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Archive for November, 2015

Artificial Pancreas

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Artificial Pancreas Therapy Performs Well in Pilot Study

Fri, 11/20/2015 – by Wiley

http://www.mdtmag.com/news/2015/11/artificial-pancreas-therapy-performs-well-pilot-study

 

Researchers are reporting a breakthrough toward developing an artificial pancreas as a treatment for diabetes and other conditions by combining mechanical artificial pancreas technology with transplantation of islet cells, which produce insulin.

In a study of 14 patients with pancreatitis who underwent standard surgery and auto-islet transplantation treatments, a closed-loop insulin pump, which relies on a continuous cycle of feedback information related to blood measurements, was better than multiple daily insulin injections for maintaining normal blood glucose levels.

“Use of the mechanical artificial pancreas in patients after islet transplantation may help the transplanted cells to survive longer and produce more insulin for longer,” said Dr. Gregory Forlenza, lead author of the American Journal of Transplantation study. “It is our hope that combining these technologies will aid a wide spectrum of patients, including patients with diabetes, in the future.”

 

Artificial Pancreas Works for Length of Entire School Term

Daniel Walls, a 12-year-old with type 1 diabetes who has taken part in the trial.

An artificial pancreas given to children and adults with type 1 diabetes going about their daily lives has been proven to work for 12 weeks – meaning the technology, developed at the University of Cambridge, can now offer a whole school term of extra freedom for children with the condition.

Artificial pancreas trials for people at home, work and school have previously been limited to short periods of time. But a study, published today in the New England Journal of Medicine, saw the technology safely provide three whole months of use, bringing us closer to the day when the wearable, smartphone-like device can be made available to patients.

The lives of the 400,000 UK people with type 1 diabetes currently involves a relentless balancing act of controlling their blood glucose levels by finger-prick blood tests and taking insulin via injections or a pump. But the artificial pancreas sees tight blood glucose control achieved automatically.

This latest Cambridge study showed the artificial pancreas significantly improved control of blood glucose levels among participants – lessening their risk of hypoglycemia. Known as ‘having a hypo,’ hypoglycemia is a drop in blood glucose levels that can be highly dangerous and is what people with type 1 diabetes hate most.

Susan Walls is mother to Daniel Walls, a 12-year-old with type 1 diabetes who has taken part in the trial. She said: “Daniel goes back to school this month after the summer holidays – so it’s a perfect time to hear this wonderful news that the artificial pancreas is proving reliable, offering a whole school term of support.

“The artificial pancreas could change my son’s life, and the lives of so many others. Daniel has absolutely no hypoglycaemia awareness at night. His blood glucose levels could be very low and he wouldn’t wake up. The artificial pancreas could give me the peace of mind that I’ve been missing.”

“The data clearly demonstrate the benefits of the artificial pancreas when used over several months,” said Dr. Roman Hovorka, Director of Research at the University’s Metabolic Research Laboratories, who developed the artificial pancreas. “We have seen improved glucose control and reduced risk of unwanted low glucose levels.”

The Cambridge study is being funded by JDRF, the type 1 diabetes charity. Karen Addington, Chief Executive of JDRF, said: “JDRF launched its goal of perfecting the artificial pancreas in 2006. These results today show that we are thrillingly close to what will be a breakthrough in medical science.”

 

Highly Sensitive Biosensor Measures Glucose in Saliva

The glucose biosensor fabricated with flexible substrates can perform in a variety of curved and moving surfaces, including human skin, smart textile and medical bandage.

Diabetic patients have to monitor blood glucose regularly and frequently, but conventional method of taking blood sample for measuring glucose level is painful. It is therefore important to develop high performance biological sensors for monitoring the glucose level at a reasonable cost.

The challenge to develop biosensor to test glucose in saliva is that the amount of glucose in saliva is too small for detection, and it requires a super sensitive biosensor to perform the job. The biosensor developed by PolyU researchers is fabricated with a glucose oxidase enzyme (GOx) layer, which is sensitive to glucose alone and nothing else. By detecting the electrical current, the glucose level can be known. However, there can be interference with current from other possible biological elements in saliva, such as dopamine, uric acid and ascorbic acid. To block such interference, researchers have coated Polyaniline (PANI) / Nafion-graphene bilayer films between the top enzyme layer and gate electrode. The strong adhesion of this top layer to the GOx layer enables the latter to stabilize and perform well in glucose detection.

Our novel biosensor is selectively sensitive to glucose, accurate, flexible and low in cost. The highly sensitive biosensor shows a detection lower limit of 10-5 mmol/L, which is nearly 1000 times sensitive than the conventional device for measuring blood glucose. This means with this biosensor, as little as 5 gram of glucose in a standard swimming pool of 50 m x 25 m x 2 m can be detected. Between the wide range of glucose level from 10-5 mmol/L up to 10 mmol/L (equivalent to 5 g – 5000 Kg of glucose in a standard swimming pool), the biosensor demonstrates linear response, which is good enough for measuring the possible range of glucose in the human body. Accuracy of the biosensor has been ascertained through laboratory experiments with repeatable results using glucose solutions of known glucose levels.

The glucose biosensor fabricated with flexible substrates can perform in a variety of curved and moving surfaces, including human skin, smart textile and medical bandage. Thus, it has great potential for development into wearable electronic applications, such as wearable biosensor for analysis of glucose level in sweat during exercise. It can also be mass produced at a low cost of HK$ 3 to 5 per test chip, which is comparable or even cheaper than the currently available commercialized products. In addition, this newly invented transistor-based biosensor platform is highly versatile. By changing to suitable enzymes, the platform can be used to measure the level of uric acid and other materials in saliva. For instance, if the biosensor is fabricated with enzyme uricase (UOx) and Polyaniline (PANI) / Nafion-graphene bilayer films, the platform can specifically be sensitive to uric acid only and other interference signals can be blocked.

 

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Unsupervised, Mobile and Wireless Brain–Computer Interfaces on the Horizon

 

Reporter: Aviva Lev-Ari, PhD, RN

Juliano Pinto, a 29-year-old paraplegic, kicked off the 2014 World Cup in São Paulo with a robotic exoskeleton suit that he wore and controlled with his mind. The event was broadcast internationally and served as a symbol of the exciting possibilities of brain-controlled machines. Over the last few decades research into brain–computer interfaces (BCIs), which allow direct communication between the brain and an external device such a computer or prosthetic, has skyrocketed. Although these new developments are exciting, there are still major hurdles to overcome before people can easily use these devices as a part of daily life.

Until now such devices have largely been proof-of-concept demonstrations of what BCIs are capable of. Currently, almost all of them require technicians to manage and include external wires that tether individuals to large computers. New research, conducted by members of the BrainGate group, a consortium that includes neuroscientists, engineers and clinicians, has made strides toward overcoming some of these obstacles. “Our team is focused on developing what we hope will be an intuitive, always-available brain–computer interface that can be used 24 hours a day, seven days a week, that works with the same amount of subconscious thought that somebody who is able-bodied might use to pick up a coffee cup or move a mouse,” says Leigh Hochberg, a neuroengineer at Brown University who was involved in the research. Researchers are opting for these devices to also be small, wireless and usable without the help of a caregiver.

Sourced through Scoop.it from: www.scientificamerican.com

See on Scoop.itCardiovascular and vascular imaging

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China still has the fastest supercomputer, and now has more than 100 in service – Digital Trends

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Perhaps unsurprisingly, China beat out the United States for the most powerful supercomputer in the world for the sixth time in a row.

Sourced through Scoop.it from: www.digitaltrends.com

See on Scoop.itCardiovascular and vascular imaging

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New treatment for AMI

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Combining Umbilical Cord Cells with Hyaluronic Acid Improves Heart Repair After a Heart Attack

 

Enabling Technologies for Cell-Based Clinical Translation:Injection of Human Cord Blood Cells With Hyaluronan Improves Postinfarction Cardiac Repair in Pigs

Ming-Yao ChangTzu-Ting HuangChien-Hsi ChenBill ChengShiaw-Min HwangPatrick C.H. Hsieh

Stem Cells Trans Med first published on November 16, 2015;doi:10.5966/sctm.2015-0092  

Injection of Human Cord Blood Cells With Hyaluronan Improves Postinfarction Cardiac Repair in Pigs

 Although safe, recent clinical trials using autologous bone marrow or peripheral blood cells to treat myocardial infarction (MI) show controversial results. These discrepancies are likely caused by factors such as aging, systemic inflammation, and cell processing procedures, all of which might impair the regenerative capability of the cells used. Here, we tested whether injection of human cord blood mononuclear cells (CB-MNCs) combined with hyaluronan (HA) hydrogel improves cell therapy efficacy in a pig MI model. A total of 34 minipigs were divided into 5 groups: sham operation (Sham), surgically induced-MI plus injection with normal saline (MI+NS), HA only (MI+HA), CB-MNC only (MI+CB-MNC), or CB-MNC combined with HA (MI+CB-MNC/HA). Two months after the surgery, injection of MI+CB-MNC/HA showed the highest left ventricle ejection fraction (51.32% ± 0.81%) compared with MI+NS (42.87% ± 0.97%, p < .001), MI+HA (44.2% ± 0.63%, p < .001), and MI+CB-MNC (46.17% ± 0.39%, p < .001) groups. The hemodynamics data showed that MI+CB-MNC/HA improved the systolic function (+dp/dt) and diastolic function (−dp/dt) as opposed to the other experimental groups, of which the CB-MNC alone group only modestly improved the systolic function (+dp/dt). In addition, CB-MNC alone or combined with HA injection significantly decreased the scar area and promoted angiogenesis in the infarcted region. Together, these results indicate that combined CB-MNC and HA treatment improves heart performance and may be a promising treatment for ischemic heart diseases.

Significance

This study using healthy human cord blood mononuclear cells (CB-MNCs) to treat myocardial infarction provides preclinical evidence that combined injection of hyaluronan and human CB-MNCs after myocardial infarction significantly increases cell retention in the peri-infarct area, improves cardiac performance, and prevents cardiac remodeling. Moreover, using healthy cells to replace dysfunctional autologous cells may constitute a better strategy to achieve heart repair and regeneration.

 

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Pharmacy International Conference

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

3rd Nirma Institute of Pharmacy International Conference
NIPiCON – 2016
January 21 – 23, 2016 ………….http://www.nipicon.org/.

Anthony Melvin Crasto   https://www.facebook.com/groups/worlddrugtracker/permalink/1170816792946389/

The pharmaceutical sciences is a dynamic and interdisciplinary field that combines a broad range of scientific disciplines that are critical to the discovery and development of new drugs and therapies. Over the years, pharmaceutical scientists have been instrumental in discovering and developing innovative drugs that save people’s lives and improve the quality of life.

NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

Pharmaceutical innovation is a complex creative process that harnesses the application of knowledge and creativity for discovering, developing and bringing to clinical use, new medicinal products that extend or improve the lives of patients.A successful pharmaceutical R&D process is one that minimizes the time and cost needed to bring a compound from the scientific ‘idea’, through discovery and clinical development, to final regulatory approval and delivery to the patient. This conference will provide an open forum for the academicians, researchers, clinicians and professionals of pharmaceutical industry to enrich their knowledge in the area of drug discovery, development and its regulatory requirements.

The conference features plenary sessions which will be delivered by eminent national and international speakers from different disciplines of pharmaceutical field. In addition, there will be invited lectures and sessions delivered by distinguished and young researchers in their respective fields during parallel technical sessions. The conference willalso provide the opportunity to scientists and research scholars from various organizations to put forth their innovative ideas and research findings by means of deliberations, discussions and poster presentations.

 

NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

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Philip Seymour Hoffman’s death

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

 

Philip Seymour Hoffman, Actor of Depth, Dies at 46

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Robin Williams death

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Lewy body: The ‘monster’ dementia blamed for Robin Williams’s death

Schneider says depression didn’t cause Williams’s death: “Lewy body dementia killed Robin. That’s what took his life.”

Strikingly, LBD – sometimes referred to as dementia with Lewy bodies or Parkinson’s with Lewy bodies, depending on symptoms – is the second-most common dementia after Alzheimer’s and affects more than 127,000 Britons. Yet most people have never heard of it.

Robin Williams who suffered from Lewy Body Dementia.

James Galvin, a neurology and psychiatry professor at Florida Atlantic University, says: “It’s the most common disease you’ve never heard of.”

“This disease is a sea monster with 50 tentacles of symptoms that show when they want,” Schneider said.

Williams suffered hallucinations, anxiety, depression, loss of motor control and problem-solving skills, sleep, balance and spatial awareness problems, and delusions.

Schneider describes one incident just weeks before Williams’s death, when she was in the shower and he was standing by the sink.

“Something didn’t seem right,” she recalls, so Schneider got out of the shower to find her husband’s head covered in blood. “He pointed to the door and I said, ‘Did you hit your head?’ and he nodded.” The incident confused her at the time. “But now, finding out all about Lewy body disease, lo and behold, their vision is affected, as is the ability to recognise and identify objects,” she says. “Now I get it.”

 

Lewy bodies are protein deposits in the brain, explains Professor David Burn, consultant neurologist and director of the biomedical research unit in LBD at the UK National Institute of Health Research (NIHR).

Discovered by Dr Frederic Lewy, a colleague of Dr Alzheimer’s, in 1912, the deposits develop inside nerve cells (neurons) in the brain, interrupting messaging and causing neurons to die. A patient’s symptoms will depend on which part of the brain is affected.

“When neurons die in the cortex, it causes dementia, but when it occurs in the brainstem, it causes motor symptoms (Parkinsonism),” says Burn.

“LBD patients face a rapid deterioration in their cognitive, physical and psychiatric function, and it tends to progress faster than other dementias,” he says.

When Paul Moynagh’s wife, Imogen, couldn’t find her way from a cafe table to the counter on a visit to a National Trust house in Devon in 2006, he thought little of it.Paul, 78, couldn’t have predicted the confusing set of symptoms that Imogen, 74, would experience. LBD is often misdiagnosed as Parkinson’s or Alzheimer’s, and it took doctors almost seven years to confirm her illness.

“Looking back, it began with little signs – loss of spatial awareness is an early symptom –  but they were so inconsistent,” recalls Paul, a retired surgeon.

First, there was a minor trembling in Imogen’s hands, then severe sleepiness during the day, along with spasms that made her right foot turn in when she walked. Then she developed depression and suffered panic attacks.

“Imogen has a pragmatic personality,” says Paul. “She used to play sports, was a keen gardener, walked everywhere and looked after our two children, Mark and Rachel. Ten years ago, if you had told her she would be afraid of being left alone, she would have laughed.”

By 2010, Imogen’s reasoning and planning skills were suffering – a key sign of LBD.

A keen bridge player, Imogen recalls: “I stopped winning, so I knew something was wrong.” (Though her speech is now slow, her sense of humour remains.)

 

Like Schneider, Paul Moynagh was also baffled by his wife’s repeated falls in the years preceding her diagnosis. “She’d had nine different broken bones, breaking her wrist twice, her ankle, and once, when she’d fallen down some stairs, her elbow.”

Imogen, like Williams and many LBD sufferers, was initially diagnosed with Parkinson’s disease.

 “She began shuffling when she walked and her voice became weak, both symptoms of Parkinson’s,” says Paul. Meanwhile, her depression was getting worse, not least because Imogen was so aware of what was happening to her.

“It’s different from Alzheimer’s in that people know exactly what’s happening, and one day can be completely lucid and the next be experiencing terrible anxiety and delusions. The more Imogen is aware of her situation, the more she gets depressed.”

When Paul Moynagh’s wife began experiencing hallucinations – a tell-tale sign of LBD – he knew that there was more to her illness than Parkinson’s. “She would see people in the windows of the conservatory and in our floor – which we made look like natural stone – she saw figures speaking to her.

“In my desperation, I would spend hours Googling Imogen’s symptoms until I stumbled on Lewy body dementia,” he says.

Brown says Robert had paranoia and hallucinations – he was frightened by faces he would see in the windows of a summer house he had built at the bottom of the garden. “One evening we were watching the Baftas on television and the camera panned, settling on various stars, and Bob turned to me and said: ‘I think Judi saw us.’ He meant Dame Judi Dench. He thought we were there and became very distressed because he wasn’t correctly dressed.”

“I’m a doctor and I had never even heard of it, and the neurologist was reluctant to accept it, but Imogen ticked all the boxes.” By 2013, a locum psychiatrist finally diagnosed Imogen with LBD. “I went along with my Google list, and she finally made the diagnosis. Two months later, the neurologist finally agreed.”

 

June Brown, who plays Dot Cotton in EastEnders, lost her husband, actor Robert Arnold, to LBD in 2003.

In a moving video made for the charity Lewy Body Society, Brown recalls: “Bob knew what was happening to him and he hated it. He once said: ‘I never thought I would go like this.'”

Unlike Alzheimer’s sufferers, LBD patients often have lucid memories. “Bob never lost his memory for people’s names. It’s the most strange disease because he would have moments of confusion and moments of clarity. It’s worse than Alzheimer’s because of this awareness of what you’re going through.”

 

Now, the only way to know that someone had Lewy body dementia is when a post-mortem examination finds Lewy bodies in the brain.

According to LBD specialist Ian McKeith, professor of old age psychiatry at the Newcastle University Institute for Ageing, LBD often gets misdiagnosed because doctors don’t know which questions to ask. He is in the middle of a study funded by the NIHR to develop a diagnostic toolkit for use in NHS practices.

Although there is no cure for LBD, doctors can treat symptoms using drugs that work on the brain’s messaging system, says McKeith. But correct diagnosis is essential. “If antipsychotic or anti-Parkinson’s drugs are given to patients with LBD, they can be fatal,” he says.

“We were living a nightmare,” Susan Schneider said of Robin Williams’s final months.

McKeith says one study found that when carers looking after someone with LBD were asked to rate their quality of life on a scale of zero to one (where zero was as bad as it could be), one in four rated it as below zero.

Still, Paul Moynagh refuses to refer to life with Imogen as a nightmare. She now needs 24-hour attention and help feeding. They recently celebrated their 50th wedding anniversary. During our interview, she turns to her husband and says slowly, with the difficulty she now has in getting words out: “Without your care, I don’t know where I would be.”

“Underneath it all, she is still the lovely person that I married,” he says.

“We still love each other as much as we did before – that hasn’t changed. If anything, I love her more.”

 

 

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Compassionate Care

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

What Price Compassion?

http://www.cancernetwork.com/blog/what-price-compassion

 

“When a person realizes he has been deeply heard, his eyes moisten. I think in some real sense he is weeping for joy. It is as though he were saying, ‘Thank God, somebody heard me. Someone knows what it’s like to be me.’”

“If I let myself really understand another person, I might be changed by that understanding. And we all fear change. So as I say, it is not an easy thing to permit oneself to understand an individual.”

— Carl Rogers, American Psychologist (1902–1987)

Oncologists, whether they like it or not, must develop some psychological skills if they ever hope to master the art of caring for people living with cancer. Among our many duties we serve as therapists to those diagnosed with, living with, and dying with cancer. Therefore, it behooves us to recognize the benefits of communicating our regard for our patients’ lives and our concern for their anxieties. Compassion, defined as sympathy for another’s woes and a desire to ease them, is succor for fear. Compassion creates a bond of trust between doctors and patients that soothes painful emotions and provides support during difficult times. Given the oncologist’s busy schedule, is compassion a superficial gratuity or does it require training and execution in order to be meaningful? How do we, who have no formal training as therapists, learn to value it for our patients and use it successfully?

The eminent psychologist Carl Rogers, known as the father of client-centered therapy and the author of the two quotations above, would be a welcome addition to the oncology staff. His philosophy of therapy emphasized letting the client (his term for patients) direct the course of discussion as a means toward deeper understanding, and he emphasized the need for the therapist to follow certain guidelines. I believe his method fits perfectly with our need to learn the skill of compassion. Let’s look at the three qualities Rogers requires the therapist to possess and how they can be used in the oncology clinic.

1. Congruence, also known as Genuineness. This is the ability to be real, to be transparent, with no façade of self-importance or didactic formality that could build a wall between the patients and us. In order to express compassion to the needy, we must project an honest image of ourselves; we must drop the mask hiding our true feelings. For example, if I’m having a bad day, I should admit it rather than act frustrated for no reason. If something funny comes to me, I will share it. I want to let my patients see me for who I truly am—a fellow human being, with no appetite for phoniness.

2. Unconditional Positive Regard. Just as it is named, this means accepting patients for who they are and eliminating any prejudices or disparaging feelings that threaten to surface. We all have personality quirks, shortcomings in communication skills, imbalances, and hidden agendas. We must not let anyone’s flaws or foibles poison our professional relationship. No matter how unpleasant, annoying, nervous, or angry our patients are, we shall respect them as unique individuals and not let them influence us in a negative, unhelpful way. Inside all of us is a yearning for respect and love. Thus, compassion is meant to be shown to all—no favoritism.

3. Empathy. Dr. Rogers believed that the therapist must be able to accurately interpret the inner emotions and struggles of the client “as if one were the person, but without ever losing the ‘as if’ condition.” Oncologists who are able to see a situation through the eyes of their patients will succeed in their mission. We must be able to “enter another’s world without prejudice,” and the best way to do this is by being perfectly comfortable in our own skin to the point that we can block our inner reactions and focus entirely on what it must be like to be the patient. Empathy will never fail to bring forth compassion.

In my opinion, compassion in the oncology clinic is 90% listening and 10% speaking, and it can only be given by those who have learned how to leave themselves out of the picture. Our opinions, biases, peculiarities, and attitudes are immaterial to the job at hand. When their lives are on the line, our patients want to know, “Does my doctor really care about me or not?” May we never be ignorant of that unspoken question, and may we always be ready to reveal the happy answer, again and again.

 

Thank you for this beautiful post. Nothing is more important, as Dr. Hildreth points out, than knowing “does my doctor really care about me or not?”
I have read other posts by Dr. Hildreth, and each and every time I have come away with a better understanding of what it means to be in this profession of treating cancer patients. I admire Dr. Hildreth’s philosophy so much. The first time I ever read one of his posts, I said to myself (and to some of my employees) “Dr. Hildreth is the kind of oncologist I would want to have if I ever had cancer myself”. Thank you so much, Dr. Hildreth, for being a beautiful human being and oncologist.

Irene Balowski

 

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Tandem Repeats, with Application to Human Population-Divergence Time

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Effective Mutation Rate at Y Chromosome Short Tandem Repeats,with Application to Human Population-Divergence Time
Lev A. ZhivotovskyPeter A. Underhill, Cengiz Cinniog˘lu, Manfred KayserBharti MorarToomas KivisildRosaria Scozzari, et al.
We estimate an effective mutation rate at an average Y chromosome short-tandem repeat locus as per 1025 years, with a standard deviation across loci of , using data on microsatellite variation within chromosome haplogroups defined by unique-event polymorphisms in populations with documented short-termhistories, as well as comparative data on worldwide populations at both the Y chromosome and various autosomal loci.This value is used to estimate the times of the African Bantu expansion, the divergence of Polynesian populations (the Maoris, Cook Islanders, and Samoans), and the origin of Gypsy populations from Bulgaria.
Microsatellites, or STR polymorphisms, are abundant in the human genome and can be easily genotyped andscored; they have thus become a useful tool for the elucidation of human population history and for forensic purposes. Knowledge of the mutation rate at STR loci isimportant, both for calibration of the molecular clock inevolutionary studies and for forensic probabilistic calculations. Increasing attention has recently been paid to microsatellite variation within Y chromosome haplo-groups defined by binary polymorphisms, such as SNPs or, as a general term, “unique-event polymorphisms”(UEPs) (Underhill et al. 1996; Zerjal et al. 1997;deKnijff 2000; Kayser et al. 2000a), many of which are specific to populations related through their recent or distant history (Underhill et al. 2000; Hammer et al. 2001; Y Chromosome Consortium2002).  Although the Y chromosome locus is the ultimate SNP-STR system, similar linked SNP and STR haplotypes are also available in autosomes (Mountain et al. 2002).
A mutation rate of per generation has been estimated for Y chromosome microsatellites by direct count in deep-rooted pedigrees (Heyer et al. 1997). A similar average mutation rate value of per locus
per generation was estimated by studying Y chromosome STRs (Y-STRs) in father/son pairs of confirmed paternity, although locus-specific values varied from 0 to 8 (Kayser et al. 2000b).  Y-STR analysis in sperm revealed an average rate of repeat gains of for two Y-STRs (Holtkemper et al. 2001); however, mutations that included repeat losses could not be considered owing to limitations of the methodology used. No germ-line mutation was observed in Y-STRsfromcelllineDNA(Bianchi et al. 1998), but this result does not differ in a statistically significant way from the mutation rate esti-mates mentioned above.By counting the number of mutations in the branches of a haplotype network from samples of Native American populations, Forster et al. (2000) found a striking difference between their “evolutionary” estimate per 20 years) and the “pedigree” estimate described above. It is unclear which rate should be used; for evolutionary studies, we need to know those mutations that are involved in differences between lineages or populations. An inappropriate choiceofthemutationratevaluemay produce a 10-fold deviation from the true age of pastpopulationevents.Thediscordancebetweenthetwokinds of estimate needs to be addressed.The estimate y Forster et al. (2000) refers to a me-dian network constructed from the Y chromosome haplotypes found in the combined data from Native American populations. However, haplotype history might not represent the population history. In addition, such a network assumes single-repeat–unit mutational changes. Multistep Y-STR mutations, which have been observed recently (Forster et al. 1998; Kayser et al. 2000b;  Nebelet al. 2001), can contribute significantly to the  effective mutation rate (with  the product of the mutation rate and the variance of mutational changes in repeat scores), which determines the rate of microsatellite evolution (Slatkin 1995; Zhivotovsky and Feldman 1995). Furthermore, Forster et al. (2000) used for calibration an estimate of the time of population expansion in North America of 20,000 before the present (BP)—an estimate upon which there is no general agreement.In the present study, we estimate the effective mutation rate, using data on microsatellite variation withinY chromosome haplogroups defined by SNPs in populations with documented short-term histories, as well as comparative data on worldwide populations at both autosomal and Y chromosome loci. Then we apply our finding to estimate the time of expansion of Bantu-speaking populations in sub-Saharan Africa, the time of differentiation of some Polynesian populations, and the time of origin of Bulgarian Gypsy populations.
Estimates of Effective Mutation Rates on the Basisof Genetic Distances
Comparison of the Maoris and Cook Islanders gavean average value (over the seven loci; see table 1; fig.1) for (dm) of 0.00998, which suggests an average effective mutation rate of 0.000312 per 25 years( ). Pairwise comparisons of the
0.00998/800Bulgarian Gypsy populations (without the Darakchiisample, in which only one M82 individual was found) gave (dmof 0.01272 (averaged across population pairs and loci) or 0.000454 for the average effective mutation rate. However, these are most probably underestimates, because the (dmdistance assumes constant size for each SNP lineage over time, and it also assumes the same within-lineage variation in an ancestral population prior to its split as at the present generation. It is more likely that each of those populations was founded by a small number of haplotypes and,thus,had lower STR variation prior to divergence; this can lead to an underestimate of the rate of divergence (Zhivotovsky 2001). Therefore, we apply the second esti-mator, the average squared difference, to the Maoriand the Gypsy populations.The haplotype network shown in table 1 and figure1 suggests two founder haplotypes for the seven loci in the Maori population, PA and PD (both present in the Cook Islanders), because these haplotypes differ at two loci with no connection by single mutations (see the network of Maori haplotypes in table 1 and fig. 1). By using the ASD
 estimator for each of the haplotype networks in table 1 and figure 1 and then averaging them with weights proportional to sample sizes, we obtain a mean SE effective mutation rate of 0.000705, with SD p = 0.00078 across loci. Each of the Gypsy populations contains haplotype A at high frequency (table 3), which suggests that it is the ancestral type. The Lom population is the only one thatcontains a different haplotype, B, at the highest fre-quency; therefore, it is likely that both A and B werefounder haplotypes in this population. The Musicians are extremely heterogeneous compared with the other populations: of 19 Y chromosomes, 6 carry haplotypes that differ from haplotype A by two alleles. No other Gypsy population displays chromosomes that diverge to this extent from the ancestral haplotype (except for the Lom, in which only 1 of 26 chromosomes differed by two alleles from haplotype A). Moreover, the distribution of chromosomes in the Musicians (with 0, 1, and 2 differences relative to haplotype A) has a mean of 0.237 and a variance of 0.417, thus deviating significantly from a Poisson distribution. (∼  2.28 sample size, and  follows a  t  distribution, with df and a one-tailed value of .018. This is not the case for the other populations, which suggests that the genetic structure of the Musicians differs fromthat of other Gypsy groups in Bulgaria. The populationof the Musicians could have been founded with multiple haplotypes and/or could have been subject to admixture;therefore, we do not include it in the analysis. After removing the Musicians, we compute  w  for each population and then weight its values with the sample sizes;this gives p = 0.000725 with 0.000187 SD across loci. For the two sets of comparisons, we use the estimates 0.000705 and 0.000725 in the subsequent analysis.
Estimates of Effective Mutation Rates Based on Comparative Variation
The variances in the number of repeats were computed for each Y chromosome locus in each of 52 worldwide populations. The variances were then converted into estimates of effective mutation rates, as described in the“Material and Methods” section. Averaging over populations gives a  SD estimate of 0.000638 – 0.000109 across loci.   (p = 0.00029)
Overall Estimate On the basis of the arithmetic mean of the above three figures (i.e., 0.000705, 0.000725, and 0.000638), we estimate of the effective mutation rate at the average Y chromosome locus.
 
Discussion
Comparison with Autosomal Loci 

Our estimate of the average effective mutation rate at Y chromosome STR loci( per 25 years) is closto those at autosomal microsatellites with tri- and tetra-nucleotide repeats, and (Zhivotovsky et al. 2000) and and (Zhivotovsky et al. 2003), which probably reflect the same slippage machinery that underlies STR mutations. Itshould be kept in mind that our estimate of effective mutation rate was based on STRs with three- and four-nucleotide motifs; inclusion of loci with dinucleotide repeatmay increase this value, because they generally have a higher (effective) mutation rate (Chakraborty et al.1997; Zhivotovsky et al. 2000).

 

Dependence of the Estimate on NongeneticInformation
Estimating mutation rates for the SNP/STR data from populations with available archaeological/historical records relies heavily on those records. For example, in the present study, we used 800 years BP as the time of arrival give a mutation rate of 0.00056. Therefore, the above mutation rate, 0.000705, which was inferred from the Maori data, might be an overestimate.Other proposed dates include 650–700 years BP (Mc-Fadgen et al. 1994), and 1,200 years BP (Bellwood 1989), leading to mutation rate estimates of of the Maoris in New Zealand. This may be a lower bound for the time of colonization, and 800–1,000 years BP seems to be an appropriate range for that event (Irwin 1992; Sutton 1994; Diamond and Bellwood 2003); the latter date would  ∼ 0.00087–0.00081 and  ∼ 0.00047, respectively.The same argument can be applied to the Gypsy data.Historical records suggest that the Gypsies arrived in Bulgaria 
700 years BP. This may be an underestimate ,since small groups are not historically “visible” until they become numerous or involved in an important event. If an actual divergence occurred 800 years BP, this would give an effective mutation rate of 0.000634 instead of 0.000725.
……
All this demonstrates that, despite variation in estimates of average Y-STR effective mutation rate (variations due to uncertainties in archaeological/historical data and in male/female population dynamics), these estimates are close to the overall point estimate ( per 25 years) and lie within the interval defined by SE, which is attributable to differences between loci. Doubling the SE, we obtain and as heuristic confidence limits for w. Potential errors in estimates of  w
 attributable to uncertainties in archaeological/historical records (see the first two paragraphs of the present section) lie within these limits. Therefore, variation among loci in effective mutation rate of various loci may be a major source of deviation of an average estimate of  w  from a true value for Y chromosome STRs. 
Between-Locus Variation in the Effective Mutation Rate
Mutation rates are reported to vary substantially among autosomal microsatellites (Di Rienzo et al.1998; Zhivotovsky et al. 2001); the same is expected for Y chromosome STRs (Forster et al. 1998; Kayser et al.2000b;
 Nebel et al. 2001). On the basis of our data, we calculate that the coefficient of between-locus variation in effective mutation rate is 0.00057/0.00069 ; a similar level of between-locus variation in effective mutation rate has been observed for autosomal loci (Zhivotovsky et al. 2001). Although sampling errors contribute to this variation, the differences in  w between loci are nevertheless important. Indeed, mutation rates can vary from locus to locus, depending on their structure. Forexample, DYS389 is a complex locus consisting of four tetranucleotide-repeat subloci (Cooper et al.1996; Rolf et al. 1998) that yield two distinctive fragments when genotyped using conventional protocols,since the forward primer anneals twice. One fragment contains all four repeat motifs (A, B, C, and D), and the other fragment, which contains just two (C and D), is often denoted by “I”. The shorter CD fragment is subtracted from the larger to yield the AB (“II”) allele. Itis important to note that the C motif is almost alwaysonly three repeats and thus is monomorphic, whereas the longer combined AB motifs are both polymorphic,thus making the AB region more mutable than the CD region. The sublocus DYS389AB can be treated as aseparate microsatellite locus that has an inherentlyhigher mutation rate than the CD sublocus. This genomic complexity and the consequent differential mutation properties of the subloci are expected to increase the overall mutation rate for DYS389. Removing DYS389 from the analysis gives . Counting that locus twice produces the same value, 0.00061. However, it is difficult to conclude that DYS389AB or other such loci will always behave—in UEP lineages or entire populations—as loci with high mutation rates,and more data will be needed to distinguish loci with different effective mutation rates. Another source of apparent between-locus variation may be different mutation rates for alleles with different numbers of repeats(Brinkmann et al. 1998). This variation actually occurswithin a locus and can greatly confound between- andwithin-locus variation. Probably, our estimate of SD,, includes both kinds of variability and therefore encompasses an entire range of “between-allele”variation.Variation in mutation rates should be kept in mind,because it might be a major source of uncertainty whena small number of loci are used. The large SE of the average mutation rate obtained here and the large SE of divergence time estimates (see below) reflect such variation. (Note that highly variable Y chromosome haplotypes cause very big CIs for coalescent times based on microsatellites [Pritchard et al. 1999]).Therefore,datinghistorical events on the basis of a small number of Y-STR loci might disagree with historical/archaeologicalrecords, although the latter might also have large “SEs.”Theoretically, hundreds of loci may be needed for precise dating of ancient demographic events (Zhivotovsky andFeldman 1995; Goldstein et al. 1996; Jorde et al. 1997), and different subsets of loci may give different estimates because of different mutation rates (Zhivotovsky et al.2003). Analysis of population divergence within UEP lineages should require fewer microsatellite loci for precise dating, because STR variation within a UEP lineage must be smaller than that in the entire UEP-heterogeneous population. The sample of Y chromosome STR loci (no more than 10 were used here) still seems too small, and a larger number of loci need to be analyzed (e.g., Seielstad et al. 2003), and
150 new Y-STRs will be available in the near future (M.Kayser, M.A.Jobling, A. Sajantila, C. Tyler-Smith, unpublished data). Futhermore, we cannot exclude the possibility that mu-tation rates at the same STR locus vary among haplo-groups because of differences in allele repeat scores, repetitive structures, or other factors (Nebeletal.2001); mutation rates might also be population specific, because of variation in genes that encode proteins involved in DNA replication and repair mechanisms or proteins that cause associated selection, if these exist (see Jobling and Tyler-Smith 2000). A large sample of loci might decrease these possible effects, but, in the absence of hard information, it seems reasonable to use the same overall average mutation rate for all instances.The estimates of average effective mutation rate and the SD can be used to obtain a two-parameter prior distribution for Y chromosome effective mutation rates for use in coalescent models.
……
The origin and time of arrival of the Samoans are inquestion. The tree in figure 3 shows that the Samoans split much earlier than the ancestral population that gave rise to the Maoris and Cook Islanders. Recall that theMaoris arrived in New Zealand 800–1,000 years BP; together with the time estimate between the two separation events in figure 3, this implies  ∼ 3,500 years BP for divergence of the Samoans from a common ancestral population. This can be compared with the time of East Polynesian settlement, estimated to have occurred by 500–1000  BC  (Irwin 1992, p. 81), and to the estimate of the early peopling of Polynesia, 3,000–4,000 years BP (Underhill et al. 2001).
Divergence between the Gypsy Populations

Computation of  T values averaged over all possible pairs of the 10 Gypsy populations (omitting both the Darakchii, with one M82 individual only, and the Musicians) and gives us an estimate of the time of founding of an ancestral population of related males sharing the same Y haplotype that gave rise to the contemporary Bulgarian Gypsy populations. This estimate gives 1,500-700 BC an upper bound for the divergence time and is compatible with the formation of the proto-Gypsies in India,predating their entry into the Byzantine Empire 900–1,000 years BP (Fraser 1992). If diversity was already substantial in the founder male population, and the estimate of divergence time would be smaller. The genetic composition of the Musicians differs greatly from that of the other studied Bulgarian Gypsy populations, a fact that points to possible differences in their evolutionary history. There are two possible explanations for this: the Musicians share the same origin but were greatly admixed with populations from South Asia that carried the M82 mutation, or they descended from an ancestral population different from that of the other Bulgarian Gypsy populations studied. The origins of the proto-Gypsies, as well as the time and number of migrations out of India, are still disputed among cultural anthropologists and linguists (Fraser 1992; Marushia-kova and Popov 1997; Hancock 2000). Our previous study (Gresham et al. 2001) suggested a common origin from a small group of ancestors. One should note, however, that the Musicians were not included in that study and that they are the sole representatives of a particular Balkan dialect of the Romanes language. In addition to the unusual distribution of M82 haplotypes, they display a generally higher diversity of Y chromosome lineages, including other uncommon types, that are unlikely to result from European admixture. If we follow the “different origins” scenario, the  TD estimator gives an upper bound of 2,600 years BP for the separation of the Musicians from a population ancestral to the other studied populations of Bulgarian Gypsies. The difference of 1,100 years between the two splits (fig. 4) allows not only for heterogeneous origins but also for the possibility of different proto-Gypsy migrations from the Indian subcontinent.

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FDAnews Drug Daily Bulletin

Pharmaceuticals / Submissions and Approvals

Teva Wins Breakthrough Therapy Designation for Tardive Dyskinesia Candidate

Nov. 16, 2015

Teva Pharmaceutical Industries has won the FDA’s breakthrough therapy designation for SD-809 for the treatment of moderate to severe tardive dyskinesia.

An oral, small molecule inhibitor of vesicular monoamine 2 transporter, SD-809 (deutetrabenazine) is designed to regulate the levels of dopamine in the brain. There are currently no approved therapies in the U.S. for tardive dyskinesia, a disorder characterized by repetitive and uncontrollable movements of the tongue, lips, face and extremities.

The Israeli drugmaker’s 117-patient Phase 2/3 study compared SD-809 to placebo for reducing the severity of abnormal involuntary movements associated with tardive dyskinesia. The compound also is being developed for treatment of chorea associated with Huntington’s disease, as well as tics associated with Tourette syndrome.

Tardive dyskinesia: a brief explanation

From Medline Plus

Tardive dyskinesia is a disorder that involves involuntary movements. Most commonly, the movements affect the lower face. Tardive means delayed and dyskinesia means abnormal movement.

Causes

Tardive dyskinesia is a serious side effect that occurs when you take medications called neuroleptics. Most often, it occurs when you take the medication for many months or years. In some cases, it occurs after you take them for as little as 6 weeks.

The drugs that most commonly cause this disorder are older antipsychotic drugs, including:

  • Chlorpromazine
  • Fluphenazine
  • Haloperidol
  • Trifluoperazine

Other drugs, similar to these antipsychotic drugs, that can cause tardive dyskinesia include:

  • Flunarizine
  • Metoclopramide
  • Prochlorperazine

Newer antipsychotic drugs seem less likely to cause tardive dyskinesia, but they are not entirely without risk.

Symptoms

Symptoms of tardive dyskinesia may include:

  • Facial grimacing
  • Finger movement
  • Jaw swinging
  • Repetitive chewing
  • Tongue thrusting

Treatment

When the drug is stopped early enough, the movements may stop.

Medications to reduce the severity of the movements may also help. Botulinum toxin (Botox) injections may be effective.

Outlook (Prognosis)

If diagnosed early, the condition may be reversed by stopping the drug that caused the symptoms. Even if the drug is stopped, the involuntary movements may become permanent, and in some cases, may become worse.

References

Flaherty AW. Movement disorders. In: Stern TA, Rosenbaum JF, Fava M, et al., eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry. 1st ed. Philadelphia, PA: Elsevier Mosby; 2008:chap 80.

Kompoliti K, Horn SS, eds. Drug-induced and iatrogenic neurological disorders. In: Goetz CG, ed. Textbook of Clinical Neurology. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2007:chap 55.

Please watch these two VIDEOS on Extrapyramidal Syndromes and Movement disorders

 

Monoamine transporters and movement disorder

Links between the monoamine transporter VMAT2 (SLC18A2 gene) and tardive dyskinesia

J Psychiatr Res. 2013 Nov;47(11):1760-5. doi: 10.1016/j.jpsychires.2013.07.025. Epub 2013 Sep 6.

Association study of the vesicular monoamine transporter gene SLC18A2 with tardive dyskinesia.

Abstract

Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular monoamine transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

Other journal articles related to VMAT2

 

 

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