A Cause of Sporadic ALS

August 28, 2015 by

Aug. 14, 2015

By Medical Discovery News

A Cause of Sporadic ALS

When the groundbreaking theoretical physicist Stephen Hawking was diagnosed with amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease at 21, he was given two years to live. Now he is 73 years old. How has he managed to survive this invariably fatal disease for so long? We may not have all the answers when it comes to ALS, but one study has brought us closer to understanding its cause.

ALS is a devastating, progressive neurodegenerative disorder characterized by gradual degeneration and death of motor neurons responsible for controlling voluntary muscles, resulting in the loss of all voluntary movement including the face, arms, and legs. The disease becomes life-threatening when the muscles in the diaphragm and the chest wall fail and the patient requires a ventilator to breathe. Most people with ALS die from respiratory failure three to five years after the onset of symptoms. Only 10 percent survive 10 years or longer.

One tragic aspect of ALS is patients usually retain their awareness, intelligence, taste, sense of smell, hearing, and touch recognition, making them acutely aware of their deteriorating condition. ALS is one of the most common neuromuscular diseases, afflicting 12,000 people in the United States. Some 90-95 percent of all ALS cases are sporadic, so they have no family history. The remaining cases, called familial ALS, have a genetic component.

While its cause has long been sought after, recently scientists conducted the largest genetic sequencing study of ALS patients thus far. The genetic information of nearly 3,000 ALS patients and over 6,400 control subjects were sequenced, leading to the identification of a new gene associated with ALS. It took a study of this size to detect such a rare gene variant, as it is only mutated in about 2 percent of sporadic ALS cases.

The gene, TANK-Binding Kinase 1 (TBK1), is involved in a cell system that degrades and recycles waste. Scientists are trying to link mutations in the gene with the accumulation of protein aggregates that are killing motor neurons. TBK1 is also important to the immune response. Scientists have long thought inflammation in the brain plays a role in ALS. Since TBK1 tamps down inflammation, a mutation in the gene could interfere with that function.

Researchers are also studying a gene, OPTN, that interacts with TBK1. Together they regulate cell waste disposal and inflammation. Scientists are experimenting on mice engineered with mutations in both genes to determine how they contribute to ALS. These models will also be used to develop future therapies. However, genetic profiling of ALS patients will be necessary to determine which therapy is appropriate depending on the gene that is mutated.

Since ALS can be caused by dozens of gene mutations, the more we can identify, the better scientists can understand their influence on the pathways that lead to this disease.

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How a Heart Fails

July 12, 2015 by

July 10, 2015

By Medical Discovery News

A heart

What exactly causes a heart to fail? It may come down to a simple protein, which scientists recently identified as having an important role in how a heart goes from weakening to failing.

Your heart is a strong, muscular pump slightly larger than your fist that pushes blood through your body. Blood delivers the necessary oxygen and nutrients to all cells in all the organs. Every minute, your heart pumps five quarts of blood. Human hearts have four chambers: two atria on top and two ventricles on bottom. Oxygenated blood leaves the lungs, enters the left atrium, moves to the left ventricle, and is then pumped out of the heart to the rest of the body. After it circulates, blood returns to the heart, enters the right atrium, moves to the right ventricle, and is then sent back to the lungs for a fresh dose of oxygen. Although your heart beats 100,000 times each day, the four chambers must go through a series of highly organized contractions to accomplish this.

Any disruption of this process can have serious consequences such as heart failure, which is clinically defined as a chronic, progressive weakening of the heart’s ability to circulate enough blood to meet the body’s demands. To compensate, the heart enlarges, which increases contractions and the volume of blood pumped. Blood vessels elsewhere in the body narrow to keep blood pressure normal. Blood can even be diverted from less important organs, ensuring more vital organs like the brain and heart are satisfied. However, such responses mask the underlying problem: the weakening heart, which continues to worsen. Ultimately, the body can no longer compensate for the heart, which is when it will start to fail.

Scientists at the University of California, San Diego School of Medicine studied the cellular changes in weakened hearts to better understand the transition from the compensatory stage, when it works harder to pump blood, to the decompensation, when it fails to pump blood sufficiently. They were especially interested in a RNA-processing protein called RBFox2 because it is involved in the heart’s early development and its continuing functions. When genes are expressed, DNA is transcribed into RNA, which is then processed and eventually used to make proteins such as RBFox2.

Sure enough, levels of RBFox2 were dramatically reduced in the hearts of mice with a condition similar to heart failure. Then they genetically engineered mice without RBFox2, which developed symptoms of heart failure. Not only are low levels of this protein connected to weakened heart muscle, without enough of it, the body cannot compensate and the heart declines more quickly. However, we still don’t know why levels of RBFox2 decline during the transition to the decompensatory phase of heart failure.

In the future, this research might be used to develop treatments that reverse the decline of RBFox2 and effectively slow or prevent heart failure.

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Chocolate on My Mind

April 25, 2015 by

April 10, 2015

By Medical Discovery News

Chocolate

Peanuts creator Charles Schulz once said, “All you need is love. But a little chocolate now and then doesn’t hurt.” New research shows he might be right. In one study, certain compounds in cocoa called flavanols reversed age-related memory problems.

Flavanols, found in a variety of plants, are potent antioxidants that help cells in the body deal with free radicals. Free radicals arise from normal cellular processes as well as from exposure to environmental contaminants, especially cigarette smoke. Unless your body gets rid of free radicals, they can damage proteins, lipids, and even your genetic information. You can get flavanols from tea, red wine, berries, cocoa, and chocolate. Flavanols are what give cocoa that strong, bitter, and pungent taste. Cocoa is processed through fermentation, alkalization, and roasting among other methods, which can influence how much of the good flavanols are lost. Among the products made from cocoa, those with the highest levels of flavanol are cocoa powders not processed by the Dutch method, followed by unsweetened baking chocolate, dark chocolate and semi-sweet chips, then milk chocolate, and finally chocolate syrup contained the least.

In the latest study, a cocoa drink specially formulated by the Mars food company to retain flavanols was compared with another drink that contained very little flavanols. The study asked 37 randomly selected adults aged 50 to 69 to take one of the drinks. One group consumed 900 milligrams per day of flavanols and the others consumed only 10 milligrams per day for three months. Brain imaging and memory tests were administered before and after the trial.

Those who consumed the high levels of cocoa flavanols had better brain function and improved memories. Before the study, the subjects on average demonstrated the memory of a typical 60-year-old person. At the end, those who consumed more flavanols exhibited the memory capabilities more closely resembling a 30- to 40-year-old. Unfortunately, the average candy bar contains only about 40 milligrams of flavanol, so you would have to eat 23 of them a day to equal the amount of flavanol used in the study, which would lead to other health problems like obesity and diabetes.

Other studies have similarly revealed that high-flavanol cocoa beverages cause regional changes in the brain’s blood flow, suggesting that it could be used to treat vascular impairments within the brain. Flavanols have also been reported to reduce blood pressure and other factors that lead to cardiovascular disease, improve insulin sensitivity, modulate platelet activity thereby reducing the risk of blood clots, and improve the activities of the endothelial cells that line our blood vessels. The Kuna indians living on the San Blas Islands near Panama, who consume a type of cocoa rich in flavanol on a daily basis, have unusually low rates of hypertension, cardiovascular disease, cancer, and diabetes.

These studies need to be repeated with larger groups to confirm the benefits of consuming flavanols and to ensure that there are no negative effects. Still, if a cocoa beverage high in flavanols could be mass produced and marketed, we could improve human health in a very tasty way.

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A Blood Test for Suicide

May 2, 2014 by

May 2, 2014

By Medical Discovery News

The 10th leading cause of death in America is completely preventable – suicide.  In 2010, 38,364 people died by suicide, more than chronic liver disease, septicemia, and Parkinson’s disease.

While strongly linked to depression, there are not always clear warning signs that someone is about to commit suicide. Unlike a viral or bacterial infection where there can be a number of signs like changes in body temperature, white blood cells, and signaling molecules, there is no simple clinical test to diagnose suicidal tendencies. Now, new research is working toward a blood test using biomarkers that may identify those likely to commit suicide. 

Biomarkers are biological materials that are seen under specific conditions. For example, during a viral infection proteins called cytokines are produced by the human body to help defend cells and tissues from the virus. Identifying these proteins is a signature of viral infection. The challenge is that these signatures change over the course of the infection and different viruses can produce different signatures. Scientists have been working extensively to use this concept of biomarkers to help with the early detection of other diseases from cancer to Alzheimer’s. 

Researchers at the University of Indiana want to design a simple blood test to detect a specific biomarker to identify those who might be at risk for suicide. They have been looking for protein biomarkers that can distinguish different psychological states. For example, can specific biomarkers tell if someone with bipolar disorder is in a high or low mood? In this recent study, researchers looked for biomarkers in individuals contemplating suicide. Every three to six months, they interviewed and drew blood from their subjects – 75 men with bipolar disorder – and rated their risk of suicide from low to high. Several proteins in the blood varied with these mood swings but one in particular caught researchers’ attention. The protein SAT1 was present in all of those with high indications of suicidal thoughts. SAT1 plays a role in the body’s response to stressful situations.

They then tested suicide victims, grouping them by age and gender, and found high levels of SAT1 in all of them. Finally, they took blood samples regularly from about 80 men with either schizophrenia or bipolar disorder. The study showed higher SAT1 levels in those who were later hospitalized for suicidal behavior. The presence of elevated SAT1 was more than 80 percent predictive of hospitalization. Overall, these are promising results.

SAT1 is not an absolute signature for suicide because many things that can affect its levels. And like any complex behavior, there are a multitude of factors involved. Other biomarkers will need to be identified to create a biosignature for suicide. But this is an exciting discovery that may be used to prevent the tragic deaths of many people in the future.   

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Silent Mad Cow

February 28, 2014 by

Feb. 28, 2014

By Medical Discovery News

Ten years after bovine spongiform encephalopathy (BSE), commonly called mad cow disease, was diagnosed in cattle in Britain, the British government admitted that it could be transferred to humans in a new form called variant Creutzfeldt Jakob disease (vCJD).

Cases of BSE spread to cattle in other countries, and more people in different countries were being diagnosed with vCJD. By 2004, the U.S. had passed various laws to eliminate BSE-infected cattle from the market. However, to this day, there are still sporadic reports of cows diagnosed with BSE both in the U.S. and abroad.

BSE and vCJD are neurological diseases that arise from prion plaques that form in the brain. Prions are simply misfolded proteins. This can be caused by a genetic mutation, spontaneous misfolding, or consuming infected beef. These misfolded proteins can convert healthy or normal proteins into misfolded ones. Once they appear, abnormal prion proteins aggregate, or clump together. Investigators think these protein aggregates may lead to loss of brain cells and other brain damage. Areas of the brain’s grey matter are slowly displaced and the brain develops holes or a spongy appearance, hence the name spongiform. There is no treatment or cure and eventually the damage is severe enough to lead to death. 

Initially cattle acquired the prion proteins in feed supplements made from infected sheep brains and spinal cord tissues. Once regulators understood the source, they passed laws banning the process of feeding dead animals to livestock. Unlike meat contaminated with bacteria, cooking does not destroy prion proteins. In an effort to eliminate prions from the food supply, the U.S. Department of Agriculture has imposed a rule that the brains and spinal cords of cattle must be removed prior to processing into edible meat. 

There have been 175 people in Great Britain diagnosed with vCJD and an additional 49 people in 11 other countries. A large study indicates that 1 in 20,000 people in Britain (30,000 total) carry the misfolded prion proteins and are at risk of developing vCJD. These new results suggest that many people in Britain may be carrying the prions but are symptomless, at least for now. This could also mean that these cases are silent carriers, who will not develop clinical vCJD. It remains a mystery that only time and additional studies will solve. 

Since there is no blood test for vCJD, carriers could unwittingly pass on this disease to others when they give blood. Earlier research suggested that the incubation period for vCJD was about eight years, but now scientists think that there are at least three types of the misfolded prion proteins, with different incubation periods and different types of prion disease.

Blood tests need to be developed to protect against the inadvertent transmission of vCJD. Better farm and food practices and laws will also help eliminate other sources of prion disease. Scientists in a number of countries are exploring potential treatments for these disorders.

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And The Winners Are

January 3, 2014 by

Jan. 3, 2014

By Medical Discovery News

The Nobel Prize

Inside each living cell is a complex system of roadways, each used to transport molecules so the cell can keep performing the processes it was made to do. Like highways that span from one state to another, cells can even use the roadways to deliver molecules to other cells. How cells are able to do this has been an intense area of study for years, and thanks to three Nobel prize-winning scientists, it’s a little more understood now.

This year’s Nobel Prize for Physiology or Medicine was awarded to scientists who have unraveled the mysteries of how cells route or traffic specific molecules to the correct locations.  The $1.4 million prize was split between Drs. James Rothman of Yale University, Randy Schekman of University of California-Berkeley, and Thomas Sudhof of Stanford University. Their work revealed a basic element of cell physiology that is essentially the same for all cells, from single-celled yeasts to complex mammals like humans.

The basic mode of transporting molecules in cells is in a vesicle – hollow, spherical structures that carry molecules inside. Molecules are packaged at different places in cells and then safely transported at the right time to the correct destination via vesicles. But how does this transportation container know where to drop off its delivery? With mail, a zip code is written on the outside of a letter specifying a precise location where it is to be delivered. With vesicles, there are specific proteins on the outside surface of the sphere that specify where its cargo is to be delivered, whether it’s within a cell or to the cell’s surface, to be released from the cell to other cells. With the right cellular zip code, molecules are delivered to the right place.

Schekman discovered the genes and proteins that regulate these vesicles. They are the traffic cops that control vesicle traffic through the cells. He found that different genes and proteins determined whether a vesicle delivered its contents to the cell’s surface or to different compartments inside a cell. While he studied this in yeast cells, similar genes and proteins have been found in more complex animals such as mice and humans.

Rothman found the specific proteins on the surfaces of vesicles that represent molecular zip codes and allow the vesicles to interact with proteins at their correct destinations. The interaction between these two groups of complementary proteins causes the vesicle to fuse with the membrane at its intended destination and release its contents.

Sudhof revealed how nerve cells communicate with each other and how calcium ions control this activity. He found that calcium ions act as a trigger, causing vesicles to fuse with cell surfaces and release the molecules to interact with neighboring cells, transmitting signals along a nerve.

This transportation system is used for critical functions in humans, like brain signals and immune responses, so problems within the system can cause disease. These pioneers have provided an incredible understanding upon which others can continue to build.

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