We're often out of our minds. But not often enough.
of the various worlds of samsara.
A mind, a seeking mind, an enlightenment, an enlightenment seeking mind -- seeking what is making its way through. Thomas Berry in his book Buddhism (c.1967) writes, "Samsara designates the phenomenal or the conditioned world; Nirvana designates the transcendent, the unconditioned world."
Is this what Jesus and the Samaritan woman conversed about at the well?
His words sound different as poetry than they do as prose.
"I am," Jesus mused, "he," he paused, "the one," he contemplated, "who is," he continued on, "speaking with," and then finally, as if caught by insight, -- "you."
Is Jesus considering God -- the one who will be worshipped in spirit and truth -- as being in, or rather, as being the conversation that is taking place between him and the woman?
The woman is feisty, aware, and wise. She engages and plays with this Jew at the well. Jesus, too, is feisty, aware and similarly wise as he engages and plays with this Samaritan at the well. Together they turn in conversation about the truth of their lives. Together they question, pry, and parry the backgrounds each is emerging from. At end she gives him what he gives her.
They give each other water for the journey, deep water for the mind, living water for a thirst that is "blissful mystery empty of all that men [and women] can really explain." They drink of the gift each reveals in the presence of the other -- the gift of spirit and truth.
This emptiness is what we might refer to as transparent reality, that which is seen as it is -- nothing added, nothing subtracted -- a clear, unobstructed view (spirit) of what is (truth). It is the play of the conversation between the Jew and the Samaritan.
It is the conversation we need to continue today. It is the pathway that will have to be cut into the ground by our footsteps as we visit each other and sip from the well together.
The food for thought is outside our minds. It is the conversation taking place between man and woman, earth and water, spirit and truth.
The treasure mountain, the enlightenment seeking mind, is now sipping water -- maybe coffee or tea -- right there in your hand. Right there in the hand of the one sitting with you.
L. distare= to stand apart; separated in a relationship other than spatial; far apart.
Gk. Christos=(fr. chriein=to anoint)=1:Messiah 2: Jesus 3: an ideal type of humanity 4 Christian Science: the ideal truth that comes as a divine manifestation of God to destroy incarnate error.
To live a religious life in the world today -- first, stay silent. That will work. No one will know what you are doing. And that's good.
To live a spiritual life in the world today -- next, open your mouth. That too will work. No one will understand the babble that tries to word the incomprehensible. Try anyway.
To live an ordinary life in the world today -- finally, practice a poem created while walking beyond your strength.
I've crossed the sea after Truth.
Knowledge, that snare, must be defied.
Here and there, I've worn out heaps of sandals.
Now -- moonlit water in the clear abyss.
There will be those who love their life -- and they will love yours.
There will be those who fear their life -- and they will fear yours.
There will be those who wander mumbling to themselves things true & improbable. Invite them in.
I have never found anyone touched by God to appear sane.
They're not. What they are is something more valuable -- they're safe, and sound.
They're the ones to sit with for a stretch of mind and time.
God is no other than love.
And love will not forget the sound of our voice attempting to pronounce its name.
As the wind blows, there's no pinning down its direction, it takes our hesitation away with it.
How can I tell you what I've seen?
Fall, stand -- it's clear at once.
Trample the old path. And the new.
For Christians, the words expressing longing and struggle to comprehend and embody Christ might sound awkward. Patterns of thought change century after century, and the wording of a core reality needs constant and refreshing expression.
The core reality doesn't disappear with new wording. Rather, it appears in new light. This requires courageous faith, good will toward God, and good will toward one's own exploration.
Christian theology says God doesn't change. God is there as we change. For Buddhists, change is all there is. Transparent awareness reveals what our rational minds cannot grasp. For both, the exploration asks for caring and careful attention.
The proposal for Meetingbrook Laura of Hermits asks into such attention.
We pray for courageous faith, good will all around.
Meetingbrook proposes a laura of hermits, an intentional community, a loosely knit association of individuals seeking what might be called Zen Contemplative Ecology.
7.	welcoming hospitality and generosity of spirit within and toward others.
8.	A Zen Contemplative Ecology is, for this proposal, the practice of seeing directly & clearly -- now, safe, & whole -- interrelationships of individuals in community, sentient beings in nourishing environments, and a cosmotheandric awareness (of earth & nature itself, divine presence, and human family) that caringly and carefully makes room for each other..
A Meetingbrook Laura of Hermits -- welcomes individuals, couples, & families. Members of any or no religion are welcome. Members of sanghas, orders, followers of specific teachers, are welcome. Those on any particular spiritual path, those willing to allow others to practice their own religious and spiritual path, are welcome. Inclusive, autonomous, & generous hearted people, are welcome. Those who appreciate diversity and a plurality of seeking, those realizing and embodying what is natural, sacred, and human – the immeasurable gift of existence and life beyond compare -- are welcome.
The mere prospect of connecting what already touches us is attractive. Identifying, consciously and intentionally as part of Meetingbrook Laura of Hermits, deepens the affection and mystery of living life alone with others. Whether you prefer: to live alone on one's own; live with others; or live alone together – we will explore how to dwell engaging solitude and community – a dedicating of life and love -- with God, each other, oneself.
If interested, come join us for some exploratory conversations toward the creation invited by a Meetingbrook Laura of Hermits. If nothing else, it might provide thoughtful considerations, laughter & a spate of belonging!
It is time to rethink the word "severity." It wishes to be known by a designation other than "strict in judgment, discipline, or punishment."
Or, what do we really think life is?
This morning, consider every breath. Every blink of the eye. Even the dozens of ladybugs at window suddenly awakened by warm February sun on attic eave. Sando snoozing. Saskia baking. The verity of Sunday morning at the edge of silence.
If we are the universe, there is much we do not yet understand.
If Awakened Buddha, Compassionate Father, Incarnated Christ, Sacred Spirit, Divine Radiance, Eternal Love, Blessed Mother -- (whichever designation brightens our eyes) -- if that personification longs to indwell this reality, there is still much we have to comprehend in order to ourselves inhabit this reality.
If life can be stripped of all denial so that we can begin to love -- there is much to let fall away. When we let this happen, there arrives a transparence that is itself true. .
In 1986, there were 22thousand cases of AIDS worldwide. In 2001 there were 38million cases worldwide. There have been 19million deaths in that time.
"We are each grains of sand on a beach," Joel Rothschild says, "And God is the beach." His book is Signals, An Inspiring Story of Life After Life.
"We are the heartbeat of the universe. There is a biological connection. Every moment in every life matters," says Rothschild speaking with Michael Thoms on New Dimensions Radio.
At the hermitage we pray for all who suffer in body, mind, or spirit. Especially those who are dying, those who will die today, and those who have died with no one to pray for them.
What is itself true? Or, what is true to itself? And, what can we say about the severity (the itself true) of love?
Even Pilate asked Jesus about severity. Following Jesus' assertion that anyone experiencing the reality he himself embodied, that person will testify to the truth. Pilate asked the reality standing before him, "'Truth,' what is truth?" Jesus remained in silence. Pilate was left to his own reflection.
Our very life depends on our reflection.
A moment of silence might help.


Shopping for a wedding band to spell out your eternal love for your other half can be quite frustrating if a) the available rings are substandard representations of your undying love, b) the pricing is unreasonably exorbitant, and c) neither of you can agree on a pair.
So, to save yourself from the headaches (and arguments), why not design your own?
Local jewellery designer Wendy Lor is a person you can turn to.
All you have to do is tell her your beautiful love story and she will convey it into exquisite bands.
Lor, with 20 years of experience, captures the emotions through her innate craftsmanship. Thus far, she has achieved a 100% success rate in terms of nailing the design according to her client's requirement.
"I bring the essence of the couple into the ring and by doing that, I believe it's no longer about Wendy Lor or the brand, but the couple," she expresses.
The 42-year old designer says that the majority of the couples that go to her, have tried shopping for rings before consulting her.
"They will say that they couldn't find anything they like but I believe it's more than not being able to find the right ring.
"I am just an instrument that helps tell their story," explains Lor, the founder of WendyLorArtisans and Unique Wedding Bands.
To begin, Lor will aks the couple to relate their courtship and romance. Every little detail helps, from favourite colour to personal likes and dislikes.
"We have to be truthful about ourselves especially when doing something sacred. The more honest they are, the better I can come up with the designs," she advises.
Whether or not it's necessary for the couple to have a preconceived idea of how they'd want their rings to look, Lor says it's not but it can be helpful.
Having said that, Lor did turn away a couple because the bride continuously rejected Lor's designs because Lor did not live up to the Tiffany & Co. design the bride wanted.
Lor is adamant that she does not do copies of designer rings as it is her duty to translate the couple's story and "materialize that desire" into the most extraordinary wedding band.
There are two categories within Unique Wedding Bands, which are Unique Message Band or The Inspired Band.
The former is crafted to articulate the secret message between the couple, which Lor describes as "a meaningful whisper of love" whilst the latter designs are constructed "to suit the couple's beautiful union".
The materials and gems are decided by Lor based on the couple's budget and from her deduction of the story.
The rings will usually be in white or yellow gold in either 9K, 12K or 18K and if gems are used, couples can expect either diamonds or genuine precious stones.
For Muslim men who don't wear gold for religious reasons, Lor makes Suasa rings with a touch of modern white, instead of the conventional reddish colour metal.
Lor, who does everything from designing to the making of the rings, always take functionality into account since the couple will be wearing the rings everyday. "I will not compromise on comfort," she says.


The price net of VAT is $ 11,21, according to the exchange rate of 1.1209 of the European Central Bank. The conversion rate of your bank (or PayPal) may vary.
Cute necklace with an edelweiss pendant and swarovski gemstones.
To be closed with a carabiner clasp and fitted with a chain extender(ca. 5cm).


The Grand Prix of Toronto (formerly the Molson Indy; tel. 416/588-7223; www.grandprixtoronto.com) takes place in July at the Exhibition Place Street circuit. Check the website for 2011 updates.
Rogers Centre (1 Blue Jays Way, on Front St., beside the CN Tower) is the home of the Toronto Blue Jays. For tickets, contact the Toronto Blue Jays at tel. 888/OK-GO-JAY (888/654-6529) or 416/341-1234, or http://toronto.bluejays.mlb.com.
Toronto's basketball team, the Raptors, has its home ground in the Air Canada Centre (40 Bay St., at Lakeshore Blvd.). The NBA schedule runs from October to April. The arena seats 19,500 for basketball. For information, contact the Raptors Basketball Club (40 Bay St.; tel. 416/815-5600; www.nba.com/raptors). For tickets, call Ticketmaster (tel. 416/870-8000).
Stephen Colbert vs. the Raptors -- Toronto's basketball team has been on Stephen Colbert's bad side since the very first episode of Comedy Central's The Colbert Report on October 17, 2005. At that time, Colbert put the Raptors "On Notice" for losing a game to Maccabi Tel Aviv, the Euroleague champions. Things got worse in early 2007: Because the Raptors' mascot came in ahead of the Saginaw Spirits' Steagle Colbeagle the Eagle (named after Colbert) in an online poll, Colbert demoted the Raptors to his "Dead to Me" board. Oh, the indignity of being on the same list as bowtie pasta, screw-cap wines, and men with beards!
Remember Kramer on Seinfeld? He would watch only Canadian football. If you're not familiar with it, here's your chance to catch a game. Rogers Centre (1 Blue Jays Way) is home to the Argonauts of the Canadian Football League. They play between June and November. For information, contact the club at tel. 416/341-2700 or visit www.argonauts.on.ca. For tickets, call Ticketmaster (tel. 416/870-8000).
Canada's national golf tournament, the Bell Canadian Open, usually takes place at the Glen Abbey Golf Club (tel. 905/844-1800) in Oakville, about 40 minutes from the city. Most years, it runs over the Labour Day weekend.
Hockey isn't Canada's national sport, believe it or not (that's lacrosse), but it's undoubtedly the most popular. The Air Canada Centre (40 Bay St., at Lakeshore Blvd.) is the home of the Toronto Maple Leafs (http://mapleleafs.nhl.com). The team hasn't won a Stanley Cup since 1967, but droves of fans stick with the franchise nonetheless. Though the arena seats 18,700 for hockey, tickets are not easy to come by because many are sold by subscription. The rest are available through Ticketmaster (tel. 416/870-8000).
Thoroughbred racing takes place at Woodbine Racetrack (Rexdale Blvd. and Hwy. 427, Etobicoke; tel. 416/675-6110 or 416/675-7223). It's famous for the Queen's Plate (usually contested on the third Sun in June); the Canadian International, a classic turf race (Sept or Oct); and the North America Cup (mid-June). Woodbine also hosts harness racing in spring and fall.
Toronto's new soccer club, the Toronto FC (http://toronto.fc.mlsnet.com), is beloved by Torontonians. It's the first non-U.S. team in Major League Soccer. They play at BMO Field at Exhibition Place; it was built for the FC, and it holds 20,195 spectators. For tickets, call Ticketmaster (tel. 416/870-8000).
Canada's international tennis championship, the Rogers Cup, takes place in Toronto and Montréal every August (the men's and women's championships alternate cities each year). In 2012, the men play in Toronto, the women in Montréal. For more information, call tel. 877/283-6647 or check www.lovemeansnothing.ca.


School administrators play integral roles in ensuring schools function smoothly. They are involved in nearly all aspects of their school's operation. Our administrators are here for you. Please contact them if there is anything they can do to assist you, or your child!


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four-channel synchronized video triptych displayed on four 55" QLED 4K flat panel displays, 27 minute loop
Currents International New Media Festival, El Museo Cultural, Santa Fe, NM
Detail, upper center channel
The Pacific Northwest rural landscape is the one I grew up in and generally regarded with a measure of melancholy for both its attractive and unattractive qualities. Manifold is an experimental, synchronized 4-channel media work experienced on four large OLED 4k flat screen monitors. Constructed almost exclusively from composited and collaged photos taken from a moving train (more than two thousand originals were shot during several trips between Seattle, Washington and the Willamette Valley in Oregon), Manifold documents a dreamlike and liminal territory of Northwest landscape where stark industrial, rural and urban tableaux are revealed in alternating succession. The work explores feelings resulting from the cult of private ownership and its effects on ecological and spiritual deterioration as the region grows and becomes more developed, and serves as a meditation on and critique of a reckless, fossil-fueled culture.

redpajama_set_name: RedPajamaCommonCrawl


text:
Results for Reality
8.855202249mHD
The family you know and love is here with a brand new series, giving an all-access pass into their lives. Kris, Kourtney, Kim, Khloé, Kendall, and Kylie bring the cameras back to reveal the truth behind the headlines. From the intense pressures of running billion-dollar businesses to the hilarious joys of playtime and school drop-offs, […]
GenresReality
CastKendall Jenner, Khloe Kardashian, Kim Kardashian West
Steve Harvey employs his own life experiences and some good old common sense as he expands his resume by taking on the roles of judge and jury in the courtroom. Harvey welcomes a variety of conflicts and characters to his courtroom — from small claims to big disputes and everything in between — where, playing […]
The Ghost Town Terror
After more than a year of paranormal attacks, including unexplained scratches, apparitions, disembodied voices and poltergeist activity, Karen and her family – daughter Chloe, 20, and sons Cameron, 21, and Colby, 15 – are distraught and in dire need of help. Paranormal investigator Tim Wood and paranormal researcher Sapphire Sandalo come to their aid and […]
GenresDocumentary, Mystery
I Am Georgina
Join Georgina Rodríguez — mom, influencer, businesswoman and Cristiano Ronaldo's partner — in this emotional and in-depth portrait of her daily life.
CastCristiano Ronaldo, Georgina Rodríguez, Ivana Rodríguez
This supersized, adult version of the beloved '90s competition series preserves many elements from the original, but this time around, the entire show is taken out of the studio and scaled up with tougher challenges. Every episode is a hero's journey through a mysterious jungle, where five teams begin the journey, but only one is […]
CastCristela Alonzo, Dee Bradley Baker
7.68202140mHD
Will Smith whose curiosity and wonder is positively infectious—is guided by National Geographic Explorers traveling to different corners of the world to get up close and personal with the weirdest, most unusual, dangerous and thrilling spectacles of the planet.
GenresDocumentary, Reality
CastWill Smith
Naked and Afraid of Love
4.3202160mHD
8 single women and 8 single men — attempt to find true love while working together to survive the elements and each other, in an unforgettable island paradise.
Twelve people think they're in the final casting round for a reality show. In fact, they're already being secretly filmed, with 100,000 euros at stake.
On the shores of paradise, gorgeous singles meet and mingle. But there's a twist. To win a $100,000 grand prize, they'll have to give up sex.
DirectorCharlie Bennett
Too Hot to Handle: Latino
7.6202140m
Singles from Latin America and Spain are challenged to give up sex. But here, abstinence comes with a silver lining: US$100,000.
CastItatí Cantoral
Status and strategy collide in this social experiment and competition show where online players flirt, befriend and catfish their way toward $100,000.
CastMichelle Buteau
Spy Game


The Thule Sport G2 W150 is suitable for mounting on the existing caravan rail. For Hobby caravans from 2004 to 2014. The bike carrier can used simultaneously with the W-150 window awning. Available for 2 bikes and expandable to 3.
- Can be extended up to 3 bikes. Set for 3rd bike is sold seperately.
Thursday, 26 July 2018, 09:54 "Now it´s mounted, but the manual is not so good.


We here at CAC offer Healthy, Tasty food at Competitive Prices, in a unique and friendly atmosphere. Remember that diner back home, where you knew everybody, and everybody knew you? It's been reincarnated here, probably because we have such awesome good karma. You should totally come see if you recognize anyone.
Cherry Alley is one of the best local events to check out live music. Comfortable atmosphere for artists and audience alike, great food and beverages, and great people.
This will be a two hour Fricknadorable show, the duo with Audra on uke that performs folk, blues, Irish tunes and Americana, as well as covers from the 70s, 80s and 90s. We look forward to seeing you there!


New ListingBrand New in Box Mens Nike Air Vapormax PlusOpti Yellow Black Bumblebee Size 12!
This page was last updated: 22-Apr 17:22. Number of bids and bid amounts may be slightly out of date. See each listing for international shipping options and costs.


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Frontiers in Cell
and Developmental Biology
Heart repair, cardiac regeneration and stem cells View all 6 Articles
Participants in Cardiac Regeneration
Improvement of Endogenous Cardiac Healing
Prospects and Conclusions
Front. Cell Dev. Biol., 29 September 2015 | https://doi.org/10.3389/fcell.2015.00057
Stimulating endogenous cardiac repair
Amanda Finan and Sylvain Richard*
Centre National de la Recherche Scientifique United Medical Resource 9214, Institut National de la Santé et de la Recherche Médicale U1046, Physiology and Experimental Medicine of the Heart and Muscles, University of Montpellier, Montpellier, France
The healthy adult heart has a low turnover of cardiac myocytes. The renewal capacity, however, is augmented after cardiac injury. Participants in cardiac regeneration include cardiac myocytes themselves, cardiac progenitor cells, and peripheral stem cells, particularly from the bone marrow compartment. Cardiac progenitor cells and bone marrow stem cells are augmented after cardiac injury, migrate to the myocardium, and support regeneration. Depletion studies of these populations have demonstrated their necessary role in cardiac repair. However, the potential of these cells to completely regenerate the heart is limited. Efforts are now being focused on ways to augment these natural pathways to improve cardiac healing, primarily after ischemic injury but in other cardiac pathologies as well. Cell and gene therapy or pharmacological interventions are proposed mechanisms. Cell therapy has demonstrated modest results and has passed into clinical trials. However, the beneficial effects of cell therapy have primarily been their ability to produce paracrine effects on the cardiac tissue and recruit endogenous stem cell populations as opposed to direct cardiac regeneration. Gene therapy efforts have focused on prolonging or reactivating natural signaling pathways. Positive results have been demonstrated to activate the endogenous stem cell populations and are currently being tested in clinical trials. A potential new avenue may be to refine pharmacological treatments that are currently in place in the clinic. Evidence is mounting that drugs such as statins or beta blockers may alter endogenous stem cell activity. Understanding the effects of these drugs on stem cell repair while keeping in mind their primary function may strike a balance in myocardial healing. To maximize endogenous cardiac regeneration, a combination of these approaches could ameliorate the overall repair process to incorporate the participation of multiple cellular players.
Despite the significant research effort that has gone into improving therapeutics and interventions for coronary heart disease, it still remains a great societal, economic and clinical burden throughout the world. In particular, myocardial infarction is attributable to more than half of the cardiovascular disease related mortality in the industrialized world (Go et al., 2014). The coronary occlusion in a myocardial infarct results in significant cardiac cell damage and death. Current therapies are able to attenuate symptoms and prolong life. However, an intervention has not yet been developed that can replace or regenerate the damaged myocardium after an infarct. This is due in part to the absence of understanding and the potential of how the heart tissue can be repaired or regenerated.
Evidence has accumulated over the past 15 years to demonstrate that there is some amount of cardiac turnover, both in healthy and injured tissue. Particular interest has focused on cardiac regeneration after ischemic events due to the large amount of myocyte death, but reports also describe cardiac proliferation in models of cardiac pressure overload and idiopathic dilated cardiomyopathy (Kajstura et al., 1998; Urbanek et al., 2003). Cardiac cell proliferation is highest in youth, reducing with increased age (Rumyantsev and Borisov, 1987; Mollova et al., 2013; Naqvi et al., 2014). In an average healthy adult, the cardiomyocyte turnover rate is controversial with reports predicting annual turnover rates ranging anywhere from 0.3% to more than 50% (Bergmann et al., 2009; Kajstura et al., 2010; Bergmann and Jovinge, 2014). Methods have been questioned in studies where turnover is on the higher end (Laflamme and Murry, 2011). Cardiomyocyte renewal is augmented in cardiac pathological settings such as myocardial infarction and heart failure (Rumyantsev and Borisov, 1987; Kajstura et al., 1998; Beltrami et al., 2001). Due to these evidences, it appears that the heart has some capacity for renewal though it is limited and unable to compensate for significant cardiac damage. It has been proposed that evolutionary mechanisms have limited pathways of cardiac regeneration to protect the heart from developing cancer (Penn, 2010). In fact, primary cardiac tumors are extremely rare, representing only 0.3–0.7% of all cardiac tumors (Leja et al., 2011). This endogenous capability to regenerate does provoke a potential target for cardiac therapies however. Reports demonstrate multiple cellular players participating in endogenous cardiac regeneration (Figure 1). The exact contribution of each cell type remains a topic of controversy in the cardiac regenerative medicine field. Focusing the repair potential to just one cell type may actually limit the therapeutic opportunities. Instead it is likely that provoking each of these players could provide an orchestrated and more complete regeneration.
Figure 1. Endogenous cardiac regeneration. After a cardiac insult, a significant number of cardiac mycoytes die and vessel density gets reduced. In a very limited way, the heart has the ability to regenerate but it is insufficient to compensate for the total damage. The cellular participants in the endogenous regeneration process may include cardiac myocytes (pink cells, black lines), local cardiac progenitor cells (blue cells), and recruited peripheral stem cells (red cells). These cells have the potential to proliferate and participate in the regeneration of cardiac myocytes, angiogenesis, and the release of trophic factors that may reduce cardiac cell death. Modes of the cells participation are identified by colored arrows (peripheral stem cell, red; cardiac progenitor cell, blue; cardiac myocyte, green). Methods that could be employed to improve these endogenous mechanisms include cell and/or gene therapy and pharmacologic treatments.
Amputation studies in zebrafish and neonatal mice brought to light the potential for cardiac regeneration by cardiac myocytes themselves (Poss et al., 2002; Porrello et al., 2011). The mechanisms proposed include the activation of cardiogenesis and cell cycle genes and dedifferentiation (Jopling et al., 2010; Kikuchi et al., 2010; Porrello et al., 2011; Mahmoud et al., 2013). However, this capacity for complete regeneration in the mouse is lost by 1 week of age (Porrello et al., 2011). Studies are incongruous on whether cardiac myocyte proliferation continues into adult life (Walsh et al., 2010; Senyo et al., 2013). It does appear likely that myocardial injury can induce to some extent pre-existing cardiac myocyte renewal (Senyo et al., 2013).
Cardiac Progenitor Cells
Cardiac progenitor cells (CPC) are an adult stem cell population residing in the heart. These cells have been identified by a number of markers including c-kit, sca-1, Isl1, Wilms tumor 1, and the ability to form cardiospheres in vitro (Beltrami et al., 2003; Genead et al., 2010; Smart et al., 2011; Hsiao et al., 2014; Uchida et al., 2013). It is evident that after a cardiac injury these cell types proliferate and increase in number (Fransioli et al., 2008; Smart et al., 2011; Uchida et al., 2013). It has even been suggested that these cells are indispensable for cardiac regeneration (Ellison et al., 2013). Disagreement exists on the exact differentiation capabilities of these cells in vivo, particularly with the c-kit+ CPC population. Research consistently reports the ability of the cells to differentiate into an endothelial cell lineage but their contribution to cardiac myocytes has been questioned (Hsieh et al., 2007; Fransioli et al., 2008; Jesty et al., 2012). Ellison et al. found that c-kit+ CPC significantly contribute to de novo cardiac myocyte generation; whereas van Berlo et al. reported that differentiation of c-kit+ cells to cardiac myocytes is negligible (Ellison et al., 2013; Van Berlo et al., 2014). This discrepancy may in part be due to the different transgenic mouse lines used between the two studies. A study with the same mouse line used in the Ellison study demonstrated that of the c-kit+ cells identified by immunofluorescence, only 32% of the cells were positive for fluorescent protein driven by the c-kit promoter (Fransioli et al., 2008). This suggests that the results of the Ellison study may potentially underestimate the involvement of c-kit+ cells. Regardless of these issues, it is evident that CPC are responsive to cardiac injury and differentiate into endothelial cells, aiding in increased vessel density, a mechanism correlated to improved cardiac function (Kim et al., 2014).
Peripheral Stem Cells
The bone marrow is a reservoir for multiple populations of adult stem cells including, but not limited to, endothelial progenitor cells (EPC), c-kit+ stem cells, very small embryonic like stem cells, mesenchymal stem cells (MSC), and hematopoietic stem cells. Bone marrow cells are mobilized into the peripheral blood after cardiac injury and are recruited to the myocardium (Mouquet et al., 2005; Finan et al., 2012). The recruitment of bone marrow cells is associated with cardiac repair and along the same lines, in studies where the bone marrow stem cells response is attenuated, reduced accumulation of bone marrow cells is associated with worse outcomes (Fazel, 2006; Sopko et al., 2010; Finan et al., 2013; Gong et al., 2014). Bone marrow stem cells can incorporate into the vasculature, differentiate into endothelial cells, and participate in vascular remodeling (Finan et al., 2013; Wu et al., 2015). Studies of gender mismatched bone marrow and heart transplant patients demonstrated that bone marrow cells have the capacity to differentiate into cardiac myocytes (Quaini et al., 2002; Deb et al., 2003). However, a recent study suggests that bone marrow cells do not directly differentiate into cardiac myocytes and instead suggests their fusion with existing cardiac myocytes (Wu et al., 2015). Bone marrow cells may also replenish the diminished CPC pool after a cardiac injury (Mouquet et al., 2005; Barile et al., 2011).
It is clear that the heart has some capacity to regenerate through various cell participants to support normal deterioration. Unfortunately, it is evident that the potential is limited and unable to compensate for the extent of damage that may occur after a myocardial infarction. A number of approaches have been attempted to improve cardiac regeneration, including cell and gene therapy. Reasonable benefits have been determined from these therapeutic approaches though the beneficial mechanisms lie in the trophic factors produced or through the activation of endogenous cardiac healing. Recently, it is has been identified that common drugs administered to patients with cardiovascular disease may alter endogenous stem cell populations. Profiting from these interactions may be a potential manner to assist in cardiac repair.
Attempts to repair the damaged myocardium with cardiac myocytes or skeletal myocytes have shown limited potential. A large amount of enthusiasm therefore has focused on the potential that stem cells could have in cardiac regenerative therapy. Many stem cell types have been examined including embryonic stem cells, induced pluripotent stem cells, various bone marrow stem cell types, and cardiac stem cells. Cell therapy efforts have been reviewed more exhaustively elsewhere (Goumans et al., 2014; Pavo et al., 2014).
Embryonic stem cells (ESC) and induced pluripotent stem cells have a great power to differentiate into all cell types making them an attractive choice for replacing lost myocardium. While efforts have been made to program these stem cell types to reduce tumor potential, it still remains a risk as well as a potential immunological challenge in the recipient (Anderson et al., 2014; De Almeida et al., 2014; Zhang et al., 2015). Cardiac myocytes derived from human pluripotent stem cells were shown to be anti-arrhythmic in a guinea pig model (Shiba et al., 2012). However, in a large primate model, the transplantation of human ESC derived cardiac myocytes was associated with ventricular arrhythmias, although they were transient and did not induce sudden death (Chong et al., 2014). As the human heart has a significantly slower heart rate and larger size than the primate model, the propensity of arrhythmias from ESC transplant increases (Lalit et al., 2014). For this reason, the transplantation of ESC derived cardiac myocytes needs to be tested with caution in humans (Anderson et al., 2014).
Due to the issues that still remain with pluripotent stem cells, adult stem cells could be a more plausible option for cell therapy. Autologous adult stem cells can be delivered to patients reducing any risk for immune complications. As these cell types have a more differentiated lineage, no concerns for tumor formation remain. In animal models, cardiac cell therapy with bone marrow stem cells or cardiac stem cells can improve cardiac function, decrease infarct size, improve myocardial regeneration, increase vascular density, and activate endogenous stem cell populations (Figure 2; Yoon et al., 2010; Loffredo et al., 2011; Dong et al., 2012; Avolio et al., 2015). These benefits seem to translate into similar results in a portion of human clinical trials. Individual reports have described improved cardiac function, decreased scar size, and improved physical capabilities, such as improvements in the 6 min walking distance test, after adult stem cell therapy (Bolli et al., 2011; Malliaras et al., 2014b; Golpanian et al., 2015; Mathiasen et al., 2015). However, results from the meta-analysis of cell based cardiac studies revealed no clinical benefit 3–12 months after cell therapy (Gyöngyösi et al., 2015).
Figure 2. Cardiac cell therapy. After a cardiac injury, a patient's adult stem cells are isolated. These cells can be isolated from either cardiac tissue or from peripheral sites. The cells are amplified to have a sufficient number for therapeutic transplant. The cells are injected into the patient either intravenously or intracardiac, alone or in the presence of pro-survival cocktails, hydrogels, or extracellular matrix patches. The injected cells can participate themselves in cardiac regeneration or improve endogenous healing by excreting paracrine factors which reduce apoptosis and increase stem cell recruitment and activity and angiogenesis to repair the damaged cardiac tissue.
The beneficial mechanism of adult stem cells has not been direct differentiation to cardiac myocytes as originally hoped for. Instead the more prominent mechanism appears to involve the activation of endogenous healing pathways through paracrine factors provided by the transplanted cells. These pathways can reduce myocardial apoptosis, activate cardiac myocytes proliferation and endogenous stem cell recruitment (Zhang et al., 2007; Fischer et al., 2009; Malliaras et al., 2014a; Avolio et al., 2015). Cell therapy also aids in improving vascular density in the damaged myocardium either through direct differentiation or activating endogenous angiogenesis. The importance of this mechanism to cardiac repair was highlighted recently (Yoon et al., 2010). In this study, infarcted mice were treated with ganciclovir after MSC therapy to induce cytotoxicity in stem cell derived endothelial cells. The death of the endothelial cells and the subsequent decrease in vessel density led to a significant deterioration of cardiac function. Even though cell therapy approaches may not themselves replace the lost cardiac myocytes, their release of trophic factors that reduce apoptosis or recruit endogenous stem cells and their ability to aid in vascular remodeling may provide a significant benefit to cardiac repair.
An additional point to note is that the retention of the stem cells in the myocardium is extremely low, reducing their potential therapeutic effects. The transplantation of sheets of cells or in combination with hydrogels or patches improve the cell engraftment rate, thus improving cardiac function (Ishii et al., 2014; Roche et al., 2014; Tano et al., 2014; Zhang et al., 2015). Interestingly, even altering the growth media of the cells can improve their retention in the tissue (Kim et al., 2014). Pro-survival cocktails can also be used to improve the duration and number of the cells in the myocardium (Laflamme et al., 2007; Gautam et al., 2015). Components of the pro-survival cocktails include growth factors, anti-apoptotic molecules such as cell-permeant Bcl-XL and caspase inhibitors, immunosuppressants, and vasodilators.
Natural reparative signaling pathways occur in the heart after a cardiac injury. However, these signals are usually transient, not enduring long enough to support complete endogenous repair (Askari et al., 2003; Schenk et al., 2007). As discussed in the previous section, transplanted stem cells provide paracrine factors that support natural tissue repair. Gene therapy is a mechanism to capitalize on these natural factors to prolong or reactivate the signals. Cardiac diseases gene therapy has encompassed delivery options including adenovirus, direct plasmid transfer, microbubbles and modified RNA.
Growth factors and chemokines are greatly implicated in cardiac repair and their expression through gene therapy techniques can improve cardiac function (Kanashiro-Takeuchi et al., 2011). Beneficial mechanisms induced by this approach include elevated proliferation, mobilization, and recruitment of endogenous local and peripheral stem cell populations (Figure 3). A number of growth factor or cytokine candidates have been demonstrated to be favorable in cardiac repair, including, but not limited to, vascular endothelial growth factor, monocyte chemotactic protein 3, and placental growth factor (Schenk et al., 2007; Iwasaki et al., 2011; Zangi et al., 2013). In particular, stromal derived factor-1 expression can recruit various C-X-C chemokine receptor type 4 positive cell populations including CPC, MSC and very small embryonic like stem cells (Askari et al., 2003; Kucia et al., 2006; Dong et al., 2012). Stem cell factor gene therapy has been described to induce cardiac myocyte and CPC proliferation (Yaniz-Galende et al., 2012; Ishikawa et al., 2015). Gene therapy by direct injection of growth factor or chemokine plasmids, namely stromal derived factor-1 and vascular endothelial growth factor, has been demonstrated in patients with ischemic heart disease to be safe and show signs of a functional benefit (Favaloro et al., 2013; Penn et al., 2013). In particular, stromal derived factor-1 plasmid injection into cardiac heart failure patients has shown functional therapeutic promise by improving ventricular remodeling in patients with more advanced cardiac dysfunction (Chung et al., 2015).
Figure 3. Cardiac gene therapy. In animal models, cardiac gene therapy has shown to be successful when delivered by direct plasmid, in a lenti- or adenovirus, or in exosomes. Growth factors, chemokines, transcription factors and miRNAs have all been tested in cardiac gene therapy. Expression of these proteins and miRNAs have the potential to improve endogenous cardiac regeneration through the recruitment, activation and differentiation of local and peripheral stem cells, improved vascular density, or by proliferation of cardiac myocytes. Additional cardiac "rescuing" gene therapy targets (e.g., Serca2a) can improve cardiac function but it has yet to been investigated if these approaches can alter endogenous cardiac regeneration.
Transcription factors have also been targeted in cardiac gene therapy. Hypoxia inducible factor 1-alpha has been an appealing target as it is protective by regulating angiogenesis and survival, as well as the expression of chemokines capable of recruiting stem cells (Semenza, 2014). Plasmid or adenovirus transfer of hypoxia inducible factor 1-alpha into the myocardium can improve cardiac repair, decrease cardiac myocyte apoptosis, mobilize bone marrow stem cells to the heart, and activate c-kit+ cells in the myocardium (Huang et al., 2011, 2014; Ong et al., 2014). In vivo reprogramming of fibroblasts with the cardiac transcription factors GATA4, Mef2c, and Tbx5 generates functional cardiac myocytes which are fully incorporated in the myocardium and decrease scar size, thus improving cardiac function (Inagawa et al., 2012; Qian et al., 2012). An additional tested approach is the manipulation directly of the proliferation of the cardiac myocytes. Injection of an adenovirus expressing cardiac specific telomerase or the Yes-associated protein can induce cardiac myocyte proliferation and improve overall cardiac repair (Bär et al., 2014; Lin et al., 2014).
MicroRNAs (miRNAs) have also been employed in gene therapy techniques to promote cardiac regeneration. miRNAs are small non-coding RNAs that bind mRNA and inhibit translation. Eulalio et al. performed a high throughput screening of miRNAs on neonatal rat cardiac myocytes to identify candidates that induce proliferation (Eulalio et al., 2012). They then demonstrated that in fact when an adenovirus expressing either miR-590-3p or miR-199a was injected at the time of myocardial infarction, they could induce cardiac myocyte proliferation resulting in decreased infarct size and improved cardiac function. Endogenous CPC proliferation was elevated after lentiviral delivery of miR-17-92 (Sirish et al., 2012). The in vivo reprogramming of cardiac fibroblasts to cardiac myocytes by lentiviral transfer of a combination of miRNAs (1, 133, 208, 499) has also been demonstrated to be a successful approach to induce endogenous cardiac regeneration (Jayawardena et al., 2015). miRNAs can also be a target of inhibition. To combat the anti-angiogenic properties of miR-92a, an antagomir was designed to inhibit the miRNA thus increasing capillary density after myocardial infarction (Bonauer et al., 2009). The potential of miRNAs in cardiac repair has been reviewed more thoroughly elsewhere (Hodgkinson et al., 2015).
Additional targets of cardiac gene therapy have included calcium cycling proteins, extracellular matrix alterations, adrenergic manipulation, and arrhythmias and have been reviewed elsewhere (Nagai and Komuro, 2012; Scimia et al., 2013). These approaches appear to have a sufficient effect on their target and improve cardiac function but besides the mention that targeting calcium cycling proteins can block cardiac remodeling, little is known on the effect of these strategies and the survival or regeneration of the tissue (Katz et al., 2014). It would be interesting to examine the cell proliferation or anti-apoptotic effects of these therapies especially as atrial fibrillation and changes in calcium channels and intracellular calcium changes can alter cardiac myocyte and CPC proliferation (Ferreira-Martins et al., 2009; Chernyavskaya et al., 2012; Gambini et al., 2012; Demion et al., 2014).
Pharmacological Interventions
The common pharmaceutics given to patients who have had a myocardial infarction include aspirin, beta blockers, ace inhibitors, angiotensin receptor blockers, and statins. These drugs aim at reducing blood clots, regulating blood pressure, stabilizing electrical activity, and reducing cholesterol. These approaches improve patient lifestyle and prolong life but they do not replace the damaged tissue that is lost after a myocardial infarction. However, evidence is mounting that these drugs may actually have either positive or negative effects on endogenous stem cell populations and cardiac myocyte survival and proliferation (Table 1). Potential may exist in refining current therapies to control their primary functions and generate a balance in myocardial healing. These drug regiments, as well as, patient's age and pathophysiological state likely have grave implications on endogenous stem cell activity as well as exogenous cell therapy approaches. Increased age and cardiovascular comorbidities have well been described to impair endogenous cardiac repair (Gambini et al., 2012; Lee and Poh, 2014; Hariharan and Sussman, 2015). Research regarding the effects of these parameters has been limited in animal studies. Awareness of these effects will allow clinicians to anticipate potential adverse effects and facilitate maximal results.
Table 1. Effects of common pharmaceuticals on cardiac myocytes and endogenous stem cells.
Aspirin can reduce the risk of myocardial infarction in high-risk patients and prevent an additional event. However, contradictions exist with aspirin including an increased risk of gastrointestinal bleeding. Chronic treatment with aspirin may inhibit the cardiac proteasome and reduce cardiac myocyte viability (Tan et al., 2013). Interestingly, aspirin may have negative effects on endogenous stem cell populations as well. Aspirin can reduce EPC number and migration capacity (Boer et al., 2011; Sato et al., 2013). Aspirin may also inhibit MSC proliferation and induce apoptosis (Deng et al., 2009). No reports have yet described the effects of aspirin on CPC but as non-steroidal anti-inflammatory drugs can negatively affect ESC cardiac differentiation, it could have an implication on in vivo cardiac differentiation as well (Chillar et al., 2011). The negative effects of aspirin on endogenous stem cells may be due to its anti-inflammatory effects. Pro-inflammatory signals have been demonstrated to aid in regulating and activating endogenous stem cell populations (Reber et al., 2006; Mirantes et al., 2014).
After a myocardial infarction, an excessive number of catecholamines are released. To reduce their deleterious action, beta adrenergic receptor blocking agents are administered to patients. These drugs aid in the prevention of additional infarcts and reduce cardiac arrhythmias. The majority of the inotropic effects of the beta adrenergic signaling pathway are mediated by the beta 1 receptor (Bristow et al., 1986). This pathway as well can promote cardiac myocytes apoptosis (Seqqat et al., 2012). Conversely, beta 2 adrenergic receptor signaling is anti-apoptotic and cardioprotective (Zhang et al., 2010). Interestingly, general blockade of beta adrenergic receptor signaling by propanolol in cardiac pressure overload actually induces cell cycle gene expression and increases the number of ki-67 proliferating cardiac myocytes primarily through the beta 2 receptor pathway (Musumeci et al., 2011).
Catecholamines can stimulate proliferation in endogenous CPC through beta 2 adrenergic receptor signaling which is the more highly expressed beta adrenergic receptor on these cells (Ellison et al., 2007). Similarly to cardiac myocytes, stimulation of beta 1 adrenergic receptor can induce CPC apoptosis (Khan et al., 2013). Remarkably, a higher number of isolated CPC has been associated with patients on beta blocker therapy (Gambini et al., 2012). Beta adrenergic signaling manipulation may also alter peripheral stem cell activity. The beta 1 specific adrenergic receptor blocker, nebivolol, can increase EPC number after myocardial infarction (Sorrentino et al., 2011). Clenbuterol, a beta 2 receptor agonist, along with the chemokine GCSF, augments peripheral blood CD34+ cells after myocardial infarction (Tanaka et al., 2013). Research is scarce on the beta adrenergic receptor signaling role in endogenous stem cell differentiation. As activation of this pathway can improve cardiac differentiation in ESC, it may be interesting in future studies to examine CPC and peripheral stem cell differentiation after manipulation of this pathway (Yan et al., 2011).
Clearly manipulation of the beta adrenergic receptor pathway may improve endogenous cardiac regeneration. Stimulating the beta 2 receptor could likely reduce cardiac myocytes apoptosis and improve the local and peripheral endogenous stem cell reservoir. It is likely that treatment with a beta 1 receptor specific blocker and a beta 2 specific agonist may provide a balance in cardiac therapy as recently demonstrated (Sun et al., 2014).
Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers
The renin/angiotensin aldosterone system (RAAS) is altered in cardiovascular diseases. In heart failure and after a myocardial infarction, drugs (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor angatonists) which block this pathway are recommended to relax blood vessels, thereby reducing blood pressure (Mentz et al., 2013). These drugs may aid in reducing apoptosis of cardiac myocytes as well. Angiotensin II signaling can increase apoptosis of cardiac myocytes (Kajstura et al., 1997; Xu et al., 2010). Conversely, the benefits of these drugs are unclear for stem cells. For example, one report described that the activation of angiotensin like-1 receptor after myocardial infarction increased the accumulation of vascular stem cells, while another article found instead that blockade of the signaling increases the number of EPC (Jung et al., 2012; Li et al., 2012). Opposing results also exist on the angiogenic properties of EPC in the presence of RAAS signaling (Thum et al., 2011; Durik et al., 2012). The RAAS may actually be beneficial for other stem cell types; improving cardiac differentiation of ESC and MSC and rendering MSC more apoptotic resistant and amplifying their growth factor expression (Durik et al., 2012; Wu et al., 2013; Liu et al., 2015). Little has been investigated on the RAAS and CPC. The only article published to date identifies a specific angiotensin 1 receptor expressing CPC population that is senescent with impaired growth and an increased susceptibility to apoptosis (D'Amario et al., 2011). Overall, the use of drugs antagonizing the RAAS are beneficial toward cardiac function and cardiac myocyte survival, but their use in stem cell mediated regeneration requires a further, more detailed investigation.
Statins are cholesterol lowering drugs and have also been associated with having anti-inflammatory and anti-thrombotic effects (Angeli et al., 2012). Statin treatment has been described to block apoptosis of cardiac myocytes and can elevate the number of proliferating cardiac myocytes after a myocardial infarct (Ito et al., 2004; Suzuki et al., 2009; Tang et al., 2011; Zhang et al., 2012). Statins also have positive effects on endogenous stem cell populations. Progenitor cells in the heart are elevated after statin treatment and myocardial infarction (Suzuki et al., 2009). The amplification potential of CPC is significantly higher from patients on statins (Gambini et al., 2012). Bone marrow stem cells and EPC are also positively regulated by statins. Elevated number, mobilization, proliferation, improved differentiation capacity, and increases in survival have all been described in peripheral stem cell populations after statin treatment (Erbs et al., 2011; Shaw et al., 2011; Cai et al., 2013; Cohen et al., 2013). Taken all together, statin therapy appears to enhance endogenous cardiac repair pathways.
Additional Approaches
A few novel approaches have been described in recent years to improve endogenous stem cell mediated cardiac regeneration. A unique idea proposed was to find a method to trap the circulating stem cells to the tissue where their action is required. Baumer et al. generated a bi-functional fusion protein that binds damaged vessels and CD133+ progenitor cells (Baumer et al., 2012). They were able to demonstrate that this molecule could improve progenitor cell adhesion thereby increasing capillary density and improving cardiac function. Tetravalent antibodies have also been employed for the same goal. These antibodies were generated to target an epitope on apoptotic cardiac myocytes, CD34, CD133, and c-kit cells (Malecki et al., 2013). This approach significantly improved the recruitment and retention of the various stem cell populations to the damaged myocardium.
As described above, stem cell populations provide trophic factors to the damaged myocardium. Due to this idea, exosomes have been exploited as a possible means to improve cardiac regeneration. In fact, ESC exosome delivery after a myocardial infarct improved overall cardiac function, increased capillary density and proliferating cardiac myocytes and CPC and decreased cardiac myocyte apoptosis (Khan et al., 2015). This suggests a unique strategy to improve endogenous cardiac repair. Future studies will determine if exosomes from other stem cells types, such as MSC which produce a large number of paracrine signals, can enhance regeneration even more.
In summary, the heart has some capacity to regenerate in response to a large insult such as a myocardial infarct, though this process needs to be amplified to repair the tissue. The endogenous regeneration requires an orchestrated participation from various cell types including cardiac myocytes and local and peripheral stem cells. It is naïve to think that only one cell type can participate in this regenerative process and may actually limit therapeutic opportunities.
As discussed in this review, known pharmacological therapies may alter endogenous cardiac regeneration. Future studies are required to expand on this topic to identify treatments that will strike a balance between the drug's primary function and ability to aid or inhibit cardiac regeneration. For example, it may be beneficial to refine the treatments so that they target only specific pathways. A good example of this is in the use of beta blockers. Physicians could choose to treat patients with a beta 1 specific adrenergic blocker, as opposed to a non-specific beta blocker, in combination with a beta 2 specific adrenergic agonist accommodating blockade of the deleterious beta adrenergic signaling (beta 1) and amplifying regenerative downstream effects (beta 2). Statins also appear to be candidates that aid in endogenous cardiac regeneration. Further studies will need to validate this and may identify the mechanisms in which statins can alter endogenous cells, potentially leading to more focused regenerative therapeutic targets. The inhibitory repair effects of drugs such as aspirin may be taken into account in determining a patient's drug regimen.
Refining current pharmacological therapies to enhance endogenous cardiac regeneration has economic and practical benefits for treatment. These drugs are already in current use in clinical practice. As well, generic, low-cost versions of these drugs are available; statin treatment may cost as little as $4 dollars per month (Lazar et al., 2011). Cell and gene therapy approaches are much more expensive and still require approval from regulatory agencies. The costs of preparation and processing of these drugs under good manufacturing procedures is very high. The first gene therapy drug on the market, although for a genetic disease, costs more than $40,000 per vial (Burger and Hirschler, 2014). Clinical administration and multiple treatments augment the price for this type of therapy even more. However, if these therapies can eventually to be proven to heal the heart, then the cost-benefit may be worth the initial price.
To truly improve endogenous cardiac regeneration, the field needs to open itself to the possibility that therapy includes more participants. A multidimensional approach will likely ameliorate the overall repair process, resulting in a more complete regeneration. This is already evident in studies combining both cell and gene therapy where a greater cardiac repair is reported (Schenk et al., 2007; Huang et al., 2014; Ong et al., 2014). One can foresee a multi-faceted treatment plan for patients including pharmacological approaches and cell and gene therapy. This perspective has the ability to translate into other fields of regenerative medicine where endogenous healing may exist, including the central nervous system, diabetes, or bone and cartilage damage.
This work was supported by a Marie Curie Actions—International Incoming Fellowship, Heart Betas - 2013 - N° 329434. Figures were generated with aid of Servier Medical Art.
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Keywords: cell therapy, cardiac progenitor cells, regeneration, gene therapy, stem cells, beta blockers, statins
Citation: Finan A and Richard S (2015) Stimulating endogenous cardiac repair. Front. Cell Dev. Biol. 3:57. doi: 10.3389/fcell.2015.00057
Received: 24 May 2015; Accepted: 08 September 2015;
Published: 29 September 2015.
Cedric Viero, Saarland University Medical Faculty, Germany
Tomo Saric, University of Cologne, Germany
Johannes Boltze, Fraunhofer-Society, Germany
Copyright © 2015 Finan and Richard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sylvain Richard, Centre National de la Recherche Scientifique United Medical Resource 9214, Institut National de la Santé et de la Recherche Médicale U1046, Physiology and Experimental Medicine of the Heart and Muscles, University of Montpellier, CHU Arnaud de Villeneuve, 371 Avenue de Doyen Gaston Giraud, 34295 Montpellier, France, sylvain.richard@inserm.fr


Based on our tracking, as well as input from our referring physicians and our clinical consultant, the initial panel to order for Lyme disease is the Complete Lyme Panel.
The Complete Lyme Panel includes the IFA, Western Blots and PCR. The IFA (Immunofluorescent Assay) is a screening test for antibodies against Borrelia burgdorferi, the causative agent of Lyme disease. The Western Blot tests determine the specific type of anti-B. burgdorferi antibodies an individual makes. The PCR tests detect B. burgdorferi-specific DNAs.
Note: If a patient's Western Blot is positive by either IgM or IgG and has only bands 31kDa and 41kDa, there is a chance that it is a false positive due to presence of antibodies to viruses or other spirochetes. Therefore, confirmation of band 31kDa is recommended – Test 488- 31kDa Epitope** for IgM and Test 489 – 31kDa Epitope** for IgG. Addition of this test improves specificity to greater than 97%.
The follow-up test for Lyme disease, if the initial panel tests are negative, is the 875 – Lyme Dot Blot and PCR Panel**. This panel looks for pieces of the bacteria in urine as well as DNA of B. burgdorferi in the urine. Most physicians use an antibiotic challenge to make the test more sensitive. The antibiotic protocol, as well as the general instructions can be found in the urine collection kit available from the laboratory.
We also offer tests for the common other tick-borne pathogens such as Babesia, Human Granulocytic Anaplasma (HGA), Human Monocytic Ehrlichia (HME), Bartonella and Rickettsia. These other tick- borne diseases are seen in approximately 20% of the patients with Lyme disease. The typical first tests to order for the other tick-borne diseases are IFA antibody tests, dependent on the region you live or have traveled in.
The CD57** test and Chlamydophila pneumoniae IgG** and IgA** ELISA tests are also available as part of the testing menu, though not Lyme specific. The CD57 test measures CD57 killer cells which can be very low in patients with chronic diseases. C. pneumoniae can cause acute respiratory disease, but it can persist in patients with chronic respiratory conditions and cardiovascular disease.
Test collection kits are available with shipping materials at no charge from IGeneX, Inc. – Call (800) 832-3200 or send an e-mail to customerservice@igenex.com. Please include your name, complete mailing address and tests to be ordered.


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Q: If I post a form which has an element named "element1" and do not specify a value in a markup, does it post empty string or null? an input text element posts an empty string
I am wondering about a form tag which has the name "form1" and no assigned value.
by null I mean "not set".

A: It'll be an empty string. . . .

A: it depends on the particular element type.
You have to ask a question of far better quality to get certain answer.
I see no point in mentioning HTTP headers here though.

A: It posts an empty string (if that's relevant to the input type).  You can't post a null because HTTP doesn't have a native representation for the concept.  (You can post, for example, a JSON string that decodes to a null, but that's not the same thing.)
It's possible that what you meant by "posting a null" is posting a set of form key:value pairs that has no key corresponding to the element in question.  That's what happens if you disable the element; if a text input, for example, is not disabled and has no value set, a key:value pair gets posted for it where the value is an empty string.

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HOW MUCH WILL IT COST? - CLUB MEMBERSHIP IS $22 PER MONTH WITH FREE SHIPPING INSIDE THE US. (ADDITIONAL $20 SHIPPING FOR MEMBERS OUTSIDE OF THE US). THERE IS NO COMMITMENT. YOU MAY CANCEL YOUR MEMBERSHIP OR CHANGE YOUR SHIRT SIZE AT ANY TIME.
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In der Liste der Bodendenkmale in Borgdorf-Seedorf sind die Bodendenkmale der Gemeinde Borgdorf-Seedorf nach dem Stand der Bodendenkmalliste des Archäologischen Landesamts Schleswig-Holstein von 2016 aufgelistet.

Weblinks
 Denkmalliste unbeweglicher archäologischer Kulturdenkmale im Zuständigkeitsbereich des Archäologischen Landesamtes Schleswig-Holstein (ALSH) (PDF; 32 MB)
 Archäologie-Atlas SH

Borgdorf Seedorf
Bodendenkmale
!Borgdorf Seedorf

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