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Human Brain is Divided on Fear and Panic

Human brain is divided on fear and panic

New study contends different areas of brain responsible for external versus internal threats

BY:

JOHN RIEHL
Brain scans
Researchers at the University of Iowa show that the human brain has new regions that sense internally derived fear. The finding comes from tests the team conducted of three women with significant damage to the amygdala (shown in the brain scans by red-dashed circles), which registers fear from external dangers. Image courtesy of Iowa Neurological Patient Registry at the University of Iowa.

When doctors at the University of Iowa prepared a patient to inhale a panic-inducing dose of carbon dioxide, she was fearless. But within seconds of breathing in the mixture, she cried for help, overwhelmed by the sensation that she was suffocating.

The patient, a woman in her 40s known as SM, has an extremely rare condition called Urbach-Wiethe disease that has caused extensive damage to the amygdala, an almond-shaped area in the brain long known for its role in fear. She had not felt terror since getting the disease when she was an adolescent.

In a paper published online Feb. 3 in the journal Nature Neuroscience , the UI team provides proof that the amygdala is not the only gatekeeper of fear in the human mind. Other regions— such as the brainstem, diencephalon , or insular cortex—could sense the body’s most primal inner signals of danger when basic survival is threatened.

“This research says panic, or intense fear, is induced somewhere outside of the amygdala,” says John Wemmie, associate professor of psychiatry at the UI and senior author on the paper. “This could be a fundamental part of explaining why people have panic attacks.

If true, the newly discovered pathways could become targets for treating panic attacks, post-traumatic stress syndrome, and other anxiety-related conditions caused by a swirl of internal emotional triggers.

“Our findings can shed light on how a normal response can lead to a disorder, and also on potential treatment mechanisms,” says Daniel Tranel, professor of neurology and psychology at the UI a nd a corresponding author on the paper.

Decades of research have shown the amygdala plays a central role in generating fear in response to external threats. Indeed, UI researchers have worked for years with SM, and noted her absence of fear when she was confronted with snakes, spiders, horror movies, haunted houses, and other external threats, including an incident where she was held up at knife point. But her response to internal threats had never been explored.

The UI team decided to test SM and two other amygdala-damaged patients with a well-known internally generated threat. In this case, they asked the participants, all females, to inhale a gas mixture containing 35 percent carbon dioxide, one of the most commonly used experiments in the laboratory for inducing a brief bout of panic that lasts for about 30 seconds to a minute. The patients took one deep breath of the gas, and quickly had the classic panic-stricken response expected from those without brain damage: They gasped for air, their heart rate shot up, they became distressed, and they tried to rip off their inhalation masks. Afterward, they recounted sensations that to them were completely novel, describing them as “panic.”

“They were scared for their lives,” says first author Justin Feinstein, a clinical neuropsychologist who earned his doctorate at the UI last year.

Wemmie had looked at how mice responded to fear, publishing a paper in the journal Cell in 2009 showing that the amygdala can directly detect carbon dioxide to produce fear. He expected to find the same pattern with humans.

“We were completely surprised when the patients had a panic attack,” says Wemmie, also a faculty member in the Iowa Neuroscience Graduate Program.

By contrast, only three of 12 healthy participants panicked—a rate similar to adults with no history of panic attacks. Notably, none of the three patients with amygdala damage has a history of panic attacks. The higher rate of carbon dioxide-induced panic in the patients suggests that an intact amygdala may normally inhibit panic.

Interestingly, the amygdala-damaged patients had no fear leading up to the test, unlike the healthy participants, many who began sweating and whose heart rates rose just before inhaling the carbon dioxide. That, of course, was consistent with the notion that the amygdala detects danger in the external environment and physiologically prepares the organism to confront the threat.

“Information from the outside world gets filtered through the amygdala in order to generate fear,” Feinstein says. “On the other hand, signs of danger arising from inside the body can provoke a very primal form of fear, even in the absence of a functioning amygdala.”

Contributing authors include Colin Buzza, Robin Follmer, and William Coryell, from the UI Department of Psychiatry; Rene Hurlemann, from the University of Bonn Department of Psychiatry; Nader Dahdaleh, of the UI Department of Neurosurgery; and Michael Welsh, UI professor of internal medicine and molecular physiology and biophysics and a Howard Hughes Medical Institute investigator. Buzza and Hurlemann are co-first authors on the paper.

The National Institute of Neurological Disorders and Stroke (grant number: 5P50NS019632-28), the National Institute of Mental Health Research (grant number: 5R01 MH085724), and the Department of Veterans Affairs helped fund the research. Other funders include a Doris Duke Clinical Research Fellowship, a McKnight Neuroscience of Brain Disorders Award, and a Starting Independent Researcher Grant, jointly provided by the Ministry of Innovation, Science, Research, and Technology of the German State of North Rhine-Westphalia and the University of Bonn.

Contacts

John Riehl, Graduate College, 319-384-1309
Richard Lewis, University Communication and Marketing, 319-384-0012

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Can You Predict How a Disease Will Spread in a Population?

How, when and where a pathogen is transmitted between two individuals in a population is crucial in understanding and predicting how a disease will spread. New research has laid the foundation for a new generation of zoonotic disease spreading models, which could allow for more targeted prevention strategies.

By using novel complexity sciences tools the study, published in Physical Review Letters, outlines a predictive model of a spatial epidemic spread in a population of territorial animals.

By quantifying the instances of transmission events, the research team, Dr Luca Giuggioli, Senior Lecturer in Complexity Sciences in the Department of Engineering Mathematics and the School of Biological Sciences at the University of Bristol, and Dr David Sanders and Master’s student, Sebastian Pérez-Becker, from UNAM, Mexico, have determined the propagation speed of a pathogen based on the knowledge of the demography of a species, the way animals wander and the degree of contagiousness of the disease.

As a large percentage of new and reemerging human infectious diseases are of animal origin, models that track how pathogens hop from one animal host to another will help develop more effective control measures that are capable of identifying specific individuals or class of individuals rather than ineffective and costly widespread culling procedures of an entire population.

Dr Luca Giuggioli said: “The research findings have the potential to be applicable to various populations of territorial animals worldwide including in the UK bovine Tb in badgers, which has enormous economic implications for the cattle industry.”

Bovine tuberculosis (Tb) in badgers, which affects cattle, the farming industry and has become a political issue, is an example of how the model could be used.  Badgers are territorial animals and do transmit the infection by passing the bacterial pathogen to individuals in neighbouring territories, which is what the researchers have quantified in their model.

Source: University of Bristol

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Global Fight Against Obesity: Help with Coke Ads

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I found this article on the http://www.coca-colablog.com,They are launching a  Coke Ads Help in Fight Against Obesity.

Together for Good in the Fight Against Obesity

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For many of us, staying active and eating a balanced diet can be a daily struggle. We make choices throughout the day, every day that will inevitably affect our overall well-being. Take the elevator or the stairs this morning?  Add or hold the mayo at lunch?  Spin class or drive home after work?  All these decisions  have an impact on our lives. At Coca-Cola, we want to help give you what you need when you make those decisions.  That’s why we’re offering more low and zero calorie drinks, sharing calorie counts on the front of nearly all of our packages and vending machines and sponsoring community sports teams.

For 126 years, Coca-Cola has been bringing people together to create positive change around the world.  It’s our history and our story and one we want to share.  That’s why Coke launched this video showcasing our ongoing efforts to inspire Americans to live happier and more active lives.

This video tells our story of how we are working to help lead in the fight against obesity.  We believe that uniting industry, government and civil societies is just the beginning in addressing one of today’s most pressing issues – obesity. We hope you will join us in our efforts to address these tough challenges, because together is always how we have made good things happen. We believe we can make an impact together. Do you believe?

http://www.youtube.com/watch?feature=player_embedded&v=ByvHJ0uiXAo

Coca-Cola may be a global company, but it is deeply rooted in local communities around the world and, like everyone, we have a vested stake in the health of people worldwide. At Coke, we also recognize that when everyone works together, good things happen.

Today, The Coca-Cola Company launches an unprecedented global campaign to help society beat one of the most serious, complex issues of this generation – obesity. In a series of new advertisements launching in the U.S. this week, we’re using our marketing power and scale to educate people about the importance of making informed choices and balancing “calories in” with “calories out.”

 

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Beginning this week, two national TV commercials will share our message in a whole new way:
• A two-minute piece, titled “Coming Together,” debuts tonight – Monday, Jan. 14 on cable news (CNN, FOX, MSNBC). Its purpose is to highlight some of the specifics behind the Company’s ongoing commitment to deliver a greater choice of beverages, including low- and no-calories options, and to clearly communicate the calorie content of all its products.
• A second spot, called “Be Ok,” will debut on American Idol on Wednesday, Jan. 16. “Be Ok” makes it perfectly clear right up front that a can of Coca-Cola has 140 calories. The spot encourages everyone to be mindful that all calories count in managing your weight, including those in Coca-Cola products and in all foods and beverages. This spot also encourages people to have some fun burning those calories off.

Our efforts don’t stop with these advertisements. We will continue to educate, innovate and act to help people lead active, healthy lives. The Coca-Cola Company has an important role in this fight. Together, with willing partners, we will succeed. Join us in these efforts by sharing how we’re taking a stand against obesity.

Visit Coke.com/ComingTogether, the “Health” section of Coca-Cola Journey and The Beverage Institute for Health & Wellness to learn more.

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Histogram and Barchart(Bar Graph)

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Difference between a Bar graph (Bar chart) and a histogram?

Histogram :

http://youtu.be/CJuDqS1b9DM

 

Notes

There are two differences, one is in the type of data that is presented and the other in the way they are drawn.

In bar graphs are usually used to display “categorical data”, that is data that fits into categories. For example suppose that I offered to buy donuts for six people and three said they wanted chocolate covered, 2 said plain and one said with icing sugar. I would present this in a bar garph as:

 

Histograms on the other hand are usually used to present “continuous data”, that is data that represents measured quantity where, at least in theory, the numbers can take on any value in a certain range. A good example is weight. If you measure the weights of a group of adults you might get and numbers between say 90 pounds and 240 pounds. We usually report our weights as pounds or to the nearest half pound but we might do so to the nearest tenth of a pound or however acurate the scale is. The data would then be collected into categories to present a histogram. For example:

 

might be a histogram for heights (with the appropriate scale on the vertical axis). Here the data has been collected into categories of width 30 pounds.

The difference in the way that bar graphs and histograms are drawn is that the bars in bar graphs are usually separated where in histograms the bars are adjacent to each other. This is not always true however. Sometimes you see bar graphs with no spaces between the bars but histograms are never drawn with spaces between the bars.

 

 

From:http://mathcentral.uregina.ca/QQ/database/QQ.09.99/raeluck1.html

 

 

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Drinking water on Empty Stomach:A Treatment for many Diseases…hoax???

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Water-Benefits

It is popular in Japan today to drink water immediately after waking up every morning. Furthermore, scientific tests have proven its value. We publish below a description of
use of water for our readers. For old and serious diseases as well as modern illnesses the water treatment had been found successful by a Japanese medical society as a 100% cure for the following diseases:

Headache, body ache, heart system, arthritis, fast heart beat, epilepsy, excess fatness, bronchitis asthma, TB, meningitis, kidney and urine diseases, vomiting, gastritis, diarrhea, piles, diabetes, constipation, all eye diseases, womb, cancer and menstrual disorders, ear nose and throat diseases.

METHOD OF TREATMENT

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1. As you wake up in the morning before brushing teeth, drink 4 x 160ml glasses of water

2. Brush and clean the mouth but do not eat or drink anything for 45 minute

3.. After 45 minutes you may eat and drink as normal.

4. After 15 minutes of breakfast, lunch and dinner do not eat or drink anything for 2 hours

5. Those who are old or sick and are unable to drink 4 glasses of water at the beginning may commence by taking little water and gradually increase it to 4 glasses per day.

6. The above method of treatment will cure diseases of the sick and others can enjoy a healthy life.

The following list gives the number of days of treatment required to cure/control/reduce main diseases:
1. High Blood Pressure (30 days)
2. Gastric (10 days)
3. Diabetes (30 days)
4. Constipation (10 days)
5. Cancer (180 days)
6. TB (90 days)
7. Arthritis patients should follow the above treatment only for 3 days in the 1st week, and from 2nd week onwards � daily..

This treatment method has no side effects, however at the commencement of treatment you may have to urinate a few times.
It is better if we continue this and make this procedure as a routine work in our life. Drink Water and Stay healthy and Active.

This makes sense .. The Chinese and Japanese drink hot tea with their meals not cold water. Maybe it is time we adopt their drinking habit while eating!!! Nothing to lose, everything to gain…

For those who like to drink cold water, this article is applicable to you.
It is nice to have a cup of cold drink after a meal. However, the cold water will solidify the oily stuff that you have just consumed. It will slow down the digestion.

Once this ‘sludge’ reacts with the acid, it will break down and be absorbed by the intestine faster than the solid food. It will line the intestine.
Very soon, this will turn into fats and lead to cancer. It is best to drink hot soup or warm water after a meal.

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A serious note about heart attacks:

  •  Women should know that not every heart attack symptom is going to be the left arm hurting,
  •  Be aware of intense pain in the jaw line.
  •  You may never have the first chest pain during the course of a heart attack.
  •  Nausea and intense sweating are also common symptoms.
  •  60% of people who have a heart attack while they are asleep do not wake up.
  •  Pain in the jaw can wake you from a sound sleep. Let’s be careful and be aware. The more we know, the better chance we could survive…

A cardiologist says if everyone who gets this mail sends it to everyone they know, you can be sure that we’ll save at least one life.
Please be a true friend and send this article to all your friends you care about.

PLEASE DON’T IGNORE SHARE IT.
THIS MIGHT SAVE SOMEONE’S LIFE.

Drink Enough Water

 

 

The Way you Drink Water can Cause Deadly Disease-Mostly Unproven!

Summary of the eRumor:
Several claims:  1.  A regimen of drinking water in the morning on an empty stomach can cure several diseases including cancer, arthritis, and diabetes.  2.  Drinking cold water with meals can cause sludge in the intestines and lead to cancer.  3.  Women should be aware of heart attack symptoms.
The Truth:
Let’s take the topics one at a time:

1.  Drink water in the morning on an empty stomach and cure diseases-Unproven!
So called “Water Therapy” is a popular recommendation among practioners of alternative medicine but we have not found any credible evidence of the value of the method suggested in this email or that it would cure serious diseases such as cancer.  Such claims are not backed up with valid research.

2.  Drinking cold water with meals can cause sludge in the intestines and lead to cancer-Unproven!
We have not found “Japanese Medical Society” referred to in the email. Although there are doctors and nutritionists who sometimes recommend not drinking water with meals, we have not found any documentation that drinking ice water clogs up the intestines.  One nutritionist we asked said it doesn’t make much of a difference because all food and drink, whether hot or cold, eventually gets to the same internal temperatures and long before getting to the intestine.

3.  Women should be aware of heart attack symptoms-Truth!
Physicians have long recommended that women be as sensitive to heart attack symptoms as men.  We found no documentation that 60% of people who have a heart attack while asleep do not wake up but the symptoms of heart attack that are described are generally true.

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ONIONS!…..Important…..Very Interesting…Wow

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Wow- very interesting….Everyone should read 🙂

ONIONS! I had never heard this!!!
PLEASE READ TO THE END: IMPORTANT

In 1919 when the flu killed 40 million people there was this Doctor that visited the many farmers to see if he could help them combat the flu…
Many of the farmers and their families had contracted it and many died.

The doctor came upon this one farmer and to his surprise, everyone was very healthy. When the doctor asked what the farmer was doing that was different the wife replied that she had placed an unpeeled onion in a dish in the rooms of the home, (probably only two rooms back then). The doctor couldn’t believe it and asked if he could have one of the onions and place it under the microscope. She gave him one and when he did this, he did find the flu virus in the onion. It obviously absorbed the bacteria, therefore, keeping the family healthy.

Now, I heard this story from my hairdresser. She said that several years ago, many of her employees were coming down with the flu, and so were many of her customers. The next year she placed several bowls with onions around in her shop. To her surprise, none of her staff got sick. It must work. Try it and see what happens. We did it last year and we never got the flu.

Now there is a P. S. to this for I sent it to a friend in Oregon who regularly contributes material to me on health issues. She replied with this most interesting experience about onions:

Thanks for the reminder. I don’t know about the farmer’s story…but, I do know that I contacted pneumonia, and, needless to say, I was very ill… I came across an article that said to cut both ends off an onion put it into an empty jar, and place the jar next to the sick patient at night. It said the onion would be black in the morning from the germs…sure enough it happened just like that…the onion was a mess and I began to feel better.

Another thing I read in the article was that onions and garlic placed around the room saved many from the black plague years ago. They have powerful antibacterial, antiseptic properties.

This is the other note. Lots of times when we have stomach problems we don’t know what to blame. Maybe it’s the onions that are to blame. Onions absorb bacteria is the reason they are so good at preventing us from getting colds and flu and is the very reason we shouldn’t eat an onion that has been sitting for a time after it has been cut open.

LEFT OVER ONIONS ARE POISONOUS

I had the wonderful privilege of touring Mullins Food Products, Makers of mayonnaise. Questions about food poisoning came up, and I wanted to share what I learned from a chemist.

Ed, who was our tour guide, is a food chemistry whiz. During the tour, someone asked if we really needed to worry about mayonnaise. People are always worried that mayonnaise will spoil. Ed’s answer will surprise you. Ed said that all commercially-made mayo is completely safe.

“It doesn’t even have to be refrigerated. No harm in refrigerating it, but it’s not really necessary.” He explained that the pH in mayonnaise is set at a point that bacteria could not survive in that environment. He then talked about the summer picnic, with the bowl of potato salad sitting on the table, and how everyone blames the mayonnaise when someone gets sick.

Ed says that, when food poisoning is reported, the first thing the officials look for is when the ‘victim’ last ate ONIONS and where those onions came from (in the potato salad?). Ed says it’s not the mayonnaise (as long as it’s not homemade mayo) that spoils in the outdoors. It’s probably the ONIONS, and if not the onions, it’s the POTATOES.

He explained onions are a huge magnet for bacteria, especially uncooked onions. You should never plan to keep a portion of a sliced onion.. He says it’s not even safe if you put it in a zip-lock bag and put it in your refrigerator.

It’s already contaminated enough just by being cut open and out for a bit, that it can be a danger to you (and doubly watch out for those onions you put in your hotdogs at the baseball park!). Ed says if you take the leftover onion and cook it like crazy you’ll probably be okay, but if you slice that leftover onion and put on your sandwich, you’re asking for trouble. Both the onions and the moist potato in a potato salad, will attract and grow bacteria faster than any commercial mayonnaise will even begin to break down.

Also, dogs should never eat onions. Their stomachs cannot metabolize onions.

Please remember it is dangerous to cut an onion and try to use it to cook the next day, it becomes highly poisonous for even a single night and creates toxic bacteria which may cause adverse stomach infections because of excess bile secretions and even food poisoning.

Please pass this on to all you love and care about.
— with Adonain Danny Rivera.

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The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review

  1. A G FraserT R OrchardD P Jewell

Azathioprine is widely used for the treatment of both Crohn’s disease and ulcerative colitis. Clinical trial data and a meta-analysis have confirmed the efficacy of azathioprine for Crohn’s disease.1–4 There are less efficacy data for ulcerative colitis and there are few data that have compared remission and relapse rates for ulcerative colitis and Crohn’s disease.5–8 There are some trial data that found that neutrophil count was a predictor of induction and maintenance of remission.9,10 This needs to be confirmed in a clinical audit as well as identifying other predictive factors for remission. It is unknown if longer duration of azathioprine treatment alters the risk of relapse after stopping treatment. A retrospective study suggested that treatment for longer than three to four years was no better than withdrawal of azathioprine treatment.11 There are no other comparable long term studies of the efficacy of azathioprine. These clinical questions cannot be answered easily by clinical trials but require audits of large clinic populations with careful and long term follow up.

Azathioprine is a purine analogue that competitively inhibits the biosynthesis of purine nucleotides. Its mode of action is not well understood. Once absorbed azathioprine is almost entirely metabolised to 6-mercaptopurine. There are two alternative pathways—one to 6-thiouric acid (mediated by xanthine oxidase) and the other to 6-methylmercaptopurine (mediated by thiopurinemethyltransferase).12 Low levels of thiopurinemethyltransferase lead to toxicity, particularly leucopenia.13 Uncertainty regarding the degree of risk from neutropenia deters some prescribers from using azathioprine at effective doses and for longer treatment durations. Side effects other than leucopenia also appear to limit the usefulness of this drug for a significant proportion of patients. Two types of side effects have been reported. Firstly, “allergic” non-dose related side effects which include pancreatitis, fever, rash, malaise, nausea, diarrhoea, and hepatitis. Secondly, there are “non-allergic” and presumably dose related side effects such as leucopenia and some forms of hepatitis. Although these side effects may be dose related, the genotype of the 6-thiopurinemethyltransferase enzyme is probably a more important determinant of developing leucopenia.14 Clinic data over a long term period of review gives a useful perspective of the clinical risk and toxicity of this drug.

METHODS

The notes of patients attending the Inflammatory Bowel Clinic at the John Radcliffe Hospital from 1968 to 1999 were reviewed. A clinic patient was defined by attendance at the outpatient clinic over a period of at least 12 months. Patients who had started azathioprine treatment at another hospital were excluded. Patients who received azathioprine primarily for other indications (renal transplant, rheumatoid arthritis, autoimmune liver disease) were excluded. Remission was defined as no need for oral steroids (either prednisolone or budenoside) for at least three months and a Harvey-Bradshaw score of 4 or less. Patients who were well on low doses of steroids were reported as “remission not achieved”. The continued use of oral 5-aminosalicylic acid compounds and steroid or 5-aminosalicylic acid enemas was allowed within the definition of remission. Relapse was defined as the need for reintroduction of steroids or the need for a surgical procedure. Relapse of short duration was defined as needing a course of steroids for less than three months while azathioprine was continued. The efficacy of azathioprine treatment was only assessed if treatment had been continued for six months or more. Patients were considered lost to follow up if there was no clinic visit within the last two years. Data were collected for azathioprine treatment only; 6-mercaptopurine was used sparingly in the Oxford Inflammatory Bowel Disease clinic. The extent of involvement of disease was defined by colonoscopic or radiological examination and not by histological evidence of inflammation. Diagnosis was based on data from the last clinical evaluation. Patients who continued to have a diagnosis of indeterminate colitis at the end of the follow up period were combined with patients with Crohn’s disease.

The dose of azathioprine for the efficacy data (mg/kg) was defined as the maintenance dose that induced remission. The initial dose was also recorded to determine if “early onset” side effects were dose related. The definition of leucopenia was a white blood count <3.0×109and/or a neutrophil count of less than 2.0×109.

Statistical analysis was performed using SPSS version 9.0. The probabilities of relapse were calculated by life table analysis. The influence of concomitant variables on time to relapse was examined by the Cox proportional hazards model. Differences between means for continuous data were tested using analysis of variance.

RESULTS

The clinical notes of 2205 patients were reviewed; azathioprine treatment was given to 622 patients. There were 272 patients with Crohn’s disease, four with indeterminate colitis (combined with Crohn’s disease data in subsequent analysis), and 346 with ulcerative colitis. Mean duration of follow up from the start of azathioprine treatment was 2518 (1995) days (6.9 (5.5) years; mean (SD)). Mean follow up after diagnosis was 4943 (3395) days (13.5 (9.3) years; 8423 patient years of follow up). Mean duration of initial azathioprine treatment was 634 (771) days (1.7 (2.1) years; 1080 patient years). One hundred and forty two patients had a second or third course of azathioprine. Mean total duration of treatment was 762 days (2.1 years; 1350 patient years).

Reasons for stopping medication

At completion of the review, 517 patients had discontinued treatment. This was after a predetermined period of treatment, usually two years, for 203 patients (39%). These patients were in remission at the time of stopping medication. The other major reason for stopping medication was side effects (152 patients, 28%). The most common side effects were nausea and vomiting (68 patients). Treatment was stopped after a mean of 106 days (range 1–395). Seventeen patients had abnormal liver enzymes; 15 had a raised alkaline phosphatase and gamma-glutamyl transferase and only two patients had elevated transaminases. The elevated liver enzymes returned to normal after stopping the medication for all 17 patients. Treatment was discontinued between 24 and 270 days after onset (mean 82 days). Severe epigastric pain was experienced by six patients although only two patients had a documented elevated serum amylase. Other side effects included generalised warts (two), paraesthesiae (one), flushing (one), and dizziness (one).

Leucopenia was observed during treatment in 29 patients (4.6%). The mean dose of azathioprine at which leucopenia was observed was 1.77 mg/kg. The azathioprine dose was ≤100 mg for 19 patients and >100 mg for 10 patients. The medication was stopped because of leucopenia in 21 patients. Other patients were managed by dose reduction or by observation (four patients in each group). Two patients had significant pancytopenia. Mean duration of treatment before the onset of leucopenia was 421 days (range 47–1514). Five patients developed leucopenia in less than three months, seven patients in 3–6 months, three patients in 6–12 months, eight patients in 12–24 months, and five patients developed leucopenia after 24 months of treatment (the highest duration of treatment was 50 months). Nine patients had episodes of sepsis during azathioprine treatment that could be related to immunosuppression. Only four episodes of sepsis were related to neutropenia. Three patients required treatment with intravenous antibiotics and there was no mortality. Five patients had infective complications but did not have neutropenia. One patient presented with a sore throat and a large mouth ulcer with a nadir of neutrophils of only 2.3×109. One patient had cytomegalovirus hepatitis, another had sacral herpes zoster infection, and two patients had generalised warts. Three patients (out of the 2205 patients with inflammatory bowel disease) had neutropenic related sepsis related to other medications. Two patients had sulphasalazine induced pancytopenia (one patient had life threatening Pseudomonas septicaemia). Another patient died from neutropenic sepsis eight years after completing a four year course of azathioprine. Neutropenia was considered to be due to chlorpromazine.

Other reasons for discontinuation of medication were that the medication was considered to be ineffective (46), surgery become necessary (68), the patient was uneasy about the potential side effects and requested stopping the medication (41), or the patient conceived or wished to become pregnant while off the medication (seven).

Induction of remission

A total of 424 patients completed six months of azathioprine treatment. For these patients remission was achieved in 64% of patients with Crohn’s disease and 87% with ulcerative colitis (p=0.0001). Overall remission rates (including all patients treated with azathioprine) were 45% and 58% for Crohn’s disease and ulcerative colitis, respectively. Factors predictive of achieving remission are listed in table 1. Significant factors were a lower white blood count (p=0.0001), lower neutrophil count (p=0.0001), higher mean cell volume (p=0.0001), and an older age when treatment was given (p=0.05). Factors that were not significant were weight, dose of azathioprine (mg/kg), age at diagnosis, and lymphocyte count. For Crohn’s disease patients analysed separately, colonic disease was associated with a higher rate of remission (p=0.03). By multiple logistic regression the independent factors in the model were white blood count (or neutrophil count) (p=0.0001), diagnosis (Crohn’s disease or ulcerative colitis; p=0.001), and mean cell volume (p=0.004). Mean cell volume and white blood count (or neutrophil count) were closely correlated (r=0.8, p=0.01) but were still independent factors in the model.

Table 1

Factors predicting remission on azathioprine treatment (mean and 95% confidence intervals)

Relapse

For the 324 patients who achieved remission, 250 patients remained in remission during the treatment period (28 were still continuing treatment at the time of follow up) (table 2). Using a strict definition of relapse (including patients with a short relapse), the proportion of patients still in remission at 12, 24, 36, 48, and 60 months was 0.95, 0.90, 0.69, 0.63, and 0.62, respectively (life table analysis; data for Crohn’s disease and ulcerative colitis combined). If patients with “short relapse” are included as “no relapse”, the proportion of patients still in remission at 12, 24, 36, 48, and 60 months was 0.99, 0.92, 0.85, 0.81, and 0.81, respectively. Factors predictive of remaining in remission (while still on treatment) were determined by the Cox proportion hazards model. The relapse rates were similar for ulcerative colitis and Crohn’s disease (p=0.5) (fig 1). Patients with a minimum white blood count of less than 5.0×109 had a lower risk of relapse (p=0.03) (fig 2). There was a trend for patients aged more than 36 years at the time when azathioprine treatment was started to have a lower risk of relapse (p=0.057). For patients with Crohn’s disease, male sex was associated with a lower risk of relapse (p=0.01). There was no sex difference for patients with ulcerative colitis. The time taken to achieve remission was not a significant factor for predicting relapse (p=0.6).

Table 2

Outcome while on azathioprine treatment for the 424 patients who were given treatment for more than six months

  Figure 1

Figure 1

Cox regression analysis of the proportion of patients remaining in remission during azathioprine treatment related to diagnosis of inflammatory bowel disease (324 patients). There was no difference in relapse rate between patients with ulcerative colitis and Crohn’s disease.

  Figure 2
Figure 2

Cox regression analysis of the proportion of patients remaining in remission during azathioprine treatment related to minimum observed white blood cell (WBC) count during treatment (324 patients). Patients with a WBC count of less than 5.0×109 were more likely to remain in remission (p=0.03).

A total of 222 patients stopped azathioprine while still in remission and therefore could be evaluated for relapse rates after stopping medication (table 3). The proportion of patients still in remission after 12, 24, 36, 48, and 60 months was 0.63, 0.44, 0.34, 0.28, and 0.25, respectively (fig 3). There were no significant predictive factors. One hundred and fifteen patients had been treated with azathioprine for more than two years, 79 patients for 2–4 years, and 36 patients for more than four years. Duration of azathioprine treatment before stopping medication did not affect the chance of staying in remission after stopping medication (p=0.40) (fig 4).

Table 3

Outcome after stopping azathioprine for 222 patients who were in remission at the time of stopping azathioprine

  Figure 3

Figure 3

Cox regression analysis of the proportion of patients remaining in remission after stopping azathioprine treatment related to diagnosis of inflammatory bowel disease (222 patients). There was no difference in relapse rate between Crohn’s disease and ulcerative colitis.

  Figure 4

Figure 4

Cox regression analysis of the proportion of patients remaining in remission after stopping azathioprine related to duration of azathioprine treatment (222 patients). There was no difference in relapse rate according to duration of treatment before stopping azathioprine.

DISCUSSION

This study confirms the safety and efficacy of azathioprine for the treatment of inflammatory bowel disease. This was a retrospective review and hence has some limitations but long term data are critical for clinical decision making and are unlikely to be obtained from prospective data.

There was no drug related mortality over a 30 year period. Neutropenic sepsis was not a major problem and in fact the most serious episode of sepsis was related to sulphasalazine. In general, the clinic followed the guidelines for follow up and blood testing suggested by St Marks Hospital (two monthly blood tests after the first three months).15 The proportion of patients with leucopenia was similar to previous reports (2–3.8%).15,16 The incidence of other side effects was also similar to previous reports except that pancreatitis appeared to be less common (although serum amylase level was not obtained in all patients).16,17 Epigastric pain requiring hospitalisation but without evidence of pancreatitis (normal amylase) was more common. Occasionally, retreatment at a later time and/or at a lower dose was successful. Nausea and vomiting did not appear to be dose related and dose reduction was successful only for a minority of patients.

This study confirms the efficacy of azathioprine for both Crohn’s disease and ulcerative colitis. The remission rates achieved and acceptable maintenance of remission with ongoing treatment make azathioprine a very valuable part of the treatment of inflammatory bowel disease. This result is consistent with clinical trial data.1–8 A meta-analysis of randomised studies of azathioprine in Crohn’s disease gave an odds ratio of 3.1 for inducing remission and an odds ratio of 2.3 for maintaining remission.4 Candy et al randomised patients with Crohn’s disease to treatment with azathioprine plus prednisone or prednisone alone. The remission rates at 12 weeks were the same but after 15 months 42% of patients receiving azathioprine achieved and maintained remission compared with 7% on placebo (p=0.001).3

The white blood and neutrophil counts were both good predictors of achieving and maintaining remission but the lymphocyte count had no value for predicting remission. White blood count and mean cell volume were closely correlated but were independent variables for predicting remission (logistic regression analysis). These data have modest clinical use because of the variable onset of fall in white blood count and significant overlap between responders and non-responders. In the first few months there may be no change in white blood count possibly because of the inflammatory activity and also because of steroid treatment. Many patients with a normal or “high normal” white blood count had a good response to azathioprine. It is debatable whether dose increases should be based on achieving a fall in white count or a rise in mean cell volume but the presence of either of these two markers is an encouraging sign for the patient and physician. In the study of Candy et al, leucopenia requiring dose reduction was associated with sustained remission. Median white blood count at completion of 15 months of treatment was 4.9×109 (interquartile range 3.9–5.7) for responders compared with 6.8×109(5.1–9.0) for non-responders (p=0.005).3 Colonna and Korelitz also found a strong positive correlation between the extent of drug induced leucopenia and clinical outcome.9 A low white blood count was also a significant variable for prediction of remaining in remission. The better outcome for older patients and male sex was also found in a French study of 157 patients with Crohn’s disease in remission for more than six months.11 The site of disease involvement for patients with Crohn’s disease was not significant in the French study although another study of 95 patients showed a better outcome for patients with colonic disease (similar to this study).18

In this study, azathioprine was more likely to achieve remission in patients with ulcerative colitis than Crohn’s disease but was equally effective for maintenance of remission. There are fewer data on the efficacy of azathioprine for the treatment of ulcerative colitis and no good comparative data with Crohn’s disease. Two controlled trials have shown a steroid sparing effect for chronic active disease and an earlier trial gave equivocal results.5–8 Hawthorne et alstudied 79 patients with ulcerative colitis who had been receiving treatment for more than six months and were randomised to continuing treatment or withdrawal of treatment (67 patients were off steroids completely). The one year relapse rate was 36% (12/33) for patients continued on azathioprine and 59% (20/34) for patients who discontinued treatment.8 For patients in remission for more than six months the relapse rate on treatment was 31% (8/26) compared with 61% (17/28) for patients discontinuing treatment. In a similar retrospective review using 6-mercaptopurine in 105 patients with ulcerative colitis the remission rate was 65% (similar to this study).19

Life table analysis shows that maintenance azathioprine treatment is effective for up to five years of treatment. There is a gradual but acceptable increase in the proportion of patients who have relapsed over time. There is no suggestion that the effectiveness of treatment “wears out” after a specific duration. There is no support for the concept that treatment should be stopped after 3–4 years (because it is no better than placebo). A French study of 157 patients with Crohn’s disease in remission for at least six months compared the relapse rate of 115 patients who continued treatment with 42 patients who stopped treatment. The proportion remaining in remission at 12, 36, and 60 months was 0.89, 0.78, and 0.68, respectively. For the 42 patients who stopped treatment the proportion of patients still in remission at 12, 36, and 60 months was 0.62, 0.39, and 0.25, respectively.11 These data are remarkably similar to our data. The authors concluded that azathioprine was effective for at least four years but observed that the two year relapse rate after four years of treatment appeared to be similar whether treatment was continued or stopped. However, this observation was based on small numbers (only nine patients). O’Donoghue et al also reported a similar relapse rate of 41% one year after stopping treatment (proportion in remission 0.61).2 Data from our study using Cox proportional hazards modelling showed that there was no difference in relapse rates for patients treated for <2 years, 2–4 years, or >4 years duration.

Azathioprine is an established medication for the treatment of inflammatory bowel disease but there are many ways in which greater benefit can be obtained. Prescribing by a strict mg/kg schedule (at least 2 mg/kg) may increase the likelihood of giving a dose that will induce remission. The lack of dose-response seen in this study may be because treatment was given over a relatively narrow dose range and few patients were treated with recommended doses—up to 2.5 mg/kg. Patients with Crohn’s disease frequently required surgery before completing a six month course of treatment. Many patients were operated on for obstructive symptoms that are less likely to respond to medical treatment. This is a justification for starting treatment early before irreversible fibrosis necessitates an operation for obstruction.

Increasing the duration of treatment will keep patients in remission for longer. A survey of British gastroenterologists showed that there was a marked variation in duration of use of azathioprine. Forty six per cent of gastroenterologists were using azathioprine for less than two years and only 17% were continuing treatment for four years or longer. Consultants with more experience of azathioprine in ulcerative colitis used azathioprine at higher maintenance doses for longer periods, and in patients with less extensive disease.20 The main argument against longer durations of treatment is the long term risk of malignancy. Connell et al observed no increased risk of malignancy in 755 patients with inflammatory bowel disease followed for a median of nine years from the start of azathioprine treatment.21 These are reassuring data but further studies from similar large clinic populations are required.

In summary, this study has shown good efficacy for azathioprine treatment sustained over at least five years with minimal toxicity and no mortality from neutropenic related sepsis over a 30 year review period.

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11 Reasons It’s Hard Being Intelligent

By JUSTIN HOOK

1. You’re not actually intelligent. You think you’re really smart, but just wait. One day soon you’ll be driving down the road, then all of a sudden you’ll get the feeling you forgot something. You’ll check your pockets — wallet, phone — and it’ll occur to you: “I forgot my car keys!” Then you’ll turn around and drive home to find them because, really, you’re not that bright.

2. You’re depressed. Intelligent people are statistically much more likely to be depressed. It’s true what they say, ignorance is bliss. You, on the other hand, realize how terrible other people are, how terrible you yourself are, how royally screwed the world is, how quickly you’re dying, how little any of that matters. Yes, your life is interspersed with moments of joy, but you can’t reason yourself into retaining happiness. That’s like telling your brain to enjoy the cookie you ate yesterday while currently eating your way out of the world’s largest jar of Vegemite. It’s not logical.

3. You’re the IT guy. Why are smart people so good with computers? Because computers aren’t that hard. Alas, your uncle is never going to figure out how to update his firmware, so that’s on you for as long as computers are a thing.

4. Your intelligence is wasted. Growing up, people said you could do anything. You got into a great college, made the Dean’s List a semester or two, and finally managed to land a coveted job at the Acme Corporation. Now you answer phones and fill out spreadsheets. Sadly that A- in calculus does little to keep you warm at night.

5. Your intelligence is ignored. One night you and a group of friends are looking up at the sky when one of them points to a bright point of light. “Look,” he says, “It’s a satellite.” Looking up, you realize he’s pointing at Venus, and you say so. But then this girl (who thinks you’re arrogant for some reason) agrees it is definitely a satellite, adding, “Sorry, but you’re wrong.” The next day, you email them a link to a site that explains satellites in geosynchronous orbit are usually too far away to be seen by the naked eye. “He’s still on about that?” they whisper when you turn your back. “What a douche.”

6. Your ignorance is magnified. Soon after the Venus/satellite incident, you let it slip that you think Desmond Tutu is a jazz musician, and suddenly your knowledge (or lack thereof) is all anyone wants to talk about. And now you have a reputation for being both arrogant and ignorant.

7. You’re not smarter than a smart phone. It used to be enough for smart people to be right 80% of the time — who was going to take the time to look up your errors in a book?! But now that every person with a smart phone has instant access to every bit of human knowledge, not only do you have to be right 100% of the time, you have to be right with stunning accuracy. Unfortunately for you, Google has better sources than “something I’m pretty sure my ninth-grade teacher said one time.”

8. You can’t think about politics without your head exploding. If you’re a fan of intelligent debate, genuinely interested in discussing the best way to govern our country, the political process should be your American Idol. The only problem is: our elections aren’t decided by the intelligentsia — they’re decided by people who watch American Idol. So get ready for another remark full of rhetoric and lacking substance, prepare for another shouting match over an irrelevant topic, and enjoy living in a world in which Sarah Palin is a formidable contender for supreme political power.

9. You have to live a respectable life. Being smart will give you access to certain opportunities, like high-paying jobs with a level of prestige. But almost all of these opportunities carry the additional requirement that you be “respectable,” meaning they’ll disappear if you go out and get a neck tattoo, drop out of society to hitchhike through Mexico, or continually update your Facebook with posts aboutGossip Girl. Yes, the kid from Heavy Weights is all grown up and playing the elevator operator. Keep that revelation to yourself and go buy some slacks.

10. You should know better. If there’s one thing the “smart” characters on every TV show have in common, it’s that they’re the spoilsports. As the person in the glasses who is capable of looking at this situation from multiple angles, you are the one whose job it is to say, “Maybe this isn’t such a good idea,” and then ultimately lament, “I knew I should have stayed home today.” Your only hope is that the charismatic guy in the baseball cap will save you from this sticky situation — and maybe teach you a lesson about life along the way.

11. Your entertainment options are limited. Face it: you’re part of a very small demographic. Enjoy those Arrested Development DVDs.

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Skin Cancer’s Real Culprit: Lack of Sun Exposure

By Kate Kunkel

We all want to enjoy some fun in and sun this summer, but with skin cancer rates on the rise, many of us duck for cover when the intense beams shine down. ELLE.com recently posted an article about the increasing rates of melanoma, especially in American women ages 15 to 39 (the rates doubled over the past 30 years). But before you slather on that sunscreen, consider the real reason for this surge in the skin cancer rates: We might actually be lacking natural sun exposure.

David Fisher, M.D., Ph.D., chairman of the Department of Dermatology at Massachusetts General Hospital, explained that humans need sun and the vitamin D it manufactures in order to survive. We also need to find a “happy medium” when it comes to soaking up rays.

According to the article, “…studies have shown that continuous sun exposure actually protects against (melanoma)…Instead, melanoma is associated with intense, intermittent UV exposure, the type you get from hitting a tanning salon—or a Caribbean beach in December.”

The article also revealed the dangers of frequently sunbathing in unnatural rays (i.e., tanning beds) because “58 percent of adolescents who use them get burned,” according to research performed by the American Cancer Society.

Holistic health counselor Cynthia Perkins, M.Ed., wrote in an article by holistichelp.net that the cause of increased skin cancer rates over the past 30 years involves “the food we eat and the use of sunscreen.”

“After the development of sunscreen, cases of melanoma skyrocketed,” Perkins wrote, adding, “Office workers have higher levels of melanoma than construction workers and lifeguards. As a matter of fact, people who spend the most time in the sun, like lifeguards and construction workers, have the lowest incidence of melanoma.”

Osteopathic physician Dr. Joseph Mercola suggested in an article by sheknows.com, you should “stay clear of sunscreen” unless you are planning on staying in the sun for a period longer than what’s considered safe.

The article revealed, “Sun block also prohibits our skin from naturally absorbing the much-needed vitamin D we receive from the sun’s rays, which is imperative to our well-being.”

Mercola said the best way to safely absorb sunshine includes allowing yourself to “gradually build up to it,” or use some form of clothing and/or shade to protect yourself from intense exposure.

When you do need sunscreen and no other form of sun protection is available, Mercola advised using natural sunscreen that contains none of the following ingredients:

Para amino benzoic acid
Octyl salicyclate
Avobenzone
Oxybenzone
Cinoxate
Padimate O
Dioxybenzone
Phenylbenzimidazole
Homosalate
Sulisobenzone
Menthyl anthranilate
Trolamine salicyclate
Octocrylene
Dioxybenzone
Oxybenzone

Always use your head when it comes to exposing yourself to sunlight. Baking pale skin in the sun or in a tanning bed for long periods of time will still result in painful, unhealthy burns, but according to Mercola, gradual exposure to natural light has numerous benefits. Natural sunlight improves cardiovascular health, cholesterol levels, muscle strength, blood pressure levels, the immune system, kidney function, and dental and bone health.

Don’t waste the summer hiding out indoors. Start (safely) reaping the benefits of those vitamin D-packed rays by soaking up some natural sun.

Sources:

http://www.elle.com/Beauty/Health-Fitness/Record-Rates-of-Melanoma

http://www.holistichelp.net/blog/7-reasons-you-shouldnt-use-sunscreen/

http://www.sheknows.com/living/articles/804155/why-you-shouldnt-use-suns…

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Symptoms of Hypo and Hyperglycemia

Hypoglycemia (Low Blood Sugar)

CAUSES: Too little food, too much insulin or diabetes medicine, or extra exercise.
ONSET: Sudden, may progress to insulin shock.
BLOOD SUGAR: Below 70 mg/dL. Normal range: 70-115 mg/dL
WHAT CAN YOU DO? Drink a cup of orange juice or milk or eat several hard candies
Test Blood sugar
Within 30 minutes after symptoms go away, eat a snack e.g. sandwich, and a glass of milk
Contact doctor if symptoms don’t stop

Top Â

Hyperglycemia (High Blood Sugar)

CAUSES: Too much food, too little insulin, illness or stress.
ONSET: Gradual, may progress to diabetic coma.
BLOOD SUGAR: Above 200 mg/dL.
Normal range: 70-115 mg/dL
WHAT CAN YOU DO? Test blood sugar
If over 250mg/dL for several tests, CALL YOUR DOCTOR!

 

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Discovery may lead to powerful new therapy for asthma

GALVESTON, Texas — University of Texas Medical Branch at Galveston researchers have found that a single enzyme is apparently critical to most allergen-provoked asthma attacks — and that activity of the enzyme, known as aldose reductase, can be significantly reduced by compounds that have already undergone clinical trials as treatments for complications of diabetes.

The discovery, made in experiments conducted with mice and in human cell cultures, opens the way to human tests of a powerful new treatment for asthma, which today afflicts more than 20 million Americans. Such a development would provide a badly needed alternative to current asthma therapy, which primarily depends on hard-to-calibrate inhaled doses of corticosteroids and bronchodilators, which have a number of side effects.

“Oral administration of aldose reductase inhibitors works effectively in experimental animals,” said UTMB professor Satish Srivastava, senior author of a paper on the discovery appearing in the Aug. 6 issue of the journal PLoS One. “If these drugs work as well in humans as they do in animals you could administer them either orally or in a single puff from an inhaler and get long-lasting results.”

Srivastava and his colleagues (postdoctoral fellows Umesh Yadav and Leopoldo Aguilera-Aguirre, associate professor Kota Venkata Ramana, professor Istvan Boldogh and LSU Health Sciences Center assistant professor Hamid Boulares) focused on aldose reductase inhibition as a possible asthma therapy after establishing an essential role for the enzyme in other diseases also characterized by inflammation. In disorders such as colon cancer, atherosclerosis, sepsis and uveitis, the Srivastava team has found, cells are hit by a sudden overload of reactive oxygen species (varieties of oxygen and oxygen compounds that are especially eager to react with other molecules). The result is a chain of biochemical reactions that leads the cells’ genetic machinery to crank out a barrage of inflammatory signaling proteins. These summon immune system cells and generate even more reactive oxygen species, producing a vicious cycle of ever-increasing inflammation.

Aldose reductase plays an essential part in the activation of the cellular machinery that produces inflammatory proteins in these diseases, the Srivastava group discovered. “We found that if you block aldose reductase, you block the inflammation,” Srivastava said. “Now, asthma, a chronic disease of inflammation is augmented by reactive oxygen species. So we thought, why not find out if aldose reductase inhibition also has an effect on asthma?”

In an initial series of in vitro experiments, the researchers applied ragweed pollen extract (ragweed pollen is notorious for provoking the allergic reactions that lead to allergies and asthmatic airway inflammation) to cultures of human airway epithelial cells —the cells that line the network of air passages within the lungs. Some of the cultures had been pretreated with an aldose reductase inhibitor, while others had not.

The untreated cells responded in much the same way airway cells do in an asthma attack, with an increased rate of apoptosis (cell suicide), a jump in the levels of reactive oxygen species, the activation of key “transcription factors” that kick-start the production of inflammatory proteins and the large-scale generation of a whole host of molecules associated with inflammation. Cells treated with aldose reductase inhibitors, by contrast, had a much lower rate of apoptosis, reduced levels of reactive oxygen species, far smaller increases in critical transcription factors and substantially lower increases in inflammatory signaling molecules.

In collaboration with Boldogh, Srivastava next investigated whether aldose reductase inhibitors could reduce the asthma-like symptoms of mice exposed to ragweed extract, a well-established clinical model mimicking the allergic airway inflammation that commonly leads to asthma in humans. When untreated mice inhaled ragweed extract, their lungs suffered an influx of eosinophils (inflammation-inducing white blood cells), a jump in inflammatory signaling molecules, a buildup of mucin (a protein component of mucus) and an increase in airway hyper-reactivity (the tendency of air passages to suddenly constrict under stress). Mice fed a dose of aldose reductase inhibitor before inhaling ragweed extract, however, showed dramatically reduced levels of these components of the asthmatic response.

“Our hypothesis performed exactly as expected, with the experiments showing that aldose reductase is an essential enzyme in the transduction pathways that cause the transcription of the cytokines and chemokines known to act in asthma pathogenesis,” Srivastava said. “They attract eosinophils and cause inflammation and mucin production in the airway.”

The next step, Srivastava said, will be clinical trials to determine whether aldose reductase inhibitors can relieve asthma in humans. The researcher expressed optimism about their potential outcome of the trials, as well as gratitude to the UTMB National Institute of Environmental Health Sciences Center and the sole supporter of his asthma work, the American Asthma Foundation, which last year awarded him a three-year $750,000 research grant.

“Really, a lot of the credit for this belongs to the AAF,” Srivastava said. “Our primary interest is in cancer and the secondary complications of diabetes, but we were attracted to asthma pathogenesis because the AAF invited me to apply for a grant. I think they’re going to be happy with the results.”

Source: University of Texas Medical Branch at Galveston

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Arthritis Diet: The Do’s and Don’ts of Arthritis Food Nutrition

The Impact of Arthritis 

Millions of individuals around the world live with arthritis daily. An estimated 15% of people in the United States are affected by this disabling disease.  The economic burden of arthritis is immense.  The cost from medication expenses to missed days of work in America is several billion dollars yearly.  The two most prevalent forms of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA).  OA is the most common joint disorder and is a leading cause of disability and pain, especially among the elderly.  Over half of individuals over the age of 65 have radiographic (x-ray) evidence of OA. An estimated 80% of those in their eighth decade of life show signs of OA.  Fortunately, not every person develops symptoms.  While it is less common than OA, RA also affects millions of individuals worldwide, with an estimated prevalence from 0.3-1.5% of the population in North America.  RA can occur at any age, with a peak incidence between the fourth and sixth decades of life.  Although their causes and disease courses differ, both OA and RA can result in significant and disabling joint pain and damage with impaired activities of daily living, and substantial healthcare costs.

 

The Arthritis Diet – Treatment Beyond Medication?

Today there are many medications that are used in the treatment of arthritis. The main drug treatments for OA are primarily focused on pain relief and anti-inflammation.  Drug treatment in RA also focuses on pain relief and anti-inflammation, as well as medications known as DMARDs (disease modifying anti-rheumatic drugs), which aim to prevent further joint damage and progression of RA.  Although drug therapy has proven to be beneficial in arthritis treatment among a majority of patients, the medications are not without risks.  It is the undesirable side-effects and high associated costs of drug treatment that has motivated many patients to seek relief in what are commonly termed “alternative therapies.”  Within this realm of alternative therapy is something that is a fundamental part of our daily lives—nutrition.

 

Note to Readers

For the purposes of this article, nutrition can be defined as a substance that provides nourishment to the body.  This includes not only the food and beverages ingested daily, but also such things as cooking oils, vitamins, and other supplements.  Many studies have looked at various components of nutrition and the effects of these components on arthritis and other diseases.  Unfortunately, while there is no shortage of studies on nutrition and arthritis, there are several conflicting data regarding the relationship between nutrition and the development, progression, and symptoms of arthritis.  Controlled studies of diet and nutrient supplementation effects on OA and RA are inherently difficult due to variability in clinical course of disease and the wide variety of individual responses to nutrition.  The use of dietary questionnaires and varied adherence to assigned diets by study subjects also make an accurate and scientific study of nutrition very difficult.

While there may be evidence supporting the benefits of a certain diet or nutrient for arthritis treatment or prevention, this does not imply a direct causal relationship.  For example, a study that shows a significant association between Vitamin D intake and a decreased incidence of RA does not imply that taking more vitamin D will prevent RA in everyone.  Rather, it offers evidence that a relationship exists between increased vitamin D intake and decreased chances of developing RA.

The importance of medications in the treatment of arthritis should not be forgotten.  Despite the cost and potential side-effects of traditional drug therapy for arthritis, millions of dollars are spent and numerous clinical trials are completed to ensure the efficacy of these medications.  Sufficient evidence must be shown that medications are effective in the treatment of arthritis before these drugs are made available to patients.  Unlike their alternative therapy counterparts, arthritis medications are followed closely to ensure their integrity and recognize significant side-effects associated with them.  Herbal and over-the-counter remedies are currently exempt from legislation governing conventional medications.  With this in mind, one should consider nutritional and supplemental treatments of arthritis as potential enhancements to traditional, proven medical therapy.  Although nutritional adjuncts are often used for arthritis treatment, patients may be hesitant to report these uses to their doctors.  Before beginning any change in arthritis treatment, including nutritional and dietary approaches, patients should be sure to speak with their physicians and discuss the potential benefits and side-effects of their new treatments.

The remainder of this article will focus on the two most common forms of arthritis, RA and OA, and provide some information on the role of nutrition in their development, progression, and potential alleviation.

 

Nutrition and Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a systemic inflammatory disease that typically occurs in the synovial membrane of joints, including the cervical spine, fingers, wrists, elbows, feet, and others.  The chronic inflammatory process of RA can eventually lead to severe joint dysfunction and deformity.  Although the exact mechanisms are unknown, the role of the immune system is considered paramount in this autoimmune disease.  Specific components of the body’s natural immune system, such as T-cells and cytokines, have been implicated as the major players in RA and its progression.  Within this paradigm, studies have generally tried to explain both the benefits and ill effects of nutritional components on their ability to modulate inflammation and inflammatory substances in the body.  There is a genetic component to the development and progression of RA.  However, many believe that environmental triggers, such as nutrition, can also play a role in RA, especially in those who are already genetically susceptible.   Despite variation among study outcomes, several nutritional components have come to the forefront as candidates in the prevention and treatment of RA.  A study involving 238 RA patients in England found that 44% of these individuals had used some sort of herbal or over-the-counter remedy in a 6 month period.  Following are some of the more widely studied nutritive components and evidence supporting or disputing their use in the treatment of arthritis.

 

Omega-3 Fatty Acids and Fish Oil

Omega-3 fatty acids, also called n-3 PUFAs (polyunsaturated fatty acids), are a naturally occurring component of certain foods and oils.  Omega-6 fatty acids are another type of PUFA.  Omega-3 and Omega-6 fatty acids are distinct and have opposing physiologic functions. Metabolism of omega-6 PUFA produces arachidonic acid (AA), which leads to certain pro-inflammatory cellular products. In contrast, metabolism of omega-3 PUFA, produces docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), which have anti-inflammatory effects that balance that of omega-6 fatty acids.  Major omega-6 and omega-3 PUFAs are linoleic and alpha-linolenic acid, respectively.  The body cannot produce these substances making them essential to the diet.  It is thought that the increased consumption of omega-6 PUFA-rich vegetable oils, such as sunflower oils and spreads in today’s Western diets, has dramatically increased the ratio of omega-6 to omega-3, shifting the balance of cellular products to a more pro-inflammatory state.

Sources of omega-3 fatty acids include: Flax seeds, seafood and fish such as chinook salmon, halibut, shrimp, and scallops, walnuts, cooked soybeans, raw tofu, winter squash, green leafy vegetables, as well as flaxseed oil and soya bean oil.  Dietary sources rich in omega-3 PUFA can increase omega-3 fatty acid tissue concentrations, but these concentrations are hard to obtain in a regular diet.  For this reason, and due to concern over mercury and other toxins in fresh fish, fish oil has recently become a popular supplement.  Fish oil contains a high content of omega-3 fatty acids and are most often available in coated gel capsules.  Dosages vary, and most recommended dosages can be quite high, in excess of 3-4 grams.  People with diabetes, bleeding disorders and patients on blood-thinners should take caution when taking large doses of fish oil.  Always discuss the potential risks and side effects before starting any new supplement with your doctor.  In addition to health benefits in heart disease and several other conditions, beneficial effects of dietary supplementation of fish oil on RA has been observed in at least 13 double-blind, placebo controlled studies since 1985.  A common feature of the studies has been a reduction in symptoms and in number of tender joints.  Decreased morning stiffness and decreased dose of analgesic medications were also noted.  One study reported a significant reduction in NSAID (non-steroidal anti-inflammatory drug) usage in patients receiving a fish oil supplement compared with those taking a placebo.

 

Olive Oil

Olive oil contains large amounts of an omega-9 MUFA (monounsaturated fatty acid) called oleic acid.  Metabolism of oleic acid produces eicosatrienoic acid (ETA).  Similar to omega-3 products, ETA competes with omega-6 PUFAs, tipping the scales to a less inflammatory state.  Some have hypothesized that the prevalence of olive oil in Mediterranean diets is one reason for the reduced incidence of arthritis in Mediterranean populations.  In a Greek population, consumers of high amounts of olive oil (almost daily throughout life) were four times less likely to develop RA than those subjects who consumed the oil less than six times per month.  Although olive oil studies are not as common as fish oil studies, there is some evidence for the potential benefit of olive oil in arthritis.  One study found that RA patients who consumed olive oil capsules (6g/day) had significant reduction in pain and joint symptoms at 6 months and some patients were able to reduce their dose of NSAIDs by 400 mg of ibuprofen/day.  Another study found a significant trend between increased olive oil consumption and decreased risk of RA development.  Although the strength of these studies is not ideal, they do present a small amount of evidence that olive oil can be beneficial in countering the inflammation of RA. With a virtually absent side-effect panel and a delicious food influence, it is certainly not unreasonable for arthritis patients to explore the option of incorporating olive oil into their diet.

 

Red Meat

Some studies have looked at possible correlations between the consumption of red meat and the incidence of RA.  Four controlled studies have looked at vegetarian diets and pooled results have implied that eliminating meat from the diet may be useful in the treatment of RA.  These studies are difficult to interpret since the effect may be a result of excluding meat, or things such as increased fruit and vegetable intake (and subsequent vitamin C intake).  One ecologic study including 16 countries demonstrated a positive correlation between the national prevalence of RA and the per capita consumption of red meat.  Interestingly, another recent study from 2004 showed a higher level of total protein intake increased the risk of inflammatory arthritis by almost three-fold.  The study concluded that high levels of red meat consumption is an independent risk factor for development of inflammatory arthritis, although they were unsure if this association was causative.

One concept that may explain this apparent association is that red meat provides a dietary source of arachidonic acid (AA), the aforementioned cellular product that is involved with production of pro-inflammatory molecules.  In addition to AA, red meat is also a large source of iron.  In animal studies, iron has been shown to accumulate in rheumatoid synovial membranes, causing tissue damage.  There is also evidence of iron-catalyzed oxidative reactions, shown to be causative in worsening synovial inflammation following iron infusions. Ironically, iron-deficiency anemia is not uncommon among RA patients.  Although not proven, it has been hypothesized that some of these anemia cases could be caused by uptake of iron by inflamed synovial tissue.

As individual needs and responses to diet may vary, arthritis patients should discuss any diet changes or reduction in dietary meat intake with their doctor and/or nutritionist prior to implementing any diet changes.

 

Coffee and Green Tea

Coffee and green tea, two of the most popular beverages in the world, have been tested in only a few arthritis studies, and they have produced conflicting inconclusive results.  One study reported that greater than 3 cups of coffee per day, especially decaffeinated coffee, is a risk factor for RA development.  Another recent study found no significant association between decaffeinated coffee consumption greater than 4 cups per day and risk of incident RA.  This same study found no relationship between caffeinated coffee consumption over 4 cups per day, or regular tea consumption, and risk for RA.  The Nurses’ Health Study is a very large, ongoing study of thousands of women.  As of 2002, this study had found no significant association between drinking coffee or tea and the risk of RA.  There are no human studies or evidence that green tea is effective for RA or other forms of arthritis.  The anti-oxidant polyphenol compounds found in green tea are thought to reduce inflammation.  As with many things, it appears that consumption in moderation may be the guideline for coffee and tea.  However, one may wish to remove coffee from their diet for a period of time to see if its removal may prove beneficial for arthritis symptoms.

 

Vitamin C

Vitamin C is well-known for its purported benefits with such things as the common cold and for its role as an anti-oxidant.  Studies of vitamin C for the treatment of arthritis have produced mixed results.  One animal study showed a decrease of inflammatory cell infiltration into synovial fluid (the fluid that is present between certain joints in the body) with the supplementation of vitamin C.  One human study from 1999 failed to show any beneficial effect of vitamin C on the synovial inflammatory process.  A population-based study of UK residents looked at dietary intake and found that over time, patients who developed inflammatory arthritis consumed less vitamin C than matched controls.  A Framingham study found that a high intake of vitamin C was associated with a three-fold decrease in risk of OA pain and progression.  There are many who advocate taking very large doses of vitamin C for many different things.  Although vitamin C toxicity is rare, it is possible with extremely large doses.  No acute dose causing toxicity has been identified, but a chronic dose of 2 grams/day has been quoted.  Signs may include renal colic (ie, nephrolithiasis), diarrhea, nausea, and occult blood in the stool.  Dietary sources of vitamin C include citrus fruits, green peppers, strawberries, tomatoes, broccoli, sweet and white potatoes.

 

Vitamin D

The role of vitamin D in prevention of bone loss and building bone mass is well known.  There are some studies that have looked at vitamin D intake and its correlation with RA.  The Iowa Women’s Health Study looked at over 29,000 women and found that a greater intake of vitamin D may be associated with a lower risk of RA in older women.  These results were not definitive by any means, but an interesting finding for further studies to build on.  There are also animal studies supporting potential vitamin D benefit in RA.  Arthritis patients taking steroids may be at risk for steroid-induced osteoporosis.  Steroids can impair intestinal absorption of calcium. It is recommended that patients should at least meet recommended vitamin D as well as calcium dietary intake guidelines.  Sources of vitamin D include cheeses, fortified milk and fortified cereals.

As with other vitamins and supplements, overdose is possible with very large supplementation.

Acute toxicity effects may include muscle weakness, apathy, headache, anorexia, nausea, vomiting, and bone pain. Chronic toxicity effects include the above symptoms and constipation, anorexia, polydipsia, polyuria, backache, hyperlipidemia, and hypercalcemia. Findings may also include calcinosis, followed by hypertension and cardiac arrhythmias.  Acute toxic dose is not established, and chronic toxic dose is more than 50,000 IU/d in adults. In children, 400 IU/d is potentially toxic. A wide variance in potential toxicity exists. The recommended daily allowance is 400 IU for persons older than 1 year.  Individual supplements are generally around 400 IU per tablet.

Vitamin E

Vitamin E (alpha-tocopherol) is most frequently recognized for its anti-oxidant properties.  Vitamin E deficiency and low tissue vitamin E has been reported to enhance inflammatory components of immune response.  The ability of vitamin E to alleviate both OA and RA symptoms has been evaluated in studies, most of them of short duration.  One study found that vitamin E worked better than NSAIDs for OA symptoms.  Another molecular study demonstrated enhanced anti-inflammatory effects of aspirin with vitamin E supplementation, suggesting a reduction in the dosage of aspirin needed for RA symptoms.  Other studies have produced conflicting results.  Arthritis patients may find benefit with vitamin E supplementation.  Recommended daily allowance is from 15-30 mg.  Although it is very rare, toxicity can occur at very high doses.  The potentially toxic dose is more than 3000 IU/d for 7-9 weeks. Supplements usually are 100-1000 IU per capsule. People with heart problems, or at risk for heart problems, should use Vitamin E with caution and only after a careful conversation with their doctor.  While some studies have suggested improved cardiovascular health with Vitamin E supplementation, at least one study has shown that in people with a history of coronary artery disease, Vitamin E may negatively influence outcomes.  Different medications may affect the relationship between Vitamin E and outcome.  Again, as with starting any supplement, discuss the potential pros and cons with your doctor.  Signs of toxicity from Vitamin E may include bleeding, especially in people taking blood-thinners.  Dietary sources for vitamin E include whole grains, nuts, wheat germ, green leafy vegetables, and some oils.

 

Selenium

It is hypothesized that selenium levels drop in response to inflammation and that selenium supplementation may have anti-inflammatory effects.  Studies of selenium supplementation in RA patients have produced conflicting results.  One of the largest studies reported a significant decrease in RA symptoms, reduced reliance on cortisone and NSAIDs, and a significant decrease in biochemical inflammation markers in a group receiving selenium.  However, both placebo and study groups were receiving fish oil as well.  Although levels of selenium are low in RA patients, it should be noted that the human body requires only very small amounts of selenium.  Side-effects of selenium supplementation may include nausea, vomiting, nail changes, and fatigue.  Good dietary sources of selenium include crab, liver, fish, poultry, and wheat.  More studies on selenium supplementation in arthritis patients are needed to accurately evaluate any benefits it may have.

 

GLA (gamma-linolenic acid)

GLA is also known as evening primrose oil or black currant oil.  Several studies have shown that GLA can ease RA pain and inflammation in humans.  GLA is an omega-6 fatty acid that, unlike the other aforementioned omega-6 fatty acids, can possibly have an anti-inflammatory effect.  GLA is available in capsules as well as oil, with a usual dosage of approximately 1800 mg per day.  It is possible that GLA can enhance the effects of blood-thinners, leading to bleeding, as well as cause nausea, diarrhea, and abdominal pain.  There are also potential drug interactions that can occur with GLA supplementation and one should always speak with a physician prior to beginning GLA supplementation.

 

Folate and B12

Folate and B12 may be of particular importance to those RA patients taking methotrexate, a very common DMARD used in the treatment of RA.  A Cochrane review of seven trials described a positive effect of folic and folinic acid supplementation in reducing gastrointestinal side-effects of low-dose methotrexate in RA patients.  A 79% reduction in mucosal and gastrointestinal side-effects were observed with folic acid supplementation alone, with no apparent differences between low and high dose folic acid.  Patients taking methotrexate for their RA may want to discuss folic acid supplementation with their physicians.

 

Cigarettes

Although it is not considered a nutrient, cigarette smoke is, unfortunately, a daily intake for many individuals.  Cigarette smoking has consistently been found to be a risk factor for the development of RA and other inflammatory arthritis conditions.  This risk factor is within every person’s control, and smoking cessation should be considered a top priority for arthritis patients.  Following are a few links that provide assistance with smoking cessation:

http://www.cdc.gov/tobacco/how2quit.htm

http://www.anti-smoking.org 

  

Nutrition and Osteoarthritis

Osteoarthritis (OA), also known as degenerative joint disease, results primarily from the normal wear-and-tear of daily joint use.  Over time the cartilage between bones begins to erode, leaving narrowed joint spaces, abnormal bone remodeling, often associated with pain.  Unlike the systemic nature of RA, OA tends to be more focused, with a predilection for weight-bearing joints such as knees and hips.

Although OA is not considered an inflammatory disease, there is evidence for pro-inflammatory cells of the body playing a role in its development and progression.  For this reason, it would appear that some of the nutritional supplements mentioned above for RA treatment could theoretically be beneficial in the treatment of OA as well.  Although the vast majority of studies focusing on nutrition and arthritis are focused towards RA, it is not unreasonable for OA patients to discuss supplements and dietary factors with their physician.

One large study found that OA progressed three times faster in people who consumed low amounts of vitamin D.  Others have shown that vitamin D intake decreased incidence and progression of hip OA.

There are two supplements that have been studied extensively for treatment of OA.  Glucosamine is a supplement derived from the chitin shells of crab, lobster, and shrimp.  Chondroitin sulfate is derived from cattle trachea.  Both of these supplements have shown promise as alternative treatments of OA.  Studies have provided evidence that both supplements can help with the pain and stiffness of OA, and possibly prevent further cartilage damage.  Glucosamine and chondroitin sulfate are often sold as a combination in a single capsule.  Many different brands exist, but one should be aware that the quality of individual brands may vary significantly.  Although side effects are rare, it is possible that people with shellfish allergies could have a reaction to glucosamine.  The recommended dose of chondroitin sulfate is 1200 mg per day, divided into two doses, while the usual glucosamine dosage is 1500-2000 mg per day taken in two doses.

 

The Impact of Weight on Osteoarthritis

A major risk factor for OA is excess body mass.  Population-based studies have shown that overweight people carry a greater risk of knee OA than people of average weight. Extra weight increases risk for getting OA in knees and possibly hips, especially in women.  In men, extra weight can also increase risk for gout.  Long-term studies also suggest that obese individuals with knee OA are at greater risk for disease progression and weight loss may decrease the symptoms of knee OA.  Research in 2004 demonstrated that exercise and diet together significantly improve physical function and reduce knee pain in people older than 60 who are overweight or obese, according to both the Arthritis Foundation and the American College of Rheumatology.

Maintaining normal weight is a crucial component in the prevention of OA, as well as in managing the symptoms and progression of OA.  Faced with the obesity epidemic in the United States today, people are increasingly at risk for development of OA.  OA and obesity can interplay in a potentially vicious cycle.  Weight loss and exercise are clearly beneficial, but as OA symptoms progress it can become difficult to tolerate exercises.  For this reason, exercises that decrease weight bearing such as biking, running on an elliptical machine, and swimming are often recommended.

Obese individuals often show an increase in inflammatory molecules in their system, and weight loss is usually associated with decreased concentrations of these inflammatory substances in the circulation.  One study looked at the effect of weight loss on production of inflammatory molecules from adipose (fat) tissue.  Results showed that weight loss resulted in decreased expression of inflammatory markers in the fat tissue of subjects, as well as an increase expression of anti-inflammatory molecules.  Another study looked at the knee joints of 142 obese and overweight OA patients, and the effect of an 18-month diet and exercise trial on the forces placed on these joints.  The results showed a significant association between weight loss and the forces applied to knee joints.  They concluded that each pound of weight lost resulted in a 4-fold reduction in knee loads.  An additional study showed that weight loss of 11.2 pounds over a 10-year period decreased the likelihood of developing knee OA by over 50%.

Clearly, in terms of nutrition, weight loss through a healthy lifestyle and diet lies at the heart of the matter for OA prevention and treatment.  Diet should be tailored to each individual, especially those with pre-existing medical conditions such as diabetes or food intolerances.  The help of a registered dietician is never a bad idea.  These individuals can be helpful in setting up diet programs and answering questions about nutrition and supplementation.  They can also provide different menus and recipes to promote healthy variety in daily meals.  Occupational and physical therapists are also a valuable addition to diet and exercise.

 

Authors:

 

Jamison J. Engle, BA, University of Iowa Medical School, Iowa City, IA

Joseph E. Herrera, DO, Mount Sinai Hospital, New York City, NY

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