Apple Cheese Cake with Autumn Attitude Crust

Sometimes, I brag and this is one of those times. Because apples are in season now, I wanted to use them in a new dessert; but last year I already did several apple cakes. Then a light went off. As I had never heard of an apple cheese cake, this became a new challenge. The first attempt was delicious but wasn’t presentable enough for photos. I also wanted to experiment more with the crust, as well as the filling. We ate our way through the week, all the variations I could think of. You get to make it one time and savor the flavors delicieux. ©Joyce Hays, Target Health Inc.




4 or 5 fresh apples

4 containers of Tofutti (soy cream cheese)

1/2 teaspoon vanilla

7 Tablespoons sugar (fine grains)

5 Tablespoons extra virgin olive oil

1 and 1/2 teaspoons baking powder

Zest of 1/2 fresh lemon

2 teaspoons fresh lemon

6 large eggs


15 graham crackers (2 and 1/2 inches x 5 inches) or 8 ounces

3 Tablespoons dark brown sugar

1 stick butter, soft and cut into pieces

1 teaspoon cinnamon

1 pinch ground nutmeg


Try to buy the best available ingredients.  ©Joyce Hays, Target Health Inc.



Do the crust first


1. Place graham crackers in the bowl of a food processor. Process until they are almost fine crumbs. Add dark brown sugar, cinnamon, nutmeg and butter. Process until mixture clumps together like damp sand.


Processing all the crust ingredients. ©Joyce Hays, Target Health Inc.


2. With the paper the butter stick was wrapped in, oil a large pie dish.

3. With your fingers, press the graham cracker mixture evenly into the bottom of a 9 or 10 inch pie dish and refrigerate 30 minutes while preparing filling.


Get the processed crust out of the food processor with a spatula and press into the bottom and sides (if only enough for the bottom, that’s fine, don’t worry about it). Press as hard as you can and make the crust even all over. Then put in fridge for 30 minutes. ©Joyce Hays, Target Health Inc.



1. Heat oven to 325 degrees.

2. If your food processor is small and you can’t do all the filling at once in it, don’t worry, simply do each step, then remove the contents from processor into a large bowl and continue with the next step, until all ingredients have gone through the processor. Then mix all ingredients in the large bowl, very well.

3. Peel skin and core 3 apples and puree in food processor until smooth


Processing the 3 apples. ©Joyce Hays, Target Health Inc.


4. Add Tofutti and process until smooth.

5. Add superfine sugar, and with motor running, add eggs one at a time.


Processing the rest of the filling. I need a new food processor; this one is too small to hold all the filling ingredients. ©Joyce Hays, Target Health Inc.


6. Add lemon or lime juice, and process until blended.

After each processing step I scrape the pureed ingredients, into a large bowl. ©Joyce Hays, Target Health Inc.


7. Cut and core (leave skin on) the other 2 apples. Then on a cutting board, chop these apples into small dice-shaped pieces and set aside.


Chopping two apples with skin left on. ©Joyce Hays, Target Health Inc.


8. Wait until crust has been in fridge for 30 minutes.


Contents of bowl have all been pureed in food processor and are now ready to pour into the crust. ©Joyce Hays, Target Health Inc.


9. Scrape all the filling out of food processor (or out of the large bowl) and into the pie dish with crust.

10. Now, with your hands or a spoon, sprinkle the cut up apple pieces with skin on, over the top of the cheese cake.


Cheese cake going into oven. ©Joyce Hays, Target Health Inc.


11. Put pie dish into the oven.

12. Bake for about 1 hour and 45 minutes, until filling is set and wobbles slightly in the center (it will continue to cook as it cools). After baking for 1 hour and 30 minutes, check to be sure cheese cake isn’t too dark around the edge.

13. When cheese cake is done and wiggling a little in center, remove and allow it to do its thing, while cooling down completely.


Just out of oven. ©Joyce Hays, Target Health Inc.


14. When cool, refrigerate overnight. Then serve the next day.


Yummy apple cheese cake; creamy filling and crunchy crust! ©Joyce Hays, Target Health Inc.


We’re drinking an icy Sauvignon Blanc from the Marlborough district of New Zealand. A delicious wine with a rating in the 90s and worth every penny (do they still exist?). We chilled the glasses first. ©Joyce Hays, Target Health Inc.


From Our Table to Yours

Bon Appetit!


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Computational model reveals insights into the mechanism underlying focal cooling in rats

October 5, 2017


Using computer simulation techniques, scientists have gained new insights into the mechanism by which lowering the temperature of specific brain regions could potentially treat epileptic seizures.



Using computer simulation techniques, scientists have gained new insights into the mechanism by which lowering the temperature of specific brain regions could potentially treat epileptic seizures. The results are published in PLOS Computational Biology.

About 50 million people worldwide deal with sudden, recurring seizures that are the hallmark of epilepsy. Treatment with medication or surgery does not work for some patients, so scientists have been investigating a potential alternative called focal cooling, in which a device would be implanted in the brain to suppress the electrical signals — discharges — that characterize epileptic seizures.

In the new study, Jaymar Soriano of Nara Institute of Science and Technology (NAIST), Japan, and colleagues, sought to better understand the mechanism by which focal cooling operates. So far, the technique has been tested only temporarily in epilepsy patients as intraoperative studies, while it has shown consistent success in rats. However, focal cooling sometimes slightly increases the frequency of epileptic discharges in rats, even while suppressing their strength.

To investigate how focal cooling suppresses epileptic discharges with possible increase in frequency, the research team took a computational approach. They employed a model of the rat brain that allowed them to simulate different mechanisms underlying the effects of a focal cooling device on epileptic discharges.

Using data from laboratory and rat studies, the researchers first simulated a mechanism by which focal cooling reduces activity at connections between neurons, resulting in less frequent discharges. However, with this mechanism alone, the model could not accurately reproduce electrical activity patterns previously observed in focal brain cooling experiments on rats with drug-induced epilepsy.

To compensate for the first mechanism, the researchers devised a second mechanism in which cooling resulted in discharges that were persistent but weaker. Incorporating both mechanisms into the model allowed the team to successfully reproduce results from previous rat experiments.

“Focal brain cooling could be an alternative treatment for epileptic seizures with lower risk of irreversible functional loss compared to surgery,” says study co-author Takatomi Kubo. “Our study attempts to start an initiative on thermal neuromodulation of brain activity using a computational approach that can elucidate its mechanism and complement animal experiments and clinical tests.”

Further investigation and laboratory studies could help the researchers refine their model and better understand the mechanisms that underpin focal cooling.

Story Source:

Materials provided by PLOSNote: Content may be edited for style and length.

Journal Reference:

  1. Jaymar Soriano, Takatomi Kubo, Takao Inoue, Hiroyuki Kida, Toshitaka Yamakawa, Michiyasu Suzuki, Kazushi Ikeda. Differential temperature sensitivity of synaptic and firing processes in a neural mass model of epileptic discharges explains heterogeneous response of experimental epilepsy to focal brain coolingPLOS Computational Biology, 2017; 13 (10): e1005736 DOI: 10.1371/journal.pcbi.1005736


Source: PLOS. “Simulating a brain-cooling treatment that could one day ease epilepsy: Computational model reveals insights into the mechanism underlying focal cooling in rats.” ScienceDaily. ScienceDaily, 5 October 2017. <>.

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New research from The Geological Society of America’s Journal Geology

October 5, 2017

Geological Society of America

Category 5 hurricanes may have slammed Florida repeatedly during the chilly Younger Dryas, 12,000 years ago. The cause? Hurricane-suppressing effects of cooler sea surface were out-weighed by side effects of slowed ocean circulation.


Figure 3 from the paper: Simulated changes in climatic controls on hurricane activity between the Younger Dryas (YD, 12.0-12.5 ka) and early Holocene (EH, 10.2-10.8 ka). A: Spatial difference in storm season surface temperature (Tsfc). B: Spatial difference in genesis potential index (GPI), averaged for each Transient Climate Evolution Experiment (TraCE) interval (see text). C: Filtered (20 yr) time series of maximum potential intensity (PI) near the Dry Tortugas (red) and Barbados (gray) from 13,850 yr ago through the EH. CAT – category; TS – tropical storm.
Credit: M.R. Toomey et al. and The Geological Society of America journal Geology



Category 5 hurricanes may have slammed Florida repeatedly during the chilly Younger Dryas, 12,000 years ago. The cause? Hurricane-suppressing effects of cooler sea surface were out-weighed by side effects of slowed ocean circulation. That’s the finding of USGS researcher Michael Toomey and colleagues in their Geology article published online today.

As the last ice age waned, undersea landslide deposits called turbidites captured the fury of Florida’s stormy days. Previously, Toomey linked turbidites in the Bahamas with modern hurricanes. For this study, the group examined turbidites in cores spanning the shift from the Younger Dryas into the warmer early Holocene, collected offshore the Dry Tortugas, Florida. The turbidites, complete with smashed up shells and jumbled sediments, reveal that in Younger Dryas days Florida was surprisingly hurricane-prone, at a time when cooler sea surface temperatures may have put the brakes on such intense storms elsewhere in the Atlantic.

To explore why, Toomey and colleagues analyzed computer models that simulated ocean and atmospheric conditions near Florida during that period. In modern times, the Atlantic Meridional Overturning Circulation (AMOC) brings cool water south and warm water north. But during the Younger Dryas the AMOC is thought to have weakened considerably, slowing circulation and reshaping environmental conditions across much of the Northern Hemisphere.

Modeling results indicated that lower sea surface temperatures in the tropical Atlantic, near Barbados, for example, corresponded with a drop in storm potential intensity. Near Florida, sea surfaces cooled as well. However, the change there was not as dramatic as further south or to the north. The relative warmth of waters offshore the southeastern U.S. compared to the regional Atlantic, explains Toomey, seems to have set the stage for intense hurricanes near Florida. “The modeling work suggests other factors, such as wind shear and humidity at mid-latitudes, outweighed changes in sea surface temperature at our core site,” he says. Models and geologic records both show that by the early Holocene, as the AMOC regained strength, Florida’s hurricanes subsided.

The results, says Toomey, reveal that when it comes to generating hurricanes, ocean circulation plays a powerful role. What’s more, he adds, the study demonstrates that on certain types of coastlines, turbidites have great potential for unraveling ancient hurricane histories. However, Toomey cautions against applying the results directly to future hurricane activity. He says for that, we need more field data and higher resolution models. “That’s where I see this work headed next.”

Story Source:

Materials provided by Geological Society of AmericaNote: Content may be edited for style and length.

Journal Reference:

  1. Michael R. Toomey, Robert L. Korty, Jeffrey P. Donnelly, Peter J. van Hengstum, William B. Curry. Increased hurricane frequency near Florida during Younger Dryas Atlantic Meridional Overturning Circulation slowdownGeology, 2017; DOI: 10.1130/G39270.1


Source: Geological Society of America. “12,000 years ago, Florida hurricanes heated up despite chilly seas: New research from The Geological Society of America’s Journal Geology.” ScienceDaily. ScienceDaily, 5 October 2017. <>.

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October 3, 2017

University of Pennsylvania

A long-standing question regarding the strength of olivine, the primary component of Earth’s mantle, has now been answered. This study has implications for how we understand now tectonic plates form and move.


Earth’s fault lines between tectonic plates. (Stock image)
Credit: © Mopic / Fotolia



No one can travel inside Earth to study what happens there. So scientists must do their best to replicate real-world conditions inside the lab.

“We are interested in large-scale geophysical processes, like how plate tectonics initiates and how plates move underneath one another in subduction zones,” said David Goldsby, an associate professor at the University of Pennsylvania. “To do that, we need to understand the mechanical behavior of olivine, which is the most common mineral in the upper mantle of Earth.”

Goldsby, teaming with Christopher A. Thom, a doctoral student at Penn, as well as researchers from Stanford University, the University of Oxford and the University of Delaware, has now resolved a long-standing question in this area of research. While previous laboratory experiments resulted in widely disparate estimates of the strength of olivine in Earth’s lithospheric mantle, the relatively cold and therefore strong part of Earth’s uppermost mantle, the new work, published in the journal Science Advances, resolves the previous disparities by finding that, the smaller the grain size of the olivine being tested, the stronger it is.

Because olivine in Earth’s mantle has a larger grain size than most olivine samples tested in labs, the results suggest that the mantle, which comprises up to 95 percent of the planet’s tectonic plates, is in fact weaker than once believed. This more realistic picture of the interior may help researchers understand how tectonic plates form, how they deform when loaded with the weight of, for example, a volcanic island such as Hawaii, or even how earthquakes begin and propagate.

For more than 40 years, researchers have attempted to predict the strength of olivine in Earth’s lithospheric mantle from the results of laboratory experiments. But tests in a lab are many layers removed from the conditions inside Earth, where pressures are higher and deformation rates are much slower than in the lab. A further complication is that, at the relatively low temperatures of earth’s lithosphere, the strength of olivine is so high that it is difficult to measure its plastic strength without fracturing the sample. The results of existing experiments have varied widely, and they don’t align with predictions of olivine strength from geophysical models and observations.

In an attempt to resolve these discrepancies, the researchers employed a technique known as nanoindentation, which is used to measure the hardness of materials. Put simply, the researchers measure the hardness of a material, which is related to its strength, by applying a known load to a diamond indenter tip in contact with a mineral and then measuring how much the mineral deforms. While previous studies have employed various high-pressure deformation apparatuses to hold samples together and prevent them from fracturing, a complicated set-up that makes measurements of strength challenging, nanoindentation does not require such a complex apparatus.

“With nanoindentation,” Goldsby said, “the sample in effect becomes its own pressure vessel. The hydrostatic pressure beneath the indenter tip keeps the sample confined when you press the tip into the sample’s surface, allowing the sample to deform plastically without fracture, even at room temperature.”

Performing 800 nanoindentation experiments in which they varied the size of the indentation by varying the load applied to the diamond tip pressed into the sample, the research team found that the smaller the size of the indent, the harder, and thus stronger, olivine became.

“This indentation size effect had been seen in many other materials, but we think this is the first time it’s been shown in a geological material,” Goldsby said.

Looking back at previously collected strength data for olivine, the researchers determined that the discrepancies in those data could be explained by invoking a related size effect, whereby the strength of olivine increases with decreasing grain size of the tested samples. When these previous strength data were plotted against the grain size in each study, all the data fit on a smooth trend which predicts lower-than-thought strengths in Earth’s lithospheric mantle.

In a related paper by Thom, Goldsby and colleagues, published recently in the journal Geophysical Research Letters, the researchers examined patterns of roughness in faults that have become exposed at Earth’s surface due to uplifted plates and erosion.

“Different faults have a similar roughness, and there’s an idea published recently that says you might get those patterns because the strength of the materials on the fault surface increases with the decreasing scale of roughness,” Thom said. “Those patterns and the frictional behavior they cause might be able to tell us something about how earthquakes nucleate and how they propagate.”

In future work, the Penn researchers and their team would like to study size-strength effects in other minerals and also to focus on the effect of increasing temperature on size effects in olivine.

Story Source:

Materials provided by University of PennsylvaniaNote: Content may be edited for style and length.

Journal Reference:

  1. Angus J. Wilkinson et al. Size effects resolve discrepancies in 40 years of work on low-temperature plasticity in olivineScience Advances, September 2017 DOI: 10.1126.sciadv.1701338


Source: University of Pennsylvania. “Earth’s tectonic plates are weaker than once thought.” ScienceDaily. ScienceDaily, 3 October 2017. <>.

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The organoids help track polycystic kidney disease progression

October 2, 2017

University of Washington Health Sciences/UW Medicine

By creating and manipulating mini-kidney organoids that contain a realistic micro-anatomy, researchers can now track the early stages of polycystic kidney disease. The organoids are grown from human stem cells.


Kidney organoids grown in the lab and suspended in a lab dish show the formation of cysts (right) in the disease model of polycystic kidney disease. Normal kidney organoids are on the left.
Credit: Freedman Lab/UW Medicine



By creating and manipulating mini-kidney organoids that contain a realistic micro-anatomy, UW Medicine researchers can now track the early stages of polycystic kidney disease. The organoids are grown from human stem cells.

Polycystic kidney disease affects 12 million people. Until recently, scientists have been unable to recreate the progression of this human disease in a laboratory setting.

That scientific obstacle is being overcome. A report coming out next week shows that, by substituting certain physical components in the organoid environment, cyst formation can be increased or decreased.

Benjamin Freedman, assistant professor of medicine in the Division of Nephrology at the UW School of Medicine, and his team at the Kidney Research Institute, led these studies in conjunction with scientists at other institutions in the United States and Canada. Freedman and his group also are investigators at the UW Medicine Institute for Stem Cell and Regenerative Medicine

They outlined their methods and results in a paper to be published Oct. 2 in Nature Materials.

“Beforehand, we had shown that these organoids could form PKD-like cysts, but what’s new here is that we’ve used the model to understand something fundamental about that disease,” said Freedman.

As one example, the team found that PKD mini-kidneys grown in free-floating conditions formed hollow cysts that were very large. These cysts could easily be seen. In contrast, PKD mini-kidneys attached to plastic dishes stayed small.

According to Nelly Cruz, the lead author of the paper, other manipulations to the organoid also affect the progression of polycystic kidney disease.

“We’ve discovered that polycystin proteins, which are causing the disease, are sensitive to their micro-environment,” she explained. “Therefore, if we can change the way they interact or what they are experiencing on the outside of the cell, we might actually be able to change the course of the disease.” Cruz is a research scientist in the Freedman lab.

In another paper to be published in Stem Cells, Freedman and his team discuss how podocytes, which are specialized cells in the body that filter blood plasma to form urine, can be generated and tracked in a lab environment. Study of gene-edited human kidney organoids showed how podocytes form certain filtration barriers, called slit diaphragms, just as they do in the womb. This might give the team insight into how to counter the effects of congenital gene mutations that can cause glomerulosclerosis, another common cause of kidney failure.

Taken together, these papers are examples of how medical scientists are making progress toward developing effective, personalized therapies for polycystic kidney disease and other kidney disorders.

“We need to understand how PKD works,” Freedman said. “Otherwise, we have no hope of curing the disease.”

“And our research,” he added, “is telling us that looking at the outside environment of the kidney may be the key to curing the disease. This gives us a whole new interventional window.

Story Source:

Materials provided by University of Washington Health Sciences/UW MedicineNote: Content may be edited for style and length.

Journal Reference:

  1. Nelly M. Cruz, Xuewen Song, Stefan M. Czerniecki, Ramila E. Gulieva, Angela J. Churchill, Yong Kyun Kim, Kosuke Winston, Linh M. Tran, Marco A. Diaz, Hongxia Fu, Laura S. Finn, York Pei, Jonathan Himmelfarb, Benjamin S. Freedman. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney diseaseNature Materials, 2017; DOI: 10.1038/nmat4994


Source: University of Washington Health Sciences/UW Medicine. “Mini-kidneys grown in lab reveal renal disease secrets: The organoids help track polycystic kidney disease progression.” ScienceDaily. ScienceDaily, 2 October 2017. <>.

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Clinical Trials Transformation Initiative (CTTI)


The Clinical Trials Transformation Initiative (CTTI) is a public private partnership with Duke University and FDA with a mission to develop and drive adoption of practices that will increase the quality and efficiency of clinical trials. Target Health has been a member of the Steering Committee since 2008, and Dr. Mitchel had the honor, between 2014-2015, to sit on the Executive Committee, representing the Steering Committee.


This past week, the Steering Committee met in D.C. with the theme of how to implement CTTI recommendations. It was a very stimulating meeting that included presentations and breakout sessions. Our take-away of the meeting is that it will take leadership and ownership to make the changes needed to completely modernize the clinical trial enterprise. All agreed that we look forward to examples of how CTTI companies are implementing changes.


At Target Health, the impact of CTTI has been in the area of managing clinical trials using principles of Quality by Design, and our approach to risk-based monitoring, based on the publication of the CTTI Monitoring Survey Project: Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices.


Target Health was also a key team member in CTTI’s Registry Trials Recommendations that has provided a pathway for registries to be used for the conduct of more efficient clinical trials, bringing new treatments to patients faster. Registries are data collection tools typically used to better understand long-term trends in a specific population, such as patients with a particular disease or exposure to a certain treatment. However, if designed appropriately, registries can be used as a data source within which clinical trials can be performed. FDA recently signaled a commitment to developing policies regarding the use of registries and other forms of “real-world evidence“ for research, including clinical trials. While registries have long been used to support safety evaluations, their use for efficacy evaluations is a newer practice. CTTI’s recommendations outline best practices for assessing and designing registries so that the data should be able to meet expectations for FDA review of new products. The recommendations can be applied to existing registries or for developing new registries. The goal is to increase the practice of leveraging registries to facilitate high-quality clinical trials at lower costs.


For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.


Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor


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Focal Dystonia and MD or Musician’s Dystonia

Focal Dystonia in a pianist. Improvement in one day – YouTube


Focal dystonia is a neurological condition, a type of dystonia, that affects a muscle or group of muscles in a specific part of the body, causing involuntary muscular contractions and abnormal postures. For example, in focal hand dystonia, the 1) ___ either curl into the palm or extend outward without control. In musicians, the condition is called musician’s focal dystonia, or simply, musician’s dystonia. In sports, it is commonly referred to as the yips.


Current medical science does not precisely describe the causes of dystonia. Misfiring of neurons in the sensorimotor cortex, a thin layer of neural tissue that covers the 2) ___, is thought to cause contractions. This misfiring may result from impaired inhibitory mechanisms during muscle contraction. When the brain tells a given muscle to contract, it simultaneously silences muscles that would oppose the intended movement. It appears that dystonia interferes with the brain’s ability to inhibit those surrounding muscles, leading to loss of selectivity. The sensorimotor cortex is organized as discrete “maps“ of the human body. Under normal conditions, each body part (such as individual fingers) occupies a distinct area on these cortical 3) ___. In dystonia, these maps lose their distinct borders and overlap occurs. Exploration of this initially involved over-training particular finger movements, in non-human primates, which resulted in the development of focal hand dystonia.


Examination of the primary somatosensory cortex in the trained animals showed grossly distorted representations of the maps pertaining to the fingers when compared to the untrained animals. Additionally, these maps in the dystonic animals had lost the distinct borders that were noted in the untrained animals. Imaging studies in humans with focal dystonia have confirmed this finding. Also, synchronous afferent stimulation of peripheral muscles induces organizational changes in motor representations, characterized both by an increase in map size of stimulated muscles and a reduction in map separation, as assessed using TMS or 4) ___ ___ ___. The cross-connectivity between areas that are normally segregated in the sensory cortex may prevent normal sensorimotor feedback and so contribute to the observed co-contraction of antagonist muscle groups, and inappropriately timed and sequenced movements that underlie the symptoms of focal dystonia. It is hypothesized that a deficit in inhibition caused by a genetically mediated loss of inhibitory interneurons may be the underlying cause of the deficits observed in 5) ___. While usually painless, in some instances the sustained contraction and abnormal posturing in dystonia cause 6) ___. Focal dystonia most typically affects people who rely on fine motor skills – musicians, writers, surgeons, etc. It is thought that the excessive motor training those skills require may contribute to the development of dystonia as their cortical maps become enlarged and begin to overlap. Focal dystonia is generally “task-specific,“ meaning that it is only problematic during certain activities.


Dystonia is often treated with injections of Botox, a commercially prepared form of botulinum toxin. Botox reduces the symptoms of the disorder but it is not a cure for dystonia. Since the root of the problem is 7) ___, doctors have explored sensorimotor retraining activities to enable the brain to “rewire“ itself and eliminate dystonic movements. The work of several doctors such as Nancy Byl and Joaquin Farias has shown that sensorimotor retraining activities and proprioceptive stimulation can induce neuroplasticity, making it possible for patients to recover substantial function that was lost to focal dystonia. Bass guitarist and instructor Scott Devine said that he wears a glove while playing bass guitar because of the condition. He finds that the glove stops the involuntary finger movements. He says it works for him but does not suggest that it may work for everyone with the condition.


Performing music at a professional level is probably one of the most complex human accomplishments. Extremely fast and complex, temporo-spatially predefined movement patterns have to be learned, memorized, and retrieved with high reliability in order to meet the expectations of listeners. Performing music requires not only the integration of multimodal sensory and motor information, and its precise monitoring via auditory and kinesthetic feedback, but also emotional communicative skills, which provide a “speaking“ rendition of a musical masterpiece. To acquire these specialized auditory-sensory-motor and emotional 8) ___, musicians must undergo extensive training periods over many years, which start in early childhood and continue on through stages of increasing physical and strategic complexities. Performance anxiety, linked to high societal pressures such as the fear of failure and heightened self-demands, frequently accompanies these learning processes. Motor disturbances in musicians are common and include mild forms, such as temporary motor fatigue with short-term reduction of motor skills, painful overuse injuries following prolonged practice, anxiety-related motor failures during performances (choking under pressure), as well as more persistent losses of motor control, here termed “dynamic stereotypes“ (DSs).


Musician’s dystonia (MD), which is characterized by the permanent loss of control of highly skilled movements when playing a musical instrument, is the gravest manifestation of dysfunctional motor programs, frequently linked to a genetic susceptibility to develop such motor disturbances. Motor failures in musicians develop along a continuum, starting with subtle transient degradations due to fatigue, overuse, or performance stress, which transform by and by into more permanent, still fluctuating motor degradations, the DSs, until a more irreversible condition, MD manifests.


 “Begin slowly and increase gradually any unaccustomed use of the hands.“ – Michael Charness, MD (The Musician’s Way, p. 237)


Violinist Peter Oundjian, guitarist Liona Boyd, pianists Leon Fleischer and Gary Graffman – all are musicians whose careers were upended by musicians dystonia (MD). Among the approximately 1% of musicians who develop MD, the effects are debilitating. Over time, usually decades, the program in the brain that they depend on to control their movements gets corrupted, and they lose command of certain task-specific actions. For instance, violinists with MD might experience curling of the left 3rd and 4th fingers when they play, but those fingers will function normally when they do other activities. Researchers also find that MD “appears more often in the more intensely used hand.“ Hence, violinists are more likely to be affected in the left hand, pianists in the right, although any muscle group could be involved, even arm or shoulder 9) ___. Some musicians diagnosed with MD seem to develop it without any precipitating factor aside from long-term repetitive movement. For others, the condition surfaces months or years following a change of instrument or technique, subsequent to a dramatic increase in playing time, or after they begin doing a new, skillful repetitive activity. In those types of situations, the process via which a musician’s brain acquires a new movement program corrupts the pre-existing one and then dystonic contractions result. On top of that, physician Raoul Tubiana reports that the musicians he diagnosed with MD displayed awkward postural and movement habits. It’s conceivable, then, that physical misuse contributes to provoking MD in some individuals, maybe because musicians who move awkwardly foster more convoluted and corruption-prone wiring in their brains. Given that MD can run in families, a genetic component seems certain. According to the Dystonia Medical Research Foundation, “At present, researchers have recognized multiple forms of inheritable dystonia and have identified at least 13 genes or chromosomal locations responsible for the various manifestations.“ Note that the forms of dystonia referred to in that quote don’t include MD, for which no culpable 10) ___ have yet been discovered. In light of the above information, it’s possible that some musicians could be genetically predestined to acquire MD no matter how gracefully they play owing to the way that prolonged repetitive motion affects their brains. The published research also implies that if we emphasize certain behaviors and avoid others, we can probably reduce the chances of MD arising.


Sources:; Wikipedia


A well-known scholar’s thoughtful follow-up on last week’s ON TARGET emphasis on Climate Change.


ANSWERS: 1) fingers; 2) brain; 3) maps; 4) transcranial magnetic stimulation. 5) dystonia; 6) pain; 7) neurological; 8) skills; 9) muscles; 10) genes


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Leon Fleisher, Child Prodigy, Struggled to Recover from Focal Dystonia

Fleisher in 1963Photo credit: Seattle Symphony Orchestra, where he was one of their featured artists for the season; photographer: Bender – eBay itemphoto frontphoto back, Public Domain,


On July 23, 1928, Leon Fleisher was born in San Francisco into a poor Jewish family from Eastern Europe. His father’s business was hat-making, while his mother’s goal was to “make her son a great concert pianist“. Fleisher started studying the piano at age four, made his public debut at age eight, and played with the New York Philharmonic under Pierre Monteux at 16. Monteux famously called him “the pianistic find of the century.“ He became one of the few child prodigies to be accepted for study with Artur Schnabel and also studied with Maria Curcio. Fleisher was linked via Schnabel to a tradition that descended directly from Beethoven himself, handed down through Carl Czerny and Theodor Leschetizky.


“My mother was very ambitious for me and gave me a choice,“ said Fleisher. “Either I was to be the first Jewish President of the United States, or a great concert pianist. Whichever it was, I had to be perfect.“


In the 1950s, Fleisher signed an exclusive recording contract with Columbia Masterworks. He is particularly well known for his interpretations of the piano concerti of Brahms and Beethoven, which he recorded with George Szell and the Cleveland Orchestra. They also recorded Mozart’s Piano Concerto No. 25, the Grieg and Schumann piano concertos, Franck’s Symphonic Variations, and Rachmaninoff’s Rhapsody on a Theme of Paganini.


In 1964, Fleisher lost the use of his right hand, due to a condition that was eventually diagnosed as focal dystonia. At the age of 36, he could barely write his name. “I was preparing for the most important tour of my life when I had a minor accident. I cut my thumb on a piece of cheap garden furniture and required a couple of stitches. When I started practicing again, things didn’t feel quite right on my right side. My fourth and fifth fingers seemed to want to curl under. I practiced even harder, not listening to my body when, through pain, it warned me to stop. Things got progressively worse and in less than a year those two fingers were completely curved under, sticking into the palm of my hand. No way could I play the piano.“ It was as if his arm were a rope becoming unbraided, with creeping numbness in his fingers. Engagements were cancelled, recordings put on hold. “I was desolate,“ he says. “My life fell apart, and this mysterious debilitating condition destroyed my relationship with my second wife, striking deep into my family.“ Doctors were perplexed and could offer no medication or surgical repair to a condition that baffled them. Fleisher even considered suicide. “I grew a beard, wore my hair long and in a ponytail, and I got a Vespa scooter. I felt I had no purpose anymore; I was simply floundering.“


After a couple of years marking time, he realized that his connection was with music, not just with playing the piano with two hands. Out of a disastrous impediment, three new careers beckoned, the first as a left-handed concert pianist. “I thought about Paul Wittgenstein, the Austrian concert pianist whose right arm was shot off in the First World War. He commissioned works for the left hand from Richard Strauss, Korngold, Hindemith, Prokofiev, Ravel and Britten, so there was existing piano literature for pianists with no function in their right hands. And there was Brahms’ magnificent arrangement for left hand of Bach’s Chaconne for solo violin. Thank goodness it wasn’t my left hand that stopped working, since there are hardly any piano works for right hand alone. There are about 1,000 pieces for the left hand out there – most of them pretty bad – but Ravel’s Concerto for left hand, which I must have played over 1,000 times and have also conducted from the keyboard, is a masterpiece in its own right.“ “Secondly, I decided to pursue a musical career through conducting, moving from a sitting to a standing position. It felt so different to be on my feet in front of an orchestra but, worse, I immediately felt my ass to be 10 times its normal size, waving around in front of the audience.“


But it was in teaching that he found real happiness. “I became far better at explaining those elusive areas of expression and nuance that are so difficult to express in words.“ Indeed, his masterclasses, in which, as tutor, it is irrelevant whether you can use five or 10 fingers, are models of gently humorous correction and deeply-felt inspiration. He never gave up the idea of returning to two-handed repertoire. After leaving the concert platform in 1965, Fleisher tried every kind of medical, psychiatric and alternative treatment, from acupuncture and hypnosis to deep-tissue massage, Tiger Balm and others, including more than a few drams of Scotch. But, as a result of conducting and grasping the baton too tightly, he developed carpal tunnel syndrome. This weakness in the forearm and hand caused by pressure on a nerve in the wrist could be alleviated only through surgery. Fleisher agreed to have his wrist cut open with a knife, to the accompaniment, he remembers, of a recording of Mahler’s First Symphony. Astonishingly, the surgery for one ailment helped the other, and his fingers began to straighten out. “After 18 years, I was able to play again. In 1982, I was invited to open the new Meyerhoff concert hall in Baltimore and made the front page of The New York Times for being able to use both hands for the first time since 1965.“ But this supposed cure proved short-lived. “I knew things weren’t quite as they should be,“ said Fleisher. “I had to change the advertised program from Beethoven’s Fourth Piano Concerto to Franck’s Symphonic Variations. It didn’t feel to me like a triumphant return. I broke down in tears in the dressing-room before the concert and felt awful at having to go through an evening of pretense.“


For the remaining 12 of that series of “comeback“ concerts, Fleisher reverted to left-hand repertoire. Only in 1995 was he finally diagnosed with a neurological disorder called focal dystonia. “It’s a malady caused by the brain learning to do a wrong thing, and though a cure has been found, I am a dystonic for life. It’s task-specific. Glass-blowers get it, computer workers can become afflicted and golfers begin to miss their putts.“ Fleisher thinks there could be 10,000 musicians around the world suffering from the condition and that the composer-pianist Robert Schumann may have been an early victim, causing permanent damage by mechanically exercising his troublesome fourth finger.


Fifteen years ago, Botox was still in its experimental stages. However, a small dose injected directly into the appropriate muscle along with holistic massage therapy involving connective tissues restored Fleisher’s fingers sufficiently for him to return to two-handed performances. A tiny amount of Botox relaxes the fingers without causing the paralysis, evident when it is used to reduce facial wrinkles by immobilizing muscles. Crucially, there is no sign of any of the negative effects, such as a diminished quality of emotional experience. In 1995, Fleisher made a second comeback, quietly and without any hype, as he tested his stamina. Only after proving himself to himself did he feel ready to resume his career as a two-handed solo pianist. In 2005, he gave 40 concerts in 31 cities and the following year enjoyed success at New York’s Carnegie Hall. The same two fingers on Fleisher’s right hand still want to curl, but Botox injections every four months keep the condition under control.


When asked if he dances, Fleisher roars with laughter. “Wouldn’t that be a lovely idea?“ he exclaims. “I’m afraid my feet follow my hands. In fact, I have two left feet! It’s a deep regret, along with the fact that I am totally ungifted when it comes to jazz.“ According to his singer-songwriter son Julian, though, Fleisher does have something in common with great jazz players: the importance he places on rhythm. Fleisher feels rhythm as the heartbeat of music. “It regulates the metabolism of the piece, motivates the music and, if it’s infectious enough, makes us tap our toes.“


In 2004, Vanguard Classics released Leon Fleisher’s first “two-handed“ recording since the 1960s, entitled “Two Hands“, to critical acclaim. Two Hands is also the title of a short documentary on Fleisher by Nathaniel Kahn which was nominated for an Academy Award for best short subject on January 23, 2007. Fleisher received the 2007 Kennedy Center Honors. Kennedy Center Chairman Stephen A. Schwarzman described him as “a consummate musician whose career is a moving testament to the life-affirming power of art.“ Fleisher’s musical interests extend beyond the central German Classic-Romantic repertory. The American composer William Bolcom composed his Concerto for Two Pianos, Left Hand for Fleisher and his close friend Gary Graffman, who has also suffered from debilitating problems with his right hand. It received its first performance in Baltimore in April 1996. The concerto is so constructed that it can be performed in one of three ways, with either piano part alone with reduced orchestra, or with both piano parts and the two reduced orchestras combined into a full orchestra.


In 2004, Leon Fleisher played the world premiere of Paul Hindemith’s Klaviermusik (Piano Concerto for the Left Hand), Op. 29, with the Berlin Philharmonic. This work was written in 1923, for Paul Wittgenstein, who disliked and refused to play it. However, he had sole performing rights and kept the score, not allowing any other pianists to play it. The manuscript was discovered among his papers after the death of his widow in 2002. On October 2, 2005, Fleisher played the American premiere of the work, with the San Francisco Symphony under Herbert Blomstedt. In 2012, at the invitation of Justice Ruth Bader Ginsburg, Fleisher performed at the Supreme Court of the United States. Fleisher has continued to be involved in music, both conducting and teaching at the Peabody Conservatory of Music, the Curtis Institute of Music, and the Royal Conservatory of Music in Toronto; he is also closely associated with the Tanglewood Music Center. With Dina Koston, he co-founded and co-directed the Theater Chamber Players in 1968-2003, which was the first resident chamber ensemble of the Smithsonian Institution and of The Kennedy Center. Among others, Fleisher has taught Jonathan Biss, Yefim Bronfman, Phillip Bush, Naida Cole, Jane Coop, Enrico Elisi, Enrique Graf, Helene Grimaud, Hao Huang, Kevin Kenner, Dina Koston, Louis Lortie, Wonny Song, Andre Watts, Jack Winerock, Daniel Wnukowski, Alon Goldstein, Dale Anthony and Orit Wolf.


His memoir, My Nine Lives, co-written with the Washington Post music critic Anne Midgette, appeared in November 2010.


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Three-In-One Antibody Protects Monkeys From HIV-Like Virus


According to an article published in Science (20 September 2017), a three-pronged antibody made in the laboratory protected monkeys from infection with two strains of SHIV, a monkey form of HIV, better than individual natural antibodies from which the engineered antibody is derived. The three-pronged antibody was created by investigators from the National Institutes of Health (NIH) and the Paris-based pharmaceutical company Sanofi, also stopped a greater number of HIV strains from infecting cells in the laboratory more potently than natural, single antibodies. This new broadly neutralizing antibody binds to three different critical sites on HIV. According to the NIH, combinations of antibodies that each bind to a distinct site on HIV may best overcome the defenses of the virus in the effort to achieve effective antibody-based treatment and prevention, and that the concept of having a single antibody that binds to three unique sites on HIV is certainly an intriguing approach.


For the study, the authors tested dozens of bispecific and trispecific antibodies in the laboratory to find the best-performing combination. Individual antibodies were combined into trispecific antibodies using technology proprietary to Sanofi. The most successful formula combines the unique structures of the broadly neutralizing HIV antibodies called VRC01, PGDM1400, and 10E8v4. The authors then tested this trispecific antibody in an experiment involving monkeys and two strains of SHIV. One SHIV strain is sensitive to neutralization by VRC01 and the trispecific antibody, but resistant to neutralization by PGDM1400. The other SHIV strain is sensitive to neutralization by PGDM1400 and the trispecific antibody, but resistant to neutralization by VRC01. Twenty four monkeys were treated: 8 with VRC01, 8 with PGDM1400, and 8 with the trispecific antibody. Five days later, the all of the 24 monkeys were exposed to both SHIV strains. Results showed that 5/8 of the monkeys that received PGDM1400 and 6/8 of the monkeys that received VRC01 became infected with SHIV, but 0/8 of the monkeys that received the trispecific antibody became infected.


Sanofi is manufacturing the trispecific antibody for use in a Phase 1 clinical trial that will be conducted by NIAID to test the antibody’s safety and pharmacokinetics in healthy people beginning in late 2018. Discussions also are under way with the NIAID-funded AIDS Clinical Trials Group to conduct a separate Phase 1 clinical trial of the antibody in people living with HIV. By binding to three different sites on the virus, the new antibody should be harder for HIV to dodge than natural, single antibodies.


According to the authors, the ability of trispecific antibodies to bind to three independent targets at once could make them a useful prototype for treatments developed not only for HIV but also for other infectious diseases, autoimmune diseases and cancers.


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Successful Treatment of Lethal Brain Cancers in Mice


High-grade gliomas cause more deaths than any other form of brain cancer, partly due to the extreme difficulty surgeons have in removing all of the tumor cells. This leaves clinicians dependent on traditional chemotherapy and radiation treatments that have limited success. Depending on the specific subtype of tumor, more than three-quarters of patients die within five years, and for the most common childhood glioma that number exceeds 99%.


According to an article published in Nature (20 September 2017), a study conducted in mice provides evidence that highly lethal brain tumors, called high-grade gliomas, stop growing when deprived of a specific molecule naturally produced when brain cells fire. The study suggest that targeting a protein called neuroligin-3 may prove beneficial in patients with these diseases. According to the NIH, this study transforms our understanding of how neurons influence the growth of gliomas, and opens a new door for potential treatments.


In a 2015 paper published in Cell, the research team identified several chemicals released by brain cells in response to neural activity that cause high-grade gliomas to grow. One of them was neuroligin-3, a protein that helps neurons communicate. In the current study, the authors extracted tumor cells from patients with several varieties of high-grade gliomas and inserted them into the brains of two breeds of mice, one normal and one lacking the gene that produces neuroligin-3. In the latter, none of the tumors grew substantially for four and a half months and roughly half remained stagnant after six months, whereas tumors grew markedly in the mice with an intact neuroligin-3 gene. Further experiments suggested neuroligin-3 triggers a series of chemical reactions that stimulates multiple signaling pathways involved in glioma growth, causing the tumors to expand.


The team also discovered that neuroligin-3 release is triggered when active neurons secrete a protein called ADAM10, which causes neuroligin-3 to detach from the surface of cells. Stopping neurons from firing prevented the release of both ADAM10 and neuroligin-3, and genetically deleting ADAM10 from neurons in mice reduced neuroligin-3 release. In addition, the team found that a group of brain cells called oligodendrocyte precursor cells can release neuroligin-3, suggesting those cells may play a role in accelerating glioma growth. Finally, the authors showed that blocking ADAM10 activity with a drug designed to treat other types of cancers dramatically reduced the growth of two types of gliomas implanted into the brains of mice.


In addition to working towards a better understanding of why gliomas are so dependent on neuroligin-3 for growth, the authors are planning to initiate a clinical trial using an ADAM10 inhibitor in human glioma patients. Although treatments targeting ADAM10 and neuroligin-3 might extend patients’ lifespans, they would not kill the tumors, making additional treatments necessary to cure the disease.


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