary, the cells were enriched a second time using a fresh magnetic-activated cell sorting column to obtain more than 99% purities.
Written informed consent was obtained in all cases according to the Declaration of Helsinki. All protocols were approved by the respective ethics boards: Institutional Review Board of Duke University Medical Center, the Human Protection Committee of Dana-Farber Cancer Institute/Harvard Medical School, University of Rochester Institutional Review Board, and the Institutional Review Board of St Luke's-Roosevelt Hospital Center Institute for Health Sciences.
Antibodies, immunofluorescence analysis, and cell sorting
Antihuman mAbs included: IgD (IA6–2) from BD Biosciences; CD21 (BU33), CD22 (RFB4), CD23 (D.6) from Ancell; IgM (MHM-88), CD1d (51.1), CD5 (UCHT2), CD19 (HIB19), CD24 (ML5), CD25 (BC96), CD27 (O323), CD38 (HIT2), CD40 (HB14), CD48 (BJ40), and CD148 (A3), tumor necrosis factor-α (TNF-α; MAb11), functional grade CD3 (HIT3a), and phycoerythrin-conjugated or unconjugated anti–IL-10 (JES3–19F1, JES3–9D7) mAbs from BioLegend. Antihuman IgM Ab was from Jackson ImmunoResearch Laboratories.
Single-cell suspensions were stained on ice using predetermined optimal concentrations of each antibody for 20 to 60 minutes and fixed as described.36 Cells with the light scatter properties of lymphocytes were analyzed by 2–6 color immunofluorescence staining and FACScan, FACSCalibur, or FACSCanto II flow cytometers (BD Biosciences). Dead cells were excluded from the analysis based on their forward- and side-light scatter properties and the use of LIVE/DEAD Fixable Violet Dead Cell Stain Kits (Invitrogen). All histograms are shown on a 4-decade logarithmic scale, with gates shown to indicate background isotype-matched control mAb staining set with less than 2% of the cells being positive. Blood CD24hiCD27+ and CD24lowCD27− B cells were isolated using a FACSVantage SE flow cytometer (BD Biosciences) with 90% to 95% purities.
Analysis of IL-10 production
Intracellular IL-10 analysis by flow cytometry was as described.12 Briefly, cells were resuspended (2 × 106 cells/mL) in medium (RPMI 1640 media containing 10% fetal calf serum, 200 μg/mL penicillin, 200 U/mL streptomycin, and 4mM L-glutamine [all from Invitrogen]) and stimulated with LPS (10 μg/mL, Escherichia coli serotype 0111: B4; Sigma-Aldrich), CpG (ODN 2006, 10 μg/mL; Invivogen), or other Toll-like receptor (TLR) agonists (TLR1, Pam3CSK4, 1 μg/mL; TLR2, heat-killed Listeria monocytogenes, 108 cells/mL; TLR3, polyriboinosinic acid/polyribocytidylic acid, 10 μg/mL; TLR5, S typhimurium flagellin, 1 μg/mL; TLR6, Pam2CGDPKHPKSF, 1 μg/mL; TLR7, imiquimod, 1 μg/mL; TLR8, ssRNA40, 1 μg/mL; Invivogen), CD40L (1 μg/mL; R&D Systems), antihuman CD40 mAb (1 μg/mL; BioLegend), PMA (50 ng/mL; Sigma-Aldrich), ionomycin (1 μg/mL; Sigma-Aldrich), brefeldin A (BFA, 1 × solution/mL; BioLegend), monensin (2mM; eBioscience), and antiIgM antibody (10 μg/mL) as indicated in 48-well flat-bottom plates before staining and flow cytometry analysis. For analysis of cell proliferation, lymphocytes were stained with carboxyfluorescein succinimidyl ester (CFSE) Vybrant CFDA SE fluorescent dye (5 μM; Invitrogen) according to the manufacturer's instructions. For IL-10 detection, Fc receptors were blocked using FcγR-binding inhibitor (eBioscience). Stained cells were fixed and permeabilized using a Cytofix/Cytoperm kit (BD Biosciences) according to the manufacturer's instructions and stained with anti–IL-10 mAb.
Secreted IL-10 was quantified by enzyme-linked immunosorbent assay (ELISA). Purified B cells (4 × 105) were cultured in 0.2 mL of complete medium in a 96-well flat-bottom tissue culture plates. Culture supernatant fluid IL-10 concentrations for triplicate samples were quantified using IL-10 OptEIA ELISA kits (BD Biosciences) following the manufacturer's protocols.
IL10 transcript expression
In some experiments, IL-10-secreting blood B cells were identified after 4 hours of in vitro stimulation using an IL-10 secretion detection kit (Miltenyi Biotec) with subsequent staining for CD19 expression before cell sorting into IL-10+CD19+ and IL-10−CD19+ populations. RNA extraction, cDNA generation, and real-time PCR analysis were as described.13 IL-10 primers were: sense 5′-CTTCGAGATC TCCGAGATGC CTTC-3′, antisense 5′-ATTCTTCACC TGCTCCACGG CCTT-3′. GAPDH primers were: sense 5′-GCCACCCAGA AGACTGTGGA TGGC-3′ and antisense 5′-CATGTAGGCC ATGAGGTCCA CCAC-3′.
In vitro functional assays
Blood CD24hiCD27+CD19+ and CD24lowCD27−CD19+ B cells from healthy controls were purified by cell sorting and stimulated with CpG (10 μg/mL) plus CD40L (1 μg/mL) for 24 hours. Naive CD4+CD25− T cells were purified by magnetic-activated cell sorting (Miltenyi Biotec) and cultured in replicate wells either alone (1 × 106/mL) or with CD40/CpG-stimulated B cells (1 × 106/mL) in tissue culture plates coated with CD3 mAb (0.5 μg/mL) for 72 hours with either BFA or phorbol ester and ionomycin plus BFA (PIB) added during the final 5 hours. The cells were stained for cell surface CD4 and cytoplasmic TNF-α expression before analysis by flow cytometry. Alternatively, CD40/CpG-stimulated sorted B-cell populations (1 × 106/mL) were cultured for 20 hours with equal numbers of blood monocytes that had been purified by plastic adherence or magnetic-activated cell sorting, with anti–IL-10 mAb (10 μg/mL) added to some cultures. The cultured cells were then washed, stimulated with LPS (1 μg/mL) for 4 hours in the presence of BFA, and stained for cell surface CD14 and cytoplasmic TNF-α or interferon-γ expression before analysis by flow cytometry.
Statistical analysis
All data are shown as mean ± SEM. Significant differences between sample means were determined using the Student t test.
Enumeration of human IL-10-producing B cells
Mouse B10-cell frequencies have been described, with background cytoplasmic IL-10 staining of less than or equal to 0.2% commonly observed with B cells from IL-10−/− mice.12,13,21 A similar strategy was therefore optimized to enumerate human blood IL-10–competent B cells. B cells spontaneously expressing IL-10 were below the threshold for reliable quantification by immunofluorescence staining, even when the cells were cultured with BFA to stop Golgi transport (Figure 1A). However, a distinct subset of cytoplasmic IL-10+ B cells was observed at low 0.25% to 2% frequencies after ex vivo stimulation using PIB (Figure 1A-B). Stimulation with PIB for 5 hours induced 0.8% ± 0.1% of blood B cells on average to express IL-10 (n = 14, 1.9 ± 0.3 × 10−3 B10 cells/mL, Figure 1B-C). B-cell stimulation with TLR agonists did not substantially alter mean B10-cell numbers, although adding either CpG oligonucleotides (CpG, TLR9 agonist) or LPS to the PIB cultures increased IL-10+ B-cell frequencies in some persons (Figure 1A-C). Stimulation beyond 5 hours or using 10-fold higher PMA or ionomycin concentrations resulted in extensive B-cell death, which complicated B10-cell enumeration. Background IL-10 mAb staining was also reduced by the exclusion of cell doublets and dead cells from the analysis. BFA was also used to block IL-10 secretion rather than monensin because it optimized human B-cell cytoplasmic IL-10 expression (Figure 1A). B cells cultured in BFA served as negative controls because they gave results similar to isotype control mAb staining. Thus, blood B10 cells were rare but readily quantified in healthy humans.
Human B10pro cell identification
In mice, B10pro cell maturation into IL-10-competent B10 cells is induced by 48 hours of stimulation with either LPS or agonistic CD40 mAb.21 Human blood B10pro cells capable of maturing into IL-10–competent cells after in vitro culture were also identified. The total frequency of B10 and B10pro cells (B10 + B10pro) is quantified in this assay, as the B cells that acquire IL-10 competence in vitro (eg, matured B10pro cells) cannot be differentiated from preexisting B10 cells that inherently express cytoplasmic IL-10 after 5 hours of PIB stimulation. Culturing human B cells in media alone for 48 hours resulted in approximately 0.2% of B cells expressing cytoplasmic IL-10 after PIB stimulation during the last 5 hours of culture (Figure 1B). Adding LPS, CpG, or recombinant CD40 ligand (CD40L, CD154) alone, together, or in combination with BFA to the 48-hour cultures did not increase IL-10-producing B10-cell frequencies. However, after PIB stimulation during the last 5 hours of culture, B10 + B10pro-cell frequencies increased to 0.6% ± 0.1%, 1.9% ± 0.4%, 0.8% ± 0.1%, 1.2% ± 0.2%, and 4.1% ± 1.0% after 48 hours of TLR1 agonist, LPS, TLR6 agonist, TLR7 agonist, or CpG stimulation, respectively (Figure 1E left panel). Compared with media or most TLR agonists alone, the addition of CD40L to the cultures significantly enhanced mean B10 + B10pro-cell frequencies (Figure 1E right panel). CD40L induced higher IL-10+ B-cell frequencies than agonistic CD40 mAb (Figure 1D). Thus, dual CD40 and TLR stimulation induced the highest frequencies of B10pro cells to become IL-10–competent B10 cells, with the highest frequencies (7.0% ± 1.4%) and numbers of IL-10+ cells (1.6 ± 0.3 × 104 cells/mL, n = 14) induced after 48 hours of CD40L plus CpG stimulation. B10-cell percentages relative to all B cells decreased with age among 60 healthy persons, with a significant inverse correlation between B10 + B10pro-cell frequencies and age (P < .05, data not shown). Thus, B10pro cell maturation in vitro optimized IL-10–competent B-cell enumeration.
B10-cell numbers in newborn blood and adult tissues
Newborn blood contained both B10 and B10pro cells. Mean B10-cell frequencies in cord blood after 5 hours of CpG + PIB stimulation were 0.45% ± 0.14% (Figure 2A). B10 + B10pro-cell frequencies were similar or higher in cord blood relative to adult blood after culture with CD40L and TLR agonists: TLR1 (2.6% ± 0.6%), LPS (7.6% ± 1.8%), TLR6 (4.2% ± 1.4%), or TLR9 (CpG, 9.6 ± 2.3%) agonists with PIB added during the final 5 hours of culture. B10 cells were also found within spleens (0.31% ± 0.06%, n = 4, CpG + PIB) and tonsils (0.31% ± 0.11%, n = 3, CpG + PIB) of adults without known disease (Figure 2B). Thus, newborn and adult blood and tissues contain quantifiable numbers of B10 and B10pro cells.
Regulation of B10 cell IL-10 production and secretion in vitro
The time course of blood B-cell IL-10 induction was assessed in vitro by quantifying IL-10 transcripts. By 12, 24, and 48 hours, B-cell stimulation with CD40L plus CpG induced 6.8-, 24-, and 5.9-fold higher IL10 transcript levels, respectively, than was observed for unstimulated B cells (P < .05; Figure 3A). Blood B cells that were actively secreting IL-10 after in vitro stimulation expressed IL10 transcripts at 19-fold higher levels than were detected in IL-10− B cells (Figure 3B). Thus, IL10 gene transcription parallels the induction of B10-cell cytoplasmic IL-10 expression.
The response of human B10 + B10pro cells to CD40L, CpG, and antigen receptor-generated signals was also examined. Compared with CD40L alone, CpG induced the highest levels of B10pro cell maturation into IL-10–competent B10 cells, which was further increased when both CD40L and CpG were added to the cultures (Figure 3C). By contrast, IgM ligation using mitogenic antibody did not induce cytoplasmic IL-10 expression but actually inhibited the B10pro cell maturation effects of CpG + CD40L stimulation. In vitro IgM signals also inhibit mouse B10pro cell maturation and cytoplasmic IL-10 induction.21 Among TLR agonists, LPS and CpG were also the most potent stimuli for inducing IL-10 secretion by human blood B cells (Figure 3D). The addition of CD40L to the cultures was not required but enhanced LPS- and CpG-induced IL-10 secretion. Thus, similar signals induce human and mouse B10pro and B10 cells to mature and express cytoplasmic IL-10 in vitro.
Phenotypic characterization of IL-10–competent B cells
Whether human B10 cells represent a unique or known B-cell subset was determined by analyzing their cell surface phenotype. Cell surface IgM, IgD, CD1d, CD5, CD10, CD19, CD21, CD22, CD23, CD24, CD25, CD27, CD38, and CD40 densities did not change when B cells were stimulated with PIB, LPS + PIB, or CpG + PIB for 5 hours and/or permeabilized. Furthermore, the transport of newly synthesized proteins to the cell surface is inhibited by the addition of BFA to the cultures. Therefore, these markers were used to phenotype freshly isolated B10 cells. Half of blood B10 cells expressed high IgM levels and low IgD levels (Figure 4A). Both CD24 and CD27 expression was high on the majority of B10 cells, whereas IL-10− B cells expressed either high or low density CD24 and CD27. CD19 and CD25 expression was also higher on B10 cells than IL-10− B cells. Otherwise, the remaining cell surface markers were absent or expressed similarly by both B10 cells and IL-10− B cells. The same results were obtained after PIB, LPS + PIB, or CpG + PIB stimulation (data not shown). Thereby, freshly isolated blood IL-10+ B10 cells were predominantly found within the CD24hi or CD27+ B-cell subpopulations.
The phenotype of blood B10 + B10pro cells was also assessed after 48 hours of culture with CD40L + CpG and 5 hours of LPS + PIB stimulation. Prolonged B-cell stimulation induced significant changes in the cell surface phenotype of both IL-10+ and IL-10− B cells, with most B cells induced to express CD25 and CD38 (Figure 4B). Nonetheless, B10 + B10pro cells on average expressed higher densities of CD1d, CD19, CD20, CD21, CD23, CD24, CD25, CD27, and CD38 compared with IL-10− B cells, consistent with an activated phenotype. Spleen B10 cells were also predominantly CD27+, although the expression of most cell surface molecules was similar if not identical for B10 cells and IL-10− B cells (Figure 4C). Spleen B10 + B10pro cells and IL-10− B cells also had similar phenotypes after 48 hours of stimulation in vitro (Figure 4D). Thereby, blood B10 cells represented a subset of the CD24hiCD27+ subpopulation, whereas IL-10 expression remained the best marker for categorizing B10 cells and B10 + B10pro cells.
Blood B10 cells are enriched within the CD24hiCD27+ B-cell subpopulation
In addition to being predominantly CD24hi and CD27+, most B10 cells also expressed additional cell surface markers of activation (CD48hi) and memory (CD148hi) that were not affected by the 5-hour culture conditions used to induce B-cell cytoplasmic IL-10 expression (Figure 5A-B). Even when the spectrum of blood donors was compared, B10 cells were always predominantly CD24hi and CD27+ (Figure 5C). Cell surface IgD, CD27, and CD38 expression profiles have also been used frequently to define human B-cell subsets.37,38 However, when blood B10 cells were analyzed based on their CD38 versus IgD, or CD27 versus IgD expression profiles, IL-10+ B10 cells from representative blood donors did not fall into distinct subpopulations (Figure 5C).
Because the CD24hiCD27+ B-cell subpopulation represented 24% ± 5% (n = 7) of blood B cells on average, it was assessed whether CD24 and CD27 could be used as overlapping markers to enrich for B10 cells. When purified CD24hiCD27+ and CD24lowCD27− B cells were cultured individually with LPS + PIB for 5 hours to induce IL-10 expression, B10-cell frequencies were more than 10-fold higher within the CD24hiCD27+ subpopulation compared with CD24lowCD27− B cells (Figure 5D). To determine whether ex vivo B10pro cells also localize within the CD24hiCD27+ subpopulation, purified CD24hiCD27+ and CD24lowCD27− B cells were cultured individually to induce B10pro cell maturation. Again, the frequency of IL-10+ B10 + B10pro cells was more than 10-fold higher within the CD24hiCD27+ subpopulation compared with CD24lowCD27− cells (Figure 5E). The capacity of freshly isolated CD24hiCD27+ and CD24lowCD27− B cells to secrete IL-10 was also assessed. Again, IL-10 was predominantly produced by the CD24hiCD27+ B-cell subpopulation in response to CD40L, LPS, LPS + CD40L, CpG, or CpG + CD40L stimulation for 72 hours (Figure 5F). Thus, blood B10 and B10pro cells predominantly represented a small subset of cells within the CD24hiCD27+ B-cell subpopulation.
Because B10 and B10pro cells express markers for activated and memory B cells, their ability to proliferate in response to mitogens was assessed. Purified blood B cells were labeled with CFSE before in vitro culture. There was little, if any, IL-10+ or IL-10− B-cell proliferation during 48-hour cultures regardless of whether the cells were stimulated with LPS or CpG. However, IL-10+ B cells proliferated significantly in response to CpG at 96 hours, whereas IL-10− B-cell proliferation was modest (Figure 5G). Thus, blood B10 and B10 + B10pro cells preferentially proliferated in response to mitogen stimulation, consistent with their CD24hiCD27+ phenotype.
B10 cells regulate innate immunity
Resting or activated mouse B10 cells do not significantly influence mitogen-driven T-cell activation or proliferation in vitro.22 However, activated B10 cells do inhibit TNF-α production by antigen-specific CD4+ T cells during antigen-driven in vitro assays. In vitro T-cell–B-cell coculture systems were therefore assessed to determine whether human B10 cells regulate mitogen-driven T-cell function. First, purified blood CD24hiCD27+ B cells or CD24lowCD27− B cells were stimulated with CD40L and CpG for 24 hours, washed extensively, and added to cultures of purified CD4+ T cells that were stimulated with plate-bound CD3 mAb for 72 hours. In these assays, both CD24hiCD27+ B cells and CD24lowCD27− B cells inhibited CD4+ T-cell expression of TNF-α equally (Figure 6A). Unstimulated B cells did not affect CD4+ T-cell expression of TNF-α in these assays, and the addition of anti–IL-10 mAb to cultures containing activated CD24hiCD27+ or CD24lowCD27− B cells did not rescue TNF-α expression by CD4+ T cells (data not shown). Thus, activated human B cells can inhibit mitogen-induced TNF-α production by CD4+ T cells through IL-10-independent pathways that are not unique to CD24hiCD27+ B cells.
Even though mouse B10-cell regulation of T-cell function may require antigen-specific in vitro assays that are not amenable to human studies, mouse monocyte cytokine production is directly regulated by B10 cells through IL-10-dependent pathways that are not antigen-specific (M.H. et al, manuscript in preparation). The ability of human B10 cells to regulate innate monocyte responses was therefore assessed. Remarkably, TNF-α production was significantly reduced when monocytes were cultured with activated blood CD24hiCD27+ B cells, and this effect was blocked by anti–IL-10 mAb (Figure 6B). The addition of anti–IL-10 mAb to monocytes cultured alone did not affect TNF-α production (data not shown), whereas CD24lowCD27− B cells variably affected monocyte TNF-α production through IL-10–independent pathways. Thus, IL-10 production by CD24hiCD27+ B cells regulates monocyte TNF-α production.
B10 cells in patients with autoimmune disease
To determine whether blood B10-cell numbers are altered during inflammation and autoimmune disease, B10 and B10pro cells were examined in 91 patients with systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis (Figure 7A-B). Most patients were undergoing active treatment with immunomodulatory agents and/or low doses of prednisone (Table 1). B10-cell frequencies were significantly higher in one pemphigus vulgaris patient (PV07) and 1 dermatitis herpetiformis patient (DH02) not undergoing immunosuppressive therapy. Two lupus patients (SLE02, SLE06) and 1 rheumatoid arthritis patient (RA03) also had significantly higher B10-cell frequencies, but retrospective evaluation of their disease status, autoantibody profile, and treatment regimen did not indicate why these persons had higher B10-cell frequencies. No patients expressed significantly lower B10-cell frequencies than age-matched controls. Mean B10-cell frequencies were significantly higher for rheumatoid arthritis patients after culture with CpG but not for other patient groups (Figure 7B), even though B10-cell frequencies increased similarly in most cases after either LPS or CpG stimulation (Figure 7C left panel).
Mean B10 + B10pro-cell frequencies from patients with autoimmune disease were significantly higher than controls after either CD40L + LPS or CD40L + CpG stimulation (Figure 7A-B). Multiple patients had significantly higher B10 + B10pro-cell frequencies, including 2 patients not undergoing therapy (SLE04, PF03; Table 1). No patients expressed significantly lower B10 + B10pro-cell frequencies relative to age-matched controls. B10 + B10pro-cell frequencies increased after either LPS or CPG stimulation, but the scatter of the results was broad, suggesting inherently different patient sensitivities to LPS and CpG stimulation (Figure 7C right panel). Patients with high blood B10-cell frequencies did not necessarily have high B10 + B10pro-cell frequencies after either LPS or CpG stimulation (data not shown). Likewise, B10 or B10 + B10pro-cell frequencies did not correlate with CD27+ B-cell frequencies (data not shown). Relative B10 and B10 + B10pro-cell frequencies did correlate with the intensity of cytoplasmic IL-10 expression, but only one patient generated significantly higher (P < .05) cytoplasmic IL-10 expression levels on a per-cell basis relative to controls and other patients (Figure 7D). Thus, blood B10 and B10pro cell numbers were not decreased in patients with systemic or organ-specific autoimmune disease compared with healthy controls but were significantly increased in some patients.
These studies demonstrate the existence of human IL-10–competent B10 cells, which were readily identified by their ability to express cytoplasmic IL-10 after in vitro stimulation for 5 hours (Figure 1). Moreover, IL-10 production by human B10 cells regulated cytokine production by monocytes in vitro, demonstrating a functional link between regulatory B cells and the innate immune system (Figure 6B). Peripheral blood B10-cell frequencies were characteristically low in most persons, consistent with their low frequencies in mice. Human B10pro cells were also identified at low frequencies by their ability to express IL-10 after in vitro maturation during 48-hour cultures. Remarkably, the adaptive and innate activation pathways that induced human B10 and B10pro cell generation, maturation, cytoplasmic IL-10 expression, and IL-10 secretion were similar to those used to characterize mouse regulatory B10 cells. Specifically, human B10 cells responded to phorbol ester/ionomycin, LPS, and CpG stimulation, with B10pro cell maturation in response to CD40-, LPS-, and CpG-induced signals. Previous studies of IL-10 production by human B cells have predominantly studied bulk B-cell populations using stimulation and assay conditions that were not optimized for quantifying or characterizing individual B cells that were competent to express IL-10.25,26,39⇓⇓⇓–43 Nonetheless, the results herein demonstrate that rare B10 and B10pro cells that are competent to express IL-10 exist in human blood and can be quantified in vitro.
IL-10–competence remains the best phenotypic marker for defining human B10 cells. However, freshly isolated blood B10 and B10pro cells were also predominantly CD24hiCD27+, with approximately 60% also expressing CD38 (Figure 5A,C). Others have found similar total numbers of IL-10+ B cells in the CD24hiCD38hi and CD24intCD38int B-cell fractions,28 in agreement with the current findings (Figure 5C). B10 cells also expressed CD48 and CD148 at high levels (Figure 5A). CD48 is up-regulated on activated B cells,44 and CD148 is considered a marker for human memory B cells.45 CD27 expression is also a well-characterized marker for memory B cells, although some memory B cells may be CD27−.38,46,47 The CD27+ B-cell subpopulation can also expand during the course of autoimmunity and may serve as a marker for disease activity.38,47 However, B10-cell frequencies did not parallel the size of the blood CD27+ memory B-cell pool in normal donors or patients (data not shown). Thus, the CD24hiCD27+ phenotype of B10 and B10pro cells may indicate their selection into the memory B-cell pool during development, or they may represent a distinct B-cell subset that shares common cell surface markers with memory B cells. Consistent with a memory phenotype, the proliferative capacity of blood B10 cells in response to mitogen stimulation was higher than that for other B cells (Figure 5F), as is seen for mouse B10 cells.21 Moreover, IL-10 was also predominantly secreted by ex vivo CD24hiCD27+ B cells (Figure 5G). However, most CD24lowCD27− B cells were not IL-10 competent, even after 48 hours of LPS or CpG stimulation along with CD40 ligation. Human transitional B cells are also rare (2%-3% of B cells) in adult blood and are generally CD10+CD24hiCD38hi cells that are also IgD+CD27−.48,49 Given that CD10 expression is a well-accepted marker for most cells within the transitional B-cell pool,50 its absence on B10 cells suggests that these cells are not recent emigrants from the bone marrow. Thereby, in addition to inherent IL-10 competence, B10 cells demonstrate elevated proliferative responses that may reflect prior antigen stimulation.
Because IL-10 is critical for B cell–regulatory activity in mice, the current studies demonstrate that B10 cells were functionally competent to express IL-10 in healthy persons and 91 autoimmune disease patients (Figure 7A-B). Blood B10-cell frequencies in most patients with lupus, rheumatoid arthritis, Sjögren syndrome, autoimmune skin disease, and multiple sclerosis were not significantly different from those observed in healthy controls, although mean B10 + B10pro-cell frequencies were significantly increased. Multiple patients also had significantly higher B10 and/or B10 + B10pro-cell frequencies, including systemic lupus and pemphigus patients with either untreated or severe disease (Table 1). Consistent with this, IL-10 production by blood B cells is reported to be higher in patients with rheumatoid arthritis, lupus, and systemic sclerosis.23,24,26 Moreover, elevated B10/B10pro-cell frequencies in humans parallel what has been found during inflammation12,13 and autoimmunity in mice.14,21 Although patient cohorts with recent-onset disease and clinically active disease across multiple organ systems will be needed to fully assess the relationship of blood B10-cell numbers with clinical, laboratory, and treatment status, none of the patients or patient groups had significantly lower blood B10-cell numbers than age-matched healthy controls. Because multiple sclerosis and lupus patient's B cells are reported to produce decreased amounts of IL-10,27,28 the current studies demonstrate that a careful enumeration of IL-10–competent B10-cell frequencies within patients will be required to interpret experimental results, particularly when mixed populations of B cells are assayed functionally. Blair et al have also functionally characterized human blood CD24hiCD38hi B cells stimulated in vitro with CD40L expressing CHO cells and shown that they reduce CD4+ T-cell expression of interferon-γ and TNF-α after T-cell stimulation with CD3 mAb.28 By contrast, we find that both activated CD24hiCD27+ and CD24lowCD27− B cells reduce TNF-α expression after CD4+ T-cell stimulation with CD3 mAb through IL-10–independent pathways (Figure 6A). Nonetheless, we have found that mouse spleen CD1dhiCD5+ B cells can inhibit CD4+ T-cell interferon-γ and TNF-α expression, which is completely dependent on IL-10 expression, but this requires B10-cell activation and is only observed with antigen-specific T-cell activation.22 Furthermore, mouse spleen CD1dhiCD5+ B cells regulate the antigen-presenting capacity of dendritic cells in vitro and can thereby also regulate CD4+ T-cell activation indirectly.22 Moreover, the ability of human B10 cells to influence innate monocyte function (Figure 6B) expands their regulatory role during immunity and disease. Thus, it is probable that IL-10 produced by human B10 cells will have pleiotrophic regulatory effects on the immune system, as occurs in mice.
In conclusion, the current findings demonstrate the existence of a small but significant subset of CD24hiCD27+ B cells that is preprogrammed in vivo to express IL-10 after ex vivo maturation/stimulation. Monitoring the numbers and ability of individual B10 cells to produce IL-10 will become even more informative once the in vivo physiologic triggers of B10 cell-regulatory activity are identified. The identification of antigen-specific B10 cells may also facilitate a further understanding of their relevance to immune responsiveness because antigen receptor specificity is important for mouse B10-cell development and in vivo functional activity in the regulation of inflammation and autoimmunity.8,12,13
Contribution: Y.I., T.M., M.H., D.J.D., K.Y., G.M.V., and T.F.T. made substantial contributions to conception and design of the study and acquisition of the data, and drafted the article; P.M.S., S.H.B., C.M.M., A.D.W., R.P.H., and E.W.S.C. provided critical patient materials, information, and input into the design of the study; and all authors reviewed the data and manuscript critically for intellectual content, analysis, and interpretation of the data, and have given final approval of the version to be published.
Conflict-of-interest disclosure: T.F.T. is a paid consultant for MedImmune Inc and a paid consultant and shareholder for Angelica Therapeutics Inc. The remaining authors declare no competing financial interests.
Correspondence: Thomas F. Tedder, Department of Immunology, Box 3010, Duke University Medical Center, Durham, NC 27710; e-mail: thomas.tedder{at}duke.edu.
The authors thank Robert Streilein, Edna Scarlett, and Yen-Yu Lin for help with patient procurement and analysis, Jacquie Bryant for statistical analysis, and Dr Max Cooper for helpful advice.
This work was supported by the National Institutes of Health (AI56363) and the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense (grant U54 AI057157, T.F.T.; grants CA122645 and CA130805, S.H.B.; and grants CA132110 and HL091749, P.M.S.).
↵* Y.I. and T.M. contributed equally to this study and share first authorship.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734.
- Submitted July 1, 2010.
- Accepted October 10, 2010.
- © 2011 by The American Society of Hematology


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Microsoft's Lumia 950 family may have literally just launched, but the company isn't holding back much in the way of phone releases yet. A new picture has emerged from the French leaker OnLeaks which purports to show the Lumia 850 in white.
As you can see, the design is cut from the same cloth Microsoft's Lumia design language, with the same curved edges, a slight camera hump reminiscent of the 640 XL and the metallic Microsoft logo on the back.
The device also appears to have a metallic trim (a feature some would have preferred to show up in the 950 family), a removable back and headphone jack placement on the bottom and is said to have the dimensions 155.9 mm x 77.23 mm x 6.92 mm (8.5 mm including the camera bulge.)
Check out the tweet linked below for more details.
Here comes your very first look at what might be #Microsoft's uncanceled canceled #Lumia850 https://t.co/UyRgddQCeC pic.twitter.com/9bO6mHLGHe
— OnLeaks (@OnLeaks) December 4, 2015
See a gallery of images below:
Update: evLeaks has also added that the device has a front-facing flash and gold trim and gold Microsoft logo.
.@OnLeaks In real, non-CAD life, Honjo has gold-colored trim and a golden Microsoft logo on the back (as well as a front-facing flash).
— Evan Blass (@evleaks) December 4, 2015


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A resident lawyer is the one who offers with the residential and skilled residential dealings. In addition to that, many actual property firms, mortgage corporations, and insurance firms require the presence of legal professionals throughout transactions. There are lots of sources from which you'll be able to cull adequate data on actual property attorneys and going by way of many an actual estate attorneys website is one such efficient method. Apart from the title, the lawyer can even overview the phrases of the contracts and the binder.
Single family homes, cottages, villas, cabins, multi family housing merchandise, duplex, courtyard houses, residences, condos, housing cooperatives are a few of the types of residential actual property. Hence, when shopping for actual property, you want a certified and skilled actual estate lawyer. For example 50% of the individuals who carry out the job of Real Property Attorney are expected to make lower than the median.
The possibilities of the negotiations on the terms of the agreement will likely be in one's favor is larger with an actual property lawyer on one's facet. Let us then start with looking at what's actual estate legislation This branch of regulation is huge and intensive. Depending on the sorts of companies rendered, real estate attorneys can cost both a flat fee or a per- hour charge.
So when you select to invest in or buy any of a majority of these homes, chances are you'll wish to look at hiring the companies of a selected lawyer meant for such areas. Though you wish to keep away from a probate, another great reason for estate planning is to cut back your estate taxes. Sales and purchases of the property the place the lawyer ensures legal guidelines are followed and real consumers are hooked with genuine sellers or landlords with real tenants.
Finding an actual estate lawyer can change into important when you're taking a look at any type of transaction related to real property. What will set apart good high quality legal knowledge is the truth that an actual property lawyer can even tell you about angles that you may by no means have thought of by yourself. For example, in New Jersey, ever actual property gross sales contract is subject to attorney's evaluation within 5 days of acceptance.


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The European Commission has come under fire following its decision not to allow a leading UK DNA scientist and entrepreneur to speak at a conference because she is pregnant. The body which is responsible for all European equal opportunities legislation, invited Dr "Sam" Decombel to speak at a conference in Brussels. However, upon discovering "Sam" was in fact "Samantha" and pregnant, the European Commission withdrew its invitation.
The European Commission invited Dr Decombel to speak at a conference on entrepreneurship and research in Brussels on 26 and 27 November. Dr Decombel is a leading scientist specialising in the use of an individual's DNA to develop personalised diet and exercise plans. Her companies, FitnessGenes and PlayDNA (which was featured on BBC2s Dragons' Den), have received public acclaim.
As Dr Decombel would be six months' pregnant by then, she explained to the European Commission she would need to travel to Brussels by train. Dr Decombel was then told she could not participate in the conference because the European Commission were not "very enthusiastic to take a risk for [Dr Decombel's] health making [her] travel to Brussels at the late stage of [her] pregnancy". Dr Decombel confirmed that she is in good health and not suffering any complications in her pregnancy, but the European Commission refused to reconsider its position.
Dr Decombel has stated "turning away a pregnant speaker, who is in excellent health, seems to me to be the perfect demonstration of why this is still such an issue for many mothers, and the absolute opposite of what I would hope the European Commission would want to convey. I am incredibly surprised to find that this is an attitude that still exists within a respected and apparently forward-thinking public body."
Michelle Last of Keystone Law who is representing Dr Decombel, has stated "Whilst pregnancy and maternity discrimination is reportedly on the increase, it is rare to see clear evidence of overt discrimination such as this. Of greater public concern is the fact that this case concerns the European Commission; the very body which is meant to be at the forefront in the protection of working mothers such as Dr Decombel. The European Commission should be setting an example, but not of this kind."
Dr Decombel is currently contemplating taking legal action against the European Commission.
This article is for general information purposes only and does not constitute legal or professional advice. It should not be used as a substitute for legal advice relating to your particular circumstances. Please note that the law may have changed since the date of this article.


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Today?s Boxster S is the most powerful roadster that Porsche has ever created.
As you press the throttle, the 3.2-liter engine sends the rev counter racing round the dial. By the time it reaches 6,200 rpm, there?s a full 258 hp at your disposal. Maximum torque of 229 lb-ft provides eager acceleration from 4,600 rpm. From a standing start, you reach 0-62 mph (100 km/h) in a breathtaking 5.7 seconds. Under the right track conditions, you can continue your run to a top speed of 164 mph (264 km/h).
This exceptional performance is achieved using a water-cooled flat six and a range of innovative technologies, such as four-valve heads, VarioCam variable valve timing, and a powerful engine management system. Immediate benefits include dynamic power delivery and throttle response.
The McPherson-strut suspension has been specially adapted to the specific performance of today?s Boxster S.
The braking system consists of four-piston monobloc aluminum fixed calipers with a distinctive red paint finish. These are combined with four internally vented and cross-drilled discs to deliver rapid and effortless response. A special ventilation system helps eliminate fading, particularly under heavy use.
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WASHINGTON--(BUSINESS WIRE)--Publishers' book sales for trade (consumer) books from Jan. to Dec. were up 0.8% to $7.2 billion compared to $7.1 billion in 2014. Despite a slow holiday season, the year ended slightly up, with a shift in sales for format and category.
Overall publisher revenue for 2015 was $15.4 billion, down 2.6% from the previous year. These numbers include sales for all tracked categories (Trade - fiction/non-fiction/religious, PreK-12 Instructional Materials, Higher Education Course Materials, Professional Publishing, and University Presses). Publisher net revenue is tracked monthly by the Association of American Publishers (AAP) and includes sales data from more than 1,200 publishers (#AAPStats).
A more detailed analysis of 2015 will be available with the StatShot Annual Report, which includes information from more than 1,800 publishers and market modeling, and will be available for purchase.
Some of the 2015 trends include:
- eBook sales declined this year – mostly from the Childrens & Young Adult category (C/YA down 43.3% from 2014).
- Downloaded audio continues to grow in popularity – this growth is most evident in the Adult Books category (Adult up 38.9% from 2014).
- Trade publishers fared better than educational or scholarly publishers.
- Adult Books performed better than other trade categories.
"For trade publishers, 2014 was a blockbuster year – especially in the Childrens and Young Adult Books category; so despite the challenging comps, increased sales in Adult Books helped the industry post gains in 2015," said Tina Jordan, Vice President of the Association of American Publishers. "We'll explore the reasons for the gains in the upcoming StatShot Annual."
Publisher sales of trade books for the month of Dec. 2015 were up 0.3% compared to Dec. 2014, and up 0.8% for the full calendar year.
- Childrens & Young Adult Books were up 7.3% compared to Dec. 2014, the category still ended the year down 3.2%.
- Adult Books were down 2.6% in Dec., but ended the year with an overall growth of 2.2%.
- Religious Presses continued several months of sales growth, up 5.6% in Dec. and 1.2% for 2015.
Trade Formats:
Downloaded audio and paperback books have grown every month in 2015 vs. the same month in 2014.
- Within Adult Books, downloaded audio is up 38.9% and paperback is up 16.2% for the year; eBooks declined 9.5% and hardback is down 0.5% for the year.
- Within Childrens & Young Adult Books, paperback is up 9.5% and board books were up 12.6%; eBooks declined 43.3% and hardback is down 7.7% for the year.
Educational Materials:
Revenues for PreK-12 instructional materials were up for the month of Dec. 2015 vs. Dec. 2014, but down 4.1% to $3.2 billion for the year.
Higher Education course materials were down 6.5% for the month of Dec. 2015 vs. Dec. 2014, and down 7.2% to $4.1 billion for the year.
Professional and Scholarly Publishing:
Sales for Professional Publishing, which includes business, medical, law, scientific and technical books and journals, were up 4.2% for Dec 2015 vs. Dec. 2014 and down slightly by 0.8% for 2015.
University Presses were down 3.1% year-over-year compared to the same 12 months in 2014.
* NOTE: Figures represent publishers' net revenue for the U.S. (i.e. what publishers sell to bookstores, direct to consumer, online venues, etc.), and are not retailer/consumer sales figures.
About AAP
The Association of American Publishers (AAP) represents about four hundred member organizations including major commercial, digital learning and education and professional publishers alongside independents, non-profits, university presses and scholarly societies. We represent the industry's priorities on policy, legislative and regulatory issues regionally, nationally and worldwide. These include the protection of intellectual property rights and worldwide copyright enforcement, digital and new technology issues, funding for education and libraries, tax and trade, censorship and literacy. Find us online at www.publishers.org or on twitter at @AmericanPublish.


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Highland Games, and Night of the Irish - Comin' Up!
Central Florida Highland Games Coming up January 19 and 20 - we'll be playing on the 20th and can't wait to be part of this fantastic event - Yep - log-tossing, huge rock-carrying, pipe band competitions, herding demos, oodles of different types of musical mayhem, tons of interesting vendors (get yer haggis!) - It's unique and always a hoot! Join us for musical mischief!
Set your calendars up for a grand event hosted by The City of Mount Dora! Night of the Irish on March 16! Irish Happy Hours start at 5 p.m. - We'll be makin' merry in the Beer Garden with some pipers from Rosie O'Grady's Highlanders, and the incomparable Inisheer Irish Dancers - we'll be "piped-in" to the main hall for a big show to start at 7 p.m. - There'll be food, goodies, rousin' fun, mischievous makin's, dancin', pipin', and not a few tall tales - a wonderful event - all in good fun!


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Consumers armed against hijackers with Norton AntiBot
Workgroup's Symantec division has announced the local availability of Norton AntiBot a proactive detection and removal tool that offers capabilities that complement existing security solutions.
AntiBot is targeted at combating the growing botnet pandemic, says Arno Fourie, Norton product manager at Workgroup. AntiBot is a real-time bot detection and removal solution for consumers. It monitors PC applications and processes around-the-clock, offering an additional layer of protection that complement existing security solutions to protect PCs from unauthorised access and tampering, he adds.
Unlike yesterday's viruses and worms, today's bots are stealth and dynamic, secretly installing on systems and turning them into "zombies". Once installed, bots can execute new commands sent by a bot master on an ongoing basis. If they are not properly removed, they can reinstall themselves, making them particularly difficult to destroy.
Norton AntiBot is designed to completely eradicate all traces of any bot or other malware from a system, once it's identified.
Consumers can reduce their exposure to bot-related attacks by deploying multiple layers of protection technologies, including
intrusion prevention, signature-based detection and behaviour-based detection, says Fourie.
By using complementary technologies, users have the most effective protection against known and unknown forms of malware, including bots.
Norton AntiBot uses an active behaviour-based heuristic detection system that is always on. This technology constantly analyses the behaviour of files and applications to ensure that otherwise invisible malware is tracked and eradicated as soon as it exhibits
harmful behaviour.
As a result, Norton AntiBot is a complementary solution to existing antivirus or security suites, including Norton AntiVirus, Norton
Internet Security and Norton 360.
Workgroup, Arno Fourie, (011) 654-6194, firstname.lastname@example.com
« Nigeria: Globacom to rollout fiber optic services Google supplies computer software to students and government in Rwanda and Kenya, »


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There are more and more books out now about Lewy Body Dementia. Some are good. Some aren't. Here is our take on a few of them:
One book we were asked about recently was Lewy Body Dementia: Causes, Tests and Treatment Options by Adam Wainwright MA, Erik Stevenson MD and Deanna R Miller RN (Apr 14, 2012). We had great hopes for this book when it first came out. Like A Caregiver's Guide to Lewy Body Dementia, it appeared to be a fairly easy to understand overview of LBD although its presentation is a little more scientific. However, upon reading it, we found that other than a section on testing, most of the information is similar to that in the Guide, but not as thorough. Also, it contains very few personal experience examples, making it a less interesting read. Although this book has been out almost a year, it has only six Amazon reviews. The last reviewer, back in July, referred readers to the Guide as a better choice. We do too.
Another book we see people ordering occasionally is Dementia with Lewy Bodies by John Hewitt MA and Michelle Gabata MD (Apr 15, 2011) The under $10 price may make it attractive but the reviews are enough to keep us from spending our money. Again, there are only six and the last three give it only one-star. One reviewer describes the book as 28 pages of subject matter, an inadequate glossary, and an unexplained 94 page directory of holistic physicians. A review from a geriatrician states that the book "could do more harm than good" and says he/she could not recommend it. Reviewers also note that the LBDA is not mentioned anywhere in the book.
A third book on our "Do not buy list" is The Official Patient's Sourcebook on Dementia with Lewy Bodies, A Revised and Updated Directory for the Internet Age, by Icon Health Publications, James Parker and Philip Parker, Eds. (2002). First, too much has happened with LBD since it was published. Secondly, it truly is only a directory of internet resources available in 2002, and not worth the high cost of nearly $30. Finally, the single (one-star) Amazon review reports that it is "more for medical students or doctors and not for the common person." We'd argue that even medical personnel would not find this book very helpful.
On the positive side, here are a couple of books that we loved:
Living with Lewy Body Dementia (Sep 5, 2012), is written by Judy Towne Jennings, a physical therapist who shares her expertise with her readers as she tells her story. The book is worth buying just for that. But it has more. She suggests looking at the Lewy journey as an adventure and doing all you can to make your life enjoyable. She and her husband traveled and she shares many traveling tips.
We also recommend Treasures in the Darkness by Pat Snyder (Apr 6, 2012). As Pat tells her story, she writes about early LBD and how to slow it down. She emphasizes decreasing stress and being prepared. Her chapter on renovating her home to be able to keep her husband home longer is great. Like Judy, she also encourages families to enjoy the life they have.
You can get the Guide and the last two books by going to the LBD Book Corner, on LBDtool.com. While you are there look around and see if there is anything else you might enjoy. Thank you in advance for doing your Amazon shopping from our website. The small fees we receive from Amazon help to pay for our work.
Website: LBDtools.com


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wooden chests
wooden chests
from 70.00
to order a small wooden chest, please go to specific chocolate listing and select "wooden crate" in gift box option. holds one packet.
each medium wooden box holds two packets of our variety selections:
survival kit: K truffles, K bears
nirvana: K truffles (2 packets)
sunny days: pecan crisps, spanish orange
make it a double!: vodka shots, scotch shots
each large wooden box holds three packets of our variety of selections:
treasure chest: bluettes, pecan krisps, snowballs
california dreaming: K bears, spanish orange, apricots
hollywood: K truffles, K bears, K truffles
lost weekend: vodka, tequila, scotch shots
to make your own selection, call 310.248.2626
gift set:


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Multi-Room Lighting
In this photo, you see the result of a combination of advanced photography techniques which result in the picture perfect image....
First, the photo is lit with studio-quality flash which represents the true colors of the room and make up for the lack of ceiling light.
Second, You can see straight through the windows, which is the result of using flash to balance out the ambient light.
Third, while the main room in the photo is lit up properly, the second room through the door is dark, requiring a second shot to be blended in within photoshop.
The combination of these techniques demonstrate just one of the ways we accomplish our goal of a picture perfect images, every time!


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The possibility of being taken from this earth prematurely or having a catastrophic accident that causes significant incapacity of physical or mental abilities is something no one wants to think about. However, carefully considering what you would want to have happen if such a catastrophe were to happen to you is something that can be very important.
For parents, one of the most precious things in their life is their children. There is little, if anything, that is more important to parents than ensuring that their kids receive the care they need. Thus, a major concern a parent may have is what would happen to his/her kids if he/she were to die or become seriously incapacitated.
Thankfully, parents don't have to leave this issue to chance. Through careful planning, a parent can take steps aimed at ensuring that their children are properly taken care of if disaster were to strike.
One step parents here in Florida can take is to create and file with a court a Declaration of Pre-Need Guardianship. This document allows a parent to designate a person to whom the duties and responsibilities of caring for the parent's minor children would be transferred in the event that the parent becomes incapacitated or dies. Parents may have a very strong view on who would be best-suited to take care of their kids if something were to happen to them, and this document allows them to legally enshrine this preference.
See our guardianship page for more information about the establishment of pre-need guardians and other guardianship issues.
Helping parents develop plans for what would happen with their kids if the worst were to happen is one of the services our firm can provide. We can assist parents with the Declaration of Pre-Need Guardianship process and related matters.


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In honor of Kentucky Derby weekend, I packed my big floppy hat and took it with me to Arizona. I purchased it earlier this spring, and was obviously excited to wear it. My belly is definitely starting to pop, and I wore this comfy outfit in Phoenix to meet my cousins for dinner. Would love to see the different ways you wore your big floppy hats that weekend! Tweet your pics my way to @popcornpandas! Of course, Preakness hats are more than welcome too. 🙂
Photos by: Zack Notes / Edited by: Myself
Big Floppy Hat: Francesca's – similar here and here / Top: Motherhood / Skirt: Motherhood – similar in gray / Sandals: Sam Edelman via Nordstrom Rack / Bag: Coach (old) / Snakeskin Bracelet: Henri Bendel – sold out – shop bangles / Bow Bracelet: Baublebar / Red and Gold Chain Bracelet: Gorjana – sold out – shop bracelets / Watch: Michael Kors / Necklace: Family Heirloom / Sunglasses: LOFT / Toes: Essie Peach Daiquiri / Lip: Lancome Red Haute
Dreary Monday here in NYC. We had a great weekend seeing family and friends that were in town visiting, and I worked on creating a baby registry for my little guy. Wow, and I thought a wedding registry was overwhelming! Boy, was I wrong! It pretty much took me all weekend, but it's finally complete. Can't believe I will be 24 weeks tomorrow! Time is flying right by.
Hope you all have a great week! Memorial Day Weekend is on the horizon.


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You can also search for providers and practices at Penn Medicine Lancaster General Health or Princeton Health.
Dr. Mohan is employed by Penn Medicine.
There is no publicly available rating for this medical professional for one of the following reasons:
A facility of the Hospital of the University of Pennsylvania
A facility of Penn Presbyterian Medical Center
A facility of Pennsylvania Hospital
Medical School: G.S.V.M. Medical College - Kanpur University
Residency: MLN Medical College
Fellowship: Sanjay Gandhi Post Graduate Institute of Medical Sciences
Residency: Sanjay Gandhi Post Graduate Institute of Medical Sciences
Fellowship: National Neuroscience Institute
Fellowship: University of Michigan Medical Center
Dr. Mohan is employed by Penn Medicine.
Scully A, Desiderio L, Stanton M, Stevens C, Pogozelski A, Mohan S, Lucas T.: MRI-Guided Laser Ablation for the Treatment of Epilepsy. 27th Annual Meeting of the Society for MR Radiographers & Technologists (SMRT), Paris, France. : 2018.
Chang B, Stein J, Sundarajan SH, Nabavizadeh SA, Mohan S: "Air Up There": A Case-Based Review of Unexpected Pneumocephalus
ARRS 2018, Washington DC : 2018.
Chawla S, Wang S, Mohan S, Nabavizadeh SA, Nasrallah MP, Brem S, O'Rourke DM, Poptani1 H.: Identification of IDH Mutant Glioblastomas by Using Diffusion and Perfusion MR Imaging. ISMRM Workshop on Advanced Neuro MR: Best Practices for Technical Implementation. : 2018.
Duda J, Botzolakis E, Chen PH, Mohan S, Nasrallah I, Rauschecker A, Rudie J, Bryan RN, Gee J, Cook T: A Bayesian Network Interface for Assisting Radiology Interpretation and Education SPIE Medical Imaging, Houston, TX : 2018.
Chen YJ, Rath TJ, Mohan S: PET-CT in Head and Neck Cancer: Current Evidence and Future Directions MR Clinics of North America 26 (1): 37-49,2018.
Chawla S, Loevner LA, Kim SG, Hwang WT, Wang S, Verma G, Mohan S, LiVolsi V, Quon H, Poptani H.: Dynamic Contrast-Enhanced MRI-Derived Intracellular Water
Lifetime (τ i ): A Prognostic Marker for Patients with Head and Neck Squamous Cell Carcinomas. American Journal of Neuroradiology. 39 (1): 138-144,2018.
Verma A, Baijal SS, Mohan S, Kathuria M, Prasad R.: Thermal Ablation of Gall Bladder in patients with unresectable hepatobiliary malignancies. 7th Asian Oceanic Congress of Radiology joint with 71st National Conference of the Indian Radiological and Imaging Association. Mumbai, India. : 2018.
Skolnik AD, Wang S, Gopal PP, Mohan S.: Pitfalls in the neuroimaging of glioblastoma in the era of antiangiogenic and immuno/targeted therapy - detecting elusive disease, defining response. Frontiers in Neurology. 6 (33): 14-18,2018.
Chawla S, Wang S, Mohan S, Nasrallah MP, VermaG, Brem S, O'Rourke DM, Wolf RL, Poptani H, Nabavizadeh SA.: Differentiation of Brain Infections from Necrotic Glioblastomas using Diffusion and Perfusion MR Imaging. Journal of Magnetic Resonance Imaging. : 2018.
Bathla G, Watal P, Gupta S, Nagpal P, Mohan S, Moritani T.: Cerebrovascular Manifestations of Neurosarcoidosis: An Under-recognized Aspect of the Imaging Spectrum. American Journal of Neuroradiology : 1-7,2017.
Congratulations to the 481 Penn physicians listed below who were included in Philadelphia Magazine's Top Docs™ 2019.
Penn Medicine is one of the world's leading academic medical centers.
A clinical trial is a research study involving patient volunteers that are conducted to find safe and effective treatments for a variety of health conditions.


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Vigil held, memorial growing at Club Blu
Where there were gunshots and chaos less than 24 hours ago, there are now flowers and candles.
Where there were gunshots and chaos less than 24 hours ago, there are now flowers and candles.
A memorial continues to grow at Club Blu, scene of a shooting that killed two teens and left 18 other people injured early Monday.
The Fort Myers community is coming together to heal, holding vigils and trying to shine light into a very dark situation.
"We are here to pray and love on the people that were touched by this tragedy," said William Glover.
Glover is 16 and attends Lehigh Senior High School. He knew many of the victims.
"When you see a rest in peace and someone's name that you're used to seeing every day, immediately it's like a 'what'?!"
Members of Next Level and Mount Hermon churches, the group Parents of Murdered Children, and just people who wanted to pay their respects came together Monday evening to offer support and prayers.
Angela McClary lost her son to gun violence in 2014. She now spearheads Lee County's Parents of Murdered Children, a group helping relatives of victims. They left ribbons in remembrance at Club Blu.
"We are here for you; we understand. These ribbons signify that we are parents of murdered children as well, and we know you're hurt," McClary said.
She now raises her son's children, who said they wanted to go to a club a few days ago.
"It devastated me because I have grandkids that age and we were just talking about they wanted to go a club, and I said that was not the right thing to do because of so much that is going in the community and they are not safe."
The chaplain for Fort Myers Police also attended the prayer circle.
"What really gets me the most is the age, you know a 14-year-old it's kind of unnatural," said Rickey Anderson.
He said he's seeing younger victims being murdered every year.
"It starts at home, the community; law enforcement can only do a portion of it. Until we come together, it's going to continue to happen it's going to get worse and worse," he said.
"I pray, I just pray that no one retaliates... Or acts off of their grief," Glover said.
Anderson said he often sees the community come together after tragedy but after a few weeks, things go back to normal.
He said everyone needs to stay united in hopes of preventing another situation like this.


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Man Dressed as Elsa from Frozen Single-Handedly Rescues a Boston Police Wagon Stuck in a Snowbank
Courtesy Drag Elsa
And PEOPLE can reveal "Elsa" is, in fact, Jason Triplett, 37, an attorney from Boston, who says the escapade was the result of cabin fever brought on by the blizzard.
Playing down his heroic feat, Triplett says his fame will be fleeting as snow on a hot day.
"Everyone will be over it by noon," Triplett tells PEOPLE. "But if this is my 15 minutes, I would like to leverage it to meet Adam Rippon."
Olympian Rippon will no doubt be impressed with Triplett's strength and dedication to his costume. The bar's guests were certainly wowed cheering him on by, yelling "Come on, Elsa! The girl we didn't deserve" and "Let Him Go."
As for how the police…
View original post 74 more words


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Arriving in Santa Marta
Even though Santa Marta has its own airport, I arrived by bus, from Cartagena.
I arrived in Cartagena on a Monday afternoon, after a hectic stay in San Andres.
Landing on Colombia's mainland was a relief. Finally, I could get a couple minutes and embrace the joy that the worst part had already gone past. I said goodbye to my travel partners, Katia, Anna and Laris, the ones I had lived this not-so-good-experience with. Cartagena was on my to-do list, but the San Andres experience made me want to get to places that were less known. Since this was Carnival season, Cartagena would be packed, busy and expensive.
Just as I stepped out of the airport, I saw a MarSol bus. I had heard much about MarSol and the amazing service they offer on the northern coast of Colombia, so I approached the driver asking if they had buses running directly from Cartagena Airport to Santa Marta. The driver was really nice, asked me a couple questions (are you travelling alone, is Santa Marta your final destination?), and passed me his mobile phone (awkward moment here!). A lady was speaking to me on the other side of the line – a speeded Spanish that was way too fast for my limited language skills! She was asking me the same questions as the driver. No, I had no mobile phone.. So I was asked to remain exactly where I was, and a car would come round and pick me up in five minutes time. For 41,000COP, and would take me directly to Santa Marta. I handed over the phone and lit up a cigarette, as the driver left on his mini-bus. Five minutes later, another bus stops nearby. The driver picked up a white cardboard that read "TANIA – SANTA MARTA".
Well, I'm guessing that's for me! No mobile phone needed.
The bus was really nice! It was a brand new Mercedes mini bus, guess it had just under 15 seats. Air-conditioning, smooth ride, comfortable seats. Perfect for a four-hour nap, I thought. Surprisingly though, roughly half-way through the journey, we pulled over – the bus broke down. Soon after we were picked up by another bus, and continued our journey.
When we were arriving in Santa Marta, the bus driver asked us – me and two other girls, who were also travelling solo, where we were going. I gave him my address – La Villana – and the two others girls theirs – they were both heading to The Dreamer. For a moment here I thought I could have the worst pick, as I was going alone to a hostel they never heard about. A million thoughts were cruising my mind. Then, for my surprise, the bus pulls over and the driver called me by my name: he was dropping me off just outside the hostel, so I wouldn't have to walk alone at night. Pretty awesome!
Hostel: La Villana
By now, it was already really late, and I was pretty exhausted. The whole San Andres experience and the long bus journey, the heat, the backpacks… It was all coming down at the same time. I hadn't had a shower for two days, and I had already been stuck at an airport, been on an abandoned site, gotten on a broken bus… I was craving for some decent food, drinkable water, a cozy bed!
As I stepped in the hostel I was greeted with a large smile from the receptionist. I dropped of my oversized backback and asked him for a minute. I wanted to go outside and breathe in the warm air of Santa Marta. I sat on the step and lit a cigarette. Relieved, as I could now get some rest.
I checked in, and was asked if I was hungry. Damn, yes! He giggled and picked up my backpack. "Come on", he said, "I'll show you around and get you some food from the restaurant". Those were the most comforting words I had heard in a week!
The hostel was amazing: the rooms were all around in a patio with a centre-featured pool. Huge palm trees surpassed the ceilings, good chill music playing, the pool lights on and some balloons resting on the water. People giggling. As we entered my dorm, I was amazed: custom-made bunks, with actual steps instead of ladders. Each bed frame had its own niche with 2 plugs and a personal night lamp. Tall ceilings made it feel airy and "light". A fan and air-conditioning would keep the temperatures down, mosquitos away, and the air refreshened. Each bed had a designated drawer to store the backpacks, plus a locker, for other more important things – the lockers are big enough for a small backpack. To top all of this, the linen provided had a flower scent – not a common feature in hostels! They also provide us with two pillows (yes, TWO) and fresh cleaned towels. I was truly impressed. I felt really welcomed, because the staff were incredible, the place was immaculate, all little details made this hostel worthy of a five-star ranking amongst the finest hotels.
When I sat at the restaurant, by the pool, I could finally breathe with relief. I got a pepperoni pizza from their italian inspired restaurant, and treated myself with a nice glass of chilled wine. And when I laid on my flower scented bed, I though even heaven could not be any better than this.
A day in Santa Marta
I was only spending a day in Santa Marta. Not a problem though, this was just enough to fall in love with this city. Even though it's not too big, it has two sides to it: contemporary and historical, despite distinct, come hand-in-hand. Santa Marta is the perfect place to get in touch with local culture – people are nice and welcoming, and you can tell it is still a "raw" and genuine place. With great cultural heritage, you can either walk though the city and visit it's local monuments, markets and plazas, or take a day trip to the nearby Taganga Bay (hostel offers this for 10,000COP, but you can get it cheaper with a mototaxi off the streets). The Catedral de Santa Marta is just next door to the hostel, and the beach just three blocks up. A variety of programmes is available, for things such as diving, snorkelling, boat trips, moto trips and museums. The hostel also provides bikes to rent, at around 5,000COP/h.
Park Tayrona is the most popular destination nearby. This is where most backpackers head towards. However, I found Santa Marta so welcoming and cozy, that I totally recommend you'd spend a night or two here (as an opposite tip from what most travel guide books will say).
Park Tayrona is closed down through November, for cleaning. If you are planning to visit, double check the exact opening / closing dates.
My stay in Santa Marta was short, but I bring it close to the heart! I would later meet up with Lucie, the french girl I had met in San Andres. We were going to go to Palomino together. I will tell you all about that on the next post! 🙂
I had a little health issue, that I think it is useful to mention. I am always extra cautious when it comes to health, as I have already mentioned here (in portuguese only).
The morning after my arrival, I woke up having the skin on my face and necks's left side with a strange texture. It was looking like some sort of a really bad allergic reaction had occured, as it was really reddish and textured. Unsure about what to do, I decided to ask the hostel receptionist about it. He pointed out immediately that it looked like an allergic reaction caused by some sort of virus, present in the northern Colombian coast only. Nothing too serious if treated in time. I went to the closest pharmacy, where I was advised to take loratadine pills (for ten days, once a day) and put some corticol gel locally. They said it'd disappear in a few hours, and it did – some three hours later, I was fine! If you ever have this reaction, go to a pharmacist as soon as possible. If not treated, symptoms can develop to fever, headaches, and sometimes diarrhoea.


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When: Friday, October 19th - Saturday, October 20th
Check-in: 6:00-8:00pm on Friday
Where: Princeton Marriott at Forrestal - 100 College Rd E, Princeton, NJ 08540
Speaker: Rev. Edwin Colon
The best way to get down to Princeton is to purchase a round trip ticket ($32 round trip) from New York Penn Station to Princeton Junction. There will be a shuttle van to pick you up from Princeton Junction at the following times: 6:45pm, 7:15pm, and 7:45pm. Please choose the time that is closest to your arrival at Princeton and plan accordingly (travel time is anywhere from 50-75 minutes). Our shuttle vans will also take you from the Marriott back to Princeton Junction on Saturday evening when the retreat is over.
CLICK HERE to view the NJ Transit train schedule for Friday, 10/19.
Please email us at firstname.lastname@example.com if you need financial assistance or if you have any other questions/concerns regarding the Fall Retreat.


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Welcome to Sale Dental Spa, South Manchester's
Leader in Cosmetic Dentistry
On Site Car Parking To Make Your Visit
Stress Free.
Evening and Early Morning Appointments Available
for the Busy Bees
We Won't Be Beaten On Quality and Price!
Before and After Pictures
Dentist in Sale
Welcome to Sale Dental Spa!
Congratulations on choosing the friendliest dental practice in Manchester where we carry out both NHS and private dentistry in Sale – you are in safe hands with us as we have been improving smiles for over 14 years with over 5,000 people trusting us for their oral health.
We are a "one stop dental shop" for all your health needs – which can range from a simple scale with our Hygienist to a full smile makeover incorporating Invisalign® braces, fixed braces, teeth whitening, composite bonding or veneers.
We can provide you with fixed metal braces, fixed ceramic braces, combination braces or a range of Invisalign® braces, including Invisalign® i7, Invisalign® Lite and Full Invisalign® (Comprehensive) braces to suit your needs. Just contact us for a FREE Consultation.
At Sale Dental Spa it's all about you! We take time getting to know you, which enables us to make tailored treatment plans which fit your needs and your budget. We believe in treating you how we would like to be treated ourselves, which results in our ever growing client base and fans. Please read our Reviews here.
The goal of our practice is not just cleaning your teeth, taking X-rays and sending you home. Our goal is to provide THE BEST CARE in a gentle and relaxed environment.
We give complete information on your dental health options and want you to know that the quality dentistry we provide is an investment in your long term health, appearance and well being.
Meet our Principal Dentist and our Dental Team in the About Us section to find out more about the people who will be looking after you and please don't hesitate to Contact Us for a Consultation.


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Mutual Bank Receives 5-Star Rating from Bauer
March 9, 2018
Wow! We are thrilled to learn that Mutual Bank has earned BauerFinancial, Inc.'s highest 5-Star Superior rating for outstanding financial service.
A 5-star rating from Bauer indicates that Mutual Bank is among the strongest financial institutions in the nation, excelling in everything from loan quality to reliability. This honor reflects the Bank's mission to provide extraordinary service in personal and business banking to the local communities of Southeastern Massachusetts.
The entire team at Mutual Bank thanks you, our exceptional customers and neighbors, for helping this community bank thrive. Here's to another great year!