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Alternative Medicines for Osteoporosis
By: Editors of Consumer Guide
Osteoporosis is a disease that causes bones to become thin and fragile. It can lead to bone fractures, typically in the hips, spine, and wrist. Over a lifetime, bones naturally lose some of their density, but osteoporosis is an exaggeration of this process. Contributing factors may include a hormone deficiency (in women), low-calcium diet, lack of exercise, smoking, and certain medications.
Nutritional Therapy for Osteoporosis
Herbal Medicine for Osteoporosis
Other Osteoporosis Therapies
For more information on osteoporosis and alternative medicine, see
Nutritional therapy, like allopathic medicine, recognizes that getting enough dietary calcium is important in treating and preventing osteoporosis. However, the dietary needs for this condition are more complex than calcium alone. Several nutritional factors either help or hinder the absorption and retention of calcium. It's interesting to note that people in parts of the world where calcium intake is low have some of the lowest rates of osteoporosis. The following factors may play a role in this fact:
Excessive protein intake is linked to osteoporosis, because protein causes calcium to be excreted from the body with urine. In addition, meat contains high levels of phosphorus, which also competes with calcium for absorption. People who follow cereal-based diets with low to moderate levels of protein, such as vegetarians, require lower levels of calcium for healthy bones. In fact, several studies have shown that vegetarians have a lower rate of bone loss than nonvegetarians.
Sodium (salt), refined sugar, and caffeine also encourage the loss of calcium through the urine.
Too much saturated fat and unusually large amounts of fiber, iron, and zinc all limit the quantity of calcium that's absorbed in the digestive tract.
Vitamin D, vitamin K, magnesium, and boron are among the nutrients that support healthy bones. (Magnesium is extremely important for keeping calcium in the bones.)So are milk and other dairy products a good thing? While they supply a lot of calcium, they usually also provide saturated fat and high levels of protein. Instead, practitioners of nutritional therapy typically recommend getting calcium from green leafy vegetables, dark-green vegetables, and certain types of beans, as well as other foods, all of which provide little or no protein and fat.
Here's a sample of good calcium sources that are low in protein and fat:
1 cup bok choy (250 mg of calcium)
1 cup kale (200 mg)
1 cup broccoli (180 mg)
1 cup great northern beans (140 mg)
5 dried figs (135 mg)
2 corn tortillas (120 mg)
Note: The Recommended Dietary Allowance for calcium for menopausal women is 1000 to 1200 mg, although a practitioner of nutritional therapy may recommend less than that, depending on the woman's typical dietary sources of protein.
Several herbs can be beneficial for preventing and treating osteoporosis when combined with a diet and exercise program. Different herbs approach the problem differently; some provide dietary calcium, some regulate the body's use of calcium, and some increase the level of certain hormones in the body. For example, horsetail (silica) is recommended to boost the body's absorption of calcium. Once this plant, which often resembles a horse's tail, is dried, it can be used as a tea or in tincture or capsule form. Other helpful herbs include:
alfalfa, black cohosh, and wild yam, which are all phytoestrogens
comfrey (This herb may cause liver toxicity if used continuously for long periods.)
false unicorn root, which stimulates the ovaries
oatstraw
To help prevent osteoporosis an herbalist may prescribe taking powdered horsetail, for example, or may suggest a more comprehensive formula, such as one that also includes alfalfa, black cohosh, wild yam, vitex, and dong quai.
Ayurvedic Medicine for Osteoporosis -- The treatment focuses on dietary changes, coupled with herbal therapy.
Traditional Chinese Medicine for Osteoporosis -- Treatment includes herbal therapy (including dong quai), acupuncture, and Tai Chi.
For more information on osteoporosis and alternative medicine, see:
Use Them or Lose Them
Regular exercise is one of the essentials of an effective osteoporosis treatment or prevention program. Particularly important are weight-bearing exercises such as aerobics, walking, jogging, weight training, and Tai Chi. Research has shown that exercise helps build bone density, even for people in their 80s
Editors of Consumer Guide "Alternative Medicines for Osteoporosis" 20 June 2007.
HowStuffWorks.com. <https://health.howstuffworks.com/wellness/natural-medicine/alternative/alternative-medicines-for-osteoporosis.htm> 1 February 2023


NEW YORK — Chicken & Egg Pictures (http://chickeneggpics.org/) has announced the recipients of their inaugural Breakthrough Filmmaker Awards. The program is designed to recognize and elevate five mid-career women directors who are poised to reach new heights and to continue to be strong filmmaker-advocates for urgent issues.
The five chosen filmmakers are Kristi Jacobson (A Place at the Table) Julia Reichert (The Last Truck), Yoruba Richen (The New Black), Elaine McMillion Sheldon (Hollow), and Michèle Stephenson (American Promise). This award consists of a $50,000 unrestricted grant and a year-long mentorship program tailored to each filmmaker's individual goals.
"Chicken & Egg Pictures continues to make bold investments in both women artists and gender equality to ensure that a greater diversity of voices are acknowledged for their participation in the storytelling that drives change," says Jenni Wolfson, executive director of Chicken & Egg Pictures. "Our hope with this new award is to provide support and a platform for these artists to continue showcasing and elevating critical social justice, environmental, and human rights issues and stories while working to increase their visibility and ensure they receive the recognition they deserve."
Kristi Jacobson is a NY-based filmmaker whose films capture nuanced, intimate, and provocative portrayals of individuals and communities. Her most recent film, A Place at the Table (Participant Media/Magnolia Pictures), called "one of the most important…and gripping non-fiction films to debut in some time" by Indiewire, premiered at the 2012 Sundance Film Festival before its theatrical release in over 35 U.S. cities. Previous films include the critically acclaimed Toots, winner of the National Board of Review's 2007 Top Documentary Award, and American Standoff (HBO), produced by two-time Oscar winner Barbara Kopple. Jacobson is a member of the Director's Guild of America, NYWIFT, and a two-time Sundance Creative Producing Fellow. She is a recipient of grants from Tribeca Film Institute, Sundance Institute DFP, Chicken & Egg Pictures, and many others. She is currently working on an upcoming HBO documentary that provides an immersive and unprecedented look inside the world of solitary confinement in the U.S.
Julia Reichert is a three-time Academy Award nominee for her documentary work. She lives in Ohio, and has chosen to focus on class, gender, and race in the lives of Americans. Julia's first film, Growing Up Female, was the first feature documentary of the modern Women's Movement. It was recently selected for the National Film Registry of the Library of Congress. Her films Union Maids and Seeing Red were nominated for Academy Awards for Best Feature Documentary, as was The Last Truck, a short (co-directed with Steven Bognar) which premiered at the Telluride Film Festival and on HBO. Her film A Lion in the House (an ITVS co-production, made with Bognar) premiered at Sundance, screened nationally on PBS, and won the Primetime Emmy for Exceptional Merit in Nonfiction Filmmaking. She co-wrote and directed the feature film Emma and Elvis. Julia is co-founder of New Day Films, the independent film distribution co-op. She is author of "Doing It Yourself," the first book on self-distribution in independent film, and was an Advisory Board member of IFP. Reichert is currently directing a film about the 9 to 5 movement, telling the stories of the millions of low wage, invisible women who populated the clerical pool, served coffee, and suffered sexual harassment before it was named. In the 1970's they gathered their courage and rose up against their bosses, large corporations, and institutions. She's also begun filming a verite follow-up to The Last Truck, chronicling the arrival of a new plant in her economically devastated Midwestern city.
Yoruba Richen is a documentary filmmaker whose work explores issues of race, space, and power. She has directed films in the U.S. and abroad, including The New Black and Promised Land. The New Black won Audience Awards at AFI Docs, Philly Q Fest, and Frameline LGBT Film Festival. The film also won best documentary at the Urbanworld Film Festival and was nominated for an NAACP Image Award and a GLAAD Media Award. The New Black opened theatrically at New York's Film Forum and aired on PBS's Independent Lens. Yoruba has received numerous grants including from Sundance Documentary Fund, Chicken & Egg Pictures, and the Ford Foundation. She won the Creative Promise Award at Tribeca All Access and was also a Sundance Producers Fellow. Yoruba is a featured TED Speaker and a Guggenheim Fellow. She is director of the documentary program at the CUNY Graduate School of Journalism. Yoruba is currently working on How It Feels To Be Free, a two-part documentary chronicling how black entertainers like Lena Horne and Cicely Tyson navigated the industry and took control of their own images, all while fighting for civil rights through their art and actions.
Elaine McMillion Sheldon is a documentary filmmaker and media artist who explores themes of identity, roots, and change. She's the director of Hollow, the Emmy-nominated and Peabody-winning interactive documentary that explores life in the Appalachian coalfields. She's also the co-producer of The Lower 9, a feature-length documentary about The Lower Ninth Ward of New Orleans after Hurricane Katrina. Sheldon's film and interactive work has been exhibited nationally and internationally, from the New York Film Festival to IDFA. Sheldon was a 2013 Future of Storytelling Fellow, and named one of the "25 New Faces of Independent Film" in 2013 by Filmmaker Magazine and one of "50 People Changing The South" in 2015 by Southern Living Magazine. She works across platforms and mediums—film, photo, audio, interactive media—to create storytelling experiences. Sheldon is currently working on several projects that employ the storytelling skills she has developed for multiple mediums, including short and feature filmmaking, longform and interactive journalism, participatory media, virtual reality, and audio storytelling. Two of the film-based projects include a feature-length documentary about home, identity, and roots of Latino families living in Appalachia, and a short-film collaboration with the New York Times Op-Docs centered on the election year in rural America.
Michèle Stephenson pulls from her Caribbean roots and international experience as a human rights attorney to tell compelling personal stories that resonate beyond the margins. Her work has appeared on a variety of broadcast and web platforms, including PBS, Showtime, and MTV. Her most recent film, American Promise, was nominated for three Emmys including Best Documentary. The film won the Jury Prize at Sundance and was selected for the New York Film Festival's Main Slate. Stephenson's community engagement work has won numerous awards including the BRITDOC Puma Impact Award and a Revere Award nomination from the American Publishers Association. Other films directed by Stephenson include Slaying Goliath and Faces of Change. Her recent book, "Promises Kept," written with co-authors Joe Brewster and Hilary Beard, won an NAACP Image Award. Stephenson is currently working on Hispaniola, a documentary chronicling the lives of families affected by the TC-186 Dominican Republic Supreme Court ruling that strips citizenship from individuals of Haitian descent who were born in the country. She's also part of the filmmaking team behind Conversations On Race, a New York Times Op-Docs series of short films that uses powerful personal narratives to elevate shared experiences of race and equality.


Suicide In The Trenches Analysis Essay Siegfried sassoon suicide in the trenches essay?
Posted on by a guest.: He made life seem easy and happy even when times were bad. It was a routine thing nowadays. Knowing this, and knowing that her… The Virgin Suicides Analysis Essay Words 12 Pages number of works that have dealt the issue of isolation, but the greatest representation of a work whose physical qualities in its representation of suburbia help to short essay about philippine political structure the ideas in the work is Jeffrey Eugenides's The Virgin Suicides. Analysis Of ' The Virgin Suicides ' Words 4 Pages The Virgin Suicides narrates the story of the Lisbon family and the multiple crises they face, particularly acute suicidal risk of all five daughters. Several poems are aimed at those on the Home Front. They are the worst place you could ever want to be.
However, the underlying argument focuses on the injustification of the government and society condemning and forbidding such an action and the creation of superstitions and falsehoods of religion and God.
This poem is a lyric which suicide in the trenches analysis essay of three stanzas each containing four lines. During college she attempted to put an end to her life by taking sleeping pills; she was placed in a mental institute… Suicide in the Trenches- Analysis Words 5 Pages Suicide In The Trenches In my analysis, I will demonstrate how Siegfred Sassoon has used many different language techniques to show his perspective on the true meaning of war.
Propaganda vs. College Education is now free! War breeds hopelessness?
Again was he wounded I the shoulder and wrote a good deal of poetry and the material he wrote at that time appeared in Counter-Attack and other poems, where I think this poem belongs to. For Sassoon war is evil; and, by his use of contrasting tones, pathos, and a judging eye, he is easily able to emote his hatred for it.
The poem describes the correlation of a destroyed college girl, who feels that she is not good enough academically. It cover letter for certified true copy a routine thing nowadays. Sassoon uses his experience to try and warn people to learn from his mistake and not to fight in the war and waste their lives. Sassoon uses hell imagery to create an evil, horrific and atrocious atmosphere for the reader.
The man who saw the scene, the suicide is experiencing these feelings.
He finally enlisted two days before the British declaration of war, and joined as a trooper but after a riding accident when he got a badly broken-arm, Sassoon was commissioned in the Royal Welsh Fusiliers. Incredible images are created in ones mind as war writings are read and heard.
Within "Suicide in the Trenches" Siegfried Sassoon evokes the image of a young man, a child, in utter despair. Essay the secret to getting a good job is to study hard the Germans turned onto the Allies, they dug trenches on the River Aisne, as a line of defence. This poem expresses pity, sorrow, misery.
How can geography coursework questions without a source of evidence? It seems like the world dies for the few months of winter. These mysterious girls sample cover letter for massage therapist seem to really be known in the town, but when the youngest, Cecilia, kills herself, it establishes "the year of the suicides" and all eyes are on them.
And that is very concerning Suicide in the trenches analysis essay techniques: He hated those who considered to be making a profit out of the war and those who were happy and proud their children going to serve their country: His younger brother was mortally wounded and buried at the sea. He studied both Law and History at Cambridge before leaving without research proposal a degree.
Siegfried Sassoon, Biography. Those with low resilience and lack of support combined with PTSD have more significant chance of trying to commit suicide, as stated….
In February he was posted to Palestine where he found himself in the front line. He used his poems to hit out at Home whom he considered to be making a profit out of the War, or those whom he felt were helping to prolong the War. But have you ever thought about why? His work has become so well recognized that he has received an O.
And that is very concerning Poetic techniques: The day began with the stand-to suicide in the trenches analysis essay which soldiers would wake up an hour before dawn and stand on the firing step, rifles in hand, to look out for a predawn attack by the enemy Feature Articles - Life in the Trenches. The poem is reminiscent of a nursery rhyme which symoblises the youth of the boys who went to war.
Throughout suicide in the trenches analysis essay three Sassoon uses a bitter angry tone as if regretting going to war and angry that men are still being recruited.
The solider boy was transformed by the trenches, just like millions of other men who had to deal with these same conditions. Sassoon writes from experience. Early in the war Sassoon's brother Hamo was fatally wounded at Gallipoli.
Therefore, the person who is experiencing these feelings is us. Furthermore, a sense of irony is created due to the dark subject matter of suicide and the poem structure of a nursery rhyme. This poem wants to make people understand that they were wrong, that the war is not like a game and that people die.
Siegfried took vengeance for his brother's death by involving himself Suicide In The Trenches Poetry Analysis words - 5 pages A lighthearted, immature, jovial boy gets thrown into the terrors of war.
Sassoon was not in a very good psychological state himself. His images of a desperate child, a desperate soldier, and the "smug-faced crowds" who too oppose war, as well as his use of contrasting tones, pathos, and a judging eye, easily enable Sassoon to emote this hatred.
Later, his friend Tommy was hit in the throat by a riffle bullet and died of the wound.
This poem expresses pity, sorrow, misery. Letter home words - 4 pages Dear Michael,It has been quite some time since I have last written, the more I learn about this god forsaken war the less I want to discuss it, however I know you are sixteen now and may see it a duty to follow my footsteps.
Some of the youngsters that enlisted in the army had no aspirations for the future and thought a good option to go to war and come back, with a good range in the army. However, as the girls become… Essay on Critical Analysis of the Virgin Suicides Words 4 Pages would do anything to get to that point of bliss. Brittany was diagnosed with an aggressive form of brain cancer at the tender age of Glum seems to sum up the whole sad feeling.
By mid-October, two lines of trenches faced each other from write thesis in r markdown Swiss border to the Channel coast Mutiny write thesis in r markdown the Trenches Essay words - 7 pages break through German lines in a mere 48 hours and critical thinking knowledges victory.
The poet wants to create a strong emotion, a young soldier who is falling into a depression so strongly that he commits suicide. War breeds hopelessness? Sylvia Plath was a troubled poet; throughout her life she had dealt with major depression.
Analysis Critique Overview Below.: Sasoon is attacking the earlier views of the war - held by 'smug faced crowds at home'. Do you always believe what they say on television documentaries? Or what do soldiers do in their trenches when they're not fighting or dying?
This child, unable to find solace in the trenches, is marked with contrasting tones in the first stanza.
The family experiences both major and minor crisis event throughout the film, ultimately ending with all five daughters completing suicide. Firstly I must enquire on the home life, how is your brother and mother?
In the second stanza, the season is described as winter; dark, gloomy, glum. According to the title of the poem, we realize that it refers war. Later, his friend Tommy was hit in the throat by a riffle bullet and died of the wound.
Sassoon affects the reader by creating a dark, dismal and gloomy atmosphere to describe how it was in the trenches in These literary resources help him to emit his hate towards war and its consequences.
The previous commander in chief, Joffre, had planned a more gradual and tentative attack. In his convalescence he also spent some time in London with Robert Ross who encouraged him to suicide in the trenches analysis essay satirical war poems.
After leaving CambridgeSassoon lived the life of a sportsman, hunter, rider, player of cricket until the outbreak of the war. And the poem is written by this point of view. War in the Trenches Essay words - 13 pages War in the Trenches Essay the secret to getting a good job is to study hard war was fought by men on foot, in a flat open country that gave no shelter from enemy fire.
The verses rhyme with the next in pairs of two a-a-b-b, c-c-d-d, e-e-f-f and all the verses have eight syllables. When Nivelle took over, he turned the plan on its head.
Subject matter: Sassoon successfully conveys that he feels the public are unable to relate and empathize with the soldiers because they cannot possibly understand what war is like without experiencing it for themselves.
The essay the secret to getting a good job is to study hard is an accurate representation of the psychological effects of war on the soldiers who were sent to fight.
It is recommended that you read and review the Research Paper Outline Instructions at this point. Random musings and papers of a psychology student.
Analysis Of ' The Virgin Suicides ' Words 4 Pages The Virgin Suicides narrates the story of the Lisbon family and the multiple crises gunsmith business plan face, particularly acute suicidal risk of all five daughters.
Although he wrote poetry before The War, he was no more than a Georgian Poet. Finally, in my opinion, the poem is a good view on the war and its worst consequence: The man who saw the scene, the suicide is experiencing these feelings.
No requests for explanation or general short comments allowed. Siegfred Sassoon concludes his poem with anger and a powerful message. He was posted back to France in and was awarded the Military Cross for bravery while in action.
Posted on by a guest.: Sassoon enlisted in the military at the age of 28 just before the draft and was eventually assigned to the Royal Welch FusiliersThe war was hard on Siegfried and his family.
Order now He was young and had no worries because he enjoyed life and did as he pleased. The neighborhood boys narrate the story. The reader almost sighs at the difficulties and harshness of the trenches. Again, we can gather from this that in the trenches, men were not happy to wake, and to them, living meant pain.
How to cite this page Choose cite format: They had nothing left they where ruined. The development of the soldier's living conditions in the following stanza is the first direct display of Sassoon's attitude toward war. In my opinion, this poem wants to revolt the reader, he wants to show him how is true life and war.
And the poem is written by this point of view. Quick fast explanatory summary.
This poem is about how people think war is glory and such but is really so horrible that the mind cannot deal with it. I am going to be telling you what Life in the trenches: However, it could also mean that he's miserable and doesn't know what makes him happy Posted on by a guest.: He shows his own point of view by doing this and he addresses the reader.
Why did he use? This is written in rhyming couplets, the style of the poem seems very simple and song-like.
Visit Milan, Italy in style!


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T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?
Benjamin Wilde1,2,
Marielle Thewissen1,
Jan Damoiseaux1,
Pieter van Paassen1,
Oliver Witzke2 &
Jan Willem Cohen Tervaert1
Anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody-mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T cells are also involved in disease pathogenesis. This review stresses the hallmarks of T cell-mediated pathology in AAV and highlights the characteristics of lesional and circulating T cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T cells are present in granulomas, vasculitic lesions, and nephritis. Lesional T cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T cells, dendritic cells are abundantly present at the sites of inflammation and locally orchestrate the immune response. Targeting the above-mentioned T cell-mediated disease mechanisms will potentially provide powerful therapeutic tools for AAV.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening form of autoimmune small-vessel vasculitis. AAV comprises three similar disease entities: Churg-Strauss syndrome (CSS), microscopic polyangiitis (MPA), and Wegener's granulomatosis (WG). These three entities have the presence of ANCA in common. CSS and MPA patients usually have ANCA directed to myeloperoxidase (MPO), whereas in WG, ANCA is in most cases directed to proteinase-3 (PR3) [1]. All three diseases are associated with systemic vasculitis and pauci-immune crescentic, necrotizing glomerulonephritis [2]. In addition, in many patients with WG or CSS, necrotizing granulomatous inflammation of the airways is observed. However, the histological findings vary slightly between the disease entities; tissue infiltration with eosinophils is observed mainly in CSS, whereas neutrophils are found in WG. Often, T cells are present within these granulomas [3]. In accordance with these findings, serum levels of markers of T-cell activity such as soluble interleukin-2-receptor (sIL-2r), neopterin, and soluble CD30 are elevated in AAV and associated with disease activity [4–6]. Increased numbers of T cells reactive to the sense or complementary Wegener auto-antigen PR3 are detectable in some but not all WG patients [7, 8]. In addition, ANCAs have an IgG isotype, suggesting that a T cell-mediated class switch has taken place. Importantly, Ruth and colleagues [9] demonstrated in an animal model of AAV that T-helper-cell depletion ameliorates the course of the disease. Specific T cell-targeted therapy is occasionally used in refractory cases with AAV and this has been demonstrated to have a beneficial effect on the course of the disease [10]. Altogether, these findings suggest that T cells are involved in the pathogenesis of AAV. The newest findings obtained during the last two decades will be discussed in this review. Hallmarks of T-cell pathology such as deficient regulation of T cells, memory T-cell expansion, persistent T-cell activation as well as T-cell polarization are dealt with; subsequently, T cell-driven granuloma and tertiary lymphoid organ (TLO) formation is discussed.
Regulatory versus effector memory T cells
Two major subsets of T cells are thought to dominate the adaptive T-cell immune response: regulatory T cells (Tregs) and CD4+ effector T cells (Teffs). Tregs limit and regulate the immune response, whereas Teffs are 'executors' controlled by Tregs. If this control is not regulated properly, excessive immune responses and loss of self-tolerance will follow (Figure 1). According to this concept, Treg and Teff subsets are the focus of research in AAV. Indeed, numerous reports have confirmed an expanded circulating CD4+CD25+ T-cell population in AAV [4, 11–13]. This T-cell subset usually contains activated Teffs as well as Tregs [14] (Table 1).
Table 1 T-cell subsets involved in disease pathogenesis of AAV.
Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis [87]. We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.
Abdulahad and colleagues [13, 15] differentiated between CD25low (activated Teff) and CD25high (Treg) CD4+ T cells and found an increase of both populations in patients with WG (Table 1). Moreover, an increase of both FoxP3+ Tregs and FoxP3- effector memory T cells (Tems) in patients with remission was described [13], whereas in a previous study by Marinaki and colleagues [11], no increase of circulating FoxP3+ Tregs was observed. Abdulahad and colleagues [15] demonstrated a functional impairment of CD25high Tregs in WG. These Tregs failed to inhibit proliferation or cytokine production of responder T cells. However, selection criteria of Tregs and their influence on the test system assessing Treg functionality have been recently studied [16]. When Tregs were sorted by CD25 and CD127, Tregs showing CD25high expression first appeared to be impaired in function; excluding CD127+ CD25high T cells restored functionality [16]. Thus, the defect of CD25high Tregs observed in WG might be biased by Treg selection criteria. In addition, there is an ongoing dispute on the specificity of the anti-FoxP3 clone PCH101 commonly used for determining Treg frequency as well as purity [15, 17, 18]. Therefore, additional studies are necessary to confirm whether there is a defect of Treg function in WG. Furthermore, functional and descriptive Treg studies using new markers such as CD127, CD39, and CD73 have not yet been published and are necessary [19, 20].
Factors influencing Treg homeostasis and function might be involved in the pathogenesis of AAV. For instance, leptin has recently emerged as a controller of immunity and especially as a controller of Tregs. Leptin itself is considered to have pro-inflammatory effects, whereas neutralization of leptin leads to Treg expansion in vitro [21]. Surprisingly, Kümpers and colleagues [22] recently found decreased levels of leptin in patients with WG and MPA during active disease. Leptin levels normalized again when entering remission. Low levels of leptin observed during active disease might lead to Treg expansion, restoration of tolerance, and attenuation of the inflammatory response [23].
Apart from an obvious CD25+ T-cell expansion both in patients with active disease and in those in remission [4], memory T cells are expanded in AAV [11] (Table 1). Marinaki and colleagues [24] described low numbers of naïve T cells in AAV as compared with healthy controls (HCs). In line with this study, Abdulahad and colleagues [15] reported an increase of circulating Tems in WG patients in remission. In active WG, the numbers of circulating Tems dropped and could be detected in urine, suggesting that Tems migrate from the circulation to inflammatory sites during active states of the disease [25].
Recently, we confirmed the findings by Abdulahad and colleagues [12, 13] and found an expansion of specific circulating CD25+ Tem subpopulations in WG. These CD25+ Tems were CD134+ and GITR+ and did not show a regulatory phenotype (Table 1). CD134+ T cells were also found in inflammatory lesions. Interestingly, the expansion of specific CD134+ and GITR+ Tem subsets was closely associated with disease activity [12]. However, these findings are in contrast to the study of Abdulahad and colleagues [13] on the overall Tem population that decreases during active disease. We postulate that specific Tem subsets increase during active disease despite a total decrease of Tems. Indeed, Tems are a heterogenous T-cell population and might show varying proliferation, survival, and migratory capacities [26].
Of special interest is the Treg/Tem balance in vivo. In the field of transplant immunology, ratios between Tregs and Tems are regarded as important for immune tolerance. Recently, Kreijveld and colleagues [27] assessed the value of these ratios before and after kidney transplantation and found that the ratio was predictive of rejection. It was demonstrated that a rejection was preceded by a shift from Tregs to Tems. One could speculate that these ratios are also skewed toward Tems in WG, especially in case of a relapse. However, this has been scarcely investigated so far. In one study, Treg/Tem ratios were assessed in WG and no differences were found when compared with HCs [13]. Furthermore, an association with disease activity was not found. Further studies are needed to see whether monitoring the Treg/Tem ratio could be an option for predicting relapses. In AAV, the balance of Tregs and Tems might be altered, leading to less strict control of the immune response (Figure 1). This might promote loss of self-tolerance and autoimmunity (Figure 1).
Aberrant T-cell activation and senescence in AAV
Aberrant T-cell costimulation and T-cell senescence might have a role in the expansion of Tems in AAV and this might facilitate the breakdown of self-tolerance. Indeed, T cells in AAV show an altered expression pattern of costimulatory molecules. This is well studied with regard to the CD28/CD80 pathway [28–30]. Normally, CD28 is present on T cells whereas CD80/86 is found on antigen-presenting cells (APCs). Antigen presentation of APCs to T cells requires additional signaling via the CD28/CD80 pathway, resulting in T-cell activation.
Strikingly, CD28 is downregulated on circulating and lesional CD4+ T-helper cells in AAV [28, 29]. These CD28null T cells are described as a major source of pro-inflammatory cytokines such as interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) [31]. Moreover, these T cells have killer cell capacities and express perforin as well as NKG2D [30, 32]. These latter features are usually confined to cytolytic natural killer-like T cells (Table 1). In AAV, CD28null T cells have shortened telomeres and they express CD57, which is indicative of replicative senescence [31, 33]. CD28null T cells are supposed to have a role in several other autoimmune diseases and are less responsive to immunoregulation [34]. Although there is a positive correlation with disease severity and the presence of CD28null T-helper cells in AAV patients, a direct pathogenic role has not been proven yet but seems to be likely. Therefore, the presence of CD28null T-helper cells might also be considered to be secondary to latent viral herpes infections such as cytomegalovirus (CMV) since these T cells have antigen specificity for CMV but not to autoantigens [34, 35]. The definitive role of CD28null T-helper cells in AAV needs to be further investigated.
The costimulatory molecules CD80 and CD86 are upregulated on T cells in WG after in vitro stimulation with mitogens and polyclonal stimuli [29]. The functional properties of CD80+ T-helper cells have not been assessed in AAV so far. However, it is known that CD80 expression on T-helper cells in general is accompanied by major histocompatibility complex class II expression [36, 37]. Therefore, CD80+ T cells might be able to present antigen to other T cells. This presentation might lead to activation or - as recently described in a mouse model - inhibition of T-cell responses [37]. Thus, it is not known whether the aberrant CD80 expression observed in AAV favors persistent stimulation of T cells or limits the immune response.
An increased expression of CTLA-4 on CD4+ T cells has been reported in WG [30]. CTLA-4 is a negative costimulator that binds to CD80/CD86 on APCs and thereby inhibits CD28-dependent T-cell activation. CTLA-4 might counterbalance T-cell activation in AAV. Overexpression of CTLA-4 is accompanied by upregulation of anti-apoptotic BCL-2 [38]. Thus, these T cells seem to be protected against activation-induced cell death [38]. Other negative costimulators such as PD-1 have not been assessed in AAV so far.
Genetic polymorphisms of CTLA-4 have also been studied in AAV [39]. Some polymorphisms of the negative costimulator CTLA-4 have a higher prevalence in AAV than in HCs [40–42]. Dinucleotide repeats within the gene encoding CTLA-4 were linked to AAV by several authors [41, 42]. Elongated repeats lead to instability of mRNA and also contribute to hyper-reactivity of T cells [43]. Other associated polymorphisms in the CTLA-4 gene are known to reduce the availability and surface expression of this negative costimulator. Thus, associated polymorphisms might limit the efficacy of CTLA-4 upregulation. Moreover, we studied polymorphisms of another negative costimulator, the PDCD (PD-1) gene [42]. Genetic variants of PD-1 were not directly linked to WG or AAV, but specific combinations of CTLA-4 and PD-1 polymorphisms were less prevalent in AAV [42].
Besides changes in the expression of costimulatory molecules, other markers of T-cell activation are either upregulated or downregulated in AAV patients. For instance, HLA-DR expression of CD4+ T-helper-cells is elevated in WG but is reported to mirror disease activity poorly [4]. In addition, levels of soluble T-cell activation markers such as sIL-2r, sCD4, sCD8, sCD30, and neopterin are increased in AAV [6, 44–46]. Some studies showed an association of these markers and disease activity, while others failed to demonstrate a correlation with disease activity [4–6, 44, 46, 47]. Taken together, T cells in AAV are in a state of persistent activation, not only during active disease but also during remission. This might be caused or followed by an aberrant expression of costimulatory molecules. This aberrant expression pattern might favor Tem expansion and thus contribute to the dysbalance of Tregs and Tems (Figure 1).
The myriad of T-helper-cell polarization in AAV
In AAV, there are differences in Teff type 1/type 2 polarization, depending on disease type and disease stage [48, 49]. As suggested by features of CSS such as asthma and eosinophilia, CSS seems to be associated with Th2 polarization. Kiene and colleagues [50] analyzed T-cell lines of CSS and WG patients. Higher levels of IL-4 and IL-13 were detected in CSS than in WG, whereas elevated levels of IFNγ were produced by T cells in both CSS and WG. Thus, a stronger Th2 polarization was seen in CSS [50] (Table 1).
T-cell polarization in MPA is not well studied and data are conflicting. Some hints point at Th1 polarization where as others indicate Th2 polarization in MPA. It has been shown that, during active disease, soluble CX3CL1 levels are elevated and that CX3CR1 expression on circulating T cells correlates with disease activity. CX3CL1 is a chemokine belonging to the fractalkine family and is suggested to be associated with a preferential Th1 response [51]. In addition, levels of the Th2- associated marker sCD30 were not elevated in MPA during active disease [52]. However, the Th1 marker sCD26 was found to be decreased in active MPA and increased during remission [52]. There are only limited data on lesional T cells in MPA; interestingly, these T cells were not capable of producing Th1 cytokines like IFNγ but instead secreted Th2 cytokines [53].
In WG, it is claimed that localized disease is associated with a preferential Th1 response whereas Th2 responses are common in systemic disease. Plasma levels of sCD26 as a marker for Th1 response are elevated in patients with localized disease [52]. Lamprecht and colleagues [54, 55] compared CCR5 (Th1) and CCR3 (Th2) expression on circulating T cells from patients with WG. In localized disease, there was a higher expression of CCR5 indicative for Th1 response whereas the two markers were expressed at equal levels in systemic disease (Table 1). Furthermore, some studies have characterized lesional T cells derived from granulomas of nasal biopsies. Interestingly, data from two studies suggest that the polarization of tissue-resident T cells depends on disease extent. In localized WG, T cells were mainly positive for CD26 and IFNγ, suggesting a preferential Th1 response, whereas in systemic WG, lesional T cells show a Th2-like response with little IFNγ and high IL-4 expression [48, 56]. In contrast to these studies, however, Csernok and colleagues [49] detected high levels of IFNγ mRNA and low levels of IL-4 mRNA produced by lesional T cells derived from nasal biopsies of patients with systemic disease. In line with this study, Komocsi and colleagues [31] characterized lesional T cells in granulomas by immunohistochemistry and found them to be main producers of IFNγ and TNFα. It remains to be confirmed whether there is a shift in T-cell polarization along with progression from localized to systemic disease.
Another T-helper-cell subset that was recently shown to be of major importance in autoimmunity is the IL-17- producing T-cell subset (Th17) [57]. There are some hints indicating that a skewed Th17 response might also contribute to the disease pathogenesis of AAV [8]. It was recently reported that WG patients in remission bear an increased number of circulating Th17 cells reactive to the autoantigen PR3 [8]. In addition, CSS patients with active disease have an increased number of circulating Th17 cells [58]. Moreover, AAV patients harbor an expanded CD45RC T-helper-cell population that is a source of IL-17 [59] (Table 1). IL-17 also facilitates the migration and activation of neutrophils by promoting the secretion of TNFα and IL-1β [60]. Since the influx of neutrophils is a hallmark of AAV, IL-17 might enable the migration of neutrophils during active vasculitis. The data on T-helper-cell polarization are inconclusive at some points and the evidence on Th17 subsets is limited, so the importance of T-cell polarization needs to be further studied in AAV patients.
Local inflammation in AAV: T cells, granuloma formation, and tissue damage
Circulating T cells migrate into tissue during the active phase of disease. These T cells, present in lesions within organs affected by AAV, have multiple important functions in driving the disease (Figure 1). In general, the following lesions are commonly found: granuloma formation with central necrosis, vasculitis of small- and medium-sized vessels, infiltration with mononuclear cells, and necrotizing crescentic glomerulonephritis without deposits of immune complexes.
Granulomas, which can be detected in WG and CSS but not in MPA, have been demonstrated to be composed of T cells, B cells, giant cells, and dendritic cells (DCs) (Figure 1). Granulomas are observed in the upper airways, the lungs, and occasionally in other organs such as the kidneys [61]. The cellular subsets participating in granulomatous inflammation are best characterized by immunohistochemistry of nasal or lung biopsies [28, 32]. In these granulomatous lesions, a dense T-cell infiltrate is usually found. CD4+ T cells slightly outnumber CD8+ T cells [56]. The T cells express CD45RO and show a CD28- phenotype. Further analysis reveals CD28null T cells as major producers of IFNγ and TNFα [31]. These phenotypic features imply that most of the T cells within the inflamed tissue belong to the senescent memory T-cell population [62]. As mentioned above, the numbers of circulating Tems are found to be decreased in patients with active disease. Given the data from biopsy studies, it is possible that memory T cells migrate from the circulation to the tissue to act as effector cells [13].
Presumably, these migrating Teffs act in different ways. It is well accepted that granuloma formation is driven by Teffs [63]. For instance, granuloma formation is severely impaired after CD4+ T-cell depletion in mice models of tuberculosis. Similarly, low CD4+ T-cell counts in HIV result in an increased susceptibility to tuberculosis and poorly organized granulomas. In addition, the importance of T cell-derived cytokines such as TNFα and INFγ to granuloma formation has been demonstrated [63]. Interestingly, Csernok and colleagues [53] reported that lesional T cells in MPA lack production of IFNγ, which is thought to be essential for granuloma formation. This finding might provide an explanation of why granulomatous inflammation is absent in MPA. Thus, the T-cell infiltrate in AAV seems to be indispensable for initiation and sustaining of granulomatous inflammation, contributing in a direct way to the tissue damage observed in AAV.
Cytotoxic CD8+ T cells are also present in inflamed tissue in AAV. These cells are capable of inducing apoptosis and may be cytotoxic for endothelial cells. Furthermore, it has been shown that CD4+CD28null T cells have cytolytic properties [34]. As these T cells are abundantly present in inflammatory lesions in AAV, a destructive role for these cells has to be considered as well [28]. In line with these findings, a recent report demonstrated that CD4+ Tems can damage endothelial cells and it was found that this process was independent of the CD28 costimulatory pathway, supporting a role for CD4+CD28null Tems in mediating tissue damage [64]. Next to CD4+CD28null T cells, CD4+CD134+ Teffs also are present in vasculitic and renal lesions [12]. It has been reported that the ligand for CD134 is expressed on endothelial cells [65]. Ligation of CD134 promotes T cells to adhere to endothelial cells and this interaction subsequently stimulates T cells to produce pro-inflammatory cytokines [66]. Indeed, pro-inflammatory cytokines are expressed in kidneys and other tissues affected by AAV [31, 67]. Although an exact mechanism of tissue damage has not yet been demonstrated for CD4+CD134+ T cells, it can be hypothesized that pro-inflammatory cytokines such as IFNγ cause direct damage to endothelial cells [68]. However, pro-inflammatory cytokines may also mediate damage by promoting neutrophil-endothelial adhesion and neutrophil activation, finally leading to tissue damage [69]. Thus, lesional T cells bear the potential to destroy tissue integrity by driving granuloma formation, by cytokine production, or by direct effects on target cells (Figure 1).
Local inflammation in AAV: tertiary lymphoid organ formation
As discussed above, T cells act as effectors in inflamed organs. The questions arises of whether there is any 'tissue-resident' surveillance on this inflammatory process. At present, it is unknown whether local activation or control of the immune response within the affected tissue itself occurs in AAV. Local control of immune responses is linked to the development of TLOs and this is also known as lymphoid neogenesis [70]. This has been described for several chronic inflammatory conditions (for example, rejection in the context of organ transplantation and inflammation in several autoimmune diseases) [70]. TLOs resemble the structure of secondary lymphoid organs and consist of B-cell follicles with a surrounding mantle zone with T cells and DCs. Within these TLOs, T-cell activation by APCs such as DCs and B-cell stimulation take place. It is likely that local, tissue-specific (auto) antigens are presented there. Whereas secondary lymphoid organs have organized lymph flow and APC trafficking, TLOs lack these features, resulting in an unrestricted access of antigens, APCs, and lymphocytes. These conditions might promote persistent and non-physiological T-cell activation in autoimmunity [70]. But is there any evidence for the presence of similar structures in AAV?
At present, granulomas are regarded as some form of TLO in which immune responses are modified [61, 71]. For instance, Csernok and colleagues [72] revealed that PR3 is abundantly present in granulomas and renders DCs to powerful Th1-cell activators. Moreover, Voswinkel and colleagues [73] demonstrated that affinity maturation of B cells, as is commonly observed in lymphoid tissue, takes place in granulomas. It is suggested that the production of ANCA takes place locally within these granulomas. Granuloma formation in a classical manner is rarely present in the kidney, but some form of lymphoid neogenesis has been frequently observed in renal biopsies of patients with AAV [74–76]. Immature DCs and T cells form aggregates suggesting a cell-cell interaction. Strikingly, these DCs display costimulatory capability by expressing CD80 [75]. We hypothesize that, in the kidney, activation of Teffs and aggravation of the immune response take place. However, a local induction of Tregs and thus an attenuation of the inflammatory process seem to be possible, too [75, 77]. Our own data indicate that FoxP3+ T cells are present in inflammatory lesions (unpublished data). The induction of Tregs is especially confined to places where abundant immature DCs bearing costimulatory properties are present [78]. Therefore, both local control of tissue inflammation and activation of Teffs at the site of inflammation are likely to occur in AAV (Figure 1).
Conclusion and implications for therapy
Circulating T cells in AAV show several abnormalities. T cells are disturbed in homeostasis and skewed toward memory and pro-inflammatory T-cell types. This knowledge might allow specific and targeted therapies in the future. At present, nearly all available treatment options for AAV are toxic and have severe side effects. Alternative treatment strategies such as cell-based therapy with ex vivo expansion of Tregs and subsequent infusion of these cells could potentially restore tolerance and T-cell homeostasis in AAV patients [79]. However, it has recently been reported that human Tregs can convert to pro-inflammatory IL-17- producing T cells in the presence of a specific cytokine environment (IL-1β, IL-21, IL-23) [80]. Thus, administration of Tregs to patients might not restore tolerance but rather enhance autoimmunity under certain not-yet-known conditions. In light of these recent findings on Treg plasticity, cell-based approaches have to be considered with caution. In addition, control of T-cell activation might pose an attractive therapeutic option. In this regard, blockade of costimulatory pathways such as CD28/CD80 has successfully been used in rheumatoid arthritis and might be a therapeutic opportunity in AAV [81]. However, since an important T-cell population (CD28null T cells) involved in AAV pathogenesis is acting independently of the CD28/CD80 pathway, this novel strategy might not be applicable to all patient cohorts. As IL-2 is also involved in T-cell activation and is regarded as a 'T-cell growth factor', IL-2Rα (CD25)-blocking agents could be of use. These agents are already used in the field of organ transplantation [82]. There is some evidence that anti-CD25 antibody therapy is effective in autoimmune diseases such as multiple sclerosis and vasculitis [83, 84]. Nevertheless, there are no reliable data available in AAV yet. Based upon the finding that CD25+ T cells are expanded in AAV and show an association with disease activity, there is at least a rationale to assume that anti-CD25 agents might have a beneficial effect. However, IL-2 has a role not only in maintaining but also in limiting immune responses. IL-2 shows homeostatic effects on Tregs and promotes activation-induced cell death; thus, adverse events facilitating autoimmunity cannot be excluded with certainty [85]. Next to the blockade of T-cell activation, it might be beneficial to interfere with T-cell trafficking into tissues and thereby dampening inflammation as well as granuloma formation. Natalizumab targets α4-integrin, which has a role in the adhesion of leukocytes to vascular endothelial cells, and thus prevents leukocyte migration [86]. It has been administered in patients suffering from inflammatory bowel disease and in cohorts with multiple sclerosis. In both cases, it was reported to be effective. However, severe side effects such as multifocal leukoencephalopathy have been reported in some cases [84]. Although the safety profile of this drug needs further clarification, the basic mechanism of blocking leukocyte adhesion might be a charming approach in AAV patients to dampen inflammation and tissue destruction. Unraveling T cell-mediated pathology in AAV will provide further insights into disease mechanisms and will potentially result in promising new therapeutic options. It is hoped that further efforts in this field will allow a sustained restoration of self-tolerance in AAV patients.
AAV:
anti-neutrophil cytoplasmic antibody
ANCA:
associated vasculitis
antigen-presenting cell
CMV:
dendritic cell
IFNγ:
interferon-gamma
MPA:
microscopic polyangiitis
PR3:
proteinase-3
sIL-2r:
soluble interleukin-2-receptor
Teff:
effector T cell
Tem:
effector memory T cell
TLO:
tertiary lymphoid organ
TNFα:
tumor necrosis factor-alpha
Treg:
regulatory T cell
WG:
Wegener granulomatosis.
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Lamprecht P, Bruhl H, Erdmann A, Holl-Ulrich K, Csernok E, Seitzer U, Mack M, Feller AC, Reinhold-Keller E, Gross WL, Muller A: Differences in CCR5 expression on peripheral blood CD4+CD28- T-cells and in granulomatous lesions between localized and generalized Wegener's granulomatosis. Clin Immunol. 2003, 108: 1-7.
Lamprecht P, Erdmann A, Mueller A, Csernok E, Reinhold-Keller E, Holl-Ulrich K, Feller AC, Bruehl H, Gross WL: Heterogeneity of CD4 and CD8+ memory T cells in localized and generalized Wegener's granulomatosis. Arthritis Res Ther. 2003, 5: R25-31.
Muller A, Trabandt A, Gloeckner-Hofmann K, Seitzer U, Csernok E, Schonermarck U, Feller AC, Gross WL: Localized Wegener's granulomatosis: predominance of CD26 and IFN-gamma expression. J Pathol. 2000, 192: 113-120.
Bettelli E, Oukka M, Kuchroo VK: TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007, 8: 345-350.
Saito H, Tsurikisawa N, Tsuburai T, Oshikata C, Akiyama K: Cytokine production profile of CD4+ T cells from patients with active Churg-Strauss syndrome tends toward Th17. Int Arch Allergy Immunol. 2009, 149: 61-65.
Ordonez L, Bernard I, L'Faqihi-Olive F, Cohen Tervaert JW, Damoiseaux J, Saoudi A: CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients. PLoS ONE. 2009, 4: e5287-
Jovanovic DV, Di Battista JA, Martel-Pelletier J, Jolicoeur FC, He Y, Zhang M, Mineau F, Pelletier JP: IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998, 160: 3513-3521.
Voswinkel J, Muller A, Lamprecht P: Is PR3-ANCA formation initiated in Wegener's granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production. Ann N Y Acad Sci. 2005, 1051: 12-19.
Sallusto F, Geginat J, Lanzavecchia A: Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004, 22: 745-763.
Co DO, Hogan LH, Il-Kim S, Sandor M: T cell contributions to the different phases of granuloma formation. Immunol Lett. 2004, 92: 135-142.
Shiao SL, Kirkiles-Smith NC, Shepherd BR, McNiff JM, Carr EJ, Pober JS: Human effector memory CD4+ T cells directly recognize allogeneic endothelial cells in vitro and in vivo. J Immunol. 2007, 179: 4397-4404.
Mestas J, Crampton SP, Hori T, Hughes CCW: Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA. Int Immunol. 2005, 17: 737-747.
Imura A, Hori T, Imada K, Ishikawa T, Tanaka Y, Maeda M, Imamura S, Uchiyama T: The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelial cells. J Exp Med. 1996, 183: 2185-2195.
Noronha IL, Kruger C, Andrassy K, Ritz E, Waldherr R: In situ production of TNF-alpha, IL-1 beta and IL-2R in ANCA-positive glomerulonephritis. Kidney Int. 1993, 43: 682-692.
Yamaoka J, Kabashima K, Kawanishi M, Toda K-I, Miyachi Y: Cytotoxicity of IFN-[gamma] and TNF-[alpha] for vascular endothelial cell is mediated by nitric oxide. Biochem Biophys Res Commun. 2002, 291: 780-786.
Bratt J, Palmblad J: Cytokine-induced neutrophil-mediated injury of human endothelial cells. J Immunol. 1997, 159: 912-918.
Aloisi F, Pujol-Borrell R: Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006, 6: 205-217.
Mueller A, Holl-Ulrich K, Lamprecht P, Gross WL: Germinal centre-like structures in Wegener's granuloma: the morphological basis for autoimmunity?. Rheumatology. 2008, 47: 1111-1113.
Csernok E, Ai M, Gross WL, Wicklein D, Petersen A, Lindner B, Lamprecht P, Holle JU, Hellmich B: Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Blood. 2006, 107: 4440-4448.
Voswinkel J, Mueller A, Kraemer JA, Lamprecht P, Herlyn K, Holl-Ulrich K, Feller AC, Pitann S, Gause A, Gross WL: B lymphocyte maturation in Wegener's granulomatosis: a comparative analysis of VH genes from endonasal lesions. Ann Rheum Dis. 2006, 65: 859-864.
Segerer S, Heller F, Lindenmeyer MT, Schmid H, Cohen CD, Draganovici D, Mandelbaum J, Nelson PJ, Gröne HJ, Gröne EF, Figel AM, Nössner E, Schlöndorff D: Compartment specific expression of dendritic cell markers in human glomerulonephritis. Kidney Int. 2008, 74: 37-46.
Wilde B, van Paassen P, Damoiseaux J, Heerings-Rewinkel P, van Rie H, Witzke O, Tervaert JW: Dendritic cells in renal biopsies of patients with ANCA-associated vasculitis. Nephrol Dial Transplant. 2009, 24: 2151-2156.
Steinmetz O, Velden J, Kneissler U, Marx M, Klein A, Helmchen U: Analysis and classification of B-cell infiltrates in lupus and ANCA-associated nephritis. Kidney Int. 2008, 74: 448-457.
Scholz J, Lukacs-Kornek V, Engel DR, Specht S, Kiss E, Eitner F, Floege J, Groene HJ, Kurts C: Kidney dendritic cells stimulate IL-10 production in nephrotoxic nephritis and attenuate disease. J Am Soc Nephrol. 2008, 19: 527-537.
Lutz MB, Schuler G: Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity?. Trends Immunol. 2002, 23: 445-449.
Trzonkowski P, Szarynska M, Mysliwska J, Mysliwski A: Ex vivo expansion of CD4(+)CD25(+) T regulatory cells for immunosuppressive therapy. Cytometry A. 2009, 75: 175-188.
Koenen HJPM, Smeets RL, Vink PM, van Rijssen E, Boots AMH, Joosten I: Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood. 2008, 112: 2340-2352.
Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor {alpha} inhibition. N Engl J Med. 2005, 353: 1114-1123.
Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, Neylan J, Wilkinson A, Ekberg H, Gaston R, Backman L, Burdick J: Interleukin-2- receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N Engl J Med. 1998, 338: 161-165.
Nieuwhof CMG, Damoiseaux J, Tervaert JWC: Successful treatment of cerebral vasculitis in an HIV-positive patient with anti-CD25 treatment. Ann Rheum Dis. 2006, 65: 1677-1678.
Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J, Wurfel J, Ohayon J, Waidmann TA, McFarland HF, Martin R: Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA. 2004, 101: 8705-8708.
Hoyer KK, Dooms H, Barron L, Abbas AK: Interleukin-2 in the development and control of inflammatory disease. Immunol Rev. 2008, 226: 19-28.
Stuve O, Gold R, Chan A, Mix E, Zettl U, Kieseier BC: alpha 4-Integrin antagonism with natalizumab effects and adverse effects. J Neurol. 2008, 255: 58-65.
van Paassen P, Tervaert JWC, Heeringa P: Mechanisms of vasculitis: how pauci-immune is ANCA-associated renal vasculitis?. Nephron Exp Nephrol. 2007, 105: e10-16.
This work was funded by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Dutch Kidney Foundation.
Department of Internal Medicine, Division of Clinical and Experimental Immunology, University Hospital Maastricht, Universiteitssingel 50, PO Box 616, 6200 MD, Maastricht, The Netherlands
Benjamin Wilde, Marielle Thewissen, Jan Damoiseaux, Pieter van Paassen & Jan Willem Cohen Tervaert
Department of Nephrology, University Duisburg-Essen, Hufelandstr. 55, 45127, Essen, Germany
Benjamin Wilde & Oliver Witzke
Benjamin Wilde
Marielle Thewissen
Jan Damoiseaux
Pieter van Paassen
Oliver Witzke
Jan Willem Cohen Tervaert
Correspondence to Jan Willem Cohen Tervaert.
Wilde, B., Thewissen, M., Damoiseaux, J. et al. T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells?. Arthritis Res Ther 12, 204 (2010). https://doi.org/10.1186/ar2923
Costimulatory Molecule
Granuloma Formation
Granulomatous Inflammation

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MODERN's COVID-19 Resource Center
by Maggie Mulhern | March 18, 2020 | Bookmark +
The professional beauty industry has been rocked by Coronavirus, COVID-19. Salons and spas are closing their doors - temporarily - while beauty professionals express concern about the health and financial well-being of their clients, friends, family and themselves.
MODERN and SALON TODAY have been gathering valuable resources to help you stay safe and give you the information you need to keep you in the know.
This portal includes links to resources both within and outside our industry, including virus trackers, health information, small business loan information, legislative updates, and information for your salon customers. Remember to also check with your local health department and your State Board of Cosmetology for guidance.
We will continue to monitor these sites and add information as it becomes available:
CORONAVIRUS TRACKER: https://ncov2019.live
Live updates on total confirmed cases and deaths, country by country and state by state.
WORLD HEALTH ORGANIZATION (WHO): https://www.who.int
This Geneva based organization works with 194 Member States, across six regions, and from more than 150 offices. WHO staff are united in a shared commitment to achieve better health for everyone, everywhere, striving to combat diseases – communicable diseases like influenza and HIV, and noncommunicable diseases like cancer and heart disease.
-County and technical guidance for COVID-19
-Novel Coronavirus Situation Dashboard
CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC): https://www.cdc.gov
The CDC fights disease and supports communities and citizens to do the same and increases the health security of our nation. As the nation's health protection agency, CDC saves lives and protects people from health threats.
-Steps to Prevent Illness
-What to Do If You Are Sick
-Coronavirus and Your Health
-What Government Agencies Are Doing in Response to the Coronavirus
AMERICAN MEDICAL ASSOCIATION (AMA): https://www.ama-assn.org
The American Medical Association is the largest association of physicians—both MDs and DOs—and medical students in the United States.The AMA's stated mission is "to promote the art and science of medicine and the betterment of public health.
-Updates on COVID-19 Diagnosis and Treatment
-Get the AMA's Physician's Guide to COVID-19
THE JOURNAL OF AMERICAN MEDICAL ASSOCIATION (JAMA): https://jamanetwork.com
JAMA is an international peer-reviewed general medical journal. JAMA is a member of the JAMA Network family of journals 48 times a year by the American Medical Association. It publishes original research, reviews, and editorials covering all aspects of biomedicine and has a full-out Coronavirus Resource Center.
-Presidential Powers and Response to COVID-19
-Coronavirus Update with Anthony Fauci, MD
CITY OF HOPE: www.cityofhope.org
City Of Hope is one of the nation's elite cancer hospitals.
-COVID 19: Advice for cancer patients, survivors and caregivers
-COVID-19 FAQs
Several medical schools are regularly updating their sites. Check out:
HARVARD MEDICAL SCHOOL: https://hms.harvard.edu
-Physicians and researchers from the HMS community provide insights into the COVID-19 pandemic
YALE SCHOOL OF MEDICINE: https://medicine.yale.edu
This link offers a variety of articles including "Wellness in the Time of Corona", "COVID-19: Who Is Infectious?" and various Virtual Town Hall Addresses
FROM YOUR INDUSTRY
PROFESSIONAL BEAUTY ASSOCIATION (PBA): https://www.probeauty.org
The Professional Beauty Association (PBA) is deeply supporting the industry during this uncertain time such as asking congress to include the 45B FICA Tax Tip Credit as part of the economic stimulus credit, which they encourage the industry to also get behind.
-What To Do When You Are Sick
-Check Your State Closure
-State Health Information
AMERICAN ASSOCIATION OF COSMETOLOGY SCHOOLS (AACS): https://www.beautyschools.org/coronavirus-resource-center/
The national nonprofit AACS is open to all privately owned schools of cosmetology artist and sciences, providing timely updates on information and resources about new teaching methods, industry events, and federal regulatory updates through a series of seminars, conferences and conventions held throughout the year.
DEPARTMENT OF LABOR (DOL): https://www.dol.gov
The DOL is designed to foster, promote, and develop the welfare of the wage earners, job seekers, and retirees of the United States; improve working conditions; advance opportunities for profitable employment; and assure work-related benefits and rights.
-Guidance for Preparing workplaces for Coronavirus
-How Do I File For Unemployment Insurance?
SMALL BUSINESS ADMINISTRATION (SBA.GOV): https://www.sba.gov
The Small Business Administration's Economic Injury Disaster Loans offer up to $2 million in assistance for small business. These loans can provide vital economic support to small businesses to help overcome the temporary loss of revenue they are experiencing. In addition, the SBA assists small businesses with counseling and navigating their own preparedness plans through its network of 68 District offices and numerous resource partners located around the country.
Recent article:
Coronavirus (COVID-19) Small Business Guidance & Loan Resources
AMERICAN ASSOCIATION OF RETIRED PERSONS (AARP): https://www.aarp.org
While comprised of different legal entities, AARP speaks with one voice — all united by a common motto: "To serve, not be served" and to improve the quality of people's lives, and empowers people to choose how they live as they age.
Coronavirus: What You Need to Know
Guide For Caregivers Dealing With Coronavirus
More Coronavirus News and Advice
DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT (HUD): https://www.hud.gov
The Department of Housing and Urban Development is the Federal agency responsible for national policy and programs that address America's housing needs, that improve and develop the Nation's communities, and enforce fair housing laws.
HUD Provides Immediate Relief for Homeowners Amid Nationwide Coronavirus Response
SOCIAL SECURITY ADMINISTRATION (SSA): https://www.ssa.gov
Learn more about office closings and COVID-19 updates
UNITED WAY 2-1-1 http://www.211.org/
Resources for the individual seeking assistance with food, electric/heating/phone bills, rent/funding – dial 2-1-1 and speak to a United Way specialist that will connect the person to local resources in their state. (*NEW*: Text your zip code to 898-211)
FOR MORE NEWS
THE NEW YORK TIMES: https://www.nytimes.com
This New York based news outlet is considered "The Newspaper of Record." The Times is providing free access on the global coronavirus crisis.
-This is the Only Way to End the Coronavirus Financial Panic
-Layoffs Are Just Starting in the US, and the Forecasts Are Bleak
-Congestion and Chaos in Europe as Borders Close
client health
MoreNews
Barber Combs Made of Black Carbon Offer an Alternative
Three Dark Stag combs provide a solution for every barbering need.
Why the First 2022 Venus+Mercury Retrograde Will Actually be a Good Thing
Celeb Astrologer Lisa Stardust says Mercury Retrograde 2022 is going to impact everyone—and some signs more than others.
Denman Wants You to Enter Their Ambassador Search
The search is on! Denman Professional tools launch their first statewide Ambassador Search.
The Hollywood Beauty Awards Return: Celebrating The Architects of Beauty
Danielle Lauder, the great-granddaughter of Estee Lauder, has been tapped as the global Ambassador for this year's award ceremony.
Great Clips Tops Entrepreneur Magazine's Hair Care Category for Franchise 500s
This is the fifth straight year that Great Clips has ranked #1, and the company ranks 23rd for franchises overall.
Carlos Valenzuela named to "The 41 List" of Honorees
The 41 List recognizes 41 LGBTQ Latinx role models. Valenzuela, a stylist, educator, former salon and school owner and author, has been recognized for his leadership and for his award-winning novella, Letters to Young Carlos.
Teresa Romero Named Sam Villa Artistic Director
Her experience and expertise in photo/video shoots and talent for identifying trends makes her a perfect fit for the brand.
Beauty Industry Leader, Alex Irving, Passes Away Suddenly
A beloved industry leader and mentor, Alex Irving passed away on December 14, 2021, in San Marcos, CA.
Sport Clips Haircuts Ranks High for Best Company Culture
The group also is named among the top 100 companies for women.
Two Reasons for the Training Gap in Salons
by Lori Fudens
Cosmetologists are not receiving the level of training they were getting even two years ago. Here's why and what salons can do about it.
PBA Announces New Dates for ISSE, NAHA, and Beacon
With consideration for higher COVID numbers, the January dates have been pushed back to spring and summer.
SalonCentric Promotes Gina Meggo-Garza to Deputy President
Meggo-Garza joined the company back in 2011 as the Senior Vice President of the Store division.
MODERN's 9 Funniest Instagram Posts of 2021
These nine memes and hilarious videos gave our followers the laughs they needed in 2021.
Consumer Spending on Beauty to Increase in 2022
After taking a much larger hit during the pandemic than overall consumer spending, personal care and beauty spending is expected to grow at an annual rate of 8.1 percent until 2025, says new research on the global wellness industry presented by Global Wellness Institute and Access Corporate Group.
Beauty Industry Leader, Karen Hodges, Passes Away Suddenly
Hodges was co‐founder and co‐author of the online learning programs on Nailcare Academy, Professional Education, and Salon Gurus, and co‐author with Marjory Grimm, well‐known educator, on Permanent Makeup Training.


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New Brunswick's 'hungry' identity and data security firm Sonrai launches new solution
By Sonrai Marketing
View article in it's entirety on ChannelDailyNews.
From Alex Coop at ChannelDailyNews.com: "Identity access is the largest source of vulnerabilities in the cloud, given the tens of thousands of identities and access levels assigned to people, pieces of compute, serverless functions, and the various access to data that they have, according to Sonrai Security co-founder Brendan Hannigan.
Understanding how to use platforms like AWS and Azure effectively, and securely, is a massive undertaking, Hannigan explained.
"Amazon has been developing a platform that has amazing flexibility and power. And when you get into an enterprise environment, the onus is on the enterprise to use these tools properly," he told the publication.
Sonrai's new solution, the Governance Automation Engine, which launched July 28, helps enterprises address pain points, including security breaches caused by identity policy misconfiguration and data risks going beyond S3 buckets. Other databases include Amazon RDS, DynamoDB, CosmosDB and many others."


Welcome on the website of Cambodia Development Organization for Children.
We are happy with your interest in our organization.
CAMDOC is an NGO in Siem Reap, Cambodia; reg.no. 2552sCN, founded in 2009 as an aid organization. CAMDOC is independent, totally relying on donations from individuals and organizations.
CAMDOC's mission is to improve the quality of life of people, in particular children, rebuild the human resources, enhance life expectation and reduce poverty, in rural Cambodia. Since CAMDOC is limited in capacity, it has chosen to start it's activities in a limited target community named Roeul, about 40 km NW of Siem Reap. With the tourist industry so close, Roeul still is one of the poorest and most indigent areas in Cambodia. CAMDOC aims to achieve its goals through a number of defined programs and projects, the last continuously subject to enhancements and improvements.
By moving the cursor over the picture in the heading a menu will appear that offers you an overview over the several web pages available, with comprehensive information on our activities about our organization, our activities and about the location where we opearte.


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Q: binary matrix in R with specific ones in each column How can I create a Binary matrix in R where there is only one 1 in each row  but it does not matter the number of ones in each column? I have this script but it is creating a random matrix. What I want is to specify the number of ones in the rows and columns:
mm <- matrix(0, 6, 5)
apply(mm, c(1, 2), function(x) sample(c(0, 1), 1))

Thanks

A: You could sample the positions rather than their values.
set.seed(42)
t(apply(mm, 1, function(x) {x[sample(1:length(x), 1)] <- 1;x}))
#      [,1] [,2] [,3] [,4] [,5]
# [1,]    1    0    0    0    0
# [2,]    0    0    0    0    1
# [3,]    1    0    0    0    0
# [4,]    1    0    0    0    0
# [5,]    0    1    0    0    0
# [6,]    0    0    0    1    0

Or using replicate,
set.seed(42)
t(replicate(6, sample(c(rep(0, 5 - 1), 1))))
#      [,1] [,2] [,3] [,4] [,5]
# [1,]    0    1    0    0    0
# [2,]    0    0    1    0    0
# [3,]    0    0    1    0    0
# [4,]    0    1    0    0    0
# [5,]    0    0    1    0    0
# [6,]    1    0    0    0    0

which you also could wrap into a function.
genBin <- function(n.row, n.col) t(replicate(n.row, sample(c(rep(0, n.col - 1), 1))))

set.seed(42)
genBin(6, 5)
# # output as one above

A: Here we create a function, foo which creates a random vector of 0s and 1s, with only one 1 and the same length as the number of columns of the required matrix. Then, replicate this nrows.
nr <- 6; nc <- 5
foo <- function() sample(c(1, rep(0, nc-1)), nc)
t(replicate(nr, foo()))

Edit: To randomly assign one 1 to each row and one 1 to each column means that the matrix would need to be square. And one way to do this is to use the sparseMatrix function from the Matrix package.
library(Matrix)
args(sparseMatrix)
# function (i = ep, j = ep, p, x, dims, dimnames, symmetric = FALSE,
#     triangular = FALSE, index1 = TRUE, giveCsparse = TRUE, check = TRUE,
#     use.last.ij = FALSE)

The i and j specify the locations of the non-zero entries of the matrix. So we can specify these using sample(1:n) where n is the number of rows and columns of the square matrix.
set.seed(1234) # For reproducibility. Omit in reality.
A <- sparseMatrix(i=sample(1:4), j=sample(1:4))
# 4 x 4 sparse Matrix of class "ngCMatrix"
# [1,] . | . .
# [2,] . . | .
# [3,] | . . .
# [4,] . . . |

Here the | represent non-zero values (TRUE).
The above matrix A can be converted into a binary matrix using as.matrix.
as.matrix(A) * 1
     [,1] [,2] [,3] [,4]
[1,]    0    1    0    0
[2,]    0    0    1    0
[3,]    1    0    0    0
[4,]    0    0    0    1

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Home / Industry / Media / Amitabh Bachchan powers KBC debut to top rating
Amitabh Bachchan powers KBC debut to top rating
Bachchan has anchored all the seasons except for the third one, which was hosted by fellow Bollywood star Shah Rukh Khan. Photo: Hindustan Times
(Hindustan Times)
2 min read . Updated: 13 Sep 2012, 05:17 PM IST Aminah Sheikh, Vidhi Choudhary
First episode of the sixth season on 7 September clocked a 6.1 television viewership rating, making it the highest for a TV show launch so far this year
Mumbai/New Delhi: The first episode of the sixth season of Kaun Banega Crorepati (KBC) on Sony Entertainment Television on 7 September clocked a 6.1 television viewership rating (TVR), making it the highest for a TV show launch so far this year and providing evidence that the drawing power of its star anchor Amitabh Bachchan remains undimmed.
The show airs Friday to Sunday at 8.30pm.
According to data compiled by TAM Media Research and provided by Sony executives, the first episode of the previous edition had a rating of 5.2.
Having Bachchan as a host gives the show a boost and has worked well for it, said a senior executive from Maruti Suzuki India Ltd, the country's largest passenger car maker and a sponsor.
"He has been away from the small screen as well movies for a while," he said. "So people want to see him. His charisma always draws attention of people."
The high ratings for KBC are also because of the lack of entertainment options currently, he said.
"The main reason for viewership being higher this time is because the Bigg Boss season on Colors hasn't started yet and there are a lot of dance shows being aired on other channels," said the executive on condition of anonymity. "Other reasons are too much of cricket happening around and not many good movies being released."
Media experts expect ratings to decline over the next few weeks.
"KBC has always clocked higher ratings in comparison with other reality shows," said Nandini Dias, chief operating officer, Lodestar Universal. "In subsequent episodes, the ratings tend to take a dip. This year, we are expecting the ratings to average around 4.5."
Based on the UK game show Who Wants to Be a Millionaire?, the Indian version is produced by Big Synergy, the television production arm of Reliance MediaWorks Ltd. The current season is the third one being aired on Sony. The first three seasons were shown on Star Plus with the 2000 debut one being credited with giving the Rupert Murdoch-owned channel the bump it needed to become the country's No. 1 general entertainment channel (GEC).
Bachchan has anchored all the seasons except for the third one, which was hosted by fellow Bollywood star Shah Rukh Khan.
The sixth season will have 57 episodes.
"The channel has made some improvements this year on the show to boost viewership, even in non-metro markets," said Lynn De Souza, chairman and chief executive, Lintas Media Group.
Rohit Gupta, president, Multi Screen Media Pvt. Ltd, the company that runs Sony Entertainment Television, said, "The show's positioning this year has helped garner record ratings. We believe the show will continue doing well as it progresses."


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Tag: philippines
What is Philippine Social Security System (SSS) Membership for Overseas Filipino Workers (OFWs)?
SSS is a social insurance agency run by the Philippine government whose goal is to protect members and its beneficiaries.
By Remitbee - Sep 30, 2021
Top 5 Filipino Groceries in Scarborough
Throughout this article, we'll go through the top 5 grocery stores in the Scarborough area where you can buy items from the Philippines.
Top 5 Traditional Filipino Cuisines
Filipino cuisine comprises a wide variety of food from more than a hundred distinct ethnolinguistic groups.
By Remitbee - Aug 25, 2021
How to Apply for a Canadian Study Permit from the Philippines?
The Philippines is one of the fastest-growing source countries for international students in Canada.
Filipino Grocery Stores in Montreal
Montreal, home to roughly 36,000 Filipinos, is Canada's sixth-biggest Filipino population.
By Remitbee - Jul 22, 2021
How to Apply for a Canadian Work Permit from the Philippines?
According to the last Canadian census, over 800,000 Filipinos are currently living in Canada.
Top 5 Filipino Grocery Store in Edmonton
To support the growing population, a number of Filipino grocery stores have sprung up.
By Remitbee - Jun 8, 2021
Cost of Living in Canada for Filipinos
Naturally, the cost of living in Canada compared to the Philippines is a major consideration for those looking to immigrate.
By Remitbee - May 31, 2021
Licensed Recruitment Agencies in the Philippines for Canada Employment
Trying to find work in a foreign country is a challenge no matter where you are coming from.
Remitbee Recipe: A Taste of Philippines - Halo Halo (Iced dessert)
We've collected family recipes from immigrants across Canada for our Remitbee Recipe series.
What It Takes to Move Abroad: Richelle's Story
Moving from country to country to provide child care is how Richelle Floreno was able to support the education of her younger siblings
By Remitbee - May 6, 2021
Top 5 Filipino Restaurants in Vancouver
While many have mastered cooking Filipino food in their own homes, sometimes we just don't have the time to be our own chef.
By Remitbee - Apr 21, 2021


Our hands are trustworthy, our hands are nimble, our long-fingered hands are excellent tools ensuring constant control over the quality of what we are working on. All our products are made by our own hands connected to our minds and acting in strict accordance with their instructions. We know what we do. We kept each single thing in our fingers and watched it with our own eyes.
when you get something from our store, you are the second person, right after us, touching it. It is like shaking our hands in silent understanding. And there is no need to speak about what handmade is and how it differs from mass production – it is when you feel the warmth of our hands on the parcel and unpack it like a contagious smile.


•Fundraisers are only available Monday through Thursday.
•You'll receive 15% of the revenue generated from your fundraiser.
•Fundraising revenue will be mailed out approximately 7-10 days upon event completion.
•You must have a minimum of $500 spent to receive your fundraising revenue.
•Beer and wine purchases are included.
•Orders must be dine-in or take-out only. Delivery orders are not included.
•Coupons, discounts, and daily specials cannot be applied.
•Event fliers must be pre-approved by Mario's management 2 weeks prior to event.
•Guests must present the approved flier or show it on their mobile device, for the sale to count towards your generated revenue.