Memory - Proteasome activity

When It Comes to Memory, It's All About Location


Published: 04/25/08
FRIDAY, April 25 (HealthDay News) -- A new report finds that where protein-destroying machines reside in the brain's nerve cells may help determine how memories are formed, a finding that may play a role in future treatments for Alzheimer's and other brain diseases.

Wake Forest University School of Medicine researchers studying mice discovered that cylinder-shaped proteasomes, which help control protein levels, play different roles in controlling synapse strength depending on where they are in the nerve cells of the hippocampus, an area of the brain linked to memory.

When humans or animals learn and store information in their memory, these connections between cells become stronger or weaker, Ashok Hegde, associate professor of neurolobiology and anatomy at Wake Forest, said in a prepared statement. For example, if people learn to do something better, such as playing softball, the synapses that control hand-eye coordination will become stronger. If they learn to ignore something, such as the barking of a neighbor's dog, then the synapses that control paying attention will become weaker.

The findings were published in the current issue of Learning & Memory.

It is known that the degradation of proteins, which are made by cells to control cell functions, plays an important role in memory function. The team found that proteasomes in the dendrites -- the branched parts of a neuron that conduct electrical stimulation -- limit the connection strength between cells. Proteasomes in the nucleus, which contains the cell's genetic material, help maintain synapse strength for long periods of time.

The researchers are now trying to learn how to block proteasome activity specifically in the dendrites of mice to increase the strength of synapses and of memory. In their ongoing studies, the mice will be analyzed on how well they can learn to navigate a maze.

"If we see a memory enhancement when we block the proteasome in dendrites, we can use this strategy to treat memory loss," Hegde said.

More information

The Alzheimer's Association has more about current treatments for Alzheimer's disease.

Last reviewed: 04/25/2008 | Last updated: 04/25/2008

Treating Osteoarthritis (Harvard Health Pubs)

Treating Osteoarthritis
Although no drug exists that will cure or reverse the progression of osteoarthritis, it is usually possible to alleviate pain and inflammation. Medications form the basis of treatment for osteoarthritis, but are best used in conjunction with other pain relief strategies, such as exercising to build your muscles and protecting your joints from injury or overuse.
Analgesics (Pain Relievers)
Topical analgesics
Topical analgesics, which are applied to the skin, offer one alternative for mild pain relief. You can use these alone or in combination with one of the medications described below. Creams containing salicylate, such as Aspercreme or Bengay, and others containing capsaicin, such as Zostrix, are available over the counter. However, it's important to avoid touching any mucous membrane (for example, around the mouth, nose, or eyes) after applying the cream, to avoid irritation.
Mild pain relievers (analgesics)
To relieve the pain and stiffness of osteoarthritis, the first step is usually an over-the-counter pain reliever. Doctors often recommend acetaminophen (Tylenol) first because it's often effective for mild pain and easy on the stomach. But remember that acetaminophen, like any drug, has its own risks — especially for the liver.

A 2005 study in Hepatology concluded that acetaminophen was to blame for 42 percent of the cases of acute liver failure seen at hospitals during the study period. Many of these poisonings were accidental and occurred in people taking the drug regularly for pain relief.

To avoid an accidental poisoning, don't exceed the recommended maximum per day — generally set at 4 grams (4,000 milligrams), the equivalent of eight extra-strength Tylenol tablets. Remember that acetaminophen is often included in combination formulas, so it's important to read all medication labels carefully. If you drink more than a moderate amount of alcohol on a regular basis (more than two drinks a day for men, and one drink a day for women), it is wise to stay well below the maximum daily dose or avoid acetaminophen altogether, because your threshold for toxicity may be lower than it is for other people.

NSAIDs
It has become clear that nonsteroidal anti-inflammatory drugs (NSAIDs) may be more effective than acetaminophen in treating osteoarthritis because they not only relieve pain, but also reduce inflammation that contributes to pain, swelling, and stiffness.

The arsenal of NSAIDs has grown over the years to include about 20 different drugs. Among them are such well-known medications as aspirin, ibuprofen (Advil, Motrin, others), and naproxen (Aleve, Naprosyn, others). These drugs reduce pain and inflammation by blocking the production of prostaglandins, leukotrienes, and other chemical mediators. For many people, they are slightly more effective than Tylenol, especially during flare-ups of pain.

The most common side effects of these medications are stomach problems, including gastrointestinal bleeding and ulcers, often occurring without warning. That is because NSAIDs work by inhibiting both the COX-1 enzyme, which helps protect the stomach lining from the corrosive effects of stomach acids and digestive enzymes, and the COX-2 enzyme, which causes pain and inflammation. One widely quoted paper, published in the New England Journal of Medicine in 1999, estimated that each year these drugs contribute to at least 16,500 deaths and more than 100,000 hospitalizations in the United States. A study of people in Spain concluded that roughly one in three hospitalizations or deaths due to gastrointestinal bleeding could be attributed to NSAIDs. It is possible in many cases to avoid such complications — but first you and your doctor must work together to determine your risk of experiencing them.

The older you are, the higher your risk of developing bleeding and ulcers. Others at risk include people who have had ulcers in the past, people with rheumatoid arthritis, and people who are also taking a blood thinner or corticosteroids. Prolonged use and higher doses of NSAIDs also increase the risk. And some NSAIDs are more prone than others to causing ulcers; for example, aspirin (Anacin, Bayer, others) and indomethacin (Indocin) appear to have the highest risk.

If you are in a high-risk group, you should probably try to avoid NSAIDs if at all possible, and try other pain relief strategies. A COX-2 inhibitor is safer, but the risk isn't zero. If you're in a high-risk group and find that these other strategies don't work, then talk with your doctor about stomach-protecting drugs to take along with the NSAID. These include histamine blockers such as cimetidine (Tagamet) and ranitidine hydrochloride (Zantac), and proton pump inhibitors such as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec). Another option is taking misoprostol (Cytotec) with the NSAID. Some medicines (such as Arthrotec or Prevacid NapraPAC) combine a medication that protects the stomach with an NSAID.

If taking NSAIDs produces stomach upset but not a bleeding ulcer, good initial strategies are to reduce the dose of the NSAID you're taking, try an entirely different pain reliever (such as acetaminophen), or switch to a drug that is more selective for COX-2. For example, celecoxib (Celebrex) is a COX-2 selective agent and might be better tolerated than indomethacin. Nabumetone (Relafen), although not officially a COX-2 selective agent, is also relatively selective for COX-2 and would be a better choice than indomethacin if stomach upset is a limiting factor. Other more selective medications to consider, as they may be more easily tolerated, are meloxicam (Mobic) and diclofenac (Voltaren).

No matter what your risk profile, to be on the safe side, use NSAIDs only under the supervision of your doctor, and do not combine NSAIDs with other medications without talking to your doctor first. Also take time at each doctor's visit to reassess the medications you are taking for your arthritis and to evaluate your symptoms. All too often, people are taking more medication than they really need. Other pain relief strategies might be used in combination with the drugs so you can lower the dose.

COX-2 Inhibitors
In 1998, the FDA approved the first of a new generation of NSAIDs. Known as COX-2 inhibitors, these prescription drugs were designed to be more selective in their effects than traditional NSAIDs. COX-2 inhibitors, as their name implies, inhibit only the COX-2 enzyme involved in pain and inflammation, while sparing the COX-1 enzyme that protects the stomach lining. As such, they were able to relieve pain as well as the strongest NSAIDs, while causing less stomach irritation (although the risk of this side effect isn't eliminated).
Eventually the FDA approved three COX-2 inhibitors: celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). But today only Celebrex is available in the United States, and it comes with a warning. The manufacturers took Vioxx and Bextra off the market after the FDA warned that these drugs could increase the risk of stroke and heart attack.

This is because both the COX-1 and COX-2 enzymes also exert effects on the arteries. The COX-1 enzyme narrows arteries and makes blood platelets sticky, while the COX-2 enzyme widens arteries. When just COX-2 is blocked, the "widen" signal is lost and the resulting combination of narrowed arteries and stickier platelets can lead to blood clots that block an artery in the heart, causing a heart attack, or one in the brain, causing a stroke.

For this reason, most people now choose to try other pain relief alternatives before taking the remaining COX-2 inhibitor on the market, celecoxib. If you do take this medication, talk with your doctor about how to take it safely, especially if you already have an increased risk of heart attack or stroke.

Talk with your doctor about your personal health risks if you are considering the long-term use of any NSAID or COX-2 medication.

Joint Reconstruction or Replacement
Doctors recommend joint reconstruction or replacement in cases of severe osteoarthritis in which the joint shows significant deterioration. Surgery can be used to correct joint deformity, to reconstruct a diseased joint, or to completely replace a diseased joint with a prosthetic device. This surgery is most often recommended for osteoarthritis of the hip or knee, because severe disease of these joints can impede movement.
Hip replacement and knee replacement are among the most common surgeries performed in the United States. A replaced joint will last an average of ten to 15 years (or even longer, because such estimates are based on operations performed at least ten years ago). But joint replacement is not an option for everyone; the ideal surgical candidate is in good general health and not overweight. However, as surgical and anesthesia techniques have improved, more and more people are becoming good candidates for surgery. Surgeons may encourage young, physically active people to delay joint replacement because artificial joints usually need to be replaced after a decade or two. The younger the patient, the more the joints are used, and the greater the number of replacements that may be necessary.

It's also important to have realistic expectations about what joint replacement surgery can and cannot do. Joint replacement doesn't guarantee that you will be able to move or use the joint in a normal way. Still, many people do experience great functional improvement. The major consistent benefit is substantial relief from pain. To maximize the chances of good results, it's important to participate in physical therapy after surgery.

Many artificial joints are attached to bone with pins and acrylic cement. Over time, these components may loosen or break, requiring repairs. Researchers believe some design improvements that have been made may make the implants last longer. For example, cementless components are now widely used. Their metallic surfaces are roughened until they become semiporous, allowing bone to grow into the surfaces, which may reduce the likelihood of loosening. However, such designs must be tested for ten to 20 years to determine how well they perform. These components haven't yet been shown to perform significantly better than a well-cemented pin.

Other Surgeries
Arthroscopy is considered minor surgery because the surgical incisions are small and the procedure generally does not require an overnight stay in the hospital. An arthroscope is an instrument with a tiny light, a camera, and a variety of surgical attachments. The surgeon inserts the instrument into the joint and performs minor surgery using the attachments. The camera enables the surgeon to see and smooth over any ragged joint edges and to locate and remove debris and loose material. Depending on the condition of the joint, this can result in mild to moderate improvement that may last several months or perhaps a few years. However, for someone with severe osteoarthritis, this approach is unlikely to offer much benefit. Studies have called into question whether this type of surgery should be routinely employed. Unless there is a specific finding or abnormality that can be addressed with this technique (such as a tear in the cartilage), arthroscopy for osteoarthritis may not be helpful.



Artificial Hip Joint

Artificial joints have metal shafts that are inserted into bone and anchored. At weight-bearing points, slick, high-density polyethyene is used to reduce friction (like cartilage in natural joints.)

Cement fastens the artificial joint to the skeleton in many joint-replacement operations. Cementless implants have a porous surface that bone tissue penetrates, thereby holding the prosthesis in place.





Range of Motion Exercises for Arthritis






Range of Motion Exercises for the Hand
Open your hand, holding fingers straight. Bend the middle finger joints. Next, touch your fingertips to the tops of your palm. Open your hand. Repeat ten times with each hand. Next, reach your thumb across your hand to touch the base of your little finger. Stretch your thumb back out. Repeat ten times.




Range of Motion Exercises for the Knee

Sit in a chair that is high enough for you to swing your legs. Keep your thighs on the seat and straighten out one leg. Hold for a few seconds. Then bend your knee and bring your foot as far back as possible. Repeat with the other leg. Repeat ten times.





Range of Motion Exercises for the Shoulder

Lie on your back with your hands at your sides. Raise one arm slowly over your head, keeping your arm close to your ear and your elbow straight. Return your arm to your side. Repeat with the other arm. Repeat ten times.





Range of Motion Exercises for the Hip

Lie on your back, legs straight and about six inches apart. Point your toes toward the ceiling. Slide one leg out to the side and then back to its original position. Try to keep your toes pointed up the whole time. Repeat ten times with each leg.





From the Harvard Health Publications Special Health Report, Arthritis: Keeping Your Joints Healthy. Copyright 2002 by the President and Fellows of Harvard College. Illustrations by Harriet Greenfield, M.A. All rights reserved. Written permission is required to reproduce, in any manner, in whole or in part, the material contained herein. To make a reprint request, contact Harvard Health Publications. Used with permission of StayWell.



Copyright © 2008 Waterfront Media, Inc.
The material on this web site is provided for educational purposes only, and is not to be used for medical advice, diagnosis or treatment. See additional information. Use of this site is subject to our terms of service and privacy policy.

Prolotherapy - NYT Article

Personal Health
Injections to Kick-Start Tissue Repair
Permalink
By JANE E. BRODY
Published: August 7, 2007
The human body is held together by a network of connective tissues that are highly vulnerable to injury — through exercise, accidents and even the normal lifting, pulling and pushing of daily life.

Stuart Bradford
Few of us, for example, get through life without spraining an ankle. And as many sadly know, once an ankle is badly sprained, it may be sprained again and again. That often happens as well with other body parts: shoulders, wrists, neck, back, jaw, feet, even fingers and toes, all of which are subject to arthritic changes after an injury.

The risk of reinjury rises when the ligaments that hold bone to bone, or the tendons that connect bone to muscle, fail to heal completely. And such failure is apparently very common. Over time, and with multiple injuries, this incomplete healing can result in lax connective tissues that cannot fully support a joint.

Dr. K. Dean Reeves, clinical associate professor of physical medicine and rehabilitation at the University of Kansas Medical Center, likens the damage to a partly shredded rope that lacks the strength of an intact one, and to stretched putty that will not return to its former length. Dr. Reeves is one of several hundred physicians and osteopaths who specialize in a therapeutic technique called prolotherapy, an alternative medicine method to promote connective tissue repair even years after the damage occurred.

The technique received an endorsement of sorts from the Mayo Clinic. In its April 2005 health letter, the clinic stated that when chronic ligament or tendon pain fails to respond to more conservative treatments like physical therapy and prescribed exercises, “prolotherapy may be helpful.” And when surgery is the only remaining option to relieve chronic pain, prolotherapy is a much less invasive and expensive technique that may be worth a try — if you can find an experienced and skilled practitioner.

What Is Prolotherapy?

Prolotherapy involves a series of injections designed to produce inflammation in the injured tissue. To appreciate the value of such a seemingly counterproductive measure, you need to know something about connective tissue and how the body normally repairs it.

When tissues are injured, inflammation is a common natural response. It stimulates substances carried in blood that produce growth factors in the injured area to promote healing. Ligaments, tendons and cartilage have very poor blood supplies, which can result in incomplete healing.

The healing process can also be impeded when injuries are treated with anti-inflammatory medications like ibuprofen or Naprosyn, or prescribed nonsteroidal anti-inflammatory drugs (Nsaids) to relieve pain and swelling.

Unlike injections of corticosteroids, which also suppress inflammation and provide only temporary relief for a chronic condition, prolotherapy injections given over the course of several months are meant to provide a permanent benefit. In effect, prolotherapy tricks the body into initiating a healing response.

The technique reactivates the healing process by injecting a mildly irritating substance — commonly a somewhat concentrated sugar solution along with the painkiller lidocaine — into the injured area to stimulate a temporary low-grade inflammation. In some cases, growth factors themselves may be injected.

With growth factors in place at the site of inflammation, new tissue is said to be produced that strengthens lax or unstable ligaments and tendons. The technique may even support damaged or degenerated cartilage, which normally does not repair itself, by strengthening the fibrous connective tissues that stabilize the area.

Practitioners cite experiments in laboratory animals that demonstrated tissue growth in ligaments and tendons stimulated by prolotherapy injections. Two animal studies also showed healing of cartilage defects.

Prolotherapy cannot correct mechanical problems like spinal stenosis, in which two bones pinch a nerve, nor does it reverse arthritic changes. But it may reduce or even eliminate the discomfort associated with arthritis by tightening the connective tissues that support an arthritic joint.

A leader in the field, Dr. Donna Alderman, an osteopathic physician who is medical director of the Hemwall Family Medical Centers in California, published two long articles on prolotherapy this year in the magazine Practical Pain Management. She wrote that “prolotherapy has been used in the United States for musculoskeletal pain since the 1930s,” that it has been endorsed by former Surgeon General C. Everett Koop, and that it is increasingly being used to treat injuries in professional athletes.

Prolotherapy is also now the subject of a controlled clinical trial sponsored by the National Center for Complementary and Alternative Medicine, part of the National Institutes of Health.

Since prolotherapy is a nonsurgical technique, patients who are now facing surgery because all else has failed might consider trying it before having an operation. Unlike many drugs and surgery, prolotherapy has minimal side effects when performed by an experienced practitioner who uses sterile techniques. Patients may experience bruising and a temporary increase in pain in the injected area because of the induced inflammation. Rare risks include infection, headache, nerve irritation or allergic reaction.

Does It Help?

There have been dozens of studies purporting to show benefits of prolotherapy for people with chronic pain as well as those with sports injuries. Among scientifically designed controlled studies, most showed a significant improvement in the patients’ level of pain and ability to move the painful joint.

According to Dr. Alderman, in a study of people with chronic low back pain resulting from injured ligaments in the sacroiliac joint, biopsies done three months after treatment showed a 60 percent increase in the diameter of connective tissue. The patients reported a decrease in pain and an increased range of motion.

In studies of knee injuries, patients with ligament laxity and instability experienced a tightening of those ligaments, including the often disabling anterior cruciate ligament in the center of the knee, Dr. Reeves showed in a double-blind study. Other studies showed a significant improvement in the symptoms of arthritis in the knee one to three years after prolotherapy injections.

Dr. Alderman cautions that prolotherapy is appropriate only for patients with musculoskeletal pain who do not have underlying conditions that would interfere with healing and who are willing to receive painful injections in an effort to recover.

A state-by-state listing of prolotherapy practitioners can be found at www.getprolo.com. Beware of practitioners who make rash promises, fail to take a full medical history and to tell you about the technique and its side effects, or who work in a disorderly or unclean facility.