The solution is simpler than previously thought

By Douglas Main

20140415-1
Sleeping
Travis Rathbone

 

How can you get over jet lag? There are hundreds of suggestions, but few of them have been rigorously tested. So some mathematicians from the University of Michigan created an app that can help you, which relies on new mathematical models and the latest science.Jet lag occurs when your body’s circadian rhythms fall out of sync with your surroundings, such as when you quickly move to an area that is 12 hours behind where you were previously. One thing that certain helps to adjust is exposure to sunlight–cells in your retina use this information to tell the brain that it is daylight, and that the body should be awake. But how much sunlight does the body need to adjust? And at what times?

Daniel Forger, a mathematical biologist at the University of Michigan who studies biological clocks and graduate student Olivia Walch created 1,000 possible trips, and combined them with studies on how light affects human circadian rhythms. They then used applied optimal control theory, a mathematical tool for finding ideal solutions. The results were published in PLOS Computational Biology, and the an app using the study’s insights is called Entrain.

It turns out that to shift your clock, you really just need to adjust what your eyes and brain perceive as dawn and dusk, as explained in Scientific American:

Shifting your clock quickly just requires a new bedtime and long periods of bright light or complete darkness. These schedules significantly outperformed previous suggestions. Using this method, it takes only four days to fully sync after a 12-hour time zone shift. With other methods, it takes seven to 13 days or more. Even better, this method helps you “partially” sync in two days, which means you can sleep just fine.

Olivia Walch, a graduate student at the University of Michigan, then developed an iPhone app with the model, called Entrain, which allows users to set tailored schedules. First, you enter your normal sleep schedule and then choose the area you’re traveling to and the type of light you’ll be encountering on your trip (Are you hiking outdoors? Or attending an indoor conference?). The app then provides a custom schedule, telling you when you should be in the light or in the dark as well as how many days it will take to fully adjust.

Head over the iTunes store and try Entrain for yourself. It’s free!

For more of the latest on high-tech snoozing, check out Popular Science’s March 2014 issue on the science of sleep.

 

Source: http://www.popsci.com/article/mathematicians-create-app-beat-jet-lag?dom=PSC&loc=recent&lnk=3&con=mathematicians-create-app-to-beat-jet-lag-

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New York City Economic Development Corporation (NCEDC) Blog Features Target Health Inc.

 

On Friday, the Blog of the NYC Economic Development Corporation did a feature on Target Health. The headline was “Made in NYC: Target Health.“ Here is the link and a brief excerpt. http://www.nycedc.com/blog-entry/made-nyc-target-health.

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Target Health is a Made in NYC health company, founded by couple Jules Mitchel and Joyce Hays. Serving the pharmaceutical community since 1993, the company has met incredible success in its 20 years through innovative optimization of drugs, biologics, and devices.

 

NYCEDC is thrilled to have witnessed and supported Target Health through its participation in our Eds and Meds series of roundtables, as well as the 2013 NYC to Israel program. We spoke with co-founder Jules Mitchel about Target Health’s mission and why they are proud to be in NYC.

 

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Joyce Hays and Jules Mitchel, Founders of Target Health

 

What is Target Health’s mission?

Target Health Inc. is committed to helping companies bring innovative and important medicines to patients through creative collaboration with the pharmaceutical community. A full-service e*CRO, our pledge is to optimize the life cycle of drugs, biologics, and devices with expertise, leadership, innovation, and teamwork.

 

What is your biggest accomplishment thus far?

The approval of taliglucerase alfa, commercially known as Elelyso. Elelyso is manufactured and distributed by New York City-based Pfizer Inc., under license from Protalix BioTherapeutics Inc. and is indicated for the treatment of Gaucher disease. Target Health collaborated with Protalix from early stage development to the NDA submission and provided regulatory, toxicology, clinical research management, data management using Target e*CRF, biostatistics, and medical writing services.

 

Why NYC?

The founders were born and bred here and we love the culture. To put our money where our mouth is: we are patrons of the Metropolitan Opera and support six theatre clubs through the city.

 

Favorite place in the city to nosh?

Giovanni VentiCinque, 25 East 83rd Street. Tell Pino we gave the recommendation.

 

ON TARGET is the newsletter of Target Health Inc., a NYC-based contract research organization (eCRO), providing strategic planning, regulatory affairs, clinical research, data management, biostatistics, medical writing and software services, including the paperless clinical trial, to the pharmaceutical and device industries.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website, and if you like the weekly newsletter, ON TARGET, you’ll love the Blog.

 

 

Joyce Hays, Founder and Chief Editor of On Target

Jules Mitchel, Editor

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The Greatest Danger from Atrial Fibrillation is Stroke; Prevention Starts with Taking an Anticoagulant

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Anticoagulants help prevent a stroke

 

Blood clots that travel to the 1) ___ cause stroke and taking a blood thinner can prevent stroke. Atrial fibrillation the most common kind of arrhythmia or irregular heartbeat, can lead to blood clots and one of the most frightening aspects of atrial fibrillation is the risk of a life-threatening stroke.

 

During atrial fibrillation, the heart’s two small upper chambers or atria beat chaotically, increasing the risk of blood clots. If a clot breaks free and travels to the brain it can result in a fatal stroke. People with atrial fibrillation are five times more likely to have a stroke than those who don’t have the condition. In fact, one in four strokes in people over the age of 80 is a direct result of atrial fibrillation. That makes stroke prevention a key part of atrial fibrillation treatment.

 

Stephen Kopecky, MD, professor of medicine at the Mayo Clinic and president of the American Society for Preventive Cardiology, said that when working with patients who have atrial fibrillation, the biggest hurdle is deciding whether to prescribe an anticoagulant – a medication to prevent blood clots from forming. Because the average age of an atrial fibrillation patient is 76, the risk of stroke has to be weighed against the risk of 2) ___. After that, he said, the decisions get easier.

 

Anticoagulants, commonly called blood thinners, are medications that slow the clotting of blood, so they help prevent blood clots from forming and traveling to the brain to reduce stroke risk. If there is a concern about stroke risk, the first line of preventive treatment is 3) ___. Since the 1950s, warfarin (Coumadin) has been the most widely used anticoagulant. In the last few years, newer anticoagulants such as apixaban (Eliquis), dabigatran (Pradaxa), and rivaroxaban (Xarelto) have gained U.S. Food and Drug Administration (FDA) approval.

 

Aspirin reduces the risk of stroke by 20%; anticoagulants reduce that risk by 80%

 

Because most people with atrial fibrillation are older, various factors need to be considered. Since the risks for stroke are higher in those who have diabetes, high blood pressure, or have experienced heart failure, making an anticoagulant may be an important part of overall treatment. Fragile patients who fall are also at increased risk of problems from internal and external bleeding, but those who can’t remember to take medication as prescribed probably shouldn’t be taking an anticoagulant. For them, , it’s probably wise to simply recommend an 4) ___ every day.

 

For atrial fibrillation patients who have equal risks of bleeding and stroke, the doctor and patient should together make an informed decision based on factors such as lifestyle, diet, physical activity, access to clinics and doctors, work, and travel. Every patient is an individual and the decision about what medication to take should be determined by a serious and detailed conversation between a patient and his/her 5) ___.

 

Warfarin is a powerful drug that reduces the chemical reaction of vitamin K in the liver that causes and lengthens the time it takes for blood to clot. Its effectiveness depends on the amount of vitamin K in the body. Vitamin K is found in many leafy, green vegetables such as spinach, Brussels sprouts, and kale. Warfarin interacts with those vegetables and with various medications, supplements, and over-the-counter drugs, making it vital that people on it be monitored at least once a month. Too much warfarin increases the risk of bleeding, and too little increases the risk of stroke. No new foods or medicines should be added or eliminated without consulting a doctor, and patients seriously need to limit the amount of alcohol. The drawbacks of warfarin are that doses have to be individually adjusted, and a patient has to carefully watch levels of vitamin 6) ___. If on is able and willing to regularly go for blood level measurement checks and keep in touch with one’s doctor about any diet or lifestyle changes, warfarin may be a good choice. Warfarin is also inexpensive when covered by insurance. Unlike some of the newer anticoagulants, an antidote exists for emergency situations such as during surgery when the drug must be immediately counteracted.

 

Newer 7) ___ have now been proven to be as effective as warfarin. According to a report in the September 2011 issue of the New England Journal of Medicine, several important studies showed they’re equal or superior at preventing blood clots than warfarin. The drugs Pradaxa (dabigatran) and Eliquis (apixaban) are taken in fixed doses twice a day, get into the blood in a matter of hours, and don’t require close monitoring or dietary considerations. Xarelto (rivaroxaban) is taken in a fixed dose once a day for prevention of stroke in atrial fibrillation. However, these are not advised for anyone with heart valve disease or serious kidney or liver problems and, unlike warfarin, they’re expensive, costing about $3,000 a year. Side effects are similar to those of warfarin.

 

“As we get to know these drugs better,“ said Kopecky, “we’re migrating toward them more.“ He said he likes to recommend them for patients younger than 65, who are active and have no other health issues. “The only considerations when deciding which medication to put a patient on now,“ he said, “are individual safety issues and 8) ___

 

Medical experts continue to say that people with irregular heartbeat should take blood thinners to prevent stroke

 

An updated guideline recommends that people with nonvalvular atrial fibrillation, or irregular heartbeat, take oral anticoagulants, a type of blood thinner pill, to prevent stroke. An updated guideline from the American Academy of Neurology recommends that people with nonvalvular atrial fibrillation, or irregular heartbeat, take oral anticoagulants to prevent stroke. The guideline was published in the February 25, 2014, in the print issue of Neurology®, the medical journal of the American Academy of Neurology. The World Stroke Organization has endorsed the updated guideline. The guideline also extends the value of this type of9) ___ thinner to many people who are generally undertreated, such as the elderly, those with mild dementia, and those at moderate risk of falls, and whose health status was long thought to be a barrier to use.


Source: American Academy of Neurology (AAN). “Guideline: People with irregular heartbeat should take blood thinners to prevent stroke, experts say.“  ScienceDaily.com; Wikipedia

 

ANSWERS: 1) brain; 2) bleeding; 3) medication; 4) aspirin; 5) doctor; 6) K; 7) anticoagulants; 8) cost; 9) blood

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Apoplexy or Stroke

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Hippocrates of Kos (460 – 370 BC; Engraving by Peter Paul Rubens, 1638
(courtesy of the National Library of Medicine, USA

 

Episodes of stroke and familial stroke have been reported from the 2nd millennium BC onward in ancient Mesopotamia and Persia. Hippocrates (460 to 370 BCE), the father of medicine, was first to describe the phenomenon of sudden paralysis that is often associated with ischemia. Apoplexy, from the Greek word meaning “struck down with violence,“ first appeared in Hippocratic writings to describe this phenomenon. The word stroke was used as a synonym for apoplectic seizure as early as 1599, and is a fairly literal translation of the Greek term. Hippocrates kept detailed records of patients suffering or dying of apoplexy. In his aphorisms, Hippocrates made the following observations: “Persons are most subject to apoplexy between the ages of forty and sixty“ (VI:57), and “it is impossible to remove a strong attack of apoplexy, and not easy to remove a weak attack“ (II:47) (Aphorisms E-book by Hippocrates 2010).

 

Although these observations might have been true at the time, modern epidemiology has demonstrated that stroke can occur throughout the lifespan. Further, novel treatments have improved the prognosis of patients with acute events.

 

Galen (born CE 131) accepted and developed the teachings of Hippocrates. He believed that apoplexy was caused by anything interfering with the flow of the ?vital spirit’ to the brain, the purpose of which consisted in inspiration and expiration of the vital spirit. The Galenic influence persisted for centuries and for a considerable period apoplexy seems to have been conceptualized mainly in terms of humoral theory in combination with various theories of obstruction.

 

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Johann Jakob Wepfer MD (1620-1695)

 

Centuries later, in the mid-1600s, the Swiss physician, Johann Jakob Wepfer (1620-1695) showed that apoplexy is due to cerebral hemorrhage. Wepfer dedicated his life to the dissection of corpses in the morgue of the University of Padua in Italy, and discovered that something disrupted the blood supply in the brains of people who died from apoplexy. In some of these cases, the arteries were blocked. In others, there had been massive bleeding into the brain tissue. Wepfer identified the main arteries supplying the brain, the vertebral and carotidarteries, and identified the cause of ischemic stroke [also known as cerebral infarction] when he suggested that apoplexy might be caused by a blockage to those vessels. In his famous work, Historiae apoplecticorum, published in 1658, is a detailed description of four cases, his first case having been studied in 1655:

 

“Johann Jacobus Reiter Kenzinga-Brisgojus, age about 45 years, with a slender build, endowed with yellow and curly hair, naturally strong; of honest parents, descended from the Consul. He acted as schoolmaster and at length was admitted to a most celebrated Monastery. He suffered from extensive gouty arthritis. In the year 1655, the seventh day of November he did much of everything-assisted the Most Reverend Lord Abbott in the carrying out of sacraments; (later that day) the Abbott by chance found him prostrate upon the ground, insensible to shouts, to shaking and pinching. I was summoned: I arrived in half an hour, I saw him livid from pallor, deprived of all sensation and animate motion, with nostrils cold to the touch. His pulse at first strong, full, quick, soon afterwards weaker, smaller and more frequent, his breathing also more laborious, soon it became irregular, and many times appeared about to cease from within. At the tenth hour before midday his body was shaken albeit by a movement and much sputum white, viscid, tenacious passed from his mouth, but indeed no blood: after this more and more his strength began to weaken and his extremities to become more cold; The first hour after midday he ceased to live. I opened the head: the skull removed and the dura mater being cut into pieces much blood flowed from the space between this and the thin meninges, copiously. Nor truly had the blood collected solely at the base of the brain, but covered it all over the top both anteriorly and posteriorly, indeed it had forced itself into nearly all the windings of the brain, as many as there are: extravasated blood totalled two pounds. The whole brain, ventricles and surface were contaminated by blood in large amounts and crumbly; I was able to find no ruptured vein or artery. This however is certain, no external violent cause, be it a blow, be it a fall, was the cause of such ruptures of the blood vessels; to settle this point with his hair cut and skin washed off he showed not the slightest trace of any contusion whatever.“

 

Wepfer was one of the earliest investigators of the cerebral vasculature. His book on diseases of the head’ provided an ample account of basilar artery migraine and its location in the brainstem, a description of a stroke in migraine in a child; and, he wrote of the visual aurae and diagnosis of migraine. He also described trigeminal neuralgia localized to the maxillary nerve.

 

Born in Schaffhausen, Switzerland in 1620, Wepfer read medicine publishing for his degree in 1647 De palpitatione cordis, which stoutly supported Harvey’s controversial ideas on the circulation of the blood. He studied in Basle, Strasbourg, and Italy, but returned to his native town where he built a successful practice. His renown spread widely, and his name was hallowed as “The Hippocrates of Helvetia.“ His considerable library and writings were bought by the University of Leyden in 1774 for 400 gold florins.

 

In the 1600s, bloodletting was the most common response to apoplexy, as one physician makes clear: “And as the Cause of the Fit, most generally arises from either a Redundancy of Blood or Phlegm obstructing the Fibres of the Brain, and thereby intercepting the Action of the Animal Faculties; so I am sensible that the Remedy first in View is to draw Blood; which is look’d upon as the most sovereign Remedy in all Cases of Apoplexies“. This popularity is perhaps surprising given that in 1628 Harvey had published his theory on the circulation of the blood.

 

Dr. Wepfer made other important contributions in the fields of experimental pharmacology and toxicology. He conducted experiments on the toxicity of water hemlock, hellebore, monkshood, and warned against the usage of arsenic, antimony, and mercury in medicine. In the fields of pharmacology/toxicology he published an influential work on water and poison hemlock called Cicutae aquaticae historia et noxae (1679).

 

Since 2005 an annual award for stroke research, named after Wepfer, is awarded at the European stroke conference.

 

From the late 14th to the late 19th century, apoplexy referred to any sudden death that began with a sudden loss of consciousness, especially one in which the victim died within a matter of seconds after losing consciousness. The word apoplexy may have been used to refer to the symptom of sudden loss of consciousness immediately preceding death. Ruptured aortic aneurysms, and even heart attacks and strokes were referred to as apoplexy in the past. Because the term by itself is now ambiguous, it is often coupled with a descriptive adjective to indicate the site of bleeding. For example, bleeding within the pituitary gland is called pituitary apoplexy, and bleeding within the adrenal glands can be called adrenal apoplexy.

 

The term cerebrovascular accident was introduced in 1927, reflecting a “growing awareness and acceptance of vascular theories and recognition of the consequences of a sudden disruption in the vascular supply of the brain“. Its use is now discouraged by a number of neurology textbooks, reasoning that the connotation of fortuitousness carried by the word accident insufficiently highlights the modifiability of the underlying risk factors. Cerebrovascular insult may be used interchangeably.

 

C Miller Fisher made several important contributions to the understanding of stroke pathogenesis. He identified the relationship between obstruction of the internal carotid arteries in the neck and cerebrovascular disease and further suggested that thrombotic debris were responsible for the event (Fisher 1951). He also described the vascular pathology underlying lacunar infarcts (Fisher 1965) and went on to describe many of the lacunar stroke syndromes, including pure motor hemiplegia, pure sensory stroke, homolateral ataxia and crural paresis, dysarthria-clumsy hand syndrome, sensorimotor stroke, and basilar branch syndromes. Kubik and Adams provided a landmark description of basilar artery occlusion (Kubik and Adams 1946). The clinical characteristics of “top of the basilar“ syndrome were described by Caplan (Caplan 1980).

 

The development of neuroimaging techniques opened a new chapter in the study of stroke. Cerebral angiography was developed by Moniz in 1927. He also gave the first description of internal carotid artery occlusion by angiography in 1937. The first ultrasonic image of the carotid arteries and the bifurcation were recorded by Reid and Spencer in 1972. Based on previous experiments using computed tomography, Hounsfield introduced CT for commercial use in 1972. The first clinical use of head CT was reported by Ambrose in1973). The term brain attack was introduced for use to underline the acute nature of stroke according to the American Stroke Association, who since 1990 have used the term, and is used colloquially to refer to both ischemic as well as hemorrhagic stroke. The application of nuclear magnetic resonance to imaging, done independently by Bloch and Purcell, led to magnetic resonance imaging. Lauterbur and Damadian developed the first low quality medical images in the early 1970s.

 

The first use of aspirin for vascular prevention is attributed to Craven in 1950. McDevitt and colleges described the effectiveness of anticoagulant therapy in 100 patients with cerebral thrombosis or embolism in the 1950s. Eastcott, Rob, and Pickering first reported reconstruction of the internal carotid artery in a patient with intermittent hemiplegia. Later, DeBakey and colleagues realized that recanalization of an occluded vessel could lead to intracerebral hemorrhage. Sources: JMSPEARCE 304 Beverle:; Road, Anlaby, East Yorks HUJO 7BG, UK Wepfer; Historiae apoplecticorum; Brian Silver MD; Wikipedia

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Spinal Stimulation Helps 4 Patients with Paraplegia Regain Voluntary Movement

 

According to a study published online in the journal Brain (8 April 2014)and funded in part by the National Institutes of Health and the Christopher & Dana Reeve Foundation, 4 people with paraplegia are now able to voluntarily move previously paralyzed muscles as a result of a novel therapy that involves electrical stimulation of the spinal cord. The participants, each of whom had been paralyzed for more than two years, were able to voluntarily flex their toes, ankles, and knees while the stimulator was active, and the movements were enhanced over time when combined with physical rehabilitation. According to the authors, the therapy has the potential to change the prognosis of people with paralysis even years after injury.

 

One of the most impressive and unexpected findings of the study is that two of the patients who benefited from the spinal stimulation had complete motor and sensory paralysis. In these patients, the pathway that sends information about sensation from the legs to the brain is disrupted, in addition to the pathway that sends information from the brain to the legs in order to control movement. The authors were surprised by the outcome; they had assumed that at least some of the sensory pathway needed to be intact for the therapy to be effective.

 

The study is the continuation of a groundbreaking pilot trial initiated in 2009 to determine whether spinal stimulation, in conjunction with daily training on a treadmill, could help patients with paralysis regain some ability to move. In that trial, Rob Summers, a young man paralyzed below his chest, had a 16-electrode array implanted on his spinal cord. He then underwent daily training in which he was suspended in a harness over a treadmill while a team of researchers supported his legs, helping him to either stand or walk. At the same time, the array delivered electrical pulses to his spinal cord just below his injury.

 

According to the authors, the goal of the stimulation was to increase the sensitivity of local circuits within the spinal cord that carry out basic motor functions without input from the brain-such as the knee jerk that occurs after stepping on a tack, or even more complex patterned movements like stepping. While not strong enough to directly induce muscle activation by itself, the authors believed the stimulation could lead to movement when combined with sensory input from stepping on a treadmill.

 

With his stimulator active, Summers was able to gradually bear his own weight and could eventually stand without assistance from physical therapists for up to four minutes. Surprisingly, seven months into the trial, Summers also discovered that he had regained some voluntary control of his legs. This was an unexpected finding, as intentional movement requires information to travel from the brain down to the lower spinal cord, a path that had been rendered nonfunctional by his injury. Other impairments caused by Summers’ injury also began to improve over time, in the absence of stimulation, such as blood pressure control, body temperature regulation, bladder control, and sexual function.

 

In this follow-up study, the authors report that three additional patients with paralysis have recovered voluntary muscle control following electrical stimulation of the spine. The three patients in the new study include two with complete motor and sensory paralysis, and one, similar to Summers, with complete motor paralysis but some ability to experience sensation below his injury. Within just a few days of the start of stimulation, all three patients regained some voluntary control of previously paralyzed muscles.

 

The authors pointed to the speed at which each subject recovered voluntary movement as evidence that there may be dormant connections that exist in patients with complete motor paralysis. They hypothesize that rather than there being a complete separation of the upper and lower regions relative to the injury, it’s possible that there is some contact, but that these connections are not functional, and that the spinal stimulation could be reawakening these connections.

 

An important aspect of the new study involved assessing the ability of each patient to modulate his movements in response to auditory and visual cues. All participants, including Summers, were able to synchronize leg, ankle, and toe movements in unison with the rise and fall of a wave displayed on a computer screen, and three out of the four were able to change the force at which they flexed their leg, depending on the intensity of three different auditory cues.

 

The same tests were also administered following several months of spinal stimulation applied in conjunction with locomotor training. During this time, patients also carried out home-based training, which consisted of hour-long stimulation while practicing intentional movements lying down. At the end of the training, some subjects were able to execute voluntary movements with greater force and with reduced stimulation, while others experienced enhanced movement accuracy. It is unclear whether the improvement was a result of the training or due to the cumulative effects of stimulation over time.

 

1. Photo of the four participants in the spinal stimulation study

2. Photo of participant Kent Stephenson raising his leg while his spinal cord is stimulated

3. Photo of participant Kent Stephenson doing voluntary training while a lab tech tracks his level of muscle activity and force.

4. Voluntary training with spinal stimulation. Video courtesy of the University of Louisville.

 

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Too Much Protein May Kill Brain Cells as Parkinson’s Progresses

 

Parkinson’s disease, which affects more than half a million people in the United States, is a degenerative disorder that attacks nerve cells in many parts of the nervous system, most notably in a brain region called the substantia nigra. The substantia nigra is an area in the brain which releases dopamine, a chemical messenger important for movement. Initially, Parkinson’s disease causes uncontrolled movements; including trembling of the hands, arms, or legs. As the disease gradually worsens, patients lose ability to walk, talk or complete simple tasks.

 

For the majority of cases of Parkinson’s disease, a cause remains unknown. However, it is known that mutations in the LRRK2 gene are a leading genetic cause and these mutations have been implicated in as many as 10% of inherited forms of the disease and in about 4% of patients who have no family history. One study showed that the most common LRRK2 mutation, called G2019S, may be the cause of 30-40% of all Parkinson’s cases in people of North African Arabic descent.

 

According to an article published online in the journal Cell (10 April 2014) it may now be possible to identify how the most common genetic cause of Parkinson’s disease destroys brain cells and devastates many patients. The investigators found that mutations in a gene called leucine-rich repeat kinase 2 (LRRK2; pronounced “lark two“ or “lurk two“) may increase the rate at which LRRK2 tags ribosomal proteins, which are key components of protein-making machinery inside cells. This process of tagging could possibly cause the machinery to manufacture too many proteins, leading to cell death. LRRK2 is a kinase enzyme, a type of protein found in cells that tags molecules with chemicals called phosphate groups. The process of phosphorylation helps regulate basic nerve cell function and health. Previous studies suggest that disease-causing mutations, like the G2019S mutation, increase the rate at which LRRK2 tags molecules. Identifying the molecules that LRRK2 tags provides clues as to how nerve cells may die during Parkinson’s disease.

 

For the study, the authors used LRRK2 as bait to fish out the proteins that it normally tags. Multiple experiments performed on human kidney cells suggested that LRRK2 tags ribosomal proteins, and that these proteins combine with other molecules, called ribonucleic acids, to form ribosomes, which are the cell’s protein-making factories. Further experiments suggested that disease-causing mutations in LRRK2 increase the rate at which it tags two ribosomal proteins, called s11 and s15. Moreover, brain tissue samples from patients with LRRK2 mutations had greater levels of phosphorylated s15 than seen in controls.

 

Next, the authors investigated whether phosphorylation could be linked to cell death, by studying nerve cells derived from rats or from human embryonic stem cells. Genetically engineering the cells to have a LRRK2 mutant gene increased the amount of cell death and phosphorylated s15. In contrast, the authors prevented cell death when they engineered the cells to also make a mutant s15 protein that could not be tagged by LRRK2.

 

How might phosphorylation of s15 kill nerve cells? To investigate this, experiments were performed using fruit flies (drosophila), the most profound research tool ever. Previous studies on flies showed that genetically engineering dopamine-releasing nerve cells to overproduce the LRRK2 mutant protein induced nerve cell damage and movement disorders. The authors found that the brains of these flies had increased levels of phosphorylated s15 and that engineering the flies so that s15 could not be tagged by LRRK2 prevented cell damage and restored normal movement. Interestingly, the brains of the LRRK2 mutant flies also had abnormally high levels of all proteins, suggesting that increased s15 tagging caused ribosomes to make too much protein. Treating the flies with low doses of anisomycin, a drug that blocks protein production, prevented nerve cell damage and restored the flies’ movement even though levels of s15 phosphorylation remained high.

 

The authors are proposing that blocking the phosphorylation of s15 ribosomal proteins could lead to future therapies as might other strategies which decrease bulk protein synthesis or increase the cells’ ability to cope with increased protein metabolism. They also think that a means to measure s15 phosphorylation could also act as a biomarker of LRRK2 activity in treatment trials of LRRK2 inhibitors.

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TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.

 

What is Breakthrough Therapy Designation?

 

Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for breakthrough therapy designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. A breakthrough therapy designation conveys all of the fast track program features (see below for more details on fast track designation), as well as more intensive FDA guidance on an efficient drug development program. The FDA also has an organizational commitment to involve senior management in such guidance. Section 902 of FDASIA requires the following actions, as appropriate:

 

1. holding meetings with the sponsor and the review team throughout the development of the drug

 

2. providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable

 

3. taking steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment

 

4. assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the cross-discipline members of the review team (i.e., clinical, pharmacology-toxicology, chemistry, manufacturing and control (CMC), compliance) for coordinated internal interactions and communications with the sponsor through the review division’s Regulatory Health Project Manager

 

5. involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review

 

What other programs does FDA have to expedite drug development for serious conditions?

 

The FDA has various programs that are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serious or life-threatening conditions. These expedited programs help ensure that therapies for serious conditions are available as soon as it can be concluded that the therapies’ benefits justify their risks, taking into account the seriousness of the condition and the availability of alternative treatment. These programs include breakthrough therapy designation as noted above, fast track designation, accelerated approval, and priority review. For purposes of this document, all references to “drugs“ include both human drugs and biological drug products regulated by CDER and CBER.

 

Fast Track Designation: Fast Track designation is intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Designation may be granted on the basis of preclinical data. A sponsor of a drug that receives fast track designation will typically have more frequent interactions with FDA during drug development. In addition, products that have been designated as fast track can submit portions of a marketing application before submitting the complete application, known as rolling review.

 

Accelerated Approval: This program can be used for speeding the development and approval of promising therapies that treat a serious or life-threatening condition and provide meaningful therapeutic benefit over available therapies. Accelerated approval allows approval of a drug that demonstrates an effect on a “surrogate endpoint“ that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit. Thus, the accelerated approval pathway is most often useful in settings in which the disease course is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Nevertheless, even after the drug enters the market, the sponsor may be required to conduct post-marketing trials to verify and describe the drug’s clinical benefit. If further trials fail to verify the predicted clinical benefit, the FDA may withdraw approval.

 

Note that a drug that has received a breakthrough therapy designation or a fast track designation can be eligible for the accelerated approval pathway, if the relevant criteria are met.

 

Priority Review: Under the Prescription Drug User Fee Act (PDUFA), FDA agreed to specific performance goals for completing the review and taking an action on an application according to a two-tiered system of review times: Standard Review and Priority Review. Priority review shortens the review goal date to 6 months from the standard review timeline of 10 months. This review designation is determined at the time of a Biologics License Application (BLA), New Drug Application (NDA), or efficacy supplement submission. Any drug, including those that have received a fast track designation, breakthrough therapy designation, or those being evaluated for accelerated approval, can be granted priority review, if the relevant criteria are met.

 

What are the differences between the breakthrough therapy designation and the fast track designation?

 

Although breakthrough therapy and fast track designation programs have similarities, as they both are intended to expedite the development and review of drugs for serious or life-threatening conditions, there are differences in what needs to be demonstrated to qualify for the programs. A breakthrough therapy program is for a drug that treats a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. In contrast, a fast track program is for a drug that treats a serious or life-threatening condition, and nonclinical or clinical data demonstrate the potential to address unmet medical need.

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Almond Holiday Chewies

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Almond Chewies, delicious with coffee, tea, milk, anything. ©Joyce Hays, Target Health Inc.

 

Delicious, not too sweet, and easy to make.

 

Ingredients

1 (7-ounce) tube pure almond paste (not marzipan; 3/4 cup)
1 cup Splenda granulated, instead of regular sugar
Pinch of Kosher salt
2 large egg whites at room temperature for at least 30 minutes

 

Directions

Preheat oven to 3000F and place racks in the upper and lower thirds of your oven. Line two large sheet pans with parchment paper.

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Pulsing paste, Splenda, salt ©Joyce Hays, Target Health Inc.

 

Pulse almond paste, sugar and salt in a food processor until broken up, then add egg whites and puree until smooth.

 

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Space the chewies far apart, on the parchment ©Joyce Hays, Target Health Inc.

 

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Going into the oven ©Joyce Hays, Target Health Inc.

 

Transfer batter to pastry bag fitted with a 3/8-inch tip and pipe 3/4-inch rounds (1/3 inch high) about 1-inch apart in pans. Dip a fingertip in water and gently tamp down any peaks. You need to leave a 1 inch space between these cookies, because suddenly, just before they’re done, they expand and puff up

 

Bake, rotating and switching position of pans halfway through (after 8 minutes), until golden and puffed, 15 to 18 minutes. The switch enables them to bake evenly.

 

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Cooling the chewies ©Joyce Hays, Target Health Inc

 

Let these chewies cool in their pans. Once cool, they’re much easier to cleanly remove from the parchment.

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I used these jams for filling. ©Joyce Hays, Target Health Inc.

 

You can make them into tiny sandwich cookies, spreading some jam (I used cherry, apricot, raspberry) between them, or ganache (3 ounces of semi-sweet chips melted with 1 to 2 tablespoons of cream). Then leave them to thicken a bit. You’ll get about twenty, if you sandwich them. The ganache is so easy to make, I would recommend this as one of your yummy fillings. Using granulated Splenda instead of sugar in the chewies, cuts the calories. Splenda is one of those sugar substitutes that works well in baking, or cooking at any temperature.

 

Chewies can be kept in an airtight container at room temperature for a day or two or frozen up to one month.

 

If you need to buy any of the following for this recipe, here’s where I got mine:

 

1. Food Processer, Wm-Sonoma, Amazon

2. Parchment paper for baking is at Food Emporium, Wm-Sonoma, Dean & Deluca

3. Pastry bag fitted with a variety of tips incl. 3/8-inch tip at Wm-Sonoma

4. Cookie sheets at Wm-Sonoma, Amazon

5. Tube of Almond paste at Dean & Deluca or Amazon

6. Granulated Splenda, from Fresh Direct, Amazon, just about anywhere

 

We’re starting our meal with glasses of icy Pino Grigio and hummus with warm pita, flat bread and raw veggie sticks. Yes, we keep on eating hummus as we never get tired of it. Next we’re having my baked zucchini sticks in marinara, with a simple turkey salad with dried cranberries, made from left-over turkey that we had last night.

 

Dessert is almond chewies and fresh blueberries. I served these almond chewies last night, but they disappeared rapidly, except for 4, so I made another batch.

 

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Bon Appetit !

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These amoebae eat human cells while they are still alive, and then move on. Terrifying.

By Douglas Main

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An amoeba bites
E. histolytica, in green, taking a “bite” out of a human red blood cell, in purple.
Katherine S. Ralston et al / Nature

 

It used to be thought that the parasite Entamoeba histolytica killed human cells with toxins and only ate them once they were dead–and that during its meals, it would eat cells by engulfing them whole, like other amoebas. But a new study shows that these parasites instead chomp on human cells while they are still alive, taking little bites until the cells die and then moving on. If people were completely rational, we would fear E. histolytica much more than something like sharks, since these tiny amoebae kill as many as 100,000 people every year (and sharks only kill about five to ten people worldwide annually).“This process of nibbling of cells went unrecognized by everyone in this field, including me, for over a hundred years,” study co-author and infectious disease specialist William Petri of the University of Virginia in Charlottesville told Science. The finding completely changes how scientists think of the parasites, and may lead to new treatments for pathogen, which lives in the gut and infects about 50 million around the world. In certain circumstances they can triggeramoebiasis, a potentially fatal diarrhoeal disease.

This habit of chewing bits of live cells in this way and moving on is remarkably strange, and basically unprecedented. “The ingestion of live cell material and the rejection of corpses illuminate a stark contrast to the established model of dead cell clearance in multicellular organisms,” the authors wrote in the study, published this week in Nature.

The scientists discovered the nibbling after introducing fluorescent material into amoebas and human cells, and observing them in a petri dish in the lab. “It was remarkable to see the amoebae were taking bites,” said microbiologist Katherine Ralston of the University of Virginia. The biting “resembled trogocytosis, a process in which immune cells extract bits of other immune cells, but was unique in that it occurred between a parasite and its host and ultimately caused cell death,” Science noted.

 

Source: http://www.popsci.com/article/science/parasitic-amoeba-eats-people-alive-bite-bite?dom=PSC&loc=recent&lnk=5&con=parasitic-amoeba-eats-people-alive-bite-by-bite

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New gravity measurements determined Enceladus has a liquid water sea about as large as Lake Superior.

By Francie Diep

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Ocean Inside This illustration shows what astronomers think the interior of Saturn’s moon Enceladus looks like. There’s a big rocky core, an icy exterior, and a large liquid sea in the south, between the core and the exterior. The illustration also shows jets of water vapor discovered on Enceladus’s southern surface in 2005. Image courtesy of NASA/JPL-Caltech

 

Buried under miles of ice, astronomers have detected a liquid water sea on one of Saturn’s moons, Enceladus. The sea is about the size of Lake Superior and it touches Enceladus’ silicate core… which means it could have minerals dissolved in it that are necessary for life. “It makes, in fact, the interior of Enceladus a very attractive potential place to look for life,” Jonathan Lunine, a Cornell University astronomer who worked on the study determining Enceladus has an ocean, said during a teleconference for reporters.

This extraterrestrial sea could also be the source of water for those funny jets Enceladus has geysering out of its south pole, but scientists don’t yet have data linking the two phenomena.

This new announcement comes from a team of Italian and U.S. scientists, who analyzed gravity data from the Cassini spacecraft. Cassini has been flying around Saturn for almost ten years now, passing close to the surfaces of Saturn’s moons and taking sexy photos of Saturn itself.

Scientists had previously suspected Enceladus may have an underground ocean. This latest study calculated the density of material in different parts of Enceladus after three gravity-measuring flybys. Those measurements revealed there’s something underneath Enceladus’ ice in the south that’s denser than the ice. Liquid water is the most likely explanation, says David Stevenson, a planetary scientist at the California Institute of Technology who also worked on the study.

 

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Enceladus In this image, you can see the fissures on Enceladus’ southern region from which its jets of water vapor emerge. Image courtesy of NASA/JPL/Space Science Institute

 

This little moon has more up its sleeve than anyone suspected.
“When you interpret data like this, gravity, of course, doesn’t tell you what kind of material [is there],” he says. However, because scientists know the most common materials in the outer solar system are rock and ice, they’re assuming the density of material on Enceladus must be explained by rock and water in different forms, Stevenson explains. Later, the study’s lead author, Luciana Iess of the Sapienza University of Rome, says the team is “very comfortable” with its results.

Scientists weren’t always this excited about Enceladus, which is just one of Saturn’s more than 50 known moons. It’s small, with a diameter about one-seventh that of Earth’s moon’s. So at first, scientists thought it was likely inactive. Small objects like Enceladus cool quickly after they form, so they don’t have warm, active cores. They also don’t have enough gravity to hold an atmosphere. But in 2005, Cassini spotted plumes of ice erupting from Enceladus’ southern surface, revealing this little moon has more up its sleeve than anyone suspected.

The secret to little Enceladus’ activity is the strong tidal force it feels from Saturn’s gravitational pull. Its parent planet pulls Enceladus’ ice out of shape, creating friction and heat and melting ice into water. The liquid water then acts as a lubricant, encouraging more ice blocks to rub against each other and create more water. It’s even possible that the moon’s ice plumes come only from water created by flexing ice, not from the newly discovered under-ice sea. So far, scientists have no way of checking whether there’s any interior plumbing connecting the sea to the plumes.

Cassini’s immediate next plans are to make repeated flybys of the Saturnian moons Titan and Dione, which may also have underground oceans.

You can read about Enceladus’ underground sea in Iess, Stevenson, Lunine and their colleagues’ paper in the journal Science.

 

Source: http://www.popsci.com/article/technology/saturns-moon-enceladus-now-top-candidate-life?dom=PSC&loc=slider&lnk=4&con=alien-ocean

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