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I have Parkinson's diseases and thought it would be nice to have a place where the contents of updated news is found in one place. That is why I began this blog.

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Saturday, May 7, 2016

Sauk Rapids veteran still fights fallout from 'missing year'

May 7, 2016
In this April 5, 2016 photo, Al Hams, 72, talks about music, theater, writing and the Vietnam War in Sauk Rapids, Minn. Al Hams is 72. He has Parkinson's disease, very likely due to his exposure to the chemical defoliant Agent Orange during the year he served with the U.S. Army in Vietnam. He calls that the "missing year" a period Hams tried to forget. (Jason Wachter/St. Cloud Times via AP) NO SALES; MANDATORY CREDIT

Read more here:

His voice is softer now, a relative whisper compared to the one that boomed theater lines and belted out songs.
His hands tremble — sometimes just slightly, sometimes more than slightly. It gets in the way of making the music that's been such a big part of his life, the St. Cloud Times ( ) reported.
"I'm trying to live with it," Al Hams said with a verbal shrug. "It's not easy. It's not fun. But it is."
Hams is 72. He has Parkinson's disease, very likely due to his exposure to the chemical defoliant Agent Orange during the year he served with the U.S. Army in Vietnam (1969-70).

He calls that the "missing year" — a period Hams tried to forget as he moved forward with a rich life filled with family, theater and music.
"I've accomplished some neat things in my life, I think," Hams said. "I'm satisfied with that. I don't think back to 'I should have done this' or 'I should have done that.'
"You get to the fork in the road, and you take it."
That's it. That's Al Hams.
No self-pity. No "poor Al."
"He's never said to me, 'This is totally not fair,' " said Teri LaPatka Hams, Al's wife since 2007 and longtime friend. "He'll say it sucks. But he won't say, 'Why me?' "
"I don't think that he feels that way," added Amanda Crisalli, the oldest of the four children Hams had with his first wife Marge. She died of brain cancer in 2001.
"I think that's part of what creative people do," Crisalli said. "When you've got something that you need to work through, you find an outlet to work through it."
Hams put his bitter Vietnam memories aside by working in a variety of ways — as an actor and musician and writer, as a parent and husband.
In 2013, that "missing year" officially returned when Hams was diagnosed with Parkinson's. Once again, he's answering with the same creativity that's been the response to the other traumas in his life.
The loss of a year. The loss of his first wife. The loss of his music, and his health.
Hams dealt with all that through creativity. That's ongoing — and Hams is going on, despite Parkinson's.
"Just never stop," he said. "Rule No. 1, Rule No. 2 and Rule No. 3 is just don't stop."
Hams is standing in the music room of his Sauk Rapids home, banging away on a guitar that he used to exclusively finger-pick.
It sounds fine, really. But it's just not the same.
"Now you've heard why I'm so frustrated about playing," said Hams, who started playing guitar before he arrived at St. Cloud State as a freshman theater major in 1961.
"It's all in my head. It's all there. I just can't connect it."
Hams is all about connections.
"Everybody knows Al. I got used to that a long time ago," said Teri Hams, who met Al when she applied for a job at Al's Music in 1985. "So many people knew Marge also."
"They know him, and they know of him, and they talk to him," Crisalli said. "But they don't know him deep down."
That's where you'll find a calm and a peace that not even Parkinson's can touch.
"People often ask me 'How's Al doing?' Considering, I think he's doing very well," said Teri, 51, who has three teen-aged children from her first marriage.
"Will people notice the changes? I think they will," she said. "He's going to keep doing what he's doing until he can't do it anymore."
He's already done a lot. Hams met musicians Doc Severinsen and Tom Paxton and Arlo Guthrie, and successfully played Stump the Band on "The Tonight Show."
He met Neil Young while selling a speed-reading course door-to-door in Los Angeles, and he was an extra in a George Hamilton movie ("Evel Knievel," 1971).
"A lot of strange things have happened," Hams said. "I introduced Ann B. Davis to smelt."
"He used to sing very loud in church," said a laughing Crisalli, 41, who's involved in theater and film in Phoenix and teaches film production at Arizona State University. "I just remember as a kid, he was very loud."
Hams is particularly proud of the years he owned Al's Music in St. Cloud (1976-2004, 2009-2014), a store that launched countless musical careers.
"I feel like I really helped a lot of people get into music — thousands and thousands of kids, from schools all around," he said. "It affected me to a huge degree."
Hams retired in 2004, and again in 2014. But not necessarily because he wanted to.
According to government statistics, U.S. military forces sprayed more than 19.4 million gallons of Agent Orange to eliminate forest cover during the Vietnam War. Most of that was between 1966-69.
More than a dozen diseases are recognized by the Veterans Administration as being related to exposure to the powerful herbicide: leukemia, diabetes, Hodgkin's disease, ischemic heart disease, multiple myeloma, non-Hodgkin's lymphoma, prostate cancer, respiratory cancer .
Parkinson's disease.
Anybody who physically served in Vietnam, or on its rivers, or worked with aircraft that delivered Agent Orange, is considered to have been exposed.
"If he set foot in the Republic of Vietnam, you qualify (for medical care)," said Barry Venable, public affairs officer at the St. Cloud VA Hospital.
"By public law, these patients are considered eligible for service in connection with Agent Orange exposure — whether it be as little as an hour on the ground, or months on the ground," added Dr. Susan Markstrom, chief of staff at the St. Cloud VA.
"It's in the water, so to speak. So you were considered to be exposed to Agent Orange."
That translates to thousands of patients at the St. Cloud facility, which in 2015 treated 38,000 patients — 55 percent of them Vietnam veterans.
"Every one of them have had potential Agent Orange exposure," Venable said. "Last year, we saw about 17,500 Vietnam-era veterans. Of those, 75 percent, or about 12,784, had indicated they were exposed to Agent Orange while in the service.
"That gives you some idea of the breadth of the exposure in the population, at least locally."
As early as 2009, Hams and his family started seeing signs that he might be one of them.
Initially, Hams thought he had restless leg syndrome. Parkinson's doesn't run in his family.
"I was having twitching at night in my sleep," Hams said, "driving my wife nuts."
"My siblings and I probably noticed the shaking before we really knew that there was a diagnosis," Crisalli said. "It was physically obvious."
Teri Hams, who works as the librarian at the Minnesota Correctional Facility-St. Cloud, first saw tremors in 2009.
"They weren't very frequent," she said. "They would usually show itself if he were a little tired, or maybe hungry."
That led her to do some research, in part because of the experience of ex-husband Tom Donahue — also a Vietnam veteran. (They divorced in 2003.)
"It was about two months before (Al and I) were going to get married," she said. "Tom came over and was standing in the driveway.
"He's telling us he has leukemia."
That was June 2007. Donahue died January 2009.
"She's a librarian," Hams said. "She started putting that all together."
Hams contacted Stearns County veterans service officer Terry Ferdinandt, who arranged for testing at the St. Cloud VA.
About six weeks later, the results came back — Parkinson's, with Agent Orange the acknowledged cause.
"The government, to their credit, said 'we can't prove it one way of the other, so we'll include it,' " said Hams, who subsequently was placed on 70-percent disability.
The "missing year" had returned.
Everything Hams had tried to forget about the draft and Vietnam came rushing back.
"I'm still resentful," he said.
It might be the only thing in life that Al Hams is actually bitter about.
"I've been carrying this bitterness about being a Vietnam vet, for years and years and years," he said.
"I didn't tell anybody I was a veteran. I just avoided the subject at all costs, because we were looked down upon."
Hams was a 25½-year-old, married, college graduate in the master's degree program at St. Cloud State University when his draft number was called in 1968.
"I had seven college deferments," he said. "They weren't gonna give me any more."
He was inducted in February 1969 at Whitehall Street in Manhattan — the same induction facility immortalized by Arlo Guthrie in his song "Alice's Restaurant."
Hams was shipped to basic training at Fort Jackson, South Carolina, where his recent temporary job at Holt Rinehart and Winston Publishing in New York came in handy.
"They said, 'Oh, I see you have an English background,' " said Hams, who characterized his job as "glorified secretary."
"'You're a journalist?' Yeah," Hams said. "So they made me an informational specialist.
"I thought, 'This is great. I'll be here for two years, and I'll be done.' "
Nope. Hams was sent to Vietnam in October 1969 and attached to the First Signal Brigade at Long Binh Base, an Army headquarters near Saigon.
He was assigned to write news releases, take photos and produce a military publication.
"We had an every-other-week, 30,000-circulation, Army newspaper," Hams said. "If a congressman was coming to visit, we had to make sure they were taken good care of. Whatever they needed, we did.
"The last six months I was there, I edited the paper. I was a 26-year-old college graduate, married, with more experience than my boss."
It was at Long Binh that Hams was exposed to Agent Orange, which was so common that he thought nothing of it.
"They'd come by with a big C-130 and just dump it down on an area," he said. "It was everywhere.
"I remember seeing pallet after pallet, big barrels. They spilled some on the tarmac, and it was like 'ho hum.'
"They just let it dry."
Hams was sent back to the U.S. in late August 1970 as the war began to draw down.
"It was 11 months," he said. "They had already started to get rid of people (in Vietnam)."
His stint was over. The interruption of his life was done. Hams got through it, and moved on.
"He never talked about Vietnam," Crisalli said. "We knew that he was there. We got a couple stories about driving important people around in the Jeep. But that was it. There was nothing graphic and nothing heartbreaking that he told us."
For many veterans, their homecoming — or lack of one — was almost worse than being in Vietnam.
"Everybody his age that went to Vietnam felt slighted," Teri Hams said. "Nobody was getting the recognition for their service."
"People would literally spit at you," said Hams, who was sent to Oakland, California, and mustered out of the Army in September 1970.
"They issued me a whole brand-new dress uniform, with all my ribbons, a whole set of dress greens, shoes, everything," he said. "In order to leave the post, we had to be in uniform. So I got on the Army bus, and went to the San Francisco airport."
That moment remains one of Hams' most vivid Vietnam-related memories.
"The first thing I did after they released me was I went inside to the bathrooms, took off my new dress uniform and threw it away," he said. "The garbage cans in the terminal were full of dress green uniforms.
"Everybody was doing it, and putting on civilian clothes."
Hams put on his civvies, boarded his plane and returned to his wife and life in Minnesota.
Al Hams left the Vietnam War — his "missing year," his unwanted memories, his Army discharge uniform — in a bathroom trash can at the San Francisco airport.
He was ready to return to the "normal" life he involuntarily left, and to put Vietnam behind him.
Until the 2013 diagnosis of his Agent Orange-induced disease, Hams generally did that.
But now, the "missing year" is back.
Hams has Parkinson's. Normal is gone.
"I don't know what normal is any more," Hams said with a chuckle. "You become very fatalistic about that.
"The first three things that go are your short-term memory . (long pause) . I can't remember the other two."
He grinned. "It's my only joke."
Hams is forging ahead with life, and with his creative process — just like he did when he left the U.S. Army in 1970, and when his first wife Marge died in 2001, and when he was diagnosed with Parkinson's in 2013.
Just like always.
"I don't think we've ever had that in our family when bad things happen, that we need something to blame or someone to blame," said Amanda Crisalli, the oldest of Hams' four children from his first marriage. "We weren't really brought up that way.
"People get things. People die before their time. It's not anything you can control. I don't think my mom was mad, either."
For Hams, the first step back to normalcy after his September 1970 discharge was letting go.
That wasn't easy for Vietnam veterans.
"When you're drafted, you go. You have a sense of duty," said Teri Hams, Al's wife since 2007. "All those guys that were in that situation, that were drafted, gave a lot — and came back to nothing.
"The resentment comes not from the military, but from the acceptance of the public at that point in time. They processed the best they could, by themselves, at that time."
Hams returned to St. Cloud and Marge, who had one semester left to finish her degree at St. Cloud State University. He worked at Mack's Music for a couple months before Marge graduated and the two aspiring actors moved to Los Angeles.
They stayed for 10 months. The highlight: Al and Marge are both extras in the 1971 movie "Evel Knievel," starring George Hamilton.
"Nice guy," Hams said. "You can see us in about five spots."
The lowlight: Everything else. Al and Marge hated Los Angeles, and moved back to St. Cloud in 1971.
Hams worked at Mack's from 1971-76, then bought out the equipment after Mack retired. He opened Al's Music — initially in a location next to Herberger's, and then on East St. Germain starting in 1989.
Hams sold the business in 2004, got back into it in 2009, and retired again in 2014.
But his life changed dramatically before all of that.
In 1999, Marge Hams was diagnosed with brain cancer. She was a St. Cloud institution in her own right, as a performer and St. Cloud Tech drama coach and business owner, and her illness hit friends and family particularly hard.
"Marge was a friend of mine. We had a connection," said Teri Hams, who helped however she could during Marge's 2½-year battle with cancer.
"If (Al) needed to vent a little bit about what was going on, that was my role," Teri said. "There were days when not everybody was getting along."
Marge died Nov. 14, 2001. Al's creative outlets — theater, music, writing — helped him recover from the loss. His first book, "Why I Didn't Make it to Woodstock," was published in 2006.
"In terms of me dealing with the death of my first wife, I'm resolved on that," Hams said. "I've moved on."
Moving on from Vietnam proved equally challenging, especially after his Parkinson's diagnosis and other medical issues.
"Sometimes it's hard — not just for Al and me, but for some of the older vets, knowing what they went through," Teri Hams said. "They just did not get support that military guys are getting today. Hopefully, we learned from that.
"That can never be repaired."
Hams began experiencing heart problems in 2004. He needed a pacemaker, and he's undergone three ablations for atrial fibrillation.
"It's an electrical problem — both of them," said Hams, who wonders if his heart issue isn't related to his Parkinson's and Agent Orange exposure. "I've been thinking of sticking my finger in a socket."
Then came the Parkinson's diagnosis. Hams' musical involvement provided one of the most tell-tale signs.
"That was the thing that told me something wasn't right," Hams said. "I can't finger-style play guitar any more. It comes and goes, but it favors my right side."
"It slowed him down, that's for sure," Crisalli said. "His fingers aren't doing exactly what they used to do."
It's all part of a new reality — for Hams, and for countless Vietnam veterans dealing with Agent Orange exposure.
"How has our life changed? He's slower. His movements are slower. Everything slows down," Teri Hams said. "It takes more patience on all of our part, not just his. It's most frustrating for him.
"It's a gradual change. There's nothing we can do to make it not be there, so how do you approach it?"
A wave of Vietnam veterans began dealing with the consequences of Agent Orange exposure at roughly the same time as Hams.
"There is a lag time before disease development related to any toxin exposure," said Dr. Susan Markstrom, chief of staff at the St. Cloud VA Hospital.
"Since these veterans are now aging, they're coming into our system," she said. "Indeed, we're seeing a surge in Agent Orange-related illnesses that we're treating."
After his initial Parkinson's diagnosis, Hams assumed it would be a while before the VA determined the level of his disability payments.
"I got a letter from the VA saying they're working on your case. We'll get back to you," said Hams, who said his experience with the VA system has been "very good."
"I figured maybe six months or a year," he said. "It was like two weeks later and I got a letter from them — we were very surprised."
Hams was placed on 70-percent disability. He's still able to walk and drive a car without much problem, at least for now.
"They're not denying anybody with those specific medical situations," Teri Hams said. "There's a list. If you have one of those, you will get some type of benefit from that.
"I think everyone is pretty much aware of the disservice that was done (to Vietnam veterans) by the American public, and the government," she said. "This is about the only way they can make some amends."
Hams does physical therapy through the Big and Loud program, which helps Parkinson's patients retrain sensory, motor and cognitive functions through intensive exercise.
Switching medications — he's now taking Levodopa — also has helped.
"The first time I saw him after I knew that he had Parkinson's, I was shocked at how his balance was off and really how unsteady he was," Crisalli said, recounting Hams' 2015 visit to Phoenix. "When I drove up (to the airport), I barely recognized him.
"He came again in February, and he was a lot more his old self. That's helped him quite a bit. He's steadier than he was for sure."
The trajectory of Hams' Parkinson's is a complete unknown.
"Parkinson's progresses, but it will progress differently for everybody," Teri Hams said. "It's hard to say where we'll be a year from now. It could be a real gradual thing, or all of a sudden things could change rapidly.
"We'll have to deal with that when that time comes. But it will continue to worsen, and we know that.
"You just don't want to go there," she said. "We just try to create our own life."
His hands don't function as well, and his voice is quieter.
"One of the symptoms of Parkinson's disease is that you get a very soft voice," Markstrom said. "You slow down. You lose your ability to project your voice."
But Hams can still bang away on the guitar.
He's also banging away at a variety of writing projects — his third book, and three one-act plays.
"He's always been busy. I don't think he'll stop now," Crisalli said. "That would go against his character."
"I'm gonna go with it until I'm satisfied with it," Hams said. "Right now, I've got four projects in the fire."
There's a one-act play called "Anger Management," about patients conversing in the waiting room at a psychiatrist's office. "By the time the shrink comes out, they decide they've cured each other," Hams said.
There's another called "The Ledge." A man gets fired from his job, goes home to jump out the window and kill himself, and surprises his wife with another man. The men end up having a conversation while hanging from a ledge — one naked, the other in a suit. "It has nothing to do with me personally," Hams said with a wry smile.
The third is called "Breakfast in the Suburbs," focusing on how people get together in relationships. "If you're old enough to remember 'The Bickersons,' it's kinda like that," Hams said.
The book is more of an autobiography, written largely for his family — and written because of Hams' own parents.
"It's important for the family to know, because of the things I wanted to know about my parents," Hams said. "They wouldn't tell me. They didn't tell me. They'd just say, 'It's not important.'
"These are things my kids don't know about me — and by and large Teri doesn't know about."
There's a Vietnam chapter, tentatively called "Missing Year." There are Parkinson's references.
But mostly, Hams just wants to fill in some blanks.
"I'm grateful now that he's willing to open up about it," Crisalli said. "I'm looking forward to hearing about it."
There's no way of knowing exactly where this is going, or how quickly.
"Best outcome is you stay home, and you're able to perform all of your activities in daily living by your own or with some aids," Markstrom said. "I think that's the best-case scenario. Stay active as much as you can."
Hams has made that his mission.
"He's being really proactive with this," Crisalli said. "He's not gonna just let it take over. He's working against it."
Hams is still writing, still creating, still living.
"The only thing I'm sorry about is that I can't play (guitar)," he said. "Music is such an important part of my life."
He's still Al. He's not going to dive into the pity pool.
"It is what it is," Hams said with another verbal shrug. "It's like crying over spilled milk.
"I'm still trying to stay active. That's as close to a solution as you can get."
Al Hams is moving ahead, with a purpose. There won't be another "missing year."
Read more here:

Friday, May 6, 2016


6th May 2016 - New research

Bradyphrenia is mental slowness. 

Bradyphrenia can consist of slowness of thought, impaired attention and motivation, lack of spontaneity, and inflexibility. Bradyphrenia was well known to occur in Parkinson's Disease. For the first time researchers have assessed how prevalent bradyphrenia is in Parkinson's Disease and what causes it.

Bradyphrenia was found to occur in as many as half of people with Parkinson's Disease. Between 11% and 51% of people with Parkinson's Disease were found to exhibit mental slowness by performing significantly worse on neuro- psychological tests including tests of attention and executive function. However, bradyphrenia was found to be uncommon in people with Parkinson's Disease who did not also have dementia or depression.

The results suggest that the depression or dementia that often accompanies Parkinson's Disease is the cause of the bradyphrenia. Bradyphrenia in Parkinson's disease may also reflect advancing age because the effects of age may be greater in some cases than the effects of basal ganglia disease once motor dysfunction has been allowed for. However, he dopamine system through the medial forebrain bundle projecting from the ventral tegmental area to the nucleus accumbens, ventral striatum (limbic striatum) and the cortex is associated with bradyphrenia.

Reference : Journal of Clinical and Experimental Neuropsychology [2016] May 1 : 1-9 [Epub ahead of print] (T.T.Vlagsma, J.Koerts, O.Tucha, H.T.Dijkstra, A.A.Duits, T.van Laar, J.M.Spikman) 

Complete abstract :
©2016 Viartis

Are we close to the stem cell revolution?

May 4, 2016
Stem cell therapy has been in use for many years, but with only limited reach. As such the oft bandied stem cell revolution has still yet to arrive. Steve Buckwell and Chris Coe explain why this is set to change and why now is the perfect time for its potential to be achieved. 
The stem cell revolution as it’s often referred to is now already in its third decade. But like the paper free office, is it just one of those envisaged futures that never seem to really happen? Embryonic stem cells were first isolated 18 years ago, but stem cell therapies have been slowed by high production costs, batch-to-batch variability and limited seed material. But we still believe the revolution will kick off some time in the second half of this decade. This is why.
Firstly the early ethical issues have, in many cases been overcome, with adult stem cells showing promise in the clinic but not requiring the embryo exploitation and destruction that made embryonic stem cell research so controversial in the years after 1998. Secondly, there is now substantial mid-stage clinical evidence that stem cells work in areas of unmet medical need, much of which has only become evident in the last five years.
There are various stem cell products in development that work allogeneically, meaning that the patient receives stem cells sourced from someone else’s body. As a general rule, allogeneic therapies are quite cost effective because they have the potential to be ‘off-the-shelf’, whereas autologous therapies (use of the patient’s own cells) can be considerably more expensive.
It has only recently been proven that stem cells can be made at industrial scale whilst conforming to Good Manufacturing Practice, the guidelines regulators require drug makers to abide by. It is this latter, the scale up from the laboratory to an ‘off the self’ product which has the capacity to slow the train down. After all, a product that can’t be manufactured isn’t a commercial product – it’s an academic curiosity. Many interesting molecules sit on the shelf in pharmaceutical companies waiting for solutions to the manufacturing challenge. Fleming discovered penicillin in 1928, but it took a World War, countless dollars and the combined brains of innumerable world class institutions to develop a working product. Initially we’ll take a look at the way stem cells are generated and expanded. This can be broken down into two areas; those produced using embryos in one form or another, and those that do not.
Back in 1998 in a stem cell ‘Eureka moment’, James Thomson and colleagues at the University of Wisconsin generated the first human embryonic stem cells (hESCs) using tissue from embryos fertilised in vitro. This method uses embryos that have been generated during IVF and are no longer required. However, hESC lines are extremely difficult to grow in culture; the cells require highly specialised growth media that contain essential ingredients that are difficult to standardise. Yet the culture conditions are critical to maintain the cells’ self-renewing and pluripotent properties, so therefore hESCs do not lend themselves to mass production.It has only recently been proven that stem cells can be made at industrial scale whilst conforming to Good Manufacturing 
"It has only recently been proven that stem cells can be made at industrial scale whilst conforming to Good Manufacturing Practice"

In 1998, James Thomson and colleagues at the University of Wisconsin generated the first human embryonic stem cells using tissue from embryos fertilised in vitro.

A second method for generating human pluripotent stem cell lines was published in 1998 by John Gearhart and co-workers at The Johns Hopkins Medical School. These researchers isolated specialised cells known as primordial germ cells (PGCs) from a five to seven week old embryo and placed these cells into culture. As with hESCs, PGCs present challenges with sustained growth in culture. Spontaneous differentiation, which hinders the isolation of pure clonal lines, is a particular issue, meaning once again this is unsuitable for scaling up. Embryos that stop dividing after being fertilised in vitro are not preferentially selected for implantation in a woman undergoing fertility treatment. These embryos are typically either frozen for future use or discarded. In 2006, scientists generated hESC lines from IVF embryos that had stopped dividing. These scientists used similar methods as described for traditional hESC line generation but with an exception – their source material was so-called “dead” IVF embryos. In one sense this method might be seen by many as a more ethical route. The human stem cells created using this technique behaved like pluripotent stem cells, including producing proteins critical for “stemness” and being able to produce cells from all three germ layers. Several other embryonic based methods of production exist, such as hESC lines from genetically abnormal embryos, from single cell embryo biopsy and those created via parthenogenesis. But again these were never going to be practical routes to the scale up challenge.
The promising area is unquestionably the creation of truly pluripotent stem cells from non-embryonic routes. When you think about it the only practical alternative to searching for an existing population of stem cells is to create a new one from a population of non-pluripotent cells. This strategy, which may or may not involve the creation of an embryo, is known as “reprogramming.” Current approaches to this include reprogramming through somatic cell transfer, cell fusion or altered nuclear transfer.
In somatic cell nuclear transfer (SCNT) human oocytes (eggs) are collected from a volunteer donor who has taken drugs that stimulate the production of more than one oocyte during the menstrual cycle. Scientists then remove the nucleus from the donated oocyte and replace it with the nucleus from a somatic cell, a differentiated adult cell from elsewhere in the body. The oocyte with the newly transferred nucleus is then stimulated to develop. The oocyte may develop only if the transplanted nucleus is returned to the pluripotent state by factors present in the oocyte cytoplasm. This alteration in the state of the mature nucleus is called nuclear reprogramming. When development progresses to the blastocyst stage, the inner cell mass (ICM) is removed and placed into culture in an attempt to establish a pluripotent stem cell line. To date, the technique has been successfully demonstrated in two primates.
There is also reprogramming though cell fusion. In 2005 researchers at Harvard University reported that they had fused cultured adult human skin cells with hESCs. The resulting “hybrid” cells featured many characteristics of hESCs, including a similar manner of growth and division and the manufacture of proteins typically produced by hESCs. Some factor(s) within the hESCs enabled them to “reprogram” the adult skin cells to behave as hESCs. However, these cells raised a significant technical barrier to clinical use, fused cells are tetraploid (they contain four copies of cellular DNA rather than the normal two copies), and scientists would need to develop a method to remove the extra DNA without eliminating their hESC-like properties. The fusion method serves as a useful model system for studying how stem cells “reprogram” adult cells to have properties of pluripotent cells. However, if the reprogramming technique could be carried out without the fusion strategy, a powerful avenue for creating patient-specific stem cells without using humans could be developed.

"Pluripotent stem cells provide a limitless starting material, derived from essentially any tissue in the body, and there are now over 300 clinical trials underway with MSC therapies"

Lastly there is reprogramming through altered nuclear transfer (ANT). This is a variation on standard SCNT that proposes to create patient-specific stem cells without destroying an embryo. In ANT, scientists turn off a gene – CDX2 – needed for implantation in the uterus in the patient cell nucleus before it is transferred into the donor egg. However, the real potential for mass production of stem cells lies with induced pluripotent stem cells (iPSCs). This is where true scalability starts to get exciting, and involves the use of identities known as mesenchymal stem cells (MSCs). MSCs are multipotent stromal cells that can differentiate into a variety of cell types. Existing methods of large scale MSC production rely on the isolation of these cells from donor tissue followed by expansion, or harvesting as it’s sometimes called. The quantity of cells produced in this way can in theory proceed by almost exponential growth, so it would seem to be suitable for industrial scale production.
However, there are difficulties with this approach since the MSCs grown start to lose potency quite quickly and ultimately stop dividing altogether in a process defined as senescence. In addition the number of cells that can be isolated from each donation is quite limited, typically being of the order of 2×104 MSCs per donation, whereas a clinical dose of around 108 MSCs would be the average requirement. With this in mind, a continuous supply of new donors would then be required and this in turn inevitably adds greatly to the cost of the therapy. Donation procedures can be both invasive and painful, especially where bone marrow is the tissue involved. Then, of course screening procedures can be time consuming. Finally there is the issue of consistency of end product. Clearly this is very difficult to achieve when relying on multiple donors for supply and so this approach therefore does not lend itself to commercial deployment.
An approach to overcome these problems is based upon the work of Professors Slukvin and Thomson et al in the generation of induced Pluripotent Stem Cells (iPSCs) – and in the discovery of Mesenchymal angioblasts (MSAs). IPSCs are essentially a man-made version of hESCs, derived from adult cells and have very similar characteristics to hESCs. They also avoid the ethical concerns, since they are not derived from human embryos. These two scientists were pioneers in the development of iPSCs and were one of two independent research groups that first reported the creation of iPSCs from human cells. Critically, iPSCs – like ESCs, can be expanded without limit, be stored over long periods and produce tissue cells of any type. This of course makes iPSCs an ideal building-block for cell-based therapies.
IPSCs themselves are not administered directly to patients as medical treatments. Instead, they are used as a starting material to produce other types of cells, which may have the potential to be used as therapeutic agents. Once these advances in research were made, it was suggested that similar techniques might be used to reprogram adult human cells. In 2007, Yamanaka et al reported that introducing the same four genetic factors that reprogrammed mouse cells into adult human dermal fibroblasts reprogrammed the cells into human iPSCs. These iPSCs were similar to hESCs in numerous ways. Moreover, the cells could differentiate into cell types from the three embryonic germ layers.
Induced pluripotent stem cells: similar to embryonic stem cells but made from adult specialised cells using a laboratory technique discovered in 2006.

The cells generated by the Thomson group met all defining criteria for hESCs, with the exception that they were not derived from embryos. The search was therefore on for precursors of MSCs – and that is where mesenchymal angioblasts come in. MCAs are an extremely important class of early clonal mesendodermal precursor cells that evolve into both MSCs and endothelial cells. Later studies by the Wisconsin group identified a common precursor of mesenchymal and endothelial cells, mesenchyme angioblasts, as the source of mesoderm-derived MSCs. In other words an exciting route to generation of MSCs had been identified – and that has led to the following route to be identified and now verified at the Wisconsin based Madison Group. So commercialisation is at last becoming a reality.
Pluripotent stem cells provide a limitless starting material, derived from essentially any tissue in the body, (although blood cells are the most commonly used), and there are now over 300 clinical trials underway with MSC therapies. A great deal of progress and hard work in this area has already been achieved by companies like Athersys and Mesoblast, which have identified the potential utility of MSCs. One technology belonging to Cynata Therapeutics Ltd and known as Cymerus combines iPSCs with MCAs and was recently validated at a US bio-manufacturing plant under Good Manufacturing Practice. Critically the Cymerus process can source all the cells ever needed from a single donor, thus eliminating product variability and the need to constantly seek out new donors. Watch this space. The industry’s ability to generate robust, consistent and inexpensive cells is set to accelerate the commercialisation of stem cell therapies worldwide.
Steve Buckwell has a PhD in physical organic chemistry and worked in pharmaceutical research until starting his own business in the 1990s.
Chris Coe has a varied background in marketing, business development and corporate finance. He has collaborated with Dr Buckwell on a number of projects.

Rhythm on the brain, and why we can’t stop dancing

May 5, 2016

Music and dance are far from idle pastimes. They are universal forms of expression and deeply rewarding activities that fulfil diverse social functions. Both feature in all the world’s cultures and throughout history.
A common feature of music and dance is rhythmic movement, which is often timed with a regular pulse-like beat. But the human capacity for rhythm presents something of a puzzle.
Even though rhythmic coordination seems fundamental to human nature, people vary widely in ability. Some have the machine-like precision of Michael Jackson, others are closer to the case of “beat-deaf” Mathieu.
What are the underlying causes of these individual differences? By looking at the way the brain responds to rhythm, we can begin to understand why many of us can’t help but to move to a beat.
Sometimes the dancing is infectious.

Power of rhythm

Rhythm is a powerful force. It can regulate mood, ranging from the arousing effect of pounding war drums to the pacifying effect of gently rocking a baby. It can even induce altered states of consciousness, as in spiritual rituals and shamanic traditions involving trance.
Rhythm and music can also be used for therapeutic purposes in the rehabilitation of conditions characterised by motor impairment, such as stroke and Parkinson’s disease.
Even more fundamentally, rhythmic skills displayed in the context of music and dance may have been essential to our evolution as a species.
In The Descent of Man (1871), Charles Darwin mused that:
it appears probable that the progenitors of man, either the males or females or both sexes, before acquiring the power of expressing their mutual love in articulate language, endeavoured to charm each other with musical notes and rhythm.

We seem naturally equipped to learn how to move to rhythm.
Rhythmically coordinated body movements may function similarly to fuel sexual attraction by providing an “honest” signal (one that can’t be faked) of an individual’s health and fitness.
Outside the competitive arena of finding a mate, coordinating with others through music and dance facilitates social cohesion by promoting interpersonal bonding, trust, and cooperation.
These prosocial effects of music and dance may have contributed to the flourishing of human culture by preventing the disintegration of early societies into antisocial mobs.
Today, they remain potent enough to be relied on, even in maximum security prisons.


But if music and dancing are so universal, why are some people simply unable to hold a rhythm?
The key to answering this question lies in how the human brain locks onto rhythms in the external environment, and how this process of “neural entrainment” supports the coordination of body movements.
Neural entrainment occurs when regular sensory input, like music with a clear beat, triggers periodic bursts of synchronised brain activity. This periodic activity can continue independently of external rhythmic input due to interactions between already excited neurons. It is as if they expect the sensory input to continue.
Entrainment can thus enhance processing of incoming information by allocating neural resources to the right place at the right time. When performing or dancing to music, entrainment allows the timing of upcoming beats to be predicted.
Sometimes we just have to move. Scott Robinson/FlickrCC BY
A recent study on individual differences in rhythmic skill identified relationships between the strength of neural entrainment and the capacity to synchronise movements with musical rhythms.
We measured entrainment to the underlying beat in two types of rhythm using electroencephalography (EEG), a technique where electrical signals reflecting neural activity are recorded via electrodes placed on the head.
One rhythm had a regular beat marked by periodically occurring sound onsets. The other was a relatively complex and jazzier “syncopated” rhythm in which sound onsets were not present on all beats: some were marked by silence.
Results indicated that the strength of neural entrainment was related to people’s ability to move in synchrony with the beat. Individuals with strong neural responses were more accurate at tapping a finger in time with the beat of the two rhythms.
We also found individual differences in brain responses to the two rhythms. While some individuals showed a large difference between strength of entrainment for the regular rhythm versus the syncopated rhythm, others showed only a small difference.
In other words: some people required external physical stimulation to perceive the beat, whereas others were able to generate the beat internally.

All cultures around the world and throughout history have engaged in dance.
Remarkably, people who were good at internally generating beats also performed well on a synchronisation task that required them to predict tempo changes in musical sequences.
So the capacity for internal beat generation turns out to be a reliable marker of rhythmic skill. This adds new meaning to Miles Davis’ reported maxim that “in music, silence is more important than sound".
But we still don’t know why individual differences in the strength of neural entrainment occur in the first place. They may reflect the efficiency of neural responses at early levels of auditory processing, such as brainstem responses. Or the degree of connectivity between higher-level auditory and motor cortical regions.
Another open question is whether rhythmic skills can be boosted by recent advances in neuroscience. Brain stimulation techniques that induce neural synchrony at specific frequencies provide a promising method for enhancing entrainment and thereby improving an individual’s capacity for rhythm.