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New Chronic Fatigue Syndrome (ME/CFS) Research Center at Harvard Fulfills Crucial Need - Health Rising
New Chronic Fatigue Syndrome (ME/CFS) Research Center at Harvard Fulfills Crucial Need
by Cort Johnson | Jul 8, 2018 | Homepage, Research | 44 comments
The new Harvard research center will focus on a crucial part of ME/CFS – the muscles
In May the Open Medicine Foundation announced they'd committed a major chunk of change – $1.8 million – to fund an ME/CFS Collaborative Research Center at Harvard Medical School affiliated hospitals. With the addition of the Harvard Center, chronic fatigue syndrome (ME/CFS) research centers are now found at two of the top four medical research universities in the U.S. (Harvard #1, Stanford #3). (With Peter Rowe at Johns Hopkins and Ian Lipkin at Columbia we have active research efforts/research centers in four of the top eleven medical research universities.)
The advent of a new research center at Harvard, of all places, further demonstrates Ron Davis's reach at the top universities in the country. The new center will be lead by OMF Scientific Advisory Board members Ronald G. Tompkins, MD, ScD, and Wenzhong Xiao, PhD. Both have been involved in Davis's ME/CFS work from the beginning and both are longtime collaborators.
A Focus on Muscles
For the time ever in chronic fatigue syndrome (ME/CFS) a concentrated effort to assess the molecular dynamics of what must be a core part of ME/CFS – the muscles – is underway. Ron Davis and other researchers are collecting mountains of data on the immune cells in the blood, but few researchers have assessed where the rubber meets the road with regards to exercise problems in ME/CFS. With Workwell's two day exercise and David Systrom's invasive exercise studies suggesting that profound problems exist with the delivery and utilization of oxygen at the muscle level this muscle study fulfills a crucial need in ME/CFS research and couldn't have come at a better time. It'll be fascinating to see how the blood and muscle results intertwine to tell us more about ME/CFS.
The New center will also establish a Clinical Trials Network that will utilize the facilities at Mass General Hospital to provide a foundation for the multi-center clinical studies we all hope will at some point break the back on this disease. Given the difficulties getting clinical trials underway in this disease nowhere is an effective and efficient clinical trials infrastructure more needed.
Extraordinary Research Team
Tompkins lead one of the biggest research efforts ever funded by the NIH
Not surprisingly given their address – Harvard – the two researchers leading the new Harvard ME/CFS Collaborative Center have extraordinary resumes.
Ron Tompkins is Professor of Surgery at the Harvard Medical School and the Chief of Trauma, Burns and Surgical Critical Care Service at Massachusetts General Hospital. He's also the founding director of the Center for Surgery, Science and Bioengineering and the Center for Engineering and Medicine. Tompkins was the lead investigator of an NIH "Glue" grant on Inflammation and Host Responses to Injury. The massive grant – the 10th largest extramural grant ever awarded by the NIH- lasted an incredible 13 years. Tompkin's has published more than 450 scientific papers.
Wengzhong Xiao has created many new data mining techniques
Wenzhong Xiao is the director of the Immuno-Metabolic Computational Center at Mass General Hospital and is an Asst. Professor of Surgery at Harvard Medical School. His bio states he is "internationally recognized in the field of Computational Genomics in Surgery and Medicine". Xiao directed the computational arm of Tompkin's massive Glue Grant study. A former study of Ron Davis's, Xiao's bio states he's collaborated with Davis to create "new bioinformatic and statistical tools for data analysis". Xiao also directs the Computational Genomics Lab at Davis's Stanford Genome Technology Center.
We're clearly lucky to have two such distinguished researchers working on chronic fatigue syndrome (ME/CFS).
The Glue Grant Project
The massive study which utilized 22 academic centers and involved dozens of researchers used (and developed) cutting edge molecular biology techniques to attempt to learn how inflammation – a protective process when kept under control – can spin out of control and cause immense damage. It's a central question – why one person is able to recover from a serious injury while another dies of inflammation (sepsis) is not so different from the question of why ME/CFS patients remain ill.
It's an important and long unanswered question. Despite billions of dollars and over 100 clinical trials, not a single drug has been produced that can successfully treat sepsis. Tompkins, Xiao, Ron Davis and others took a deep dive into molecular biology in an attempt to understand it.
The Glue Grant project proved to be a fertile ground of creativity. It pioneered a multi-systemic approach to severe trauma and burn patients which involved the integration of large-scale cellular and physiologic, proteomic, genomic and gene expression data. The massive amounts of data (petabytes – millions of gigabytes) obtained required the development of new analytic procedures by Wenzhong Xiao and his computational team. Another group of researchers spread across multiple laboratories developed experimental models of tissue injury, blood loss, and endotoxemia. Another group developed new ways to assess biological data including new microarrays which contained >6.9 million features. In all the new techniques pioneered by the team over the course of the study were published in 19 papers.
The Glue Grant project transformed how the medical profession views trauma
The Glue Grant ended up transforming how the medical profession views trauma. By 2015 the medical profession's paradigm of sepsis – that a deficient initial systemic inflammatory response which left behind unresolved infections/ damaged cells and then created problems when a later anti-inflammatory response kicked in- was overturned. Plus the mouse model investigators had relied on for decades to understand sepsis was shown to be almost completely faulty. A central conclusion of the Glue Grant project was that to understand sepsis in humans you're going to have to study humans – which is just what this project did.
The criteria for entry into the trauma study were stark; patients had to experience "blunt trauma", display significant metabolic alterations (acidosis) and require a blood transfusion to treat severe anemia because of blood loss. To ensure that the participants received a standardized level of optimal care, the study mostly took patients from four elite trauma centers in the U.S. By 2015 complete data from over 2,800 critically injured or burned patients had been included.
In 2015 Tompkins produced a review article describing one aspect of the project called "Genomics of Injury: The Glue Grant Experience". In it,Tompkins stated that he believed the trauma and burn findings would apply to severe infection as well. Glue grant studies indicated that generating an inflammatory response and flu-like symptoms in healthy controls using a single dose of an endotoxin (bacterial toxin) replicated almost 50% of the gene expression found in severe burns and trauma. Given that that was a mild hit to the immune system, it was no surprise to find that Tompkins called the gene expression response in sepsis, ARDS (acute respiratory distress syndrome) and infections "almost identical" to that seen in the trauma patients.
Takeaways from the project included the occurrence of a "genomic storm" which altered the expression of about 80% of the patients' white blood cell genes. As probably occurs in sudden onset ME/CFS patients, the vast majority of the gene changes occur in the first 24 hours. During that period the gene expression of cells associated with our innate immune system – the rapid response arm of the immune system – dramatically increased. Meanwhile the gene expression of cells associated with the adaptive immune response such as T and B-cells dramatically decreased – probably to avoid triggering an autoimmune response to the many new molecules found in the blood.
In a huge surprise, the suspected reason for the decline into sepsis and often death – a cytokine storm – was not present. Even with the massive and unprecedented changes in gene expression seen in these patients' white blood cells, the cytokine levels of the recovering vs. declining patients were almost indistinguishable from each other. Cytokines were not driving the illness process.
Most of the gene expression in the two patient cohorts (recovered vs. still ill) were similar as well, but major differences did show up, interestingly, not in the hugely up regulated innate immune genes but in the down regulated adaptive immune genes. Adaptive immune gene expression suppression (HLA-DQ, HLA-DA; interferon genes IFIT 1,2,3,5) was much more dramatic in the still ill patients. About half of the overly down regulated genes were downstream of interferon – a result that no one suspected – but which has created new opportunities for treatment.
In another surprise, no late anti-inflammatory response showed up. Instead, the changes in gene expression associated with poor recoveries began very early and were sustained throughout the study period, suggesting that, as is suspected with ME/CFS and FM, people who failed to recover from the trauma were in some way primed to stay sick once it occurred.
It's hard not to think that a touch of serendipity has struck ME/CFS. Whitney Dafoe's severe illness brought his father Ron Davis into the picture and, in turn, Davis brought in Ron Tompkins and Wenzhong Xiao – two researchers who've spent more than a decade studying how inflammation – long believed to be a key part of ME/CFS – can turn into chronic illness.
The Ron Tompkins Interview
After hearing that a Harvard ME/CFS center might be in the works, I spoke to Tompkins at the Montreal ME/CFS Conference. He was excited about the possibility of running an ME/CFS research center, and in particular, having one at Harvard – a presence that can only boost the prestige of this field.
After the Center was announced, I asked Tompkins questions that were related mostly to a recent paper he had co-authored which described the systemic metabolic and mitochondrial changes that occurred after burns.
In one study you found that burn activated the mTORC1 protein complex and hypoxia-inducible factor (HIF)-1α. In parallel with activation of these two factors came all sorts of mitochondrial issues including morphological alterations (i.e., enlargement, partial loss of cristae structure) and impairment of the respiratory supercomplex. Are these the kind of things you'll be looking for in your biopsy studies?
The new research center will examine the mitochondria in the muscles of ME/CFS patients to see if the triggering event altered them.
Burn injury and massive blunt trauma are very severe forms of stress that require a human to respond. Serious viral or other infections are other forms of severe stress. Most patients ultimately recover to a condition that is near to their normal homeostatic state. Some patients do not ever make it back to that same "normal" condition. We do not understand why this happens. The abnormalities mentioned above regarding mTORC protein complex, HIF activation and mitochondrial abnormalities are likely also seen in ME/CFS. There are differences, however, and we need to better understand those differences.
We will be evaluating these and many other ways that mitochondria respond to severe stress but might not recover completely after that initial stress resolves and what persistent abnormalities might be found in ME/CFS.
The 2016 Lancet paper you worked on demonstrated that a metabolic shift occurs after severe burns which affects the entire body – not just the burned area. It's as if this trauma – which you note produces an almost unparalleled stress response – resets how the body functions for years. One of the things believed to happen is that the muscles become a nitrogen source for the rest of the body. Some studies, if I remember correctly, suggest that problems utilizing fats for aerobic energy production might be similar to the process occurring in ME/CFS. If that process is occurring, would you be able to tell that from your studies?
Serious stress from massive blunt trauma and serious burns results in severe inflammation that places patients in a new steady-state. Immediately after the injury, the inflammation causes phosphorylation of the enzyme pyruvate dehydrogenase and impairs its function and that of citrate synthetase. This blocks three carbon molecules from entering the TCA cycle. This impairs ATP generation from the "burning of glucose" in the peripheral tissues (e.g. skeletal muscle and skin). Simultaneously, peripheral triglyceride is broken down and fatty acid flux increases by many fold. Peripheral tissues dramatically prefer to "burn" or oxidize fats in order to generate ATP – a switch to beta oxidation. Elements of these same effects are seen in ME/CFS, but we need to understand the extent and relevance of these well-known phenomena.
In both sepsis and burn a metabolic shift from aerobic energy production in the mitochondria to ATP synthesis by anaerobic glycolysis occurs. The strange thing is that it occurs in the presence of abundant oxygen. This process, known as the Warburg effect or aerobic glycolysis, can be induced by inflammation. Do we know why the body would at times prefer a less efficient, less effective and more toxic way to generate energy (glycolysis) when a more efficient process (oxidative phosphorylation) is available?
Tompkins suggested that uncovering the processes occurring in ME/CFS could help our understanding of other poorly understood conditions
This is a very interesting point. I can best explain it by teleological arguments. I'd be happy to discuss with you when we next meet. It's more of a conversation. The points you are making are extremely insightful and I would hope to provide multiple publications to begin to explain this very interesting story to follow.
This process is initiated by a master transcription factor called hypoxia-inducible factor (HIF)-1α which upregulates the activity of genes involved in glycolysis (glucose transporter-1 (Glut1) and pyruvate dehydrogenase kinase-1 (PDK1) genes. Could a similar process be occurring in ME/CFS? Will you be looking for upregulation of these genes in your studies? Or is it more likely that the shift to glycolysis in ME/CFS is occurring because of low oxygen levels?
Yes. The HIF process might not be the only mechanism, but we need to start there. The good news is that this is a general and very important process, so that understanding how this works and how to modulate it is very important, not only for ME/CFS, but also for other important diseases and disorders. This level of importance can make progress in ME/CFS move forward faster as its mechanisms are likely shared by many other very poorly understood conditions. These responses do not necessarily require tissue hypoxia.
Some studies suggest that problems with the blood vessels could result in reduced oxygen or hypoxic conditions in the muscles in ME/CFS patients. That, in turn, would lead to a reliance on glycolysis, reduced energy and increased levels of lactate. If the muscles are getting less oxygen in ME/CFS, would this show up in your muscle studies?
This is a very complex matter. There are no appropriate data to actually understand the oxygen tension in skeletal muscle in ME/CFS, but there is a great deal of presumption. Actual tissue hypoxia requires a great deal more direct evaluation before I can respond to your questions appropriately. I am quite familiar with hypovolemic conditions after serious injury and I am aware of the reduced blood volumes in ME/CFS but I am uncomfortable making any predictions of fact regarding ME/CFS until the condition is properly determined without ambiguity.
With regards to establishing an ME/CFS clinical trials network, how can the Harvard Center help with that? What kind of resources does it bring to bear? Would this network begin by testing substances that Ron Davis's work at Stanford suggests might be useful?
The new Center aims to support large, rigorously produced multi-center clinical trials.
The Harvard Center intends to support systematic multi-center study groups who agree upon definitions, allow audits of their investigational infrastructure, and comply with terms and conditions agreed upon by the consortium. So many clinical studies to date in ME/CFS are single site studies either with or without confirmation with studies done in other sites. Large-scale consortium results add an additional dimension to the relevance of the conclusions of interventional or observational studies. This is true in any field, not just ME/CFS. It is harder and more expensive, but required to move a field forward with understanding.
The Harvard Center is fully open to any investigators wishing to participate. We would hope to eventually be funded at a level to accomplish this condition. We intend to collaborate with the Stanford ME/CFS Collaborative Center and take forward those promising tools and techniques developed by Ron Davis and his colleagues. We also intend to provide patient tissues and materials that will propel studies at the Stanford ME/CFS Collaborative Center. We also intend to collaborate with the three NIH funded ME/CFS Collaborative Centers in a similar manner as well as the expected new Collaborative Center in Canada.
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Aidan on July 8, 2018 at 7:40 am
I mentioned to Ron Davis Team in a message we need Dr. Rodney Graham onboard from the Hypermobility Unit in London he knows more about connective tissue research than anyone out there & also where Funding
should be going into he is the best in Ehlers Danlos Syndrome on the globe I am shocked he is not part of these Teams & not getting Funding from them now…This Harvard Team should also reach out to him as well
he would know what needs to be done to possibly find answers 'issues with tissues' 100% involved it also explains PEM involvement…
Cort Johnson on July 8, 2018 at 8:05 pm
I agree that EDS is a critical factor for a subset of patients. I would caution, though, in assuming that Ron and his team can cover everything in this disease. The team is only so big, there is only so much money, and there are only so many hours in the day.
From what I can tell Davis is focused on uncovering the molecular roots of ME/CFS; those roots should, I would guess, uncover disturbed pathways which are associated with connective tissue problems; i.e. EDS.
David on July 8, 2018 at 7:54 am
Sounds like a long road. I wonder are we looking at decades rather than years
Cort? Timelines like 5 years, 10 years seem reasonable to find treatments but beyond that it will be too late for many. What are your thought Cort? I'm talking about treatments that can keep us out of bed and allow us to live to some degree, not a cure.
perrier on July 8, 2018 at 8:44 am
Your points are well taken. After reading the article, I also feel that we are looking at decades and decades.
I'm starting to feel that it may be like in MS and RA, where there has been volumes of research and folks still suffer.
I'm very discouraged.
For the bed bound and severely ill, this is all too hard.
Any news on the metabolic trap experiment with Dr Phair?
Cort Johnson on July 8, 2018 at 9:41 am
The fact that Ron Davis would commit money to a clinical trials network suggests to me that there's a good chance he will use that network; i.e. find treatments to test. I am also encouraged by Nancy Klimas's work and the idea that she has a model that explains me/Cfs, data that the model was built on and a putative treatment plan. There's also Cortene and the Rituximab sub-set which we will shortly find out about. Mestinon is another interesting which David Systrom is finding very helpful in ME/CFS. I think there's a good chance that something will show up which will help in the next 5 years. It may not be a new drug but a new way of looking at any CFS that uses repurposed drugs.
If we can get ME/CFS 30% better that will provide a lot of relief and take a lot of people out of danger.
perrier on July 8, 2018 at 11:23 am
Dear Core
Dr Davis is heaven sent. I trust his judgement implicitly. His motivations are completely unselfish.
Thank you for the reminders of the other possible routes for help.
Even 5 more years for the bed bound is too long, however. The problem is that there is no med for the flu feeling, toxic feeling, and the crippling malaise, except to lie still and not move.
Our family member who is very ill and bed bound says the preference would be imprisonment because at least prisoners have 'yard,' a library, and can do exercises.
I am praying that the metabolic trap thesis proves to be helpful.
I do hope something turns up soon.
I really think that if we can come up with something that is just 20-30% effective to start with it will be very helpful to those who don't see how they're going make it. Davis has large set of drugs to test against his nanoneedle. If he can find just one that really moves the needle (pun intended) it would make a huge difference.
dejurgen on July 12, 2018 at 2:35 am
"I really think that if we can come up with something that is just 20-30% effective to start with…"
What I am surprised at is that the effect of long term IV saline is nowhere studied in this regard. It has shown promise before. It also has shown several times to potentially disrupt studies, like the rituximab one. The study failed. However, both rituximab (given as a medication via IV saline if I get it correct) and the IV saline "placebo" yielded good results. I'll copy part of a former post I made here:
https://www.healthrising.org/blog/2017/04/15/saline-pots-chronic-fatigue-syndrome/
"At some point 50 of the participants reported no need for further infusions, except during times of stress, within six months of starting the infusions. "
"So how did the authors believe that IV infusions every ten days or so which provided symptom relief for about three days translate into long-term relief? They didn't know, but their best idea was that IV infusions gave the POTS patients a window to increase their activity levels and relieve the effects of deconditioning that often come with the disease. Ultimately, many didn't feel the need to have more IV infusions at all."
=> THE PLACEBO MAY NOT BE THE PLACEBO BUT (part of) THE WORKING INGREDIENT!
=> Few research is done on long term effect of regular IV saline, so doses and interval in the few trials might have been far less than optimal. Rituximab and Cyclophosphamide chemotherapy may provide better doses and intervals by chance.
=> If this could be true, optimal dosed IV saline may be cheaper, safer and would need no long test and approval faze.
A new idea upon information I found might help understand how IV saline *could work* is hypoxia inflammation of a large part of the digestive tract. I wrote a comment on Merida's observation in https://www.healthrising.org/blog/2018/06/27/neuffer-hospital-fears-chronic-fatigue-fibromyalgia-life/
Some form/variant of hypoxia is believed by many to be common in ME. Large parts of the digestive tract are far more vulnerable to hypoxia then "critical" parts like the brain. Or better said the digestive tract takes a big portion of the hypoxia to save the brain and liver. Bowel inflammation is very often said to lead to , amongst others, poor cardiac output and reduced lung function. That in term is a good recipe for increased vulnerability to hypoxia… …with in turn can strengthen inflammation and hypoxia in the rest of the digestive tract and the whole body. That's a vicious circle.
Regular saline injections *could* for some patients brake this circle by at least providing enough blood flow to "service" non-critical functions such as digestion. It may also dilute pro inflammatory / pro problematic chemicals in the blood and it does increase hydration and NaCl availability that can increase stomach acid production if it is insufficient. In some cases that *might* significantly boost digestion and lead to a slow "auto-improvement" of digestive tract health.
I hope they both above look into seeing if there are connections to (SPS) GAD-65 Antibodies in blood & also spinal fluids & the Glycine Antibodies of (PERM) as well which I am now seeing in some but not sure what percent have these combined with ME/CFS Fibro EDS diagnosis…
Erik on July 8, 2018 at 9:03 am
How ironic.
At Dr Davis's Open Medicine Foundation symposium last year, I told Dr Xiao about "Mold at Ground Zero for CFS"
Showed him my poster made up of documents which prove it.
And explained how the "Big Data" or "We won't know anything about anything until we know everything about everything" philosophy actually subtracted all the evidence to the point that not a single "evidence reason" for the creation of the CFS syndrome remains as "part of the syndrome"
Dr Xiao did not follow up, so this already suggests that he will probably not be doing anything to solve the original CFS evidence base.
Just like all the rest, they intend to "Invent their own CFS" and solve that instead.
Actually I think this group is doing the opposite of inventing chronic fatigue syndrome. They're Gathering hordes of data and seeing what shows up and then creating hypotheses. Both Mark Davis and Ron Davis have said we're in the data gathering phase. That might seem disappointing but it's a heck of a lot better than studying false hypotheses to the bitter end and wasting years doing it.
Erik Johnson on July 8, 2018 at 12:29 pm
There was a time when there was only one "Chronic Fatigue Sydnrome"
It was a small dataset, easy to study.
Now they have so many "CFS's" that they don't even think the syndrome has anything to do with that original one.
As a result, not a single evidential reason for the creation of this syndrome is believed by them to even be part of "CFS"
They don't even know why Cheney and Peterson called the CDC for help.
And more, they don't care.
So I can't say as I care too much for their way of doing research.
They threw the Tahoe outbreak right off the cliff.
I don't think they're trying to prove or disprove reasons at this point. They're just gathering as much data as they can and see what pops out. I imagine the mold subset and other subsets will pop out at some point.
Erik Johnson on July 8, 2018 at 3:14 pm
By disregarding the original mystery that CFS was coined for, their "invention of alternate CFS's" is automatic.
Misha on July 10, 2018 at 5:36 am
Agreed Mold at ground zero and spinal virus are integral to ME CFS root cause studies
Debra on July 8, 2018 at 9:22 am
I want to highlight the idea that these researchers should collaborate with Dr. Graham in England. His research into EDS-H could be deep resource for the Harvard group and the Ron Davis team.
Perhaps this idea should be presented to Dr. Graham as well. If he were to reach out across the pond, busy researchers would notice!
lee kon joo on July 8, 2018 at 9:31 am
Our body controlled major control system. The major control system ordered by brain signals. If all of the major our body control systems inhibited or blocked, we enter many abnormal conditions. We call the many abnormal conditions is CFS/ME. If we cure the CFS/ME, remove the pathogenic source and reactivation of the body control system. Brain signal may electric and can't control with the chemical system(drug). CFS/ME treatment may same the piano tuning, auto tuning, computer virus threat. CFS/ME may instantly FIX with tuning the body electric flow. It needs inspiration and breakthrough. I can do.
Cheryl on July 8, 2018 at 9:32 am
I have Fibromyalgia and Chronic Fatigue diagnosed by Rheumatologist/Pain Doctor since 2008. Just in June 2018 I had 10 vials of blood taken and put in intensive care. I was kept one day, released but not told results of tests or reasons for tests. I have been rushed by ambulance four times for diagnosed Secondary Hypertension diagnosed by Arkansas Heart Hospital. Just on June 19, 2018, once again problems with heart plus have now since 3/12/18 syncope fall down stairs five steps up I incurred concussion with brain damage.
I was in CHI St Vincent Hospital, Little Rock, AR from 3/12/18 -3/19/18 and then sent to CHI St. Vincent Rehabilitation from 3/19/18-3/26/18. There I was through physical, occupational, respiratory, and social rehabilitation under doctor, respiratory therapist, registered nurses, social workers, psychiatrists, dietary regimen, and regimented physical therapy and all-mind/body care 8 hours a day. It seemed since trauma of concussion and diagnosed toxic metabolic encephalopathy by hospital/rehabilitation institutions well my whole life changed.
I now have high blood pressure called Secondary Hypertension which I was told only 5% of world has. I have Bradycardia (Remicade infusions every four weeks) pacemaker put in 12/29/15 when lay so weak just stayed in Baptist Hospital, Little Rock, AR for a week. No high blood pressure but still on oxygen 24/7 until rushed to AR Heart Hospital early June 2018. After potassium and magnesium levels corrected I walked out no use of oxygen except when nap/sleep Oxidation problematical stop breathing and Pulmonary doctor told me to never go to sleep without oxygen…..not even for a short doze.
Pulmonary Dr Hunan Makhoul said I am in real bad shape with 7 autoimmune diseases plus Fibromyalgia, Chronic Fatigue, Toxic Metabolic Encephalopathy, and seven autoimmune diseases are, Sjogrens, Scleroderma, Endometriosis, Vasculitis, Crohns, Colitis, and Diviticulitis. I have HLA-Bh27 marker missing diagnosed by Dr Leonard, Rheumatologist, Little Rock, AR February 1997. I also have Spondylotis diagnosed 2010. Therapy facet joint injections two times 2002…..made me able to teach 24 years. I had to go on Social Security Disability 2008 due to Crohns and Fibromyalgia/Chronic Fatigue. Life is Hospital stays, too tired to have family life, and 10 doctors care always tests, Hospital stays, operations.
Please consider me as patient to do clinical study on; I have been diagnosed with Sepsis 2011. I am 66 years old and all my sicknesses began with Endometriosis…..Over 30 operations to date and two more I'm looking at this month. I will have biopsy of larynx next week tumor in lymph node under left ear for 1 1/2 years. It seems never ending. I need help and I wish to help others. Thank you. Phone 501-425-8099
Issie on July 8, 2018 at 8:55 pm
Your history sounds similar to mine. Please look in to Mast Cell Activation Syndrome (MCAS).Endometriosis has been connected to it.
Also look into mold exposure (CIRS). Some of us have a genetic inability to throw off mold and biotoxins. (Addressing this and Lyme with coinfections has changed my life.)
I had to completely change my diet and do an elimination diet to figure out issues. I find a low lectin, low amylose diet to be helpful. No grains or dairy. If there is a mold/fungal issue – makes sense that it affects the colon. Also makes sense that immune system is affected as so much of our immune system lies in the intestines. I also addressed parasites and bacteria. Seems that is a factor for many. I do feel our immune systems and inflammation are "core" causes.
I have EDS and that is not my "cause". It's a piece of my puzzle.
Bethe Burke on July 8, 2018 at 12:35 pm
hi I am coming up on my 17th year w ME/CFS also have FM.
I live about 1.5-2 hours away from Harvard U. How do/ Can I?
help as a volunteer patient for studies ??
I'm still sick but have issues understanding all the info so
just putting this out there
did put my name into the biobank in past few years..
konijn on July 8, 2018 at 4:33 pm
oh Cheryl,
what you have been through!
I wish I could help you but I can not.
I want to wish you enourmous strenght and hope that they are once able to help you to feel better.
I also once (when I was still able to go to specialists with help -am now long term bedridden) diagnosed with metabolic toxic encephalopathie. But another neurologist said it was not so. I was to ill to go further for more opinions but tryd to look it up on the internet what toxic metabolic encephalophathie ment. The methabolic encephalopathie I found but the toxic not.
Do you know what it means? I was not on any drug or so, so why toxic?
when I read the 5 year plan I was indeed also down because I will live (survive) no more 5 years. And indeed it looks like decades and decades of research as in other deseases but they can do things now, they could not do before (think at the nanoneedle). And there is not enough money also for all redaerchers. It go's way to slow forthe severelly ill who get worse and worse and are just dying. I am also alone and desperate when there is no help. I hope they find something that helps a little bit vrry soon.
But for the young and not so severelly ill patients, ron davis is trying hard to turn every stone around to find the caus(es) and diagnostic tests and treatments.
I just wish I could go to an end stage care unit like for MS patients.
I don't know how they will work the samples that Ron Tompkins needs whether they will get them from the Stanford Center or if they will recruit patients from the Boston area. I imagine we will find out at some point.
Tally on July 8, 2018 at 1:34 pm
I noticed from the link you supplied that Stanford is not actually #4 but tied for #3
I apologize to all Stanford alumni for misrepresenting their actual rank and have corrected it 🙂
Pat S. on July 8, 2018 at 3:35 pm
It does seem that just as hope begins to falter, usually around a birthday or ME/CFS anniversary date, you manage to post something encouraging enough to keep hope alive. I think folks tend to forget sometimes that you are a patient yourself, and yet, you have continued to serve our patient community for decades. I see this as a form of ministry for you and I, for one, am truly grateful. Thank you for all you do Cort.
Thanks Pat! When I see researchers like Tompkins and Xiao get involved I truly get excited. 🙂
hi cort,
when are you going to write about nancy klimas? you promissed it so long.
when is she starting her trial?
The Klimas Trial like so many trials and studies is apparently taking longer than expected to get going. (The Cortene trial was recently delayed for a few months because of manufacturing issues). I thought it would have started by now but apparently it hasn't. As soon as I know more I will let you know. Because Klimas is using the same procedures to create the trial that's she's used in GWS in trials that I believe are underway now, I feel confident that it will occur. I will try to find out the GWS trials.
thank you cort!
Katie Liz on July 8, 2018 at 11:00 pm
How can I get seen in this clinic? Enrolled in a trial? I Iive in a healthcare dessert and cannot get adequate care!
Tuha on July 9, 2018 at 12:58 am
On the end did they move significantly in their sepsis research after years of research and millions of dollars? They didnt find any drug for it but do they understand it better or did they just overturn the previous understanding of sepsis? Could they use it in ME/CFS?
Great to see such a group in ME/CFS research. Hopefully their previous research will help us and lead to a treatement.
I know that the death rate has been cut in half in some centers as a result of the procedures Tompkins required and that we know have a much clearer conception of what happens during sepsis but I don't know if a specific treatment has resulted.
Interestingly or rather horrifyingly the Trump administration is stopping public disclosure of hospital infections which was a great incentive for hospitals to clean up their act and stop the infections that can kill people during sepsis – https://www.usatoday.com/story/news/politics/2018/06/19/feds-oppose-public-reporting-hospital-infections/710682002/
Dana Lauren on July 9, 2018 at 8:06 am
What if you highly suspect you suffer from ME/CFS? Are they asking for volunteers for Trial Studies at this point?
Not that I know of…
Chris Frates on July 9, 2018 at 7:42 pm
I have been lightly following the work of Dr. Jarred Younger at UAB. My understanding is that he is also working on CFS, along with pain studies and inflammation. He was very recently a professor at Stanford. I believe he has been at UAB for 4 years. I never see his name mentioned as a collaborator or otherwise. Does anyone know how his research is going? Is there an issue with him and Stanford? Cort?
Jarred Younger has been doing a great job. He's a very impressive researcher and I have an interview coming up with him shortly. As you know he's running his own Lab at the University of Alabama. He actually was I believe a member of Doctor Montoya's application to host an NH funded Research Center. I think he's doing just fine and we're going to hear a lot from him over the years.
Anthony Ross on July 9, 2018 at 10:05 pm
Hi Cort… thanks again for all you do to keep hope alive for us bed bound folk. I had a muscle biopsy which revealed moderately reduced muscle glycogen- I am wondering based on what we know from current glycolysis findings how this might fit into the Me/cfs picture?
Francis Martin on July 10, 2018 at 6:42 am
This is taken from Fluge and Mella's paper [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]
"We hypothesize that aberrant PDK and SIRT4-mediated inhibition of PDH, and consequent obstruction(s) in central energy metabolism, occurs early during ME/CFS pathogenesis, followed by metabolic adaptations serving to maintain ATP production."
Interesting that PDH/PDK turn up in sepsis as well. Possibly supports the theory that ME/CFS is chronic sepsis.
Xiao presented results from a gene expression study which indicated that ME/CFS most closely resembled sepsis (2017 OMF Community Symposium).
So possibly ME/CFS is chronic sepsis relating to leaky gut?
https://en.wikipedia.org/wiki/Ischemic_colitis may be a potential route to this.
As I described in a far too long comment in this blog ischemic inflammation of a large part of the digestive tract may be common in ME.
"Ischemic colitis is a medical condition in which inflammation and injury of the large intestine result from inadequate blood supply." That's just one of them that can be inflamed. However according to the link it all by itself can:
"most patients are treated supportively and recover fully, while a minority with very severe ischemia may develop sepsis and become critically,[5] sometimes fatally, ill.[6]"
"Those with severe ischemia who develop complications such as sepsis, intestinal gangrene, or bowel perforation" -> one large bowel perforation or many many tiny ones may be considered "a form of leaky gut" IMO; a "half dead" part of the bowel (parts (small or big, few or many) with intestinal gangrene) could be leaky too IMO.
"Most patients make a full recovery; occasionally, after severe ischemia, patients may develop long-term complications such as a stricture[7] or chronic colitis.[8]" -> So not all patients recover yet become chronically ill
I can only imagine if the small bowel, stomach, stomach acid production, pancreatic enzyme production, gal bladder… are affected to some extend as well that outlook becomes even worse. And if that/inflammation/hypoxia in turn hits the lungs/muscles/brain/blood vessels that it becomes highly problematic.
Jack on July 13, 2018 at 2:34 pm
Sometimes the ME/CFS or Fibromyalgia is due to viruses & other pathogens and sometimes it is due to Lyme Disease. I put together tons of evidence here that Lyme can cause pain (Fibromyalgia) & CFS, including exercise intolerance. https://www.facebook.com/jack.dupre.5/posts/1444094105620664
Learner1 on July 19, 2018 at 9:03 am
Thank you for reporting on this, Cort. Though I've seen mention that physical trauma, like an auto accident, can trigger ME/CFS, this is the first place I've seen where there's potentially a scientific basis for how and why this might happen.
Alma on September 29, 2018 at 8:39 am
Hi Cort
I am wondering if you knew from your interview whereabouts the Canadian center will be?
Cort Johnson on September 29, 2018 at 1:37 pm
No idea I'm afraid. I don't think its up yet…
Francis Martin on December 28, 2018 at 3:27 am
Possibly this study will help to fill some of the gaps in our knowledge:
"Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation" by Julia Oh &
Derya Unutmaz et al.
https://www.nature.com/articles/s41385-018-0072-x
Seems like the MAIT cells could be the source of the inflammation signalling which causes the SEPSIS type reaction.
New Harvard Chronic Fatigue Syndrome (ME/CFS) Research Center Fulfills Crucial Need – The York ME Community - […] Link to ME story […]
HealthRising: New Harvard Chronic Fatigue Syndrome (ME/CFS) Research Center Fulfills Crucial Need | Open Medicine Foundation - […] Reprinted with permission from HealthRising. Visit the original article here. […]
Harvard study on muscles – Susan Thompson's Medical Blog - […] https://www.healthrising.org/blog/2018/07/08/new-harvard-chronic-fatigue-syndrome-me-cfs-research-ce… […]


text:
Colleges in Kentucky
Gateway Community and Technical College
Florence, KY, USA
Just across the river from Cincinnati, Gateway Community and Technical College is a 2-year college in northern Kentucky. While most of Gateway's over 30 academic programs are available at its main Urban Metro facility, the college's healthcare and advanced manufacturing programs are both housed in separate campuses. In order to provide support for its LGBTQ+ population, Gateway hosts the Gender & Sexuality Alliance of Gateway student advocacy organization and all campuses feature gender-neutral restrooms. The college is also home to a Cyber Defense team training students in principles of cybersecurity by hosting cyberspace defense competitions throughout the year.
At least 2, but less than 4 academic years
Ashland Community and Technical College
Ashland, KY
Berea, KY
Georgetown College
Georgetown, KY
Morehead State University
Morehead, KY
Northern Kentucky University
Highland Heights, KY
Thomas More University
Crestview Hills, KY
University of Cincinnati-Main Campus
Cincinnati State Technical and Community College

redpajama_set_name: RedPajamaCommonCrawl


GAAR abbreviation stands for general-anti-avoidance rules and it has been introduced in India due to VODAFONE case ruling in favour of this company by the Supreme Court. The new rules will come into effect from 01 April, 2012.
Indian Government is trying to give powers to income tax authorities as implementation of GAAR provides tremendous powers to deny tax benefit to an entity if a transaction has been carried with the sole intention of tax avoidance. Due to powers in the hand of taxmen, now innocents may be harassed by them.
FII & FDI money coming to India through Mauritius route will now become taxable.
The onus lies on the assesse to prove that there is no tax benefit and the transaction is not an avoidance transaction.
To make it easier to understand GAAR; we can say that suppose a person or a company is setting up business in Gulf Country and its clear intention is to claim exemption from capital gains tax, in such a scenario Indian govt has the right to deny the legitimate claim for exemption provided under DTAA as it falls under tax avoidance and Indian govt is trying to plug the loopholes.
2) What are its implications: It empowers officials to deny the tax benefits on transactions or arrangements which do not have any commercial substance or consideration other than achieving tax benefit. It contains a provision allowing the government to retroactively tax overseas deals involving local assets (like Vodafone). It could also be used by the government to target participatory notes (P-Notes).
3) Will P-Notes be targeted: Investments into Indian stock markets through participatory notes might slow after the introduction of GAAR. According to data from market regulator SEBI, P-notes issuance reached Rs 1.83 trillion at the end of February, about 16.4% of total assets under the foreign investor inflow scheme. P-Notes are instruments used by investors or hedge funds that are not registered with the SEBI to invest in Indian securities and they offer the buyer anonymity. The tax would be imposed on the registered financial firm buying the security on behalf of the client, meaning the brokerage would then pass on the taxes to the end investor.
"To avoid tax altogether under GAAR, an investor may now have to prove the P-note was not set up specifically to avoid paying taxes or to prove that the deal has "commercial substance," Edelweiss said.
4) What happens to the Mauritius route: GAAR could give powers to the tax department to deny double taxation treaty benefits to foreign funds based out of tax-havens like Mauritius. India has a Double Taxation Avoidance Agreement with Mauritius. Overseas portfolio investors, routing their investments via countries like Mauritius, currently do not pay any tax on short-term capital gains.
5) What do investors say: The proposed law gives the legal right to the government to go after anyone and it added ambiguity over the taxation. Indian equities will see selling by foreign investors & less money will be coming into India consequently. Investors are very uncomfortable about GAAR in current form. FIIs run global portfolios & some invest just 1% in India. After this they might say its not worth the hassle. The move is bad for Indian economy, bad for Indian corporate, bad for Indian capital markets.


Next up, Back to School! The kids started back 2 weeks ago since they're in year round school. We start earlier and stay later but we like the schedule with the 2 week Oct and May breaks. Gabby is a big time 3rd grader now and my baby Peter is a 1st grader. And I still want to scream NOOOO every time I say that.
Gabby girl is doing great in 3rd grade. Or at least the portion that she's been there after that pesky little walking pneumonia episode. Her teacher is Mrs. Clark and we LOVE her so far. She's very upbeat and fun but also structured and organized. Just right for our little perfectionist (what can I say, she get's it honest!). And this girl is so ready to be a big girl. She's outgrown silly things like princesses, backpacks and children's menus. It's all about Disney Descendants (if you haven't heard of it, Gabby can tell you ALL about it), non cartoon tween shows, messenger bags, and ordering $8 adult food. Where did my little girl go?
Peter on the other hand is not loving 1st grade so far. He has Mrs. Brazzeal and she also seems very organized and structured which is what Peter needs to help him stay on track. But he gets very nervous and stressed every morning and even the night before and always asks not to go. He just told me at the end of last week that he has been crying "a little" every day at school when he starts his work. He thinks that it's too hard and I think that he is afraid to ask his teacher questions. But he came home last Thursday and Friday and said that they were the best days yet and he didn't cry at all. It breaks my heart to know that he's going to school anxious and upset but we're working through it with him slowly and surely and trying to encourage him as much as possible. I think that he'll outgrow it as he gets more confident with what he can do and everything isn't so new.
He was excited to get a desk this year instead of being at a table.
I'm a little behind on the last couple of weeks but better late than never. I think just about everyone knows about our most recent family addition but I'll still document it here for memories sake.
We've been talking about getting another dog for a couple of years but I keep putting the brakes on it because I just wasn't ready for that responsibility again. But I finally gave in and told a very happy family that I was ready. Around 2 years ago we saw a greyhound at a neighborhood block party and loved it. Michael started researching them and convinced me that was the dog for us. They're beautiful, well mannered, don't bark, are crate trained, usually house trained, not a lot of health problems and they only have energy in short spurts. Otherwise they just lay around for the most part. That's our kind of dog!
We started researching where to adopt greyhounds and found a shelter in Springfield. We've been looking at the adoptable dogs for years but again, mommy just wasn't ready. So when I finally gave the all clear we had to fill out an application, have a home inspection/interview process (including personal references) and FINALLY pick out our new dog. Not a quick process but our boy was so worth the wait.
The weekend before school started we drove to Silver Dollar City for one more hoorah and stayed over in Springfield so we could visit the dogs the next day. We were going to see 3 dogs, Judy, Petals and Cher. She also told me that she was getting another dog that week but didn't know the details yet. We had looked at each of the dogs pictures, read their descriptions over and over as well as talked to the shelter director about them. We met Cher on Friday morning before SDC because she was staying in a different home and fell in love. She was very shy and hesitant but so sweet. She had not been a racer so she hadn't been been given the best care. And then we saw our Stan man on Saturday and fell in love with him too. He was so beautiful and easy going and HUGE. She had 10 greyhounds there and he was the biggest one. We talked it over and decided that Stanley would just be a better fit for us and might have an easier transition than Cher. So we loaded him up in the back which was no easy feat for an 80 lb dog that doesn't know how to ride in a car. It was very odd leaving with a dog that we didn't know anything about when we had spent so much time dreaming about the other dogs. But it didn't take us long to fall in love with our big boy. He spent most of the first day in his kennel, wary of us and our crazy kids. But by the second day he was comfortable in his bed sleeping most of the day.
He's raced in 75 races and won 13 of those. His racing name was Country Stanley and his brother, Country Sammy is still racing. The foster home we went through, www.gpamo.com, also adopted out his mom a few years ago and remembered her as a sweet lovable girl. We couldn't find pictures of his mom but he looks exactly like his maternal grandpa and great grandpa. Right down to the white patch on his chest.
Stanley is adjusting to being a house dog quite nicely. He gets up a little early for us and is ready to go at 6:00 every morning. And he's definitely a morning dog. He goes outside then comes in ready to play. So far that's included playing with my bedroom curtains, pillows off the bed and a pair of pants I left out. Not to mention his other favorite pastime of raiding the kids rooms of stuffed animals and pillows. But after he's had his breakfast he retires to his bed for most of the day. He LOVES to eat! He has playful spurts with us outside where he can run. We still need to take him to the dog park to really let him run but it's been a little too warm. He gets hot and gives out very easily. He loves attention and is so gentle with everyone. We took him to the square Friday night and he did so good. He never showed his stress and met lots of new people. The only problems we're having is getting him to walk on tile/wood floors. He does NOT like those and slips and slides everywhere. And he is just about impossible to get in the car. It's a 2 person job so no quick rides to school for this boy. And it's been an interesting adjustment to go from a 3 lb Chihuahua to an 80 lb small horse. Everything is just so big! But that's what we wanted and Michael is so proud to have such a manly dog after having our little girly girl Ellie. Stanley has been a gentle, sweet, loving addition to our family!
One of Stanley's races before he retired. He's the one in front!
This is his "I hear you but I'm not worried about it" look.
Just watching a plane go by.
Peter was doing a little morning "fishing" and caught more than he bargained for.


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text:
As We Saw It – Part 2: Paris Builds Recently built: Louis Vuitton Foundation, Foundation Jérôme Seydoux-Pathé, New Palais de Justice, The Canopy of Les Halles
Posted on September 29, 2018 December 1, 2018 by RickMegh
The four recently completed architectural works that accompany the documentary "Paris Builds" send powerful messages of what is possible to elevate the quality of life in the city.
Gehry's Louis Vuitton Foundation is not only an architectural masterpiece and a new icon in a city where icons abound, but it also brings an example of what is possible to cover urban spaces, an alternative to Buckminster Fuller-like geodesic domes.
Renzo Piano's Foundation Jérôme Seydoux-Pathé is a hidden gem that exemplifies what is possible in a small site surrounded by historic buildings.
Paris' new Palais de Justice, also designed by Renzo Piano, responds to a very complex program – ninety new courtrooms built vertically – while confronting sustainability and the creation of new green spaces on roofs.
Also, the Canopy of Les Halles, designed by architects Patrick Berger and Jacques Anziutti, sensibly responds with daring technology to an urban place crossed daily by tens of thousands of people, in a historic location that Emile Zola called "The Belly of Paris."
The Louis Vuitton Foundation
Commissioned by Bernard Arnault, head of the LVMH luxury brand empire, the complex houses his collection of modern and contemporary art and hosts temporary exhibitions. Built on public land with private funds, it will be given as a gift to the city in 55-years time.
Inserted in the middle of Bois de Boulogne's woodland park, the building is an assemblage of white blocks, so-called "icebergs," clad in panels of fiber-reinforced concrete, surrounded by twelve immense glass "sails" supported by wooden beams. The sails give Fondation Louis Vuitton its transparency and sense of movement while allowing the building to reflect the water, woods and garden, and continually change with the light.
The ground-level entrance hall is designed as an active social space, featuring a restaurant and bookstore. The ample, multi-purpose space directly adjacent to the entrance hall may be used as an auditorium accommodating 350 persons, an exhibition space, or an event venue.
The upper floors accommodate straightforward gallery spaces. Of the 11,000 m2 across which the building spreads, just 3,850 m2 are exhibition rooms. More than 3,600 glass panels and 19,000 concrete panels that form the façade were simulated using mathematical techniques and molded using advanced industrial robots, all automated from the shared 3D model. The new software was developed specifically for sharing and working with the complex design.
The structure of the glass roof allows the building to collect and reuse rainwater and improves its geothermal power. Besides, the Foundation has attained its overall goal to reach HQE (Haute Qualité Environmentale) certification noted as Très Performant. The steps taken to achieve this level of certification could be considered equivalent to LEED Gold.
Scheme by Frank Gehry Courtesy of Frank Gehry Partners
Plan Courtesy of Frank Gehry Partners
Section Courtesy of Frank Gehry Partners
Bernard Arnault and Frank Gehry
Approach view
Dancer on the plaza
The Foundation Jérôme Seydoux-Pathé
The new headquarters of the Fondation Jérôme Seydoux-Pathé, by architects from Renzo Piano Building Workshop, is an unexpected presence, a curved volume glimpsed floating in the middle of a courtyard, anchored on just a few supports. It is complemented by a group of birch trees, a floral island set in the dense mineral context of the city.
This "organic creature" is located in the courtyard of a 19th-century block that includes a complex of historical Hausmann-era buildings. This structure houses the headquarters of the Foundation Jerôme Seydoux-Pathé, a foundation dedicated to preserving the history of the French film company Pathè and to promote cinematography.
The 839 m2 headquarters are located in Paris' 13th arrondissement and their construction has been completed in September 2014. The clever use of the site includes a main entrance on a restored and preserved facade along the Avenue des Gobelins which features sculptures by Auguste Rodin. This stone-made building is not only a historical landmark, but also an icon and symbol for the Gobelins area of Paris.
Section – Courtesy of RPBW
Theater area – Courtesy of RPBW
Offices area – Courtesy of RPBW
Upper floor – Courtesy of RPBW
New Paris Palais de Justice
Since the Middle Ages, Parisian justice has been dispensed from the famous building that surrounds the Sainte-Chapelle on the Île de la Cité. However, over the years an increasing shortage of space has resulted in many good offices having to be located in a multitude of locations spread out over all four corners of the city. The new Paris law courts at the Porte de Clichy will enable the judicial institution's courtrooms and offices to occupy the same building.
The new law courts stand 160 meters high, has an internal area of around 100,000 m2 and accommodates up to 8,000 people per day. The building's facades are fully glazed. On the three blocks of the tower, fine blades extend the glazing beyond the facade, exalting its verticality. The building's primary structure, robust and orthogonal, ensures flexibility over the long term that will be able to accommodate future requirements and any changes in the way the justice system operates.
In developing the scheme, the architects sought to reduce the apparent scale of the building by breaking it down into four volumes of decreasing size.
50 desks within the reception areas minimize visitor waiting time, while three atria ensure that space is filled with natural light. A system of vertical and horizontal circulation routes lead to the 90 courtrooms above. The subsequent three volumes, which contain around ten-story each, include offices and meeting rooms: the second is the domain of the magistrates, the third of the public prosecutor's offices, and the fourth and final volume houses the presiding judges.
The stacked system results in large roof terraces — around a hectare in total — which have been landscaped and planted with trees and other vegetation. From an environmental standpoint, the project employs a range of strategies including the use of natural ventilation, the incorporation of photovoltaic panels on the façade, and the collection of rainwater.
View from lobby
The Canopy of Les Halles
The long-awaited cultural center and metro station created by architects Patrick Berger and Jacques Anziutti on the site of a historic Paris marketplace is now a new urban reality. The design at Les Halles is known as the Canopy due to its enormous umbrella-like glass roof, which comprises 18,000 pieces of glass supported by 7,000 tons of steel.
Construction on the €1bn (US$1.42bn) project, funded by the City of Paris, began ten years ago following several architecture competitions to choose a design popular with both politicians and the public.
The completed Canopy and the center below replaces a deeply unpopular concrete shopping complex – nicknamed 'the hole of Les Halles' – which was built in the place of the market's original 19th-century glass and iron buildings designed by architect Victor Baltard. They were demolished in the 1970s in an act many critics have described as cultural vandalism.
The new center features shops and high-end retailers, some of which are located underground, and these combine with leisure facilities such as a new library, a conservatory for the arts and a hip-hop center, all underneath the 270,000sq ft (25,000 m2) roof – described by Berger as a "translucent envelope".
Explaining the design, Berger said: "The shape, its spaces, and its materialization arise from a confrontation between the state of things and the emergence of new energy to Les Halles. "The Canopy is designed as a substance. The ceramic glass material means that light diffuses in the day and it becomes a chandelier at night. It's also a shelter at an urban scale against the weather, protecting a global space where one can travel at all times and in all seasons. The morphology of the architecture is the result of a balance between the building's program and its dynamic location."
Park facing the Canopy
Canopy – Courtesy of Bernard Lege
View od Saint Eustache from Les Halles – Courtesy of Bernard Lege
View towards the Canopy
architecture Art Canopy design Frank Gehry Les Halles Paris Renzo Piano Rick Meghiddo Ruth Meghiddo sustainability www.archidocu.com www.architectureawareness.com
As We Saw It – Part 1: Parisians Paris
As We Saw It – Part 3: Paris Green Urbanity


"Hairy" exterior is perhaps the defining characteristic of this micro-office by 2hD Architecture Workshop in the UK—the outer facades are entirely clad in natural coco-fiber broom heads.
The details and junctions of the broom heads are largely concealed as to let the broom bristles interlock, providing a continuous and visually diffuse surface. This hides any clue as to what is occurring on the interior—the structure existing merely as an object of intrigue. Nicknamed "Mission Control," the project is an exercise in teleportation, designed to take users from the everyday hustle-and-bustle to another world, one of calm, quiet and focus. The intention was to create an antithesis of a "contemplation space with landscape views and flowing inside-outside space." In contrast, it is an almost monastic cell, removed from physical context and worldly distraction—perfect for tackling a day's worth of tasks. Inside, "Mission Control" is a comfortable, serene space. The interior walls and ceilings are clad with whitewashed plywood and wrapped with sheep's wool insulation, create a healthy, natural feeling environment which is easily heated by body warmth and waste heat computers. A single skylight illuminates the space, and in the middle are nested two back-to-back desks. As the door clunks shut behind you, the box seals itself and the separation is complete.


list GET /activity/users/userKey or all/applications/applicationName Retrieves a list of activities for a specific customer's account and the Admin console application or the Google Drive application. For more information, see the Developer's Guides for administrator and Google Drive activity reports. For more information about the activity report's parameters, see the activity parameters reference.
watch POST /activity/users/userKey or all/applications/applicationName/watch Start receiving notifications for account activities. For more information, see Receiving Push Notifications.
For CustomerUsageReports Resource details, see the resource representation page.
get GET /usage/dates/date Retrieves a report which is a collection of properties and statistics for a specific customer's account. For more information, see the Customers Usage Report Developer's Guide. For more information about the customer report's parameters, see the customers usage parameters reference.
For UserUsageReport Resource details, see the resource representation page.
get GET /usage/users/userKey or all/dates/date Retrieves a report which is a collection of properties and statistics for a set of users with the account. For more information, see the Users Usage Report Developer's Guide. For more information about the customer report's parameters, see the users usage parameters reference.
For EntityUsageReports Resource details, see the resource representation page.
get GET /usage/entityType/entityKey or all/dates/date Retrieves a report which is a collection of properties and statistics for entities used by users within the account. For more information, see the Entities Usage Report Developer's Guide. For more information about the entities report's parameters, see the entities usage parameters reference.


text:
Q: Java: Game of Craps: Exiting a loop then re-entering This is a program that similates the dice game Craps. The rules are if you roll a 7 or 11, you win. If you roll a 2, 3, or 12, you lose. If you roll anything else you get a "point" and are allowed to roll again. If you allot 2 points you win as well.
The trouble I'm having here is with the point system. I dont know how to store the point, then exit the loop and prompt the user to roll again to re enter the loop.
import javax.swing.JOptionPane;

public class DiceGame {

    public static void main(String args[ ]) {

        // declarations

        int dieNumber1,
                dieNumber2,
                point,
                score;

        // initializations

        dieNumber1 = (int)(Math.random( ) * 6 + 1);
        dieNumber2 = (int)(Math.random( ) * 6 + 1);
        score = dieNumber1 + dieNumber2;

        // executable statements

        for (int i = 0; i < 10000; i++)
        {

            System.out.println ("Roll the die");
            System.out.println ("You rolled a " + score);

            if (score == 11 || score == 7)
            {
                System.out.println ("You Win!");
                break;
            }

            if (score == 2 || score == 3 || score == 12)
            {
                System.out.println ("You Lose.");
                break;
            }

            if (score == 4 || score == 5 || score == 6 || score == 8 || score == 9 || score == 10)
            {
                point = 1;
                System.out.println ("You got a point.");
            }

        }

        System.exit(0);

    } // end of the main method

} // end of the class

A: You may want to think explicitly about how your program's flow should run. Namely: each roll has three outcomes: win, loss, and point. When do we want to loop? I assume (your answer may be different) when we want to roll again. When do we want to roll again? I assume (your answer might be different) when the user gets a point. Therefore, the point case should be the outcome in which we loop, and any other outcome should result in not looping.
Note that because we always need to roll before proceeding with any other logic (can't decide on a win/loss/point if we don't roll), we put the rolling logic inside the loop:
So what will our code look like?
import javax.swing.JOptionPane;

public class DiceGame {

    public static void main(String args[ ]) {

        // Initialize some things (omitted)

        while(true) { // NOTE: it's generally good form to use while(true) for a loop that could continue forever, instead of a for-loop with a very high number
            // Roll the dice (omitted)
            if (score == 11 || score == 7)
            {
                System.out.println ("You Win!");
                break; // Game over. Get out of our infinite loop.
            }
            if (score == 2 || score == 3 || score == 12)
            {
                System.out.println ("You Lose.");
                break; // As above
            }
            else // If our score is anything else we must have gotten a point
            {
            point = 1; // Don't break. We want to roll again
            }
        }
    }
}

A: You need to move your initialization inside the loop, wait for some user input to roll again and increase the points if they get a point.
This should give you what you need
import javax.swing.JOptionPane;
import java.util.Scanner;

public class DiceGame {

    public static void main(String args[ ]) {

        // declarations
        int dieNumber1 = 0,
            dieNumber2 = 0,
            point = 0,
            score = 0;

        Scanner scanner = new Scanner(System.in);

        // executable statements
        // Repeat until score is 2 (or break is called)
        while( point < 2 ){

            // initializations
            dieNumber1 = (int)(Math.random( ) * 6 + 1);
            dieNumber2 = (int)(Math.random( ) * 6 + 1);
            score = dieNumber1 + dieNumber2;

            System.out.println ("Roll the die");
            System.out.println ("You rolled a " + score);

            if( score == 11 || score == 7 ){
                System.out.println ("You Win!");
                break;
            }

            if( score == 2 || score == 3 || score == 12 ){
                System.out.println ("You Lose.");
                break;
            }

            if( score == 4 || score == 5 || score == 6 || score == 8 || score == 9 || score == 10 ){
                point = point + 1; // You could use point++ or point += 1 as well

                System.out.println ("You got a point. Total number of points: " + point);

                if( point == 2 ){
                    System.out.println("You Win!");
                }
                else{
                    // Wait until user presses Enter, then roll again
                    System.out.println ("Press Enter to roll again.");
                    scanner.nextLine();
                    scanner.reset();
                }
            }

        }

        System.exit(0);

    } // end of the main method

} // end of the class

redpajama_set_name: RedPajamaStackExchange


Visited Hong Chang Soon, Lee Hong Tae at Assistant Caring Home at 1301 East 13th St. for worship, singing, conversation, etc. Visited Paul Nancarrow at E 29th Nursing Assistant Home for worship, prayer, conversation, etc.
Shared kale bread with 24 people: Kook He Kim, Shin Ja Young, Kim Young Ja, Han Hae Bok, Kim Ok Ryun, Mrs. Rev. Kim (IHSS), Kim Bun Phil, Park Young Sook, Susan Kim, Kim Byung Yeup (IHSS), Oh In Sook, Kim Kwi Nam, Kim Dong Ha, Buena vista people, etc.
VIsited Kim Shin Hyuk, Han Hae Bok, Kim Young Ja at Alice Apt.
Gave ride to the church for Lee Kang Chul from 28th St.
Visited Lim In Ho, Choi Eun Ja in San Lorenzo for worship. Delivered Kalbi (Short-rib, 5lb marinated), Tteokguk (korean traditional rice cake soup) as well as groceries.
Visited Choo Young Kyu, Choo Young Oh at Walnut Creek Kaiser. Shared kale bread with 18 people with Kim Kook Hee and her apartment residents at Alice Apt.
Gave Lee Kang Chul and his daughter ride to 28th St.
Visited Kim Kum Hyun at 28th St.
Visited Alice Apt and shared kale bread with 24 people: Shin Ja Young, Susan Kim, IHSS Lady, Kim Bun Phil, Park Young Sook, Kim Ok Ryun (IHSS), Kim Kwi Nam, Kim Dong Ha, Oh In Sook, etc.
Hayward, San Lorenzo Visited Cho Hye Young at Hayward, San Lorenzo. Visited Lim Im Ho, Choi Eun Ja for worship & grocery shopping help. Choi Eun Ja got in an accident and hurt her left foot ankle.
Visited Choo Young Kyu (87 years old) at Walnut Creek Kaiser with Coo Young Ok, Cho Jae Kak, Cho Yoon Kyung, Lee Ok Bae. Ate lunch together.
Visited Alice Apt, shared kale bread with 18 people: Susan Kim, Helper IHSS, Shin Ja Young, Kim Young Ja (Daughter-in-law), granddaughter, Kim Byung Yup, Kim Kwi Nam, Kim Bun Phil, Park Young Sook, Kim Ok Ryun - helper IHSS, Rev. Mrs. Kim Kook Hee and her apt people.
Hong Chang Soon passed away to heaven (97 years old). She passed away 11 days after communion and worship service.
Jenny Kwon and I went to open an account at Bank of America.
Visited Choo Young Kyu, Choo Young Ok at Walnut Creek Kaiser for worship and praying. Ate lasagna, chicken soup, and kale bread.
Met people at Alice Apt, shared kale bread with 16 people.
Visited Mrs. Oh Eun Soon for worship and shared kale bread with her daughter and son-in-law as well as 24 other people at Market Apartment on 14th St and Mrs. Kim Kook Hee, the previous minister's wife and her apartment people.
Prepared kale bread materials from Berkeley Bowl.
65 people attended OKUM church (attached program) from 10am to 2pm - happy day! 5 members of the Jango team played traditional music, with yoga, singing, quiz games, and exercise. Lunch was so wonderful! In the afternoon around 2:15pm, went to Walnut Creek nursing home to visit and pray together with 6 people, Kwi Im Kim, Jung Woo Nam, Kyung Sook Park, Song Ja Kwak, and Kum Hee Lewis. Everyone was in a great mood together and was happy! Absent congregation members got some food delivered for 16 people. Therefore 66 + 15 = 81 people ate lunch!
Same day shared kale bread with 24 people.
Visited Susan Kim at Marina Nursing Home in Alameda with fruit and food. Met with 5 people: Soon Chan Kim, Jung Ja Jung, In Sook Lee, Hye Young Cho, and Susan Kim.
Visited 1301 E 13th St. Nursing home and had worship with Hong Tae Lee and Marina Hwang. Met Kook Hee Kim and shared kale bread with 24 people.
Met Susan Yoon at Alice Apt to deliver kale bread to Choo Young Ok/Young Kyu to share with them too. Had worship and nice conversations.
Visited Alice Apt to meet Shin Ja Young, Kim Byung Yup, Kim Kwi Nam, Kim Ok Ryun, Mrs. Rev (IHSS), Kim Bun Phil, Park Young Sook, and Kim Shin Youk to have worship individually and share kale bread and stew.
Met people who have lost family. Shim Jum Sook lost her husband, so comforted her. Had lunch with Kook Hee Kim and K.H. Lewis at Alameda. Shared kale bread and prayed together.
Visited Mr. CHoo and his wife Young Ok Choo at nursing home at Pleasant Hill. Gave them kale bread, stew, and pesto sauce with shell pasta.
Shared kale bread with 24 people who live in Bellave Ave, Kook Hee Kim and her residents, and the Korean community center people.
Took Mrs. Choi Eun JA who has wounded her ankle on 2/26/15 as she still cannot walk very much. Her problem is no car to drive and have to take paper work for EDD for disability form.
Grocery shopping for kale bread and chicken soup.
Went with Kim Kook Hee to meet Kang Chul Lee at 28th St Apt to have worship and conversation. After went to see Eun Soon Oh at 1515 Lakeside Apt to have worship and conversation. Eun Soon Oh was so happy, singing and singing again and dancing. Had a nice conversation for a long time. Wnet to see Kang Chul Lee at 28th St. Apt to have worship as well. He did not attend Sunday worship because of a bad cold. God with us! Everyone was so happy, and shared kale bread.
Took Kook Hee Kim, Sang Ho Cho, Hye Young Cho at Alameda to eat lunch at Sushi House. Afterwards went to see Young Ok Choo and Young Kyu Choo at Pleasant Hill Nursing home to have nice worship and conversation. Young Kyu Choo is so happy and his condition is better than before. Young Ok Choo was so appreciative and happy as well. Had such a wonderful time all together. Gave them chicken soup and kale bread.
Visit Alice Apt people to have worship individually with Shin Ja Young, Kim Byung Yup, Kim Kwi Nam, Kim Bun Phil, Park Young Sook, Kim Ok Ryun. Afterwards, went to meet Susan Kim at Marina nursing to have worship and gave some rice cake and 2 cup ramens. She was so happy to see us.
Visited Joon Yuel Choi at Alta Bates Summit Hospital #9735 to pray with Jung Kyu Chang and Yoo Ik Chang, also had a nice conversation.
Visited Joon Yul Choi and Jung Yeon Choi at Alta Bates Summit Hospital to have worship and also met Yoo Ik Chang and Jung Kyu Chang. Afterwards visited Kang Chool Lee and Michelle Lee and had worship in their home at 28th St apartment #406. After, visited Kum Hyun Kim and her helper IHSS lady at her home #1030 to have worship and nice conversation.
Visited Young Kyu Choo and Young Ok Choo and had worship with Susan Yoon at Pleasant Hill nursing home. Shared stew with beef and kale bread. Visited previous Rev. Kim's wife Kook Hee Kim and shared kale bread with her residents. Gave to Hyeon Il Kwon and Jenny Kwon some beef stew and kale bread. They had an auto accident 2 weeks ago - last week shared chicken soup and kale bread as well.
Visited Kang Chul Lee at Highland Hospital and had a worship and conversation!
Visited Kook Hee Kim to share Kale Bread with her Apartment residents (2 people) and helped Eun Ja Choi at 164th avenue for E.D.D. paper work and translated.
Visited Korean Community Center to meet about Oakland Local Senior Ministry, members are 12 people to share Kale Bread and plan another senior meeting event. After, visited Kang Chul Lee & Michelle Lee & Kum Hyun Kim had worship and conversation. Their condition slowly declined.
Visited 1301 E 13th st, Nursing home to meet Hong Chang Lee & Marina Hwang to have worship and conversation.
Visited Kum Hyun Kim and her helper at 28th st Apt #1030, and had worship and conversation with Rev. Lee's wife, Young Jae Lee. Went to Kang Chul Lee & Michelle Lee's home and had worship and conversation and had kale bread. After, met Eun Ja Choi to translate for EDD work.
Met Young Kyu Choo, and Young Ok Choo at Walnut Creek nursing home and had worship and conversation, and had kale bread. Visited Susan Kim at Bellaken Garden to have worship and conversation to share kale bread.
Visited several residents at Alice Apartments to have worship and conversation individually, Ja Young Shin, Byung Yup Kim, Kwi Nam Kim, Young Shin Cho, Bun Phil Kim, Young Sook Park, Ok Ryun Kim and Rev Mrs. Kim. They talked about all kind of past life, traveling, suffering and hard work they had to go through in care for their family. Listened to their story and a nice conversation together.
Visited Kook Hee kim to share kale bread and met Ok Ryun Kim to share bread with Young Ja Kim, Haebok Han and had conversation. In the afternoon, met Tae Bong and Sook He Jun at Rossmore to share comfort and their life story about their situation.
Visit Bun Phil Kim & Shin Hyuk Kim at her apartment at Alice St, had worship and nice conversation.
Visited Ja Young Shin, Ok Ryun kim and Bun Phil Kim at their apartment and had worship and nice conversation.
Visited Byung Yup Kim and KwiNam Kim, Dong Ha Kim at their apartment had a worship and nice conversation.
Visit Bun Phil Kim and Ja Young Shin and had worship and nice conversation.
Visited Hong Tae Lee & Marina Hwang at 1301 E 13th st, Nursing Home, had worship and nice conversation. Went shopping to make chicken soup and kale bread materials to Berkeley Bowl.
Visit Kum Hyun Kim at 28th St apartment to have worship and nice conversation. Met Kang Chul Lee & Michelle Lee had a worship also, had a nice conversation to share kale bread with 24 people. Went to see Young Ok & Young Kyu Choo family at Walnut Creek nursing home and had worship and nice conversation. Visited Sook He & Tae Bong Jin family at Rossmore.
Visited Hong Tae Lee & marina Hwang at 1301 E 13th Street Nursing Home and had worship and nice conversation.
Visited Kum Hyun km and Kang Chul Lee and Michelle Lee and had worship and nice conversation. Also visited Young Jae Lee and Yoo Kwon sa nim and Jae-Sook Yang at 28th street apartment and had wonderful conversation. After lunch, went to meet Young-Kyu & Young-Ok Choo at nursing home at Walnut Creek shared kale bread.
Met Eun- Ja Choi at the Highland Hospital to help her and her doctors conversation to translate for her paper work for E.D.D problem.
Ordered lunch boxes at Sushi House at 1:30 pm to get out tomorrow at 11:30 for 40 people.
Took Bok Won Lee at her apartment at Harrison St and went to pick up more congregation at Alice Apartment congregation. They went to picnic to SF after they return to eat lunch at the church with 40 people. Paid $430 dollars for all materials.
Visited Hong Tae Lee & Marina Hwang at 1301 E 13th St Nursing Home and had a worship and conversation.
Visit Kum-Hyun Kim and Kang Chul Lee and Michelle Lee at their home and had worship and nice conversation, after visited jin's family at walnut creek and visit Choo's family again had worship and nice conversation. Got Kale Bread Materials at Berkeley Bowl.
Had worship at Market Apartment with 9 people to share kale bread.
Checked High blood pressure and oxygen level and Diabetes etc. Served Breakfast and coffee for 28 people.


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Hard-working employees are key ingredients to any corporate profit. These team players will do what is asked of them, and it is important that they understand what their job duties are. That is one thing that a job description will do. It serves as a reference for these people as they go about their daily tasks. Writing a job description is not as easy as it may seem. Professional assistance may be needed.
Job description writing should be concise and clear. Writing kids description content for some managers is like writing a novel. Many times the job is broken down into so many incremental parts that the text can have numerous paragraphs. That really doesn't help. An employee needs to know what is his or her general responsibilities are, and that person can then provide the service.
We have written job descriptions for a variety of organizations and we are familiar with the right language. We can take information from a client about job duties, and condense it into several very usable paragraphs. People who are writing a position description should think of using a Goldilocks approach: not too long and not too short, but just right. That is how we do things.
The writer assigned to a particular project is a professional at writing descriptions for a job postings. He or she can take the client order and compose the material in very understandable language. The first draft is always submitted to a client for review, and any revision will be done. We do not use boilerplate job descriptions and plagiarism is something we are never guilty of doing. All of the content of a job description we write is original and reflects the corporate activity of the client. We make a point of finishing all projects within the deadlines requested by the client. We also offer a 100% money back guarantee if the client is not satisfied with our work.
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text:
Q: Converting ampersand (&) and blank space to a dash (-) in URLs using regex With the code below, I have converted the following names into URL such as

*

*Love & Relationships to http://domain.org/love-relationships

*Career & Guidance to http://domain.org/career-guidance
filter('ampToDash', function(){
    return function(text){
        return text ? String(text).replace(/ & /g,'-'): '';
    };
}).filter('dashToAmp', function(){
    return function(text){
        return text ? String(text).replace(/-/g,' & '): '';
    };
})

However, I have a new set of names and I can't figure out how to do both at the same time.

*

*Being Human to http://domain.org/being-human

*Competitive Exams to http://domain.org/competitive-exams
filter('ampToDash', function(){
    return function(text){
        return text ? String(text).replace(/ /g,'-'): '';
    };
}).filter('dashToAmp', function(){
    return function(text){
       return text ? String(text).replace(/-/g,' '): '';
    };
})

How do I combine both the regex codes so it can work hand in hand?

A: You may also want to extend your replacement criteria to cover all "non-word" characters, instead of just accounting for the ones you're currently aware of (& and space). This would be more future-proof, and perhaps easier to reason with:
String(text).replace(/\W+/g, '-')

(\W+ means any sequence of non-word characters.)
Example:
'Jack & Jill went up the @$%#! hill'.replace(/\W+/g, '-')

Yields:

Jack-Jill-went-up-the-hill

And because there's loss of information (i.e. you don't know what exactly leads to a '-' by looking at the transformed string), a way you can find the original string is to simply store it and look up by the transformed string. To elaborate: You're probably going to be looking up some document from this new string (a "slug", as others pointed out). Store the slug along with the document and just look up the document (and its original title) from your database.

A: It looks like you simply want to change any instances of an ampersand with leading or trailing white-space or just white-space to a single hyphen. If so, you could just use the following expression :
// Replace any strings that have leading and trailing spaces or just a series of spaces
String(text).replace(/(\s+&\s+|\s+)/g,'-'): '';

Example

var input = ['Love & Relationships', 'Career & Guidance', 'Being Human', 'Competitive Exams'];
for (var i in input) {
  var phrase = input[i];
  console.log(phrase + ' -> ' + phrase.replace(/(\s+&\s+|\s+)/g, '-'));
}

A: I think you are looking for a lib that converts a string into a slug.
You can do this manually, but you'll probably have hard time covering other edge cases.
I would suggest you to use something like :
https://github.com/dodo/node-slug
Or check out this gist if you really want to stay with the regex way : https://gist.github.com/mathewbyrne/1280286

A: You have two separate problems:

*

*how to 'slugify' a string

*how to undo / reverse the slugify.

To answer 1: A generic slugify method would be something like: text.replace(/\W+/g, '-')
To answer 2: you can't.  You have a function (ampToDash) that can produce the same output given different inputs.  i.e. there is NO equivalent of dashToAmp any more.


Ngawang Lobzang Gyatso / 5th and 6th Dalai Lamas, were Dzogchenpas, see the kLa Kang murals.
Asked myself always why he /they did not integrate Dzogchen in the Gelug as highest teaching / practice.
The Great Fifth was very powerful with the Mongolian army at his back.
- How do we call this Dzogchen Lineage in Gelug, based on the Great Fifth ?
- Is this an unbroken Lineage ?
Yes, it is an unbroken lineage.
The current HHDL has written books and given teachings on Dzogchen.
I was told that the current HH the Dalai Lama took Dzogchen teachings from Ven. Lama Gonpo Tsetan Rinpoche.
I took this picture. I met ChNNR at this retreat when he visited. They sang old songs together and it was wonderful.


In this important new book, Mark Casson argues that the fundamental significance of entrepreneurship requires it be fully integrated into core social science disciplines such as economics and sociology, as well as into economic and business history. This book shows how this can be done. It formalises the role of the entrepreneur as innovator, risk-taker and judgemental decision-maker, and relates these functions to the size and growth of the firm. Mark Casson discusses entrepreneurship as a form of strategic networking, showing how entrepreneurs gain access to established networks in order to source information, and then create their own networks to exploit this information. Applying these insights to historical evidence leads to a radical re-interpretation of key issues in economic and business history, including the emergence of trading companies, the spread of empires, the rise of the modern corporation and the globalisation of the firm.


text:
Q: Android: Part of my extras are getting lost in pending intent I am making an Android app for the first time and I am having this problem.
When a user A sends a friend request to another user B, user B gets a notification. I wish when the user B click on the notification to be redirected to user A profile.
The main activity (Home in app) opens different fragments depending on from where the user is coming. A user profile is one such fragment.
This is how I am sending the notification from a presenter class for Main Activity.
Intent notificationIntent = new Intent(activity.getApplicationContext(), MainActivity.class);
notificationIntent.setFlags(Intent.FLAG_ACTIVITY_SINGLE_TOP);

Bundle extras = new Bundle();
extras.putString("name" ,this.friendRequestFromUserName.toString());
extras.putString("email", this.friendRequestFromUserEmail);
extras.putString("notification", "notificationFriendRequest");

notificationIntent.putExtras(extras);

System.out.println("PUTTING EXTRA");
System.out.println(notificationIntent.getExtras().toString());
// output here is:
//Bundle[{name=The Lion King, email=mufasa@lionking.com, notification=notificationFriendRequest}]

NotificationCompat.Builder builder = new NotificationCompat.Builder(activity)
    .setSmallIcon(R.drawable.ic_notification)
    .setContentTitle("New friend!")
    .setContentText(this.friendRequestFromUserName + " wants to be friends.")
    .setAutoCancel(true)
    .setOnlyAlertOnce(true)
    .setOngoing(false)
    .setContentIntent(PendingIntent.getActivity(activity.getApplicationContext(), 0, notificationIntent, 0));

builder.setOngoing(false);
builder.setAutoCancel(true);

Notification not = builder.build();
not.flags = Notification.FLAG_AUTO_CANCEL;
NotificationManager manager = (NotificationManager)this.activity.getApplicationContext().getSystemService(Context.NOTIFICATION_SERVICE);
        manager.notify(123, not);

However in the main activity when user clicks on the notification only part of the Bundle is "arriving".
Here are the ways I tried to get the extras:
    extraName = intent.getStringExtra("name");
    extraMail = intent.getStringExtra("email");
    extra = intent.getStringExtra("notification");

and
    System.out.println(intent.getExtras().toString());
    //Bundle[{notification=notificationFriendRequest}]

I also tried putting arrays as extra with the same result. Since part of my extra is arriving, but other is not, and I couldn't find similar topic and problem I decided to ask if somebody can help or explain why or how this can happen. Thanks.

A: So as pskink suggested I added unique requestCode and PendingIntent.FLAG_UPDATE_CURRENT flag and that solved it.
.setContentIntent(PendingIntent.getActivity(activity.getApplicationContext(), Math.abs(generator.nextInt()), notificationIntent, PendingIntent.FLAG_UPDATE_CURRENT));

Since I don't see how to mark a suggestion as an answer 'cause that is my first question here I am answering it myself. Thank you again, pskink!

A: You are getting values in wrong way. As you are passing everything as a bundle in Intent , then first you have to get Bundle object first from intent like this
Bundle extras = getIntent().getExtras();
and then get other strings from bundle object

A: try to get fist the bundle object and then get the values like this, I hope this can help you.
@Override
protected void onCreate(Bundle savedInstanceState) {
     super.onCreate(savedInstanceState);

     try{
          Bundle data= this.getIntent().getExtras();
          extraName = data.getString("name");
          extraMail = data.getString("email");
          extra = data.getString("notification");
     }catch(Exception e){
          e.printStackTrace();
     }
}


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text:
PAUL SMITH CT
Loom de Nimes, a sister company to Antanna (also co-owned by Anthony and Anne Keyworth) acquired the retail license to operate British fashion label Paul Smith in South Africa, where it owned and operated two shops.
The first shop, designed by architect Sarah Calburn, opened in Johannesburg on the corner of 7th Street and 4th Avenue in the leafy suburb of Parkhurst in mid-November 2007. Later that month the Cape Town shop opened inside the V&A Waterfront's Victoria Wharf's luxury retail wing in amongst Louis Vuitton and Burberry.
In 2012 the V&A Waterfront shop closed its doors. It relocated to an upgraded retail space in the heart of Cape Town's CBD and is now situated on the highly visible corner of Bree and Wale streets.
The upgrade entailed the acquisition of a historical building that dates back to 1860. Anthony and Anne Keyworth undertook an in-depth research process (which entailed lengthy consultation with heritage experts to investigate the property's rich history), extensive property renovation, plus the re-branding of the Cape Town shop from a Paul Smith Prestige store to a Paul Smith Jeans shop, which is far more relaxed and reflects the more casual style of dressing, which Cape Town has become accustomed to.
In January 2014 Anthony and Anne Keyworth sold the Paul Smith business to The Surtee Group, which owns a number of world-class luxury fashion stores in South Africa including Burberry, Dunhill, Hugo Boss, Hackett, Mont Blanc and Zegna. The sale of the Paul Smith brand successfully concluded Loom de Nimes's 7-year business strategy in clothing retail.