A Cause of Sporadic ALS

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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Microlesions in Epilepsy

June 26, 2015

By Medical Discovery News

Humans have been recording and diagnosing epilepsy for at least 4,000 years, but it only began to be understood a few hundred years ago. While doctors noticed some epileptic patients had brain lesions, others did not have any that were visible – until now. Using a combination of gene expression analysis, mathematical modeling, and microscopy, scientists have found microlesions in the brains of epilepsy patients, which may explain the cause of seizures in some people.

Epilepsy is characterized by unpredictable seizures that result from groups of neurons firing abnormally. Some people experience symptoms prior to a seizure that allows them to prepare. In some cases, seizures can include jerking, uncontrolled movements, and loss of consciousness. In others, the seizure may only cause confusion, muscle spasms, or a staring spell. Epilepsy patients experience repeated seizure episodes.

Epilepsy is a relatively common brain disorder affecting about 1 percent of people – 65 million worldwide, 3 million in the United States. Some causes of epilepsy are strokes, brain tumors or infections, traumatic brain injuries, lack of oxygen to the brain, genetic disorders such as Down syndrome, and neurological diseases such as Alzheimer’s. However, for two-thirds of people with epilepsy, there is no known cause. Not all seizures are related to epilepsy, as they can also be caused by low blood sugar, high fever, and withdrawal from drugs and alcohol.

Epilepsy can be treated using anti-seizure medications that control the spread of seizure in the brain, but about one-third of epileptic patients don’t respond to current medications. Some cases are treated by surgically removing or killing cells in the region of the brain that are responsible for the aberrant electrical signaling. If neither of those are options, a device can be implanted that stimulates the vagus nerve, which is part the autonomic nervous system that controls involuntary bodily functions such as heart rate and digestion.

In some people with epilepsy, the cause was traced to a visible abnormality in the brain. Now, scientists have identified millimeter-sized microlesions that could explain why a seemingly normal brain suffers seizures. Scientists compared the genes expressed in the microlesions of 15 people with epilepsy. Using mathematical modeling called cluster analysis, they discovered 11 groups of genes that were either expressed too much or too little in brain tissues experiencing the high electrical activity that causes seizures.

Based upon what these genes encoded, they predicted certain brain cells would be reduced and immune response or inflammation would increase in the microlesions. That’s exactly what they found when they stained those sections of the brain and examined them under a microscope. Brain cells lost communication with each other, limiting the brain’s communication network. This probably leads to the abnormal electrical signals that trigger seizures.

This conclusion still needs to be confirmed, but in the future it may guide the development of new treatments for epilepsy.

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Maggots Heal

May 17, 2013

By Medical Discovery News

Maggots are slimy, squirmy little creatures that make their home in dead and decaying flesh. As such, they are commonly featured in zombie movies and forensics TV shows. But maggots aren’t just a staple in science fiction. For thousands of years healers relied on maggots to cleanse their patients’ serious wounds, and the therapy is resurging as a modern medical tool.

The ancient Mayans began using maggots, which are the larvae of fly species, to disinfect wounds because maggots efficiently consume decaying flesh without affecting healthy tissue. Today, an average application of sterile or bacteria-free maggots can consume 10 to 15 grams of dead tissue per day.

Doctors began returning to maggot therapy in the last twenty years when certain bacterial infections stopped responding to antibiotics. Maggots secrete proteases, which are enzymes that liquefy dead tissue. When they ingest the tissue, they consume any infecting bacteria which are then destroyed during the larvae’s digestion. But the maggot secretion itself has healing properties that lower inflammation and prevent the growth of bacteria, both of which scientists had no explanation for, until a recent study.

A team led by surgical resident Gwendolyn Cazander of Leiden University Medical Center in the Netherlands may have figured out how maggots promote healing. They took blood samples from people whose wounds were treated with maggots and those without maggot therapy. After measuring blood samples for proteins involved in inflammation, they found two complement proteins, C3 and C4, decreased up to 99.9 percent in samples from those with maggot treatment. Only pieces of the complement proteins were left in wounds where maggots had secreted their special enzymes.

Maggot secretions are tough – even after sitting on a shelf for a month and being boiled, they still reduced the levels of inflammatory proteins. It makes sense that maggots have developed the ability to reduce the host’s inflammatory response in order to prevent an attack on them by the immune system while they infest a wound.

Researchers still don’t know what exactly in maggot secretions reduces inflammation and they’re working to identify that now. Most likely, it’s a variety of mechanisms that make this once archaic therapy a valuable clinical tool. Maggots are now ideal for wounds that get little to no blood flow, or tissue in the process of regenerating. In these cases, antibiotics cannot be carried to the site by blood which increases the risk of infection. Maggots are also ideal when serious infection has set in such as gangrene and foot infections in diabetics.

At times, they’re even better than surgeons in eliminating all traces of an infection, which can be difficult to spot. No wonder maggot therapy got a fancy, more appealing name: biosurgery.

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