BIOCHEMISTS SOLVE ADDRESS PROBLEM IN CELLS THAT LEADS TO LETHAL KIDNEY DISEASE

Research by UCLA biochemists may lead to a new treatment -- or even a cure -- for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson's disease, Alzheimer's disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme -- called alanine: glyoxylate aminotransferase, or AGT -- goes to the proper "address" in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal's print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria -- tiny power generators in cells that burn food and produce most of the cells' energy -- which causes PH1.

Koehler's team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

"In many mutations that cause diseases, the enzyme doesn't work," Koehler said. "In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria 'mailbox' and takes it to the peroxisome address instead."

How often did it work?

"All the time," said Koehler, a member of UCLA's Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar "correct address" strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson's, Alzheimer's and other diseases.

PH1 -- short for primary hyperoxaluria 1 -- starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists' ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

"It's exciting that our studies in baker's yeast, a typical laboratory model, might be able to help kids with a complicated disease," Koehler said.

Neuropathy A Daily Problem Personal Account

Today's post from bobisdysautonomia.blogspot.com (see link below) is a powerful reminder that neuropathy can cause extreme symptoms that make a normal life practically impossible. Hopefully, in your case, the symptoms are milder than this lady's but because the symptoms are so recognisable, we can all identify with the daily tortures she has to put up with - it becomes a matter of degree. Luckily, she can write about it with a measure of humour but she deserves our fullest sympathy and secret prayers that our own symptoms don't progress as far as hers.

Neuropathy is a large pile of suckage.
Michelle Roger: Wednesday, 10 December 2014 
 
Mornings are the worst. I'm unsteady, nauseous, my blood pressure non existent, and life just seems to suck more. Not that I have ever been a morning person. Way back in the dim distant past that was my pre-sick life, I was a night owl who greeted mornings with dread and expletives. Now I have the added pressure of a body that dehydrates overnight until I feel I must look like a dried up prune (mirrors are avoided at this hour for fear I'll be turned to stone should I glance at one. So the prune thing is supposition. I may be more sultana than prune, who knows). I also have body that hates to be upright at the best of times and is very reluctant to move from a night spent horizontal when Freyja starts whining at the door desparate for her morning pee.

This morning as I stumbled into the bathroom I hit my knuckles on the door frame. Hard. So hard it made Freyja jump. I let out an instinctive yelp. And then realised it didn't hurt. Not a bit. I looked down at my red and swollen knuckles. I'd heard the noise. I could see the result. But nothing. No pain. Even in my muddled morning state I had a hmmm...? moment.

I flopped down onto the tiles and looked at my hand which is apparently so inept that it can't even register pain. Sure, I pushed on it and I could feel that. But still no pain. Another defective part of my body to add to the list.

Neuropathy for the win!

It's a weird beast. How can I be in so much pain in some parts and so little in others? Yesterday, I lay on my bed trying not to cry as the pain shooting through the toes of my left foot was so intense. Today, I whack my hand and nothing.

It's not the first time.

I cut my leg whilst shaving and left a blood trail round the bathroom. If I hadn't noticed the blood I would never have known I cut myself.

I've pulled rose thorns from my skin, only noticed because something was tugging on my clothing.

I burn myself on the stove on a regular basis. And the oven. I have been burnt by steam and by splattering oil.

Even when I sliced my thumb the other day the pain was not what it should have been given I had a 1cm cut deep through my nail and top of my thumb.

When I had my last Evoked Potentials test done, the tech kept asking me if I was okay as he kept turning up the device while I sat there unmoved.

Temperature sensation is long gone in my legs and halfway up my arms. I have a spot on my back that is still able to register temperature but no where else. If not for the raging red colour on my skin I wouldn't know the shower was too hot. And I've had burns from heat packs I didn't know had been overheated.

And yet, as I sit here typing I can feel my feet burning, only somewhat dulled by the Lyrica. I can feel the tasaring in my left foot. And the small spot on my lower back that feels like you are rubbing salt and ground glass into an open wound from just the pressure of the air in the room.

And the pain on the right side of my stomach that my gastro decided was neuropathic. It varies from knives, to Knives, to KNIVEESSSSSS!!!!!!!

One part the fiery pits of hell and tear inducing pain, another nothing but void.

I can't even be broken in a consistent manner.

Maybe that's why my doctors keep telling me I'm "special."

Neuropathy is a large pile of suckage.

Michelle :)

http://bobisdysautonomia.blogspot.com/2014/12/neuropathy-is-large-pile-of-suckage.html

HIGH SUGAR DIET NO PROBLEM FOR GENETIC MUTANTS

Imagine being able to take a pill that lets you eat all of the ice cream, cookies, and cakes that you wanted -- without gaining any weight.

New research from USC suggests that dream may not be impossible. A team of scientists led by Sean Curran of the USC Davis School of Gerontology and the Keck School of Medicine of USC found a new way to suppress the obesity that accompanies a high-sugar diet, pinning it down to a key gene that pharmaceutical companies have already developed drugs to target.

So far, Curran's work has been solely on the worm Caenorhabditis elegans and human cells in a petri dish -- but the genetic pathway he studied is found in almost all animals from yeast to humans. Next, he plans to test his findings in mice.

Curran's research is outlined in a study that will be published on Oct. 6 by Nature Communications.

Building on previous work with C. elegans, Curran and his colleagues found that certain genetic mutants -- those with a hyperactive SKN-1 gene -- could be fed incredibly high-sugar diets without gaining any weight, while regular C. elegansballooned on the same diet.

"The high-sugar diet that the bacteria ate was the equivalent of a human eating the Western diet," Curran said, referring to the diet favored by the Western world, characterized by high-fat and high-sugar foods, like burgers, fries and soda.

The SKN-1 gene also exists in humans, where it is called Nrf2, suggesting that the findings might translate, he said. The Nrf2 protein, a "transcription factor" that binds to a specific sequence of DNA to control the ability of cells to detox or repair damage when exposed to chemically reactive oxygen (a common threat to cells' well being), has been well studied in mammals.

Pharmaceutical companies have already worked to develop small-molecule drugs that target Nrf2, in hopes that it will produce more anti-oxidants and slow aging.

Though the promise of a pill to help control your body's response to food is enticing, it is not without risk, Curran said. Increased Nrf2 function has been linked to aggressive cancers.

"Perhaps it is a matter of timing and location," Curran said. "If we can acutely activate Nrf2 in specific tissues when needed then maybe we can take advantage of its potential benefits."

The problem with Statins

You have probably heard of Statins. Statin drugs work by blocking a key enzyme in the production of cholesterol. Cholesterol is a natural product of the liver and in the right amounts does not pose a problem to the body. The body, however, sometimes produces too much cholesterol and that is often caused by poor dietary choices (you know what you eat!).

Statin drugs block the enzyme linked to the liver’s cholesterol production, thus inhibiting the liver’s ability to produce LDL. Your LDL cholesterol levels will often be measured in a standard HIV blood test and you may have heard that LDL levels should be lower and HDL cholesterol levels should be higher. Statin drugs can achieve this for people with cholesterol problems. Studies have also shown that statin drugs can help the body reabsorb cholesterol that has accumulated on the artery walls.

As HIV patients we have to be more aware of our cholesterol levels than most. HIV patients are at a higher risk for cardiovascular disease in part due to lipid abnormalities that can occur with the use of certain antiretroviral therapies so Statin drugs may be prescribed to help maintain healthy cholesterol levels.

However... Statins themselves can cause Neuropathy!

Time to talk to the doctor again, if you are advised to take these drugs. If you don't already have neuropathy, there isn't too much risk until you begin to show symptoms but if you already have neuropathic problems, it's important to discuss the consequences of statin use with your doctor. It's also important to realise that statins can have other side effects too; especially muscle pain or weakness. Sometimes just one more side effect can be one too many for the long-suffering HIV patient. Always ask - there may be an alternative available.

The following article is from Science Daily: http://www.sciencedaily.com/releases/2002/05/020514075710.htm
from the American Academy of Neurology.

Statin Drugs May Increase Risk Of Peripheral Neuropathy

Statin drugs can increase the risk of developing peripheral neuropathy, according to a study published in the May 14 issue of Neurology, the scientific journal of the American Academy of Neurology.

Peripheral neuropathy results from damage to the peripheral nerves and causes weakness, numbness and pain in the hands and feet. Statin drugs are prescribed for millions of Americans to lower cholesterol.

People taking statins were 14 times more likely to develop peripheral neuropathy than people who were not taking statins, according to the Danish study. However, the overall risk of developing neuropathy is rare, said study author David Gaist, MD, PhD, of the University of Southern Denmark in Odense

"The positive benefits of statins, particularly on reducing the risk of heart disease, far outweigh the potential risk of developing neuropathy," Gaist said. "These findings shouldn't affect doctor or patient decisions to start using statins. But if people who take statins develop neuropathy symptoms, they should talk with their doctor, who may reconsider the use of statins."

For the population-based study, the researchers used a patient registry to identify all of the first-time cases of peripheral neuropathy with no known cause (such as diabetes) in Funen County, Denmark, over a five-year period. Each case was matched to 25 people of the same age and sex with no neuropathy as a control group. The use of statins was then determined for each group.

They identified 166 cases of first-time neuropathy with no known cause. Of those, 35 had a definite diagnosis, 54 were probable cases and 77 were possible cases. Nine of the people with neuropathy had taken statins. They had taken statins for an average of 2.8 years.

For those with a definite diagnosis of neuropathy, the statin users' risk of developing neuropathy was 16 times higher than for the control group. When all cases of neuropathy were taken into account, the statin users' risk of developing neuropathy was four times higher than the control group's risk. Taking statins for longer periods of time and taking higher doses of them increased the risk of developing neuropathy.

Statins lower levels of low-density lipoprotein (LDL) cholesterol by blocking the production of a liver enzyme used by the body to make cholesterol.

For more information about the American Academy of Neurology, visit its web site at http://www.aan.com.

Sciatica A Localised Nerve Problem

Today's post from neuropathytreatments.com (see link below) talks about a common nerve problem that many people confuse with neuropathy, or see as a form of neuropathy. In the case of Sciatica, the nerve is not so much damaged (as in standard neuropathy) as inflamed or irritated, leading to significant pain, mostly in the backs of the legs. This can come from a trapped nerve in the lower spine, or a herniated disc. This article explains the condition and gives several useful tips as to what to do to relieve the pain. Worth a read if sciatica is a problem for you.
 

Sciatica 
Posted on February 12, 2014

Sciatica is nerve pain from irritation of the sciatic nerve. The sciatic nerve is the largest nerve in the body and begins from nerve roots in the lumbar spinal cord in the low back and extends through the buttock area to send nerve endings down the lower limb. Sciatica pain is typically felt from the lower back to behind the thigh and radiating down below the knee. The pain of sciatica is sometimes referred to as sciatic nerve pain. Treatments for sciatica depend on the underlying cause and the severity of the pain.

Causes of Sciatica

Any cause of irritation or inflammation of the sciatic nerve can reproduce the symptoms of sciatica. However, the most common cause is a herniated disk in the lumbar region that is pressing on a nerve. Other than a pinched nerve from a disc, other causes of sciatica include irritation of the nerve from adjacent bone, tumors, muscle, internal bleeding, infections, injury, and other causes. Sometimes sciatica can occur because of irritation of the sciatic nerve during pregnancy.

Degenerative arthritis of the lumbar spine, lumbar disc disease, and trauma or injury to the lumbar spine are all risk factors for sciatica.

Symptoms

Lumbar pain, buttock pain, hip pain, and leg pain are the results of sciatica. This condition causes pain, a burning sensation, numbness, or tingling radiating from the lower back and upper buttock down the back of the thigh to the back of the leg Sometimes the pain radiates around the hip or buttock to feel like hip pain. Sciatica can make walking difficult and severe sciatica may make walking almost impossible. Sometimes the symptoms of sciatica are aggravated by walking or bending at the waist and relieved by lying down. The pain relief by changing positions can be partial or complete.

Diagnosis and Treatment

A physical exam and medical history usually diagnoses sciatica. The typical symptoms and certain examination maneuvers also help with diagnosis. Sometimes, X-rays and other tests, such as CT scan, MRI scan, and electromyogram, are used to further define the exact causes of sciatica.

There are treatment options for sciatica. Back in the day, doctors would recommend bed rest but research has derailed that presumption. Today, other treatments have shown promise of relief. One option is to address the underlying problem. For example, relieving a herniated disk may help relieve sciatica. Surgical procedures can sometimes be required for persistent sciatica that is caused by nerve compression at the lower spine. Some patients respond to medications for the pain and others turn to physical therapy to reduce symptoms. A variety of low back conditioning and stretching exercises are employed to help people recover from sciatica.

Tips for Pain Relief

Most cases of sciatica improve over a month and go away on its own without any medical intervention. However, there are some things you can do at home to help with symptoms. 

Resume normal activity as soon as possible but activities should be done without strain or stretching.

Avoid intense exercise and physical activity, particularly heavy lifting and trunk twisting, if there is serious back pain.

Try an over-the-counter nonsteroidal anti-inflammatory as these medicines often provide significant benefits.

Apply heat to the painful area. Heat may work better than medicine. One research group found that people with low back pain who wear low-level heat wraps for eight hours a day have significantly less pain and disability.

Supportive back belts, braces, or corsets may help some people temporarily, but these products can reduce muscle tone over time and should not be used over a long period of time.

Get plenty of sleep. Healthy sleep plays a vital role in recovery. It is often difficult to get a good night’s sleep when suffering from back pain, particularly because the pain can intensify at night. Avoid caffeine and unwind before bed by taking a warm bath or practicing relaxation techniques. Some people may need medicine to help manage nighttime pain or treat sleeplessness. Lying curled up in a fetal position with a pillow between the knees or lying on the back with a pillow under the knees may help.

According to one study, yoga relieves low back pain better than conventional exercise or self-help books.

Exercise, diet, stress, and weight can influence back pain. Changing certain lifestyle factors can help reduce, and possibly prevent, backaches.

Sciatica can be very debilitating for patients. Proper care must be taken to help with the pain from this condition. Causes vary but most cases of sciatica heal themselves over time. Several tips can help with pain symptoms. Sciatica cannot always be prevented but maintaining a healthy lifestyle and using practical sense when it comes to lifting and bending will keep sciatica from becoming a frequent visitor.

http://neuropathytreatments.com/2014/02/

Concentrating On Your Own Neuropathic Problem Vid

Today's short video post from the useful beatingneuropathy.tv (see link below) series by Dr John Hayes, talks about how important it is to resist the temptations of medical advertising and concentrate on what really is good for you and treating your problem. We are flooded with remedies for this and that and are often tempted to try this one or the other but then we don't stop and end up taking countless pills a day without remembering the original reason why. Almost everything you put in your mouth to try to help with neuropathy symptoms should be discussed with your doctor and remember, if supplements and the rest don't work, don't continue to take them. Concentrate on what really is good for you and really addresses your problem and follow your doctor or specialist's advice.


Episode 29 – Focusing on Health!Posted by John Hayes Jr Thursday, October 10th, 2013

Dr. Hayes talks about how easy it is to get wrapped up in diagnoses and prescriptions–don’t focus on what you have, focus on your overall health!




http://beatingneuropathy.tv/2013/10/episode-28/

Erectile Disfunction Can Be A Neuropathic Problem

Today's post from uk-med.co.uk (see link below) talks about erectile disfunction, the elephant in the room for many men living with neuropathy. Women can have problems in this area too, especially concerning dryness but this article concentrates on men. For once it is a study which looks at the problem from another angle, in that it looked at men with impotence and found that many of them also suffered from neuropathic problems. Usually, ED is seen as a possible side effect of neuropathy but it can also be said that neuropathy is a co-problem with erectile disfunction. Many people don't need studies to know that ED can be a depressing problem to add to the symptoms of neuropathy but dicussing it with your doctor may lead to satisfactory modern treatments improving the situation.

Smoking doesn't help guys!

 Neuropathic Pain Connection With Erectile Dysfunction

       
A recent research paper written by Dr Consuelo Valles-Antuna at the University Central de Asturias in Spain, has found a connection between nerve impairment in the peripheral nervous system and its effect on erectile dysfunction.

 They studied 90 patients that displayed acute signs of peripheral neuropathy and the added problem of erectile dysfunction, needing intensive therapy. Current drug treatments for erectile dysfunction include Viagra and Cialis.

Patients that volunteered for the research had an average age of 54 years, 10% under 40 years and 2% were over 70. No interconnection with the IIEF-5 (International Index of Erectile Function) summary was found in the older test subjects, by way of making them more susceptible, if anything the younger participants had lower IIEF-5 scores. Breakdown of other medical backgrounds was; 30% cardiovascular disease, 16% neurogenic conditions, 16% diabetes, 7% mental health and 11% no risk factors.

Those presenting with worse cases of peripheral neuropathy also had very low IIEF-5 results. Neurophysiological investigations supported evidence that 69% had neurological pathology and 8% of these had myelopathy, which affects the spinal cord. Over a third had polyneuropathy, with small percentages were exhibiting small fibre and pudendal neuropathy, which causes problems in the pelvic area.

 Dr Valles-Antuna believes that this is a unique study, that covers the full spectrum of peripheral nerve fibre conditions in a non-selected group presenting with erectile dysfunction. Using the information gathered from the sufferers, combined with neurophysiological tests has shown that peripheral neuropathy is prevalent amongst men with impotence. With reference to this information, it is advised that medical practitioners’ should perform neurophysiological examinations on erectile dysfunction patients and establish that the pelvic area has been screened effectively.

http://www.uk-med.co.uk/Health/Neuropathic-Pain-Connection-With-Erectile-Dysfunction

Falling On The Stairs A Neuropathy Problem

Today's post from webmd.boots.com (see link below) looks at how risky having neuropathy in feet and legs can be if you have to climb stairs frequently. As is so often the case, it is addressed at diabetic neuropathy sufferers but whatever the cause of your neuropathic problems, this will apply to you to. It's a short article but an interesting one. Worth a read.

Diabetic neuropathy increases stair falls risk
By Nicky Broyd WebMD UK Health News 17th September 2014 - Medically Reviewed by Dr Keith David Barnard

  New UK research suggests that people with diabetic peripheral neuropathy (DPN), a complication of diabetes that affects the nerves in the limbs, often sway more during stair climbing and are, therefore, more likely to fall.

The researchers, from Manchester, acknowledge that while it would be impractical to suggest patients with DPN avoid stairs completely, they are at higher risk of having a fall and should take measures to keep themselves safe.

They say: "Avoiding particularly steep and/or long flights of stairs may be advisable, especially if an elevator is available as an alternative. Using a handrail on stairs if available could also help patients with DPN prevent falls."
Stairs

Patients with DPN are known to be unsteady on their feet and to have an increased risk of falling. Whilst some studies have found increased postural sway during quiet standing and walking on level ground in patients with DPN, no data exists on measures of balance when using the stairs.

Since walking on stairs is one of the most dangerous daily activities in terms of fall risk, this study, which has been conducted by researchers at Manchester Metropolitan University and the University of Manchester, investigated the underlying mechanisms of unsteadiness in patients with DPN during stair ascent and descent.

Measuring sway

Motion and pressure data were collected for 22 diabetes patients with DPN (average age 57) and 40 diabetes patients without DPN (average age also 57), plus 32 healthy people without diabetes (average age 50 years). All patients were from Manchester or the surrounding area.

Movement was measured using a 3D motion analysis system from reflective markers placed on the body to calculate whole-body centre-of-mass.

The centre-of-pressure under the feet was measured using sensitive pads mounted into the middle four steps of a seven step staircase, which participants ascended and descended at least three times.

The ability of a person to maintain balance was quantified by assessing the separation between the centre-of-mass and centre-of-pressure.

Findings

The authors conclude: " Diabetes patients with peripheral neuropathy display greater extremes in magnitude of medial-lateral sway during stair ascent and descent as well as displaying higher variability during stair ascent and descent. This indicates that patients with DPN have difficulty regulating control of balance during this challenging task.

"A larger and more variable medial-lateral sway means that patients with DPN are more likely to lose control of balance and experience a fall during what is known to be an activity —using stairs —where the risk of falls is already very high."

The findings have been presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD) in Vienna, Austria.
Future interventions

The Manchester research team is carrying out more investigations to identify and further understand factors that may contribute to unsteadiness and in turn the increased risk of falls.

They add: "Many issues that affect balance in patients with DPN stem from deterioration of muscle size and function, so whilst it is not currently possible to positively improve the sensory deterioration, we have been looking at elements that we can positively influence, such as strength training and interventions to help vision focus and avoidance of obstacles. We are investigating the impact of such interventions and how they might translate to improvements in gait and balance control."

http://www.webmd.boots.com/diabetes/news/20140917/diabetic-neuropathy-stair-falls-risk