Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as ‘Lou Gehrig’s disease’

Date:
November 16, 2017

Source:
University of Montreal Hospital Research Centre (CRCHUM)

Summary:
A drug used to treat schizophrenia has the potential to slow the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which there is currently no effective cure. After six years of research on several animal models and a few patients, researchers discovered that pimozide stabilizes the disease in the short term. A clinical trial must confirm the efficacy and safety of the drug before it is offered to patients.

 

Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as “Lou Gehrig’s disease.”
Credit: Alex Parker and Pierre Drapeau

 

 

Researchers from the University of Montréal Hospital Research Centre (CRCHUM) and the Cumming School of Medicine (CSM) at the University of Calgary have discovered a medication that could make it possible to treat individuals with amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.

An article published today in JCI Insight concludes that pimozide was found to be safe and over the short term, preliminary data shows that it could stabilize the progression of ALS. This neurodegenerative disease normally leads to a progressive paralysis of the skeletal muscles and, on average, three years after the onset of symptoms, to death.

“This medication alleviates the symptoms of ALS in animal models,” said Alex Parker, a CRCHUM researcher and professor at Université de Montréal. “Riluzole and edaravone, the drugs currently used, have modest effects. Other studies must be conducted to confirm our results, but we believe that we’ve found a medication that may prove to be more effective in improving patients’ quality of life.”

From worm to man

The story behind the discovery began six years ago with a little millimeter-long nematode worm called C. elegans. In his laboratory, Parker genetically modified the worms so that they would exhibit aspects of the human form of ALS. Simultaneously, his colleague Pierre Drapeau did the same thing to another animal, the zebrafish, a tiny tropical fish only 5 centimetres long.

The two scientists obtained funding from the U.S. Department of Defense to test medications on these worms and fish born with ALS. “We sifted through a library of 3,850 molecules approved for the treatment of other diseases, and found a class of antipsychotic drugs that stabilize mobility in worms and fish,” said Drapeau, a CRCHUM researcher, professor at Université de Montréal and principal investigator on the study. “Pimozide works especially well in preventing paralysis in fish by preserving the neuromuscular junction.”

Subsequently, Université de Montréal Professor Richard Robitaille performed electrophysiological tests on mice in his laboratory and reached the same conclusion. Thus, pimozide was shown to maintain neuromuscular function in three different animal models: worms, fish and mice.

At the annual ALS Canada Research Forum in 2012, the researchers met Dr. Lawrence Korngut, an Associate Professor at the CSM, member of the Hotchkiss Brain Institute (HBI) and Director of the Calgary ALS/Motor Neuron Disease Clinic. “Pimozide is a drug that has been well-known for 50 years,” the neurologist said. “It was approved for treating certain types of psychiatric conditions, like schizophrenia, and costs only 9 cents per pill. Other recent studies have shown genetic links between schizophrenia and ALS. The next logical step was to test it on human volunteers with ALS.”

In 2015, the first preclinical trial for ALS was launched in Canada with a small group of 25 patients who had ALS. Funding was provided by the Quirk family of Calgary, by the HBI, and the Clinical Research Unit at UCalgary.

“We found the highest dose most likely to be tolerated in individuals with ALS — a lower dose than that used in other conditions — and we have preliminary proof showing that pimozide may be useful,” said Korngut.

The initial clinical trial was modest in scope. But after only six weeks, the researchers had a first indication of the drug’s efficacy. Loss of control of the thenar muscles, located in the palm of the hand between thumb and index finger, is usually one of the first signs of ALS. For patients who took pimozide, this function remained stable. This observation is tempered by the very limited size and length of the clinical trial.

“For us, this is an indication that we found the right therapeutic target,” said Drapeau. “Pimozide acts directly on the neuromuscular junction, as shown in our animal models. We don’t yet know whether pimozide has a curative effect, or whether it only preserves normal neuromuscular function to at least stabilize the disease. This is also the first time that a potential drug for human patients was discovered based on basic research on small organisms such as worms and fish.”

Now comes the next step: a phase II clinical trial on 100 volunteers, funded by the “The Ice Bucket Challenge” through a partnership between ALS Canada and Brain Canada to begin in the next few weeks. Headed by Korngut in Calgary and conducted in nine hospital centres across Canada, the study aims to confirm that pimozide is safe and to measure, over a six-month period, its effect on the progression of the disease and its symptoms and on patients’ quality of life.

Daniel Rompré, 47, father of two teenage girls, hopes to participate in the new study. He was diagnosed with ALS in March 2016. The muscles of his upper body are getting weaker, he is beginning to have trouble speaking, and he can no longer use his left arm. “It is hard to maintain a positive outlook,” Rompré said. “You ask yourself: ‘Why me?’ But at least it’s encouraging to see that research is advancing. There has been more progress in the last five years than in 100 years of research on the disease.”

It is too soon to draw firm conclusions about the safety and efficacy of pimozide. “At this stage, people with ALS should not use this medication,” Korngut emphasized. “We must first confirm that it is really useful and safe in the longer term. It is also important to be aware that pimozide is associated with significant side effects. Therefore, it should only be prescribed in the context of a research study.”

Story Source:

Materials provided by University of Montreal Hospital Research Centre (CRCHUM)Note: Content may be edited for style and length.


Journal Reference:

  1. Shunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, Pierre Drapeau. Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosisJCI Insight, 2017; 2 (22) DOI: 10.1172/jci.insight.97152

 

Source: University of Montreal Hospital Research Centre (CRCHUM). “Discovery of a promising medication for amyotrophic lateral sclerosis (ALS): Experiments conducted on worms, zebrafish, mice and, finally, on human subjects in a limited clinical trial conclude that pimozide may be effective in treating what’s known as ‘Lou Gehrig’s disease’.” ScienceDaily. ScienceDaily, 16 November 2017. <www.sciencedaily.com/releases/2017/11/171116104804.htm>.

So much snow that researchers needed the help of tractor-mounted snowblowers

Date:
November 15, 2017

Source:
National Science Foundation

Summary:
A 6-foot-wide snow blower mounted on a tractor makes a lot of sense when you live on the Tug Hill Plateau. Tug Hill, in upstate New York, is one of the snowiest places in the Eastern US and experiences some of the most intense snowstorms in the world. This largely rural region, just east of Lake Ontario, gets an average of 20 feet of snow a year, and a new report explains why.

 

Why does New York’s Tug Hill Plateau get so much snow? Scientists faced blizzards to find out.
Credit: University of Utah

 

 

A 6-foot-wide snow blower mounted on a tractor makes a lot of sense when you live on the Tug Hill Plateau. Tug Hill, in upstate New York, is one of the snowiest places in the Eastern U.S. and experiences some of the most intense snowstorms in the world. This largely rural region, just east of Lake Ontario, gets an average of 20 feet of snow a year.

Hence the tractor-mounted snow blower.

The region’s massive snow totals are due to lake-effect snowstorms and, it turns out, to the shape of Lake Ontario.

Lake-effect storms begin when a cold mass of air moves over relatively warm water. The heat and moisture from the water destabilize the air mass and cause intense, long-lasting storms. Lake-effect snow is common in the Great Lakes region and in areas downwind of large bodies of water, including the Great Salt Lake.

Researchers, including the University of Utah’s Jim Steenburgh and University of Wyoming’s Bart Geerts, now report that these intense snowstorms are fueled by air circulation driven by the heat released by the lake, and that the shoreline geography of Lake Ontario affects the formation and location of this circulation. The result? Very heavy snowfall.

The findings, published in three papers, show how the shorelines of lakes may help forecasters determine the impacts of lake-effect storms.

“Lake Ontario’s east-west orientation allows intense bands of snow to form,” said Ed Bensman, a program director in the National Science Foundation’s (NSF) Division of Atmospheric and Geospace Sciences, which funded the research. “This study found that the shape of the lake’s shoreline can have an important influence on the low-level winds that lead to bands of snow for long periods of time — and to heavy snow totals. The research team analyzed the strength of these snow bands, and their formation and persistence. Snow bands were often active for several days.”

Lake-effect

When land breezes move offshore from places where the coastline bulges out into a lake, unstable air masses form and drive a narrow band of moisture that dumps its moisture as snow on a strip of land downwind of the lake.

Steenburgh said it’s long been known that breezes coming from the shore onto a lake help initiate and direct the formation of snow bands. Steenburgh and Geerts, and colleagues from universities in Illinois, Pennsylvania and upstate New York, traveled to Lake Ontario as part of an NSF-funded project called Ontario Winter Lake-effect Systems (OWLeS). The scientists investigated several questions about lake-effect systems:

  • What environmental factors have the greatest influence on the amount of snowfall and location of snowbands over and near Lake Ontario?
  • How does the interplay between wind and clouds produce long-lived snowbands far downstream of open water?
  • How does the local terrain influence the strength and longevity of these systems?

To find out, Geerts’ team flew a Wyoming King Air research plane through winter storms, and Steenburgh’s group set up weather monitoring equipment, including profiling radars and snow-measurement stations, to monitor the arrival of lake-effect storms near Tug Hill.

The researchers witnessed the region’s intense snowfall, including one storm that dropped 40 inches in 24 hours. Snowfall rates often exceeded 4 inches per hour. “That’s an amazing rate,” Steenburgh said. “It’s just an explosion of snow.”

The role of the bulge

Wyoming Cloud Radar aboard the King Air plane detected an intense secondary air circulation across the main snow band. “This circulation had a narrow updraft, creating and lifting snow like a fountain in a narrow strip that dumped heavy snow where it made landfall,” Geerts said. Using a weather model, Steenburgh’s team found that this circulation’s origin was a land breeze generated by the lake’s uneven shoreline geography.

In some cases, another land breeze generated a second snow band that merged with the first. “The intense secondary circulation, with updrafts up to 20 miles per hour, had never been observed before,” Geerts said.

One particular shoreline feature played a large role: a gentle, broad bulge along Lake Ontario’s southern shore that extends from about Niagara Falls in the west to Rochester, New York, in the east.

“This bulge was important in determining where the lake-effect snow bands developed,” Steenburgh said. “A bulge near Oswego, New York, on the southeast shore, also contributed to an increase in the precipitation downstream of Lake Ontario over Tug Hill.”

Steenburgh says the residents of the region take the heavy snowfall in stride. Roads are kept plowed, and the team found that on many days, the biggest challenge was just getting out of the driveway of the house they stayed in. Once the tractor-snow blower was fired up, however, the researchers had a clear shot.

“We’re a bunch of snow geeks,” Steenburgh said. “We love to see it snowing like that. It’s really pretty incredible. And our friends on Tug Hill made sure we could do our research.”

Better forecasts

Incorporating considerations of shoreline geography into weather forecast models can help predict which communities might be most affected by snowstorms, Steenburgh said. Understanding the effect of breezes that arise from the shore’s shape is the key.

“If we want to pinpoint where the lake-effect is going to be, we’re going to have to do a very good job of simulating what’s happening along these coastal areas,” he said.

Story Source:

Materials provided by National Science FoundationNote: Content may be edited for style and length.


Journal References:

  1. Philip T. Bergmaier, Bart Geerts, Leah S. Campbell, W. James Steenburgh. The OWLeS IOP2b Lake-Effect Snowstorm: Dynamics of the Secondary CirculationMonthly Weather Review, 2017; 145 (7): 2437 DOI: 10.1175/MWR-D-16-0462.1
  2. Leah S. Campbell, W. James Steenburgh. The OWLeS IOP2b Lake-Effect Snowstorm: Mechanisms Contributing to the Tug Hill Precipitation MaximumMonthly Weather Review, 2017; 145 (7): 2461 DOI: 10.1175/MWR-D-16-0461.1
  3. W. James Steenburgh, Leah S. Campbell. The OWLeS IOP2b Lake-Effect Snowstorm: Shoreline Geometry and the Mesoscale Forcing of PrecipitationMonthly Weather Review, 2017; 145 (7): 2421 DOI: 10.1175/MWR-D-16-0460.1

 

Source: National Science Foundation. “Shape of Lake Ontario generates white-out blizzards, study shows: So much snow that researchers needed the help of tractor-mounted snowblowers.” ScienceDaily. ScienceDaily, 15 November 2017. <www.sciencedaily.com/releases/2017/11/171115175313.htm>.

Spanish researchers have discovered this effect in granular media, opening the door to the theoretical understanding of the Mpemba effect

Date:
November 14, 2017

Source:
Universidad Carlos III de Madrid

Summary:
A team of researchers has defined a theoretical framework that could explain the Mpemba effect, a counterintuitive physical phenomenon revealed when hot water freezes faster than cold water.

 

Icicles (stock image).
Credit: © Lela Kieler / Fotolia

 

 

A team of researchers from Universidad Carlos III de Madrid, the Universidad de Extremadura and the Universidad de Sevilla have defined a theoretical framework that could explain the Mpemba effect, a counterintuitive physical phenomenon revealed when hot water freezes faster than cold water.

The researchers, who have recently published the findings in Physical Review Letters, have confirmed how this phenomenon occurs in granular fluids, that is, those composed of particles that are very small and interact among those that lose part of their kinetic energy. Thanks to this theoretical characterization, “we can simulate on a computer and make analytical calculations to know how and when the Mpemba effect will occur,” said Antonio Lasanta. Lasanta is from the UC3M Gregorio Millán Barbany University Institute for Modeling and Simulation on Fluid Dynamics, Nanoscience and Industrial Mathematics. “In fact,” he said, “we find not only that the hottest can cool faster but also the opposite effect: the coldest can heat faster, which would be called the inverse Mpemba effect.”

The fact that preheated liquids freeze faster than those that are already cold was observed for the first time by Aristotle in the 4th century AD. Francis Bacon, the father of scientific empiricism, and René Descartes, the French philosopher, were also interested in the phenomenon, which became a theory when, in 1960, a Tanzanian student named Erasto Mpemba explained to his teacher in a class that the hottest mixture of ice cream froze faster than the cold one. This anecdote inspired a technical document about the subject, and the effect began to be analyzed in educational and science magazines. However, its causes and effects have hardly been studied until now.

“It is an effect that, historically, has not been addressed in a rigorous manner but merely as an anomaly and a didactic curiosity,” said Antonio Prados, one of the researchers from the Universidad de Sevilla Department of Theoretical Physics. “From our perspective, it was important to study it in a system with the minimum ingredients to be able to control and understand its behavior,” he said. This has enabled them to understand what scenarios it is easier to occur in, which is one of the main contributions of this scientific study. “Thanks to this, we have identified some of the ingredients so that the effect occurs in some physical systems that we can describe well theoretically,” stated researcher Francisco Vega Reyes and Andrés Santos, from the Universidad de Extremadura Instituto de Computación Científica Avanzada (Institute of Advanced Scientific Computation).

“The scenario that the effect will most easily occur in is when the velocities of the particles before heating or cooling have a specific disposition — for example, with a high dispersion around the mean value,” he said. This way, the evolution of the temperature of the fluid can be significantly affected if the state of the particles is prepared before the cooling.

This research of “basic science,” in addition to contributing to improving fundamental knowledge, might have other applications in the mid or long term. In fact, this group of researchers is planning to carry out an experiment that verifies the theory. Learning to emulate and use this effect might have applications in our daily life, according to scientists. For example, it could be used to make electronic devices which we want to cool faster.

Video (Spanish with English subtitles): https://youtu.be/esHynYASgeY

Story Source:

Materials provided by Universidad Carlos III de MadridNote: Content may be edited for style and length.


Journal Reference:

  1. Antonio Lasanta, Francisco Vega Reyes, Antonio Prados, Andrés Santos. When the Hotter Cools More Quickly: Mpemba Effect in Granular FluidsPhysical Review Letters, 2017; 119 (14) DOI: 10.1103/PhysRevLett.119.148001

 

Source: Universidad Carlos III de Madrid. “Why hot water freezes faster than cold water: Spanish researchers have discovered this effect in granular media, opening the door to the theoretical understanding of the Mpemba effect.” ScienceDaily. ScienceDaily, 14 November 2017. <www.sciencedaily.com/releases/2017/11/171114104825.htm>.

Date:
November 14, 2017

Source:
Scripps Research Institute

Summary:
NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

 

Researchers are hopeful that a new drug may be able to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).
Credit: © Lori Werhane / Fotolia

Scientists have performed a successful test of a possible new drug in a mouse model of an autism disorder. The candidate drug, called NitroSynapsin, largely corrected electrical, behavioral and brain abnormalities in the mice.

NitroSynapsin is intended to restore an electrical signaling imbalance in the brain found in virtually all forms of autism spectrum disorder (ASD).

“This drug candidate is poised to go into clinical trials, and we think it might be effective against multiple forms of autism,” said senior investigator Stuart Lipton, M.D., Ph.D., Professor and Hannah and Eugene Step Chair at The Scripps Research Institute (TSRI), who is also a clinical neurologist caring for patients.

The research, published on today in the journal Nature Communications, was a collaboration involving scientists at the Scintillon Institute; the University of California, San Diego School of Medicine; Sanford Burnham Prebys Medical Discovery Institute and other institutions. Lipton’s fellow senior investigators on the project were Drs. Nobuki Nakanishi and Shichun Tu of the Scintillon Institute in San Diego.

ASD is brain development disorder that affects 1 in 68 children in the United States alone. Because ASD has been diagnosed more often in recent years, most Americans now living with autism diagnoses are children — roughly 2.4 percent of boys and 0.5 percent of girls.

Genetic Analysis Leads to Potential Treatment

The new study stemmed from a 1993 study in which Lipton and his laboratory, then at Harvard Medical School, identified a gene called MEF2C as a potentially important factor in brain development.

This breakthrough led Lipton and colleagues to the discovery that disrupting the mouse version of MEF2C in the brain, early in fetal development, causes mice to be born with severe, autism-like abnormalities. Since that discovery in mice in 2008, other researchers have reported many cases of children who have a very similar disorder, resulting from a mutation to one copy of MEF2C (human DNA normally contains two copies of every gene, one copy inherited from the father and one from the mother). The condition is now called MEF2C Haploinsufficiency Syndrome (MHS).

“This syndrome was discovered in people only because it was first discovered in mice — it’s a good example of why basic science is so important,” Lipton said.

MEF2C encodes a protein that works as a transcription factor, like a switch that turns on the expression of many genes. Although MHS accounts for only a small proportion of autism disorder cases, large-scale genomic studies in recent years have found that mutations underlying various autism disorders frequently involve genes whose activity is switched on by MEF2C.

“Because MEF2C is important in driving so many autism-linked genes, we’re hopeful that a treatment that works for this MEF2C-haploinsufficiency syndrome will also be effective against other forms of autism,” Lipton said, “and in fact we already have preliminary evidence for this.”

For the study, the researchers created a laboratory model of MHS by engineering mice to have — like human children with MHS — just one functioning copy of the mouse version of MEF2C, rather than the usual two copies. The mice showed impairments in spatial memory, abnormal anxiety and abnormal repetitive movements, plus other signs consistent with human MHS. Analyses of mouse brains revealed a host of problems, including an excess in key brain regions of excitatory signaling (which causes neurons to fire) over inhibitory signaling (which suppresses neuronal activity).

In short, these two important kinds of brain signals were out of balance. A similar excitatory/inhibitory (E/I) imbalance is seen in most forms of ASD and is thought to explain many of the core features of these disorders, including cognitive and behavioral problems and an increased chance of epileptic seizures.

The researchers treated the MHS-mice for three months with NitroSynapsin, an aminoadamantane nitrate compound related to the Alzheimer’s FDA-approved drug memantine, which was previously developed by Lipton’s group. NitroSynapsin is known to help reduce excess excitatory signaling in the brain, and the team found that the compound did reduce the E/I imbalance and also reduced abnormal behaviors in the mice and boosted their performance on cognitive/behavioral tests — in some cases restoring performance essentially to normal.

Lipton and colleagues are currently testing the drug in mouse models of other autism disorders, and they hope to move NitroSynapsin into clinical trials with a biotechnology partner.

The work also has support from parents of children with MHS. “We are all hanging on to the hope that one day our children will be able to speak, to understand and to live more independent lives,” said Michelle Dunlavy, who has a son with MHS.

In fact, Lipton’s group is also now using stem cell technology to create cell-based models of MHS with skin cells from children who have the syndrome — and NitroSynapsin appears to work in this ‘human context’ as well. Dunlavy and other parents of children with MHS recently organized an international, Facebook-based support group, which is coordinating to assist in Lipton’s research going forward.

In an amazing twist, the scientific team also found in Alzheimer’s disease models that the new NitroSynapsin compound improves synapse function, the specialized areas for communication between nerve cells. Thus, the ability of the drug to improve ‘network’ communication in the brain may eventually lead to its use in several neurological diseases.

Story Source:

Materials provided by Scripps Research InstituteNote: Content may be edited for style and length.


Journal Reference:

  1. Shichun Tu, Mohd Waseem Akhtar, Rosa Maria Escorihuela, Alejandro Amador-Arjona, Vivek Swarup, James Parker, Jeffrey D. Zaremba, Timothy Holland, Neha Bansal, Daniel R. Holohan, Kevin Lopez, Scott D. Ryan, Shing Fai Chan, Li Yan, Xiaofei Zhang, Xiayu Huang, Abdullah Sultan, Scott R. McKercher, Rajesh Ambasudhan, Huaxi Xu, Yuqiang Wang, Daniel H. Geschwind, Amanda J. Roberts, Alexey V. Terskikh, Robert A. Rissman, Eliezer Masliah, Stuart A. Lipton, Nobuki Nakanishi. NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autismNature Communications, 2017; 8 (1) DOI: 10.1038/s41467-017-01563-8

George Washington was Inaugurated in New York City

 

On Thursday, April 30, 1789, on the balcony of Federal Hall in New York City, New York George Washington was inaugurated as the first President of the United States. Thus ends the final chapter of a fascinating book entitled, “A Brilliant Solution: Inventing the American Constitution,“ by Carol Berkin. This is a must read for anyone fascinated by the foundations of the American experience in governing. But most important to note is the profound insight our founders had into human behavior and the human psyche, and the intelligent and prescient controls they put in place to avoid concentration of power. Our goal is to share a copy of the book on your next visit to our offices.

 

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

 

QUIZ

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Pericarditis

Figure A shows the location of the heart and a normal heart and pericardium (the sac surrounding the heart). The inset image is an enlarged cross-section of the pericardium that shows its two layers of tissue and the fluid between the layers. Figure B shows the heart with pericarditis. The inset image is an enlarged cross-section that shows the inflamed and thickened layers of the pericardium.

Graphic credit: National Heart Lung and Blood Institute (NIH) – National Heart Lung and Blood Institute (NIH), Public Domain, https://commons.wikimedia.org/w/index.php?curid=29590112

 

Pericarditis is inflammation of the pericardium (the fibrous sac surrounding the heart). Symptoms typically include sudden onset of sharp chest 1) ___. The pain may also be felt in the shoulders, neck, or back. It is typically better sitting up and worse with lying down or breathing deep. Other symptoms may include fever, weakness, palpitations, and shortness of breath. Occasionally onset of symptoms is gradual. The cause of pericarditis is believed to be most often due to a viral infection. Other causes include bacterial infections such as tuberculosis, uremic pericarditis, following a heart attack, cancer, autoimmune disorders, and chest trauma. The cause often remains unknown. Diagnosis is based on the chest pain, a pericardial rub, specific 2) ___ changes, and fluid around the heart. Other conditions that may produce similar symptoms include a heart attack.

 

Treatment in most cases is with NSAIDs and possibly colchicine. Steroids may be used if those are not appropriate. Typically, symptoms improve in a few days to weeks but can occasionally last months. Complications can include cardiac tamponade, myocarditis, and constrictive pericarditis. It is a less common cause of chest pain. About 3 per 10,000 people are affected per year. Those most commonly affected are 3) ___ between the ages of 20 and 50. Up to 30% of those affected have more than one episode. The characteristic pain of pericarditis includes substernal or left precordial pleuritic chest pain with radiation to the trapezius ridge (the bottom portion of scapula on the back), which is relieved by sitting up and bending forward and worsened by lying down (recumbent or supine position) or inspiration (taking a breath in). The pain may resemble the pain of angina pectoris or 4) ___ attack, but differs in that pain changes with body position, as opposed to heart attack pain that is pressure-like, and constant with radiation to the left arm and/or the jaw. Other symptoms of pericarditis may include dry cough, fever, fatigue, and anxiety. Due to similarity to myocardial infarction (heart attack) pain, pericarditis can be misdiagnosed as an acute myocardial infarction (a heart attack) solely based on the clinical data and so extreme suspicion on the part of the diagnostician is required. Acute myocardial 5) ___ electrocardiogram (heart attack) can also cause pericarditis, but the presenting symptoms often differ enough to warrant diagnosis.

 

The classic sign of pericarditis is a friction rub heard with a 6) ___ on the cardiovascular examination usually on the lower left sternal border. Other physical signs include a patient in distress, positional chest pain, diaphoresis (excessive sweating), and possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus, and the Beck’s triad of low blood pressure (due to decreased cardiac output), distant (muffled) heart sounds, and distension of the jugular vein (JVD). Pericarditis can progress to pericardial effusion and eventually cardiac tamponade. This can be seen in patients who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration), low blood 7) ___ (due to decreased cardiac index), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid. In such cases of cardiac tamponade, diagnostic tools such as an ECG or Holter monitor will then depict electrical alternans indicating wobbling of the heart in the fluid filled pericardium, and the capillary refill might decrease, as well as severe vascular collapse and altered mental status due to hypoperfusion of body organs by a heart that cannot pump out 8) ___ effectively.

 

The diagnosis of tamponade can be confirmed with trans-thoracic echocardiography (TTE), which should show a large pericardial effusion and diastolic collapse of the right ventricle and right atrium. Chest X- 9) ___ usually shows an enlarged cardiac silhouette (“water bottle“ appearance) and clear lungs. Pulmonary congestion is typically not seen because equalization of diastolic pressures constrains the pulmonary capillary wedge pressure to the intra-pericardial pressure (and all other diastolic pressures).

 

In the developed world viruses are believed to be the cause of about 85% of cases. In the developing world tuberculosis is a common cause but it is rare in the developed world. Viral causes include coxsackievirus, herpesvirus, mumps virus, and HIV among others. Pneumococcus or tuberculous pericarditis are the most common bacterial forms. Anaerobic bacteria can also be a rare cause. Fungal pericarditis is usually due to histoplasmosis, or in immunocompromised hosts Aspergillus, Candida, and Coccidioides. The most common cause of pericarditis worldwide is infectious pericarditis with 10) ___.

 

Myocarditis

 

Pericarditis

 

Myocarditis and Pericarditis: Khan Academy

 

Answers: 1) pain; 2) electrocardiogram; 3) males; 4) heart; 5) infarction; 6) stethoscope; 7) pressure; 8) blood; 9) -ray; 10) tuberculosis

 

Frederic Chopin’s Cause of Death

Chopin plays for the Radziwills, 1829 (painting by Henryk Siemiradzki, 1887)

Credit: Henryk Siemiradzki – images.fineartamerica.com, Public Domain, https://commons.wikimedia.org/w/index.php?curid=1086097

 

In 2014, a team of medical experts received permission to remove Polish genius, Frederic Chopin’s preserved heart from the Holy Cross Church in Warsaw, where it had ultimately been interred, and examine it for clues that might shed light on the mysterious ailment that led to Chopin’s death at the age of 39. The diagnosis, published in the American Journal of Medicine this past week, is the latest and most convincing foray into the long-running dispute over the likely cause of Chopin’s slow decline and death in his 30s. This published paper suggests that the composer died of pericarditis, a complication of chronic tuberculosis. Other suggested causes of his debilitation and death have included the inherited disease cystic fibrosis; alpha-1-antitrypsin deficiency, a relatively rare genetic ailment that leaves individuals prone to lung infections; and mitral stenosis, a narrowing of the heart valves. Used for the recent analysis and diagnosis was the great composer’s heart, stored in a jar of cognac for 170 years.

 

An autopsy was performed to try to solve the mysterious cause of the 39-year-old’s death. His heart was removed and later stored in a jar of cognac, then interred in a church pillar in Poland. But when the researchers recently examined the jar containing Chopin’s heart – kept in the crypt of the Holy Cross church in Warsaw – they noted the heart was covered with a fine coating of white fibrous materials. In addition, small lesions were visible, the telltale symptoms of serious complications of tuberculosis, concluded the team. “We didn’t open the jar,“ team leader Professor Michael Witt of the Polish Academy of Sciences told the Observer. “But from the state of the heart we can say, with high probability, that Chopin suffered from tuberculosis while the complication pericarditis was probably the immediate cause of his death.“

 

The new study is the latest chapter in the strange story of Chopin’s heart. After the composer died in October 1849 in Paris the rest of his remains were buried in the city’s Pere Lachaise cemetery, also the last resting place of Marcel Proust, Oscar Wilde and Jim Morrison. However, his status as a Polish national hero ensured that his heart became embroiled in controversy. Chopin’s health began to falter in the late 1830s, ultimately making it difficult for him to continue composing music. Over the years, a number of diseases have been named as the culprit of his physical decline, from cystic fibrosis to alpha-1-antitrypsin deficiency, a rare genetic condition that eventually leads to lung disease. According to a 2014 article by Alex Ross of the New Yorker, Ludwika Jedrzejewicz, Chopin’s eldest sister, smuggled the organ past Austrian and Russian authorities on her way to Poland, hiding the jar that held the heart beneath her cloak. The jar was subsequently encased in a wooden urn and buried beneath a monument at the Holy Cross Church.

 

In the early 20th century, Chopin, as one of Poland’s most famous native sons, became the focus of nationalist fervor in the country. During the WWII-era, Nazi occupiers recognized the symbolic significance of Chopin’s legacy and sought to block the performance of his music. But his heart was removed from the Holy Cross and given to the S.S. officer Heinz Reinefarth, who claimed to admire the composer and kept the heart safe at Nazi headquarters in Poland. The organ was returned to Holy Cross in 1945, where it remained until church officials and medical researchers collaborated to dig it up. The examination of the heart by Professor Witt and colleagues was the first since 1945. “We found it is still perfectly sealed in the jar,“ said Witt. “Some people still want to open it in order to take tissue samples to do DNA tests to support their ideas that Chopin had some kind of genetic condition. That would be absolutely wrong. It could destroy the heart and in any case, I am quite sure we now know what killed Chopin.“ The recent examination of Chopin’s heart is unlikely to quell discussion over the cause of his death. As Nature reports, the organ has never been tested for cystic fibrosis, another proposed cause of Chopin’s demise. And some scholars have cast doubt on whether the heart belonged to Chopin at all. But for now, the (possible) relic of the composer can rest undisturbed. Researchers will not be permitted to examine the heart again for another 50 years.

Sources: The Guardian; The Smithsonian; Wikipedia

Read more: http://www.smithsonianmag.com/smart-news/chopins-preserved-heart-may-offer-clues-about-his-death-180967168/#1mR2vDjK42vsapca.99

 

Chopin on His Deathbed, by Teofil Kwiatkowski, 1849, commissioned by Jane Stirling. Chopin is in the presence of (from left) Aleksander Jelowicki, Chopin’s sister Ludwika, Princess Marcelina Czartoryska, Wojciech Grzymala, Kwiatkowski. Credit: Teofil Kwiatkowski – www.psm.vin.pl, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9613090

 

Funerary monument on a pillar in Holy Cross Church, Warsaw, enclosing Chopin’s heart.

Photo credit: Nihil novi – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=2704160

 

Chopin’s grave in Paris

Photo credit: Auguste Clesinger – Marcin L., 26 December 2005, Public Domain, https://commons.wikimedia.org/w/index.php?curid=479220

 

Here are some favorite Chopin masterpieces.

Frederic Chopin – Prelude in E-Minor (op.28 no. 4)

Chopin Nocturne C sharp minor (1830) (Arjen Seinen).

Chopin Ballade in G Minor Scene; Pianist, Wladyslaw Szpilman

Chopin, Nocturne in C sharp Minor (1830); Pianist, Jan Lisiecki

Chopin Nocturne No. 20; Pianist, Wladyslaw Szpilman

Chopin Piano Concerto No 1 in E Minor; Pianist, Land Lang

 

ONCOLOGY

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Low-fat Dietary Pattern and Pancreatic Cancer Risk in Women

 

Observational studies suggest that diet may influence pancreatic cancer risk. As a result, a study published in the Journal of the National Cancer Institute (18 August 2017) investigated the effect of a low-fat dietary intervention on pancreatic cancer incidence.

 

The Women’s Health Initiative Dietary Modification (WHI-DM) trial is a randomized controlled trial conducted in 48,835 postmenopausal women age 50 to 79?years in the United States between 1993 and 1998. Women were randomly assigned to the intervention group (n=19,541), with the goal of reducing total fat intake and increasing intake of vegetables, fruits, and grains, or to the usual diet comparison group (n=29,294). The intervention concluded in March 2005. The current study evaluated the effect of the intervention on pancreatic cancer incidence with the follow-up through 2014. In the intention-to-treat analyses, which included 46,200 women, there were 92 vs 165 pancreatic cancer cases in the intervention vs the comparison group (P =0.23). The multivariable hazard ratio (HR) of pancreatic cancer was 0.86, and risk was statistically significantly reduced among women with baseline body mass indexes (BMIs) of 25kg/m2 or higher (HR=0.71), but not among women with BMIs of less than 25kg/m2 (HR=1.62; P=0.01). According to the author, a low-fat dietary intervention was associated with reduced pancreatic cancer incidence in women who were overweight or obese.

 

Higher Brain Glucose Levels May Mean More Severe Alzheimer’s

 

According to an article published online in Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association (6 November 2017), higher brain glucose levels may mean more severe Alzheimer’s, and thus showing connections between glucose metabolism and Alzheimer’s pathology, symptoms. For the first time, a connection was found between abnormalities in how the brain breaks down glucose and the severity of the signature amyloid plaques and tangles in the brain, as well as the onset of eventual outward symptoms of Alzheimer’s disease. For the study, the authors looked at brain tissue samples at autopsy from participants in the Baltimore Longitudinal Study of Aging (BLSA), one of the world’s longest-running scientific studies of human aging. The BLSA tracks neurological, physical and psychological data on participants over several decades. For the study, the authors measured glucose levels in different brain regions, some vulnerable to Alzheimer’s disease pathology, such as the frontal and temporal cortex, and some that are resistant, like the cerebellum. They analyzed three groups of BLSA participants: those with Alzheimer’s symptoms during life and with confirmed Alzheimer’s disease pathology (beta-amyloid protein plaques and neurofibrillary tangles) in the brain at death; healthy controls; and individuals without symptoms during life but with significant levels of Alzheimer’s pathology found in the brain post-mortem.

 

Results showed distinct abnormalities in glycolysis, the main process by which the brain breaks down glucose, with evidence linking the severity of the abnormalities to the severity of Alzheimer’s pathology. Lower rates of glycolysis and higher brain glucose levels correlated to more severe plaques and tangles found in the brains of people with the disease. More severe reductions in brain glycolysis were also related to the expression of symptoms of Alzheimer’s disease during life, such as problems with memory.

 

While similarities between diabetes and Alzheimer’s have long been suspected, they have been difficult to evaluate, since insulin is not needed for glucose to enter the brain or to get into neurons. The authors tracked the brain’s usage of glucose by measuring ratios of the amino acids serine, glycine and alanine to glucose, allowing them to assess rates of the key steps of glycolysis. Results showed that the activities of enzymes controlling these key glycolysis steps were lower in Alzheimer’s cases compared to normal brain tissue samples. Furthermore, lower enzyme activity was associated with more severe Alzheimer’s pathology in the brain and the development of symptoms.

 

Next, the authors used proteomics — the large-scale measurement of cellular proteins — to tally levels of GLUT3, a glucose transporter protein, in neurons. They found that GLUT3 levels were lower in brains with Alzheimer’s pathology compared to normal brains, and that these levels were also connected to the severity of tangles and plaques. Finally, the team checked blood glucose levels in study participants years before they died, finding that greater increases in blood glucose levels correlated with greater brain glucose levels at death.

 

According to the authors, the findings point to a novel mechanism that could be targeted in the development of new treatments to help the brain overcome glycolysis defects in Alzheimer’s disease. However, the authors cautioned that it is not yet completely clear whether abnormalities in brain glucose metabolism are definitively linked to the severity of Alzheimer’s disease symptoms or the speed of disease progression. The next steps for the authors include studying abnormalities in other metabolic pathways linked to glycolysis to determine how they may relate to Alzheimer’s pathology in the brain.

 

First Treatment Approved for Certain Patients with Erdheim-Chester Disease

 

Erdheim-Chester Disease (ECD) is a slow-growing blood cancer that originates in the bone marrow, and causes an increased production of histiocytes, a type of white blood cell. Excess histiocytes can result in tumors infiltrating many organs and tissues throughout the body, including the heart, lungs, brain and others. ECD is estimated to affect 600 to 700 patients worldwide. Approximately 54% of patients with ECD have the BRAF V600 mutation. Patients with ECD also have very limited life expectancies.

 

The FDA has expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with ECD. Zelboraf is indicated to treat patients whose cancer cells have the BRAF V600 mutation. This product was first approved in 2011 to treat certain patients with melanoma that harbor the BRAF V600E mutation. This is the first FDA-approved treatment for ECD.

 

Zelboraf is a kinase inhibitor that works by blocking certain enzymes that promote cell growth. The efficacy of Zelboraf for the treatment of ECD was studied in 22 patients with BRAF-V600-mutation positive ECD. The trial measured the percent of patients who experienced a complete or partial reduction in tumor size (overall response rate). In the trial, 11 patients (50%) experienced a partial response and 1 patient (4.5%) experienced a complete response. Common side effects of Zelboraf in patients with ECD include joint pain (arthralgia); small, raised bumps (maculo-papular rash); hair loss (alopecia); fatigue; change in the heart’s electrical activity (prolonged QT interval) and skin growths (papilloma). Severe side effects of Zelboraf include the development of new cancers (skin cancer, squamous cell carcinoma or other cancers), growth of tumors in patients with BRAF wild-type melanoma, hypersensitivity reactions (anaphylaxis and DRESS syndrome), severe skin reactions (Stevens-Johnson Syndrome and toxic epidermal necrolysis), heart abnormalities (QT prolongation), liver damage (hepatotoxicity), photosensitivity, severe reactions in the eye (uveitis), immune reactions after receiving radiation treatment (radiation sensitization and radiation recall), kidney failure and thickening of tissue in the hands and feet (Dupuytren’s contracture and plantar fascial fibromatosis). Zelboraf can also cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

 

The FDA granted this application Priority Review and Breakthrough Therapy designations for this indication. Zelboraf also received Orphan Drug designation for this indication, which provides incentives to assist and encourage the development of drugs for rare diseases.

 

The FDA granted the approval of Zelboraf to Hoffman-LaRoche, Inc.

 

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