Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials

Original Text

Dr Roberta T Chow MBBS a Corresponding AuthorEmail Address, Prof Mark I Johnson PhD b, Prof Rodrigo AB Lopes-Martins PhD c, Prof Jan M Bjordal PT d e
Summary
Background
Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain.

Methods
We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale.

Findings
We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1�69 (95% CI 1�22�2�33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4�05 (2�74�5�98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19�86 mm (10�04�29�68). Seven trials provided follow-up data for 1�22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22�07 mm (17�42�26�72). Side-effects from LLLT were mild and not different from those of placebo.

Interpretation
We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain.

________________________________

a Nerve Research Foundation, Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia
b Faculty of Health, Leeds Metropolitan University, Leeds, UK
c Institute of Biomedical Sciences, Pharmacology Department, University of S�o Paulo, S�o Paulo, Brazil
d Faculty of Health and Social Science, Institute of Physiotherapy, Bergen University College, Bergen, Norway
e Section of Physiotherapy Science, Institute of Public Health and Primary Health Care, University of Bergen, Bergen, Norway
Corresponding Author Information Correspondence to: Dr Roberta T Chow, Honorary Research Associate, Nerve Research Foundation, Brain and Mind Research Institute, University of Sydney, 100 Mallett Street, Sydney, NSW 2050, Australia

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961522-1/fulltext

LASER THERAPY IN ACUPUNCTURE IS EFFECTIVE AND PAINLESS. This Naeser Protocols May be used with Carpal Tunnel Syndrome; or mild-moderate hand paresis (weak, clumsy hand) or stiff hand which is in spasm (fisted hand in flexion) due to stroke, head injury, encephalitis, or M.S. Also for Reynaud's syndrome or peripheral neuropathy in the hands, rheumatoid arthritis (especially earlier stages) or osteoarthritis. Treat at least 4 - 8 weeks.

A 5 mW, 670 nm (red beam) laser lecture pointer is used on the Jing-Well points, and other acupuncture points, for at least 4 Joules/cm2 per point, on the affected hand/wrist area. The tip of the laser pointer physically touches the skin, but the pointer is not pressed down so hard that the tip leaves a very deep indentation on the skin. These points include:

1. Lu 11, LI 1, PC 9, TW 1, Hrt 9, SI 1. These are the most important points.
2. Optional points for severe finger cases: Extra points at ends of all major finger creases at the joints, on edges of fingers. These are the proximal and distal interphalangeal joints. There are 4 of these extra points on each finger, and 2 on each thumb. Dr. So refers to them as "Wen Tao."
3. Distal Ba Xie points in the webs between the fingers.
4. Lu 9, PC 7, Hrt 7. These are especially important for Carpal Tunnel, especially PC 7. Higher doses around 32 J/cm2 may be necessary (Branco & Naeser, 1999).
5. Other hand points, LI 4 or TW 3, but the laser pointer is used only on shallow points, on adults. (On babies and children, any body points can be used; but for only 5-10 seconds per point. It is forbidden to shine the laser onto the unclosed fontanelles on the head of babies.)
6. Acupuncture needles are used for other appropriate points, especially non-shallow points on adults, such as LI 11, LI 15, TW 9, etc.
7. The laser may be used for even 4-8 Joules/cm2 or more, on very painful joints/areas.



Sample FOOT Laser Acupuncture Research Treatment Protocol

May be used with peripheral neuropathy (of diabetic, AIDS, or neurological origin) or poor circulation to the feet, including foot ulcers. (AIDS patients taking certain medications can develop serious, painful, peripheral neuropathies in the ankles/feet.) This protocol could also be tried with stroke patients or M.S. patients with mild ankle dorsi-flexion problems ("foot drop").

A 5 mW, 670 nm (red beam) laser lecture pointer is used on the Jing-Well points, and other acupuncture points, for at least 4 Joules/cm2 per point, on the affected foot/ankle area. The tip of the laser pointer physically touches the skin, but the pointer is not pressed down so hard that the tip leaves a very deep indentation on the skin. These points include:

1. Sp 1, Liv 1, St 45, GB 44, Bl 67. These are the most important points; others are optional.
2. Points in the webs between the toes.
3. Ki 6, Sp 5, Liv 4, St 41, GB 40; Ki 3, Bl 60; and/or other shallow ankle and foot points.
4. The laser pointer is used on only shallow points, on adults. (On babies and young children, any body points are used; but for only 5-10 seconds per point. It is forbidden to shine the laser onto the unclosed fontanelles on the head of babies.)
5. Acupuncture needles are used for other appropriate points, especially non-shallow points on adults.
6. The laser may be used for even 8 Joules/cm2 or higher, on very painful joints/areas.

If you need LASER ACUPUNCTURE training or more information visit my website www.medaku.com

Combinatorial Multi-Component Therapies of Drugs using Pruned GMDH Algorithm

Tejinder M Aggrwal1, Abhijit Pandya1 and Larry Liebovitch2
1Florida Atlantic University, Department of Computer Science and Engineering, Boca Raton, FL 33431
2Florida Atlantic University, Center for Complex Systems and Brain Sciences, Center for Molecular Biology and Biotechnology, Department of Psychology, Department of Biomedical Science, Boca Raton, FL 33431

ABSTRACT
Multi-component therapies, originating through deliberate mixing of drugs in a clinical setting, through happenstance, and through rational design, have a successful history in a number of areas of medicine, including cancer, infectious diseases, and CNS disorders. Use of single drug for complex biological processes, where in fact redundancy and multi-functionality are the norm, fundamentally limits the therapeutic index that can be achieved by a most potent and highly selective drug. Thus, it will almost certainly be necessary to use even new �targeted� pharmaceuticals in combinations. Drugs designed for a specific target are always found to have multiple effects. Rather to hope that one bullet can be designed to hit only one target, nonlinear interactions across genomic and proteomic networks could be used to design Combinatorial Multi-Component Therapies (CMCT) that are more targeted with fewer side effects.
This paper reviews the opportunities and challenges inherent in the application of non-linear interactions of neural networking using pruned GMDH Algorithm with specific reference to the possibility of achieving combinatorial selectivity with multi-component drugs. Using a nonlinear model of how the output effect depends on multiple input drugs, an artificial neural network can accurately predict the effect of all 215 = 32,768 combinations of drug inputs using only the limited data of the output effect of the drugs presented one-at-a-time and pairs-at-a-time. Systematic combination screening may ultimately be useful for exploring the connectivity of biological pathways. When performed this approach may result in the discovery of new combination drug regimens having least side effects targeting multiple actions.
Combination or multi-component therapy, in which one or more drugs are used at the same time, was first explored at a theoretical level (Loewe, 1928) and typically has several goals, such as: reducing the frequency at which acquired resistance arises by combining drugs with minimal cross-resistance; lowering the doses of drugs with non-overlapping toxicity and similar therapeutic effects so as to achieve efficacy with fewer side effects; using one or more chemotherapeutic drugs to sensitize cells to the action of additional drugs; exploiting additivity, or better-yet, synergism, in the biochemical activities of two drugs so as to achieve significantly greater potency than is possible with either drug on its own.
. Neural networks are generally considered "black boxes" of memory (Pandya and Macy, 1995). In other words a researcher may know the precise values of inputs, the precise values of outputs and the precise values of the connections weights without any knowledge of precise mathematical expressions for the relationships, because, such modeling is quite difficult with complex networks. Most of the programs available for neural networks do not design the network by assigning weights but they train the networks to give desired output for given input, and then record the weights.
The algorithm developed in this paper provides a solution to the above problem. Each neuron in the hidden layer can be represented using a quadratic polynomial equation involving any two neurons from the previous layer. This gives insight into the network and clearly defines the relationship between the neurons in a layer and the neurons in a previous layer making it easier to understand even for complex networks. Such visualization shows the dynamics of learning allow for comparison of different networks and show differences due to regularization and optimization procedures.
GMDH (Ivakhnenko, 1971) algorithm forms a basis for the algorithm proposed in this work. However several modifications are made to the basic GMDH algorithm to meet all the goals of the proposed algorithm and provide a pruned network. The new algorithm follows a similar method as that used in regression analysis in order to calculate the weights for the neuron functions. Though not originally designed for the purpose of calculating weights in a neural network, it can be easily adapted for this modern purpose. The proposed algorithm combines the best procedures from the variations on the GMDH method (Kondo & Pandya, 2000) in order to quickly produce the smallest, most accurate network possible.
This algorithm is then applied to analyze Drug Test Data (Liebovitch et al, 2006). The development of a new drug is a complex and expensive process. Current estimates place the total development costs of a new drug (including the writing off of false starts, clinical trials and tests required by regulatory authorities) somewhere in the region of 800 million dollars. As using combination of drugs to determine which combination can provide a better therapeutic effect is an expensive procedure, the algorithm developed in this work is applied to train the network using a small training set to determine which pathways in these networks interact and can maximize therapeutic effects.
The pruned GMDH is used to train a network on inputs of drugs presented one-at-time and predict the output when the input set includes pairs-at-a-time, three at a time etc. This algorithm was successful in developing the network for an input set of drugs which was limited to one-at-a-time. The algorithm was then used to train the network when the input set was changed to one-at-a-time and pairs-at-a-time, where it was able to predict the output for test set (includes drugs provided three-at-a-time, four-at-a-time etc) with an accuracy rate of 91%. The test results suggest that this approach may be of great value in the analysis of combination of drugs to produce maximized therapeutic effects.

REFERENCES:

1. Ivakhnenko, A.G. �Polynomial Theory of Complex Systems.� IEEE Transactions on Systems, Man, and Cybernetics, vol. 1, pp. 364-378, 1971
2. Kondo T, Pandya A.S, �GMDH type neural networks with radial basis functions and their application to medical image recognition of stomach�. Proc. of the 39th SICE Annual Conference, International Session Paper, 313A-4, pp. 1-6, 2000
3. Liebovitch L, Nicholas and Pandya A. S. �Developing Combinatorial Multi-Component Therapies (CMCT) of Drugs that are More Specific and Have Fewer Side Effects than Traditional One Drug Therapies�, pre-print, 2006
4. Loewe, �Quantitation Probleme der Pharmakologie�. Ergeb Physiol Biol Chem Exp Pharmakol 27, pp. 47-187, 1928
5. Pandya, A. S. and Macy, R. B., �Pattern Recognition using Neural Networks in C++�, IEEE Press and CRC Press, 1995

INTRODUCTION:

Osteoarthritis (OA) is the commonest form of arthritis found worldwide that can affect the hands, hips, shoulders and knees. It is responsible for the largest burden of joint pain and is the single most important rheumatological cause of disability and handicap.1,2 In Osteoarthritis, the cartilage that protects the ends of the bones breaks down and causes pain and swelling. Drug and non-drug treatments are used to relieve pain and/or swelling. Osteoarthritis commonly affects the hands, feet, spine and large weight-bearing joints, such as the hips and knees. Most cases of osteoarthritis have no known cause and are referred to as primary osteoarthritis. When the cause of the osteoarthritis is known, the condition is referred to as secondary osteoarthritis. These are food supplements show promise for helping people with osteoarthritis, those are Glucosamine sulphate, Chondroitin sulphate, SAMe (s-adenosylmethionine), Vitamin C ( ascorbic acid), Beta Carotene3 and many more.
Glucosamine:
Glucosamine is almost synonymous with osteoarthritis as it has benefits for osteoarthritis. It can be found naturally in the body and is used by the body as one of the building blocks of cartilage.Glucosamine is an amino sugar produced from the shells of shellfish (chitin) and it is a key component of cartilage. Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and many higher organisms, glucosamine is one of the most abundant monosaccharides.3
Glucosamine is necessary for the construction of connective tissue and healthy cartilage. It is the critical building block of proteoglycans and other substances that form protective tissues. These proteoglycans are large protein molecules that act like a sponge to hold water giving connective tissues elasticity and cushioning effects. This also provides a buffering action to help protect against excessive wear and tear of the joints. Without glucosamine, our tendons, ligaments, skin, nails, bones, mucous membranes, and other body tissues can not form properly.

Glucosamine works to stimulate joint function and repair. Everyone produces a certain amount of glucosamine within their bodies. Normally we generate sufficient amounts of glucosamine in our bodies to form the various compounds needed to generate connective tissue and healthy cartilage. But gradually the rate at which our bodies use glucosamine begins to gradually change with our increased athletic activity, injuries, burns, arthritis and other inflammatory disorders, age and other chronic degeneration.3 In such situations our bodies may not be able to keep up with the demand for glucosamine, leading to a decrease in the amount of proteoglycans produced. This can lead to a decrease in the amount of protective lubricating substances like the synovial fluids, which cushion our joints, and protects them from damage. In a nutshell, more glucosamine is needed but less is produced.
As the age advances, body loses the capacity to make enough glucosamine. Having ample glucosamine in the body is essential to producing the nutrients needed to stimulate the production of synovial fluid, the fluid which lubricates cartilage and keeps the joints healthy. Without enough glucosamine, the cartilage in weight-bearing joints, such as the hips, knees, and hands deteriorates. The cartilage then hardens and forms bone spurs, deformed joints, and limited joint movement. This is how the debilitating disease of osteoarthritis develops.4
Therefore, in short, glucosamine is a major building block of proteoglycans needed to make glycosaminoglycans, proteins that bind water in the cartilage matrix which also acts as a source of nutrients for the synthesis of proteoglycans and glycosaminoglycans. It is also a stimulant to chondrocytes and playing key factor in determining how many proteoglycans are produced by the chondrocytes needed to spur chondrocytes to produce more collagen and proteoglycans acts as a regulator of cartilage metabolism which helps to keep cartilage from breaking down. 5
Glucosamine is the supplement most commonly used by patients with osteoarthritis. It is an endogenous amino sugar that is required for synthesis of glycoproteins and glycosaminoglycans, which are found in synovial fluid, ligaments, and other joint structures. Exogenous glucosamine is derived from marine exoskeletons or produced synthetically. Exogenous glucosamine may have anti-inflammatory effects and is thought to stimulate metabolism of chondrocytes.
Glucosamine is available in multiple forms. The most common are glucosamine hydrochloride and glucosamine sulfate. Some products contain a blend of these, and many combine one of the forms with a variety of other ingredients. Glucosamine has been safely used in long-term clinical trials Overall, the evidence supports the use of glucosamine sulfate for modestly reducing osteoarthritis symptoms and possibly slowing disease progression.
Chondroitin
Chondroitin, an endogenous glycosaminoglycan, is a building block for the formation of the joint matrix structure. Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan.6 Chondroitin sulfate is an important structural component of cartilage and provides much of its resistance to compression. Along with glucosamine, chondroitin sulfate has become a widely used dietary supplement for treatment of osteoarthritis. Chondroitin is a molecule that occurs naturally in the body. It is a major component of cartilage,the tough, connective tissue that cushions the joints. Chondroitin helps to keep cartilage healthy by absorbing fluid (particularly water) into the connective tissue. It may also block enzymes that break down cartilage, and it provides the building blocks for the body to produce new cartilage.
Chondroitin sulphate Chondroitin is the most abundant glycosaminoglycan in cartilage and is responsible for the resiliency of cartilage and it has various effects in relieving symptoms of osteoarthritis and those are its anti-inflammatory activity, the stimulation of the synthesis of proteoglycans and hyaluronic acid, and the decrease in catabolic activity of chondrocytes inhibiting the synthesis of proteolytic enzymes, nitric oxide, and other substances that contribute to damage cartilage matrix and cause death of articular chondrocytes. chondroitin sulfate reduced the IL-1β-induced nuclear factor-kB (Nf-kB) translocation in chondrocytes. In addition, chondroitin sulfate has recently shown a positive effect on osteoarthritic structural changes occurred in the subchondral bone.7 A number of scientific studies suggest that chondroitin may be an effective treatment for osteoarthritis
Therefore, chondroitin sulphate is effective as it reduces osteoarthritis pain, improves functional status of people with hip or knee osteoarthritis, reduces joint swelling and stiffness and ultimately provides relief from osteoarthritis symptoms for up to 3 months after treatment is stopped
S-Adenosyl methionine
S-Adenosyl methionine (SAM, SAMe, SAM-e) is a dietary supplement that has been clinically shown to support and promote joint health, mobility and joint comfort.It is a compound produced by our bodies from methionine. Methionine is an amino acid found in protein-rich foods and a common co-substrate involved in methyl group transfers. SAM-e is critical in the manufacture of joint cartilage and in the maintenance of neural cell membrane function.8
Administration of SAMe exerts analgesic and antiphlogistic activities and stimulates the synthesis of proteoglycans by articular chondrocytes with minimal or absent side effects on the gastrointestinal tract and other organs and improving pain and stiffness related to osteoarthritis
Vitamin C
Vitamin C( ascorbic acid) may help reduce the progression of osteoarthritis. Vitamin C is involved in the formation of both collagen and proteoglycans (two major components of cartilage, which cushions the joints). Vitamin C is also a powerful antioxidant that helps to counteract the effects of free radicals in the body, which can damage cartilage. Ascorbic acid(vitamin c) is a sugar acid with antioxidant properties. Its appearance is white to light-yellow crystals or powder, and it is water-soluble. One form of ascorbic acid is commonly known as vitamin C. In human plasma, ascorbate is the only antioxidant that can completely protect lipids from detectable peroxidative damage induced by aqueous peroxyl radicals. Ascorbate appears to trap virtually all peroxyl radicals in the aqueous phase before they diffuse into the plasma lipids. Ascorbate is a highly effective antioxidant, as it not only completely protects lipids from detectable peroxidative damage, but also spares alpha-tocopherol, urate, and bilirubin.Ascorbic acid stimulates collagen synthesis and modestly stimulates synthesis of aggrecan (a proteoglycan present in articular cartilage), Sulfated proteoglycan biosynthesis is significantly increased in the presence of ascorbic acid thus it may offer some protective effect against the super oxide and free radicals and limiting and delaying the osteoarthritis progression

Beta-carotene
Beta-carotene belongs to a family of natural chemicals known as carotenoids. Widely found in plants, carotenoids along with another group of chemicals, bioflavonoids, give color to fruits, vegetables, and other plants.
Beta-carotene is another antioxidant that also seems to help reduce the risk of osteoarthritis progression. Beta-carotene is a particularly important carotenoid from a nutritional standpoint, because the body easily transforms it to vitamin A. While vitamin A supplements themselves can be toxic when taken to excess, it is believed (although not proven) that the body will make only as much vitamin A out of beta-carotene as it needs. Assuming this is true, this built-in safety feature makes beta-carotene the best way to get your vitamin A. A high dietary intake of beta-carotene is associated with a significantly slower progression of osteoarthritis, according to a study in which researchers followed 640 individuals over a period of 8 to 10 years .10
Conclusion:
In conclusion,there are nutrients and foods that may help to halt the progression osteoarthritis before it becomes severe as well as helping to reduce the pain and inflammation associated with it.



n.b.: This article was an exercise of e learning by final year medical student Saleh from Melaka Manipal Medical College


REFERENCES

1) Clinical Practise Guidelines. Management of Osteoarthritis http://www.msr.org.my/html/Bookleta.pdf accessed on 13 February 2010
2) Cochrane Library. Glucosamine Therapy for Treating Osteoarthritis http://www.cochrane.org/reviews/en/ab002946.html accessed on 13 February 2010
3) Spark People Life. Dietary Supplement for Osteoarthritis
http://www.sparkpeople.com/resource/nutrition_articles.asp?id=865 accessed on
14 February
4) Horton D, Wander JD (1980). The Carbohydrates. Vol IB. New York: Academic
Press. pp. 727�728.
5) Glucosamine and Osteoarthritis,How it works
http://www.arthritis-glucosamine.net/glucosamine-osteoarthritis.php accessed on
14 February 2010
6) Jamie G. Barnhill, Carol L. Fye, David W. Williams, Domenic J. Reda, Crystal L. Harris, and Daniel O. Clegg. Chondroitin Product Selection for the Glucosamine/Chondroitin Arthritis Intervention Trial. J Am Pharm Assoc. 2008; 46:14�24.
7) Davidson EA, Meyer K (2007). "Chondroitin, a mucopolysaccharide". J Biol Chem 211 (2): 605�11.
8) S-adenosyl methionine [SAMe]. Research Reports http://www.oralchelation.com/technical/SAM.htm accessed on 15 February 2010
9) McAlindon TE, Jacques P, Zhang Y, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum. 1996;39:648-656.
10) iHerb. Com. Beta Carotene http://healthlibrary.epnet.com/GetContent.aspx?token=e0498803-7f62-4563-8d47-5fe33da65dd4&chunkiid=21547 accessed on 16 February 2010

Ulcerative Colitis and New Possible Treatments

Ulcerative colitis is a disease that causes inflammation and sores, called ulcers, in the lining of the rectum and colon. Ulcers form where inflammation has killed the cells that usually line the colon, then bleed and produce pus. Inflammation in the colon also causes the colon to empty frequently, causing diarrhea.
When the inflammation occurs in the rectum and lower part of the colon it is called ulcerative proctitis. If the entire colon is affected it is called pancolitis. If only the left side of the colon is affected it is called limited or distal colitis.
Ulcerative colitis is an inflammatory bowel disease (IBD), the general name for diseases that cause inflammation in the small intestine and colon. It can be difficult to diagnose because its symptoms are similar to other intestinal disorders and to another type of IBD called Crohn�s disease. Crohn�s disease differs because it causes inflammation deeper within the intestinal wall and can occur in other parts of the digestive system including the small intestine, mouth, esophagus, and stomach.
Ulcerative colitis can occur in people of any age, but it usually starts between the ages of 15 and 30, and less frequently between 50 and 70 years of age. It affects men and women equally and appears to run in families, with reports of up to 20 percent of people with ulcerative colitis having a family member or relative with ulcerative colitis or Crohn�s disease. A higher incidence of ulcerative colitis is seen in Whites and people of Jewish



Symptoms of Ulcerative Colitis ?



The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Patients also may experience
� anemia
� fatigue
� weight loss
� loss of appetite
� rectal bleeding
� loss of body fluids and nutrients
� skin lesions
� joint pain
� growth failure (specifically in children)
About half of the people diagnosed with ulcerative colitis have mild symptoms. Others suffer frequent fevers, bloody diarrhea, nausea, and severe abdominal cramps. Ulcerative colitis may also cause problems such as arthritis, inflammation of the eye, liver disease, and osteoporosis. It is not known why these problems occur outside the colon. Scientists think these complications may be the result of inflammation triggered by the immune system. Some of these problems go away when the colitis is treated.
Causes ulcerative colitis?
Many theories exist about what causes ulcerative colitis. People with ulcerative colitis have abnormalities of the immune system, but doctors do not know whether these abnormalities are a cause or a result of the disease. The body�s immune system is believed to react abnormally to the bacteria in the digestive tract.
Ulcerative colitis is not caused by emotional distress or sensitivity to certain foods or food products, but these factors may trigger symptoms in some people. The stress of living with ulcerative colitis may also contribute to a worsening of symptoms.
Diagnosis
Many tests are used to diagnose ulcerative colitis. A physical exam and medical history are usually the first step.
Blood tests may be done to check for anemia, which could indicate bleeding in the colon or rectum, or they may uncover a high white blood cell count, which is a sign of inflammation somewhere in the body.
A stool sample can also reveal white blood cells, whose presence indicates ulcerative colitis or inflammatory disease. In addition, a stool sample allows the doctor to detect bleeding or infection in the colon or rectum caused by bacteria, a virus, or parasites.
A colonoscopy or sigmoidoscopy are the most accurate methods for making a diagnosis of ulcerative colitis and ruling-out other possible conditions, such as Crohn�s disease, diverticular disease, or cancer. For both tests, the doctor inserts an endoscope�a long, flexible, lighted tube connected to a computer and TV monitor�into the anus to see the inside of the colon and rectum. The doctor will be able to see any inflammation, bleeding, or ulcers on the colon wall. During the exam, the doctor may do a biopsy, which involves taking a sample of tissue from the lining of the colon to view with a microscope.
Sometimes x rays such as a barium enema or CT scans are also used to diagnose ulcerative colitis or its complications.
A major genetic link to the development of Crohn's disease and ulcerative colitis, as well as other inflammatory diseases, has been revealed in a recent study. "This genetic discovery is special because it may have a rapid impact on diagnosis and treatment of these chronic digestive diseases," says Jonathan Braun, M.D., Ph.D., Chair of the National Scientific Advisory Committee of the Crohn's & Colitis Foundation of America (CCFA)

Previous genetic studies uncovered a link between Crohn's and variants of the gene CARD15 (also known as NOD2), but this gene plays a role in only some Crohn's patients, and does not affect the risk for colitis. The new discovery, which involves a gene called the interleukin-23 (IL-23) receptor, has a much larger effect on these inflammatory diseases.
Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway.



Colon Cancer:
About 5 percent of people with ulcerative colitis develop colon cancer. The risk of cancer increases with the duration of the disease and how much the colon has been damaged. For example, if only the lower colon and rectum are involved, the risk of cancer is no higher than normal. However, if the entire colon is involved, the risk of cancer may be as much as 32 times the normal rate.
Sometimes precancerous changes occur in the cells lining the colon. These changes are called "dysplasia." People who have dysplasia are more likely to develop cancer than those who do not. Doctors look for signs of dysplasia when doing a colonoscopy or sigmoidoscopy and when examining tissue removed during these tests.
According to the 2002 updated guidelines for colon cancer screening, people who have had IBD throughout their colon for at least 8 years and those who have had IBD in only the left colon for 12 to 15 years should have a colonoscopy with biopsies every 1 to 2 years to check for dysplasia.

Differential Diagnosis:
The entire length of the colon, starting at the rectosigmoid junction and ending at the cecum, can be visualized by transabdominal sonography after retrograde water instillation into the colon. By this method, termed hydrocolonic sonography, it is possible to evaluate in detail the lumen, the colon wall, and the surrounding tissue. Five layers of different echogenicity can be differentiated within the colon wall.
METHODS: In a prospective study of 440 patients, it had been compared the value of conventional abdominal sonography and hydrocolonic sonography with that of colonoscopy, in the diagnosis and differential diagnosis of ulcerative colitis and colonic Crohn's disease.
RESULTS: In 93% of patients with Crohn's disease, the normal five-layer structure of the colonic wall was no longer in evidence, and the wall appeared hypoechogenic and clearly thickened.
In patients with ulcerative colitis, the five-layer structure could clearly be discerned, and although the colon wall remained hypoechogenic, it was only moderately thickened.
Colonic Crohn's disease and ulcerative colitis were detectable by hydrocolonic sonography, with a sensitivity of 96% and 91%, respectively.
The sensitivity achieved by conventional abdominal sonography is only 71% and 62% respectively. Furthermore, hydrocolonic sonography made possible the differentiation of Crohn's disease from Ulcerative colitis in 93% of the cases.
Pathological Diagnosis:
Crohn's disease and ulcerative colitis are distinct entities, but in 5 to 10% of patients and resected specimens, a clear separation may not be possible. The pathological diagnosis and differential diagnosis of Crohn's disease, including ulcerative colitis, indeterminate colitis and other diseases may mimic Crohn's disease. It is often difficult or impossible to distinguish diversion colitis and pouchitis from recurrence of Crohn's disease.
Increased expression of CD44v6 and CD44v3 in Ulcerative Colitis but not colonic Crohn's Disease:
Immune mechanisms, possibly involving cell-surface molecules such as CD44, have been invoked to explain the pathogenesis of inflammatory bowel disease. Monoclonal antibodies were used against epitopes encoded within the variable region of CD44 to investigate CD44 isoform expression in colon, small intestine, and liver in patients with various intestinal disorders and in controls. Biopsy samples from patients with ulcerative colitis showed significantly increased epithelial expression of CD44 isoforms containing the v6 and v3 epitopes, detected with antibodies 2F10 and 3G5, respectively. CD44v6 was detected on colonic crypt epithelial cells in 23 of 25 ulcerative colitis samples compared with 3 of 18 colonic Crohn's disease samples (p = 3.0 x 10(-6); odds ratio 57.5 [95% CI 6.83-702]) and 3 of 52 controls (22 normal colon, 10 infective colitis, 2 radiation colitis, and 18 colonic Crohn's disease; p < 1 x 10(-8); odds ratio 199 [25.5-2294]). No significant expression of CD44v6, CD44v3, or CD44v8/9 was found in samples of normal proximal colon from 4 patients with distal ulcerative colitis, whereas samples from the affected area showed staining for CD44v6 and CD44v3. No expression of CD44 variants was found in 15 samples of normal small intestine, 11 small-bowel pouchitis, 8 coeliac disease, 3 small-bowel Crohn's disease, 6 normal liver, 6 primary biliary cirrhosis, or 9 primary sclerosing cholangitis. The high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in ulcerative colitis suggests that CD44 isoforms may have an important role in ulcerative colitis. Their detection could have diagnostic potential in differentiating ulcerative colitis from other forms of colonic inflammation including Crohn's disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed
&cmd=Retrieve&dopt=abstractplus&list_uids=7537840
Poor diagnostic value of colonic CD44v6 expression and serum concentrations of its soluble form in the differentiation of Ulcerative Colitis from Crohn's disease:
Increased expression of CD44v6 on colonic crypt epithelial cells in ulcerative colitis has been suggested as a diagnostic tool to distinguish ulcerative colitis from colonic Crohn's disease. AIMS: To investigate colonic CD44v6 expression and serum concentrations of soluble CD44v6 (sCD44v6) in patients with ulcerative colitis and Crohn's disease.
METHODS: Colonic biopsy samples were obtained from 16 patients with ulcerative colitis, 13 with ileocolonic Crohn's disease, and 10 undergoing polypectomy. Serum samples were obtained from 15 patients with active ulcerative colitis, 20 with active Crohn's disease, and 20 healthy donors. Colonic CD44v6 expression was evaluated immunohistochemically by monoclonal antibody 2F10 and the higher affinity monoclonal antibody VFF18. Serum sCD44v6 concentrations were measured by ELISA.
RESULTS: 2F10 stained colonic epithelium of inflamed ulcerative colitis and Crohn's disease samples in 80% and 40% of cases, respectively, and VFF18 in 95% and 87%, respectively. Both monoclonal antibodies displayed a sensitivity and specificity of 60% and 87% to differentiate ulcerative colitis from colonic Crohn's disease. Serum concentrations of sCD44v6 were lower in patients with ulcerative colitis (median 153 ng/ml; interquartile range (IQR) 122-211) compared with Crohn's disease (219; IQR 180-243) and healthy donors (221; IQR 197-241 (p = 0.002)). Its sensitivity and specificity to discriminate ulcerative colitis from Crohn's disease was 75% and 71%, respectively.
CONCLUSION: Colonic CD44v6 and serum sCD44v6 concentrations do not facilitate reliable differential diagnosis between ulcerative colitis and Crohn's disease.
Evaluation of serological markers to differentiate between ulcerative colitis and Crohn's disease: pANCA, ASCA and agglutinating antibodies to anaerobic coccoid rods
The value of these serological tests in differentiating ulcerative colitis from Crohn's disease is limited when used separately but, by combining two or more tests, the positive predictive value and specificity can be improved substantially. These tests might be of help in studying disease heterogeneity, and may contribute to defining various subgroups of patients with different pathogeneses.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=abstractplus&db=pubmed
&cmd=Retrieve&dopt=abstractplus&list_uids=12352222
Genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed
&list_uids=8119534&dopt=Abstract
Cytokine profile in colonic mucosa of ulcerative colitis correlates with disease activity and response to granulocytapheresis
http://www.blackwell-synergy.com/links/doi/10.1111/j.1572-0241.2002.07029.x/abs/
Use of CT findings in differential diagnosis:
The mean colon wall thickness in Crohn colitis (11.0 mm +/- 5.1) is significantly greater than in ulcerative colitis (7.8 mm +/- 1.9) (P < .002). Submucosal fat deposition, not observed in the acute colitis, is significantly present more oftenly in ulcerative (61%) than in Crohn colitis (8%) (P = .0001). Exclusive involvement of the right colon and small bowel was most frequent with Crohn and infectious colitis. Abscess was associated almost exclusively with Crohn colitis (35%) but was seen in one patient with radiation colitis.
CONCLUSION: Although many CT findings in patients with colitis are nonspecific, some features are helpful in suggesting a specific diagnosis.

Available treatment for ulcerative colitis:
1. Aminosalicylates: drugs that contain 5-aminosalicyclic acid (5-ASA), help control inflammation. Sulfasalazine is a combination of sulfapyridine and 5-ASA.
2. Corticosteroids such as prednisone, methylprednisone, and hydrocortisone also reduce inflammation. They may be used by people who have moderate to severe ulcerative colitis or who do not respond to 5-ASA drugs.
3. Immunomodulators such as azathioprine and 6-mercapto-purine (6-MP) reduce inflammation by affecting the immune system. These drugs are used for patients who have not responded to 5-ASAs or corticosteroids or who are dependent on corticosteroids. Immunomodulators are administered orally, however, they are slow-acting and it may take up to 6 months before the full benefit.
4. Surgery (a) Ileostomy, (b) Ileoanal anastomosis.

New Possible Treatments:
1. Dr. Braun notes that while the disease state of all Crohn's and colitis patients is not likely to be driven by IL-23, the drugs necessary to affect change in the behavior of this protein receptor already exist. In fact, one such therapy was recently reported by a team at the National Institutes of Health (NIH). The investigators were able to show that therapy targeting p40 a subunit of IL-23 can inhibit the activity of IL-23 in Crohn's disease (Mannon P, N Engl J Med 351:2069, 2004). This genetic discovery is likely to accelerate tests of this and other drugs, and to better identify which patients will benefit from such diseases, and affects risk for both Crohn's and Colitis.

"The genetic variants in the IL-23 receptor gene have been identified that confer increased risk for IBD, but we are most excited about our discovery of a genetic factor in the same gene that confers protection against developing IBD," said Dr. Duerr. "There is hope that ongoing research will tease out the specific downstream effects of these genetic variants so that this knowledge can be used to develop better, more targeted therapies for patients with IBD.�.
2. LCAP (Leucocytapheresis)
Leukocyctapheresis (LCAP) is a blood purification treatment for ulcerative colitis (UC) [1]. LCAP is known to have a low incidence of side effects. LCAP is carried out using a column (Cellsorba E) filled with a non-woven fabric made up of polyester fibers. The fabric had a dual structure; an inner layer composed of superfine fibers 0.8-2.8 in diameter, and an outer layer composed of fibers 10-40 in diameter. The blood is filtrated from the outside into the inside of the non-woven fabric wound into a cylindrical shape in the column, and leukocyte components are removed. The blood, with leukocyte removed, is guided out from the column and heated, and the returned to the corresponding vein of the patient�s other arm or leg of the patient. The blood flow rate is set at 30-50 , and 2-3 L of blood is treated in each session of LCAP. The treatment is carried out for one hour per session once in a week, for 10 wks.

3. Non-pathogenic Escherichia coli versus Mesalazine for the treatment of ulcerative colitis:
Ulcerative colitis has been suggested to be caused by infection and there is circumstantial evidence linking Escherichia coli with the condition. I had been tried to find out whether the administration of a non-pathogenic strain of E. coli (Nissle 1917) is as effective as mesalazine in preventing relapse of ulcerative colitis. It has also been examined whether the addition of E. coli to standard medical therapy increased the chance of remission of active ulcerative colitis.
Trial study: This was a single-centre, randomised, double-dummy study in which 120 patients with active ulcerative colitis were invited to take part. 116 patients accepted; 59 were randomised to mesalazine and 57 to E. coli. All patients also received standard medical therapy together with a 1-week course of oral gentamicin. After remission, patients were maintained on either mesalazine or E. coli and followed up for a maximum of 12 months. A two-stage, conditional, intention-to-treat analysis was done.
FINDINGS: 44 (75%) patients in the mesalazine group attained remission compared with 39 (68%) in the E. coli group. Mean time to remission was 44 days (median 42) in the mesalazine group and 42 days (median 37) for those treated with E. coli. In the mesalazine group, 32 (73%) patients relapsed compared with 26 (67%) in the E. coli group. Mean duration of remission was 206 days in the mesalazine group (median 175) and 221 days (median 185) in the E. coli group.
INTERPRETATION: The results suggest that treatment with a non-pathogenic E. coli has an equivalent effect to mesalazine in maintaining remission of ulcerative colitis. The beneficial effect of live E. coli may provide clues to the cause of Ulcerative Colitis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed
&list_uids=10466665&dopt=Citation

References:
http://ccfa.i33.com/media/pdf/profchallenges.pdf
http://www3.interscience.wiley.com/cgi-bin/abstract/108061210/ABSTRACT?CRETRY=1&SRETRY=0
http://jimmunol.highwire.org/cgi/content/abstract/172/1/525
http://jimmunol.highwire.org/cgi/content/abstract/170/11/5438
http://jimmunol.highwire.org/cgi/content/abstract/173/3/1887
http://www.journals.uchicago.edu/cgi-bin/resolve?id=doi:10.1086/425021
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed
&list_uids=16290228&dopt=Citation
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed
&list_uids=15158199&dopt=Abstract&holding=f1000,f1000m,isrctn
http://jimmunol.highwire.org/cgi/content/abstract/166/12/7563
Ubiquitous Transgenic Expression of the IL-23 Subunit p19 Induces Multi-organ inflammation, Runting, Infertility, and Premature Death
Dr Tejinder M Aggrwal
GAMS, MBBS &
RESEARCH ASSOCIATE
CSE & BIO-INFORMATICS
FAU BOCA RATON 33431 FL USA