The Tome brings you a review of the Heirs of Ash trilogy of Eberron novels. Will and Geoffrey D. Winn are our reviewers for this episode. And the episode is sponsored by Sinister Adventures.
If your interested in the books check them out here or the Tome's Amazon Store.
And feel free to visit the website, email the show, and of course swing by the forums.
The Tome continues to be a proud member of the Fist Full of Comics and Games Cooperative as well as Goblin, the Gaming Broadcast Network.
The Tome brings you an interview with Ed Healy and Rone Barton (Werecabbages), editors and project manager of Blight Elves and the Blighted Beastiary. Two books about the horrid elven beings in the True20 setting from Reality Deviant Publications called the Blood Throne.
You can find these books at Drive Thru RPG (from One Book Shelf), Paizo, Your Games Now, RPG Objects.
Also mentioned and promo'd in this episode is once again Wapcaplets.


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Cynthia Prouder was born on June 13, 1963 in Columbus, Mississippi and came to Los Angeles, California when she was 6 years old with her single mother and older brother, Alvin. She was raised in Culver City where her mother put she and her brother into a karate class to keep them away from drugs and the gangs. Alvin became an international karate and kickboxing champion, and a boxing champion and Cynthia followed in his footsteps competing in karate and kickboxing and then, in 1997, she began training seriously as a boxer, becoming a Super-Featherweight boxer. Her boxing lead to her becoming a stuntwoman and actress. Cynthia Prouder is known for her work on Million Dollar Baby (2004), Man on the Moon(1999) and Under Lock and Key (1995).
Cynthia Prouder got into the entertainment industry after a call came into the gym where she and other female boxers were working out. Nike needed extras for a commercial, and Cynthia Prouder decided to get on board. As a featherweight fighter with a 5-9-1, record, she trained full time so she could reach her goal of becoming a champion.
Nike already had a professional actress hired to play the boxer, but after Prouder let loose on the bag, the casting directors changed their minds and gave Cynthia Prouder the job as the boxer. After the Nike commercial began running on national television, Cynthia Prouder quit her job as a Frito-Lay sales representative and she went back to full time training as a boxer.
Alvin lived and healed and came back, but not on the same level so he and his sister opened a martial arts and boxing studio at Crenshaw Boulevard and Slauson Avenue, where he taught karate, boxing and kickboxing and she taught karate, boxing, kickboxing and aerobics. Eventually their school moved to La Brea Ave in Inglewood, California.
Even after her brother was hurt, Cynthia kept motivated working with former boxer and kickboxer from Detroit, Eric Brown, who trained, managed and inspired Cynthia.


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Lists values that specify the format applied to cells by the GridViewFormatConditionHighlightBuilder condition.
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Lists values that specify filter row behavior.
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Lists values that specify the position of the new item row within the GridView.
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Specifies the help text horizontal alignment.
Lists values that specify the image position within an element.
Lists values specifying the content loading mode.
Lists values that specify the position of the summary text within a pager.
Specifies the position of the page size item within a pager.
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8) Any supplementary or special requirements.


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text:
Who pays the Ferryman?
Written by Ellan Vannin
When I taught adults in a mature learning setting, I suggested that our own view of a situation was what influences our perception of the same facts and the same scenario.
I cited the tale of the flooded river. The bridge was washed away and a young woman was left on one side of the river, her fiance on the other. She desperately wished to get across the river to her beloved, but the only way was by ferry and there was only one ferry.
She approached the owner of the ferry and explained her situation. He said that he would ferry her across, on the condition that she slept with him.
Horrified, she left and sought the aid of her fiance's best friend who shook his head and replied, "I don?t want to get involved. It is not my problem.? "
After some time passed, she returned to the ferryman and accepted his offer. He ferried her across the river and she ran into the embrace of her beloved.
She burst into tears and confessed the price that she had paid the ferryman.
He was horrified and declared that she was no longer part of his life and he did not wish to ever see her again.
In order, from the worst to the least bad, how would you place the key players?
There is no right or wrong answer; but this simple story tells us a lot about ourselves, OUR own perceptions and OUR own place in the world where decisions are often made because of emotional involvement with the scenario.
Over the years that I posed this question, the order of players varied ? not according to age, gender, socioeconomic or religious backgrounds ? but with deeply held personal views.
This is the dilemma that faces us today across all spectrums.
You see, all we have in this story are facts.
BUT NOT ALL THE FACTS.
My story above leaves out so many details.
Did the girl have a past history of sleeping with the ferryman?
Had she run to her fiance's friend before alleging rape or sexual harassment? Had she cried wolf once too often?
Was the ferryman her old boyfriend and had she dumped him in favour of her new fiance? Or did he have a history of this sort of behavior?
On face value, it was an emotional story and one that would be answered EMOTIONALLY.
What we do not expect, however, is for our leaders to make a decision based on emotion. That is not what he or she was " hired " to do.
Many leaders make hasty decisions based on militant tweeters rather than common sense rationale.
Military leaders make decisions based on the best outcome and the best strategy. Our community leaders offer the view which they feel best represents the majority of their constituents and the advice received from the military and faith leaders, from our police, our emergency services and our intelligence community. All of those groups give their input, based on the best information that they have. It is then up to our politicians to engage with our Leaders, and our leaders then make the call.
It is either a massive cover up or a massive balls up.
It all happened too fast.
New Zealand saw the Waiho River Bridge destroyed and the people of the West Coast left on one side of the river, the rest of us on the other.
The gun laws were changed faster than a baby's nappy. The internet was censored quicker than a wet rat up a drain pipe.
Did Jacinda Ardern make decisions based on personal perceptions or based on facts? Or, worse still, based on what someone else was whispering in her ear?
Is Scott Morrison making decisions based on facts or tweets?
We may never know, because, increasingly, we are being sold emotion instead of facts.
As my teacher of many years ago said, ?A reporter?s job is to report, not distort. Otherwise, we would call them Distorters.?
As the saying goes,
Act in haste, repent at leisure"
Yes, fine for our Politicians but who will pay the price? Who will pay the Ferryman?
The voters, the People, people like us.

redpajama_set_name: RedPajamaCommonCrawl


text:
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MS and Age
Everyday Health Neurology Multiple Sclerosis
No More Needles? An Update on Pills to Treat MS
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Jason's Story: Documenting Life With MS
Sign Up for Our Living with Multiple Sclerosis Newsletter
Are you ready to toss out your injection needles and take a pill instead to treat your MS?
Join us as leading experts discuss the possible oral disease-modifying drugs for MS. You'll learn about treatments currently in development that may someday replace injectable drugs or be used in conjunction with them. And you'll find out how effective these pills may be, what their side effects are and when they're expected to hit the market. Plus, our guests explain how some of the new drugs are related to chemotherapy and whether you can expect to experience chemotherapy-like side effects.
Now here's your host, Trevis Gleason.
Trevis L. Gleason:
Hello and welcome to another HealthTalk multiple sclerosis webcast, No More Needles? An Update on the Pills to Treat MS. I'm your host, Trevis Gleason.
There are some 400,000 of us living with multiple sclerosis in the United States. Over 300,000 of us are on some form of a disease-modifying drug therapy. We either stick ourselves with needles or have a loved one do it, often lovingly referring to them as the shot giver, once a week, every other day, or every day depending on our regimen. Or some of us are on the infusable drugs. This means that we trot ourselves off to an infusion center on a regular schedule, go through complicated tracking procedures and spend half a day getting our dose of that particular drug. I don't know about you, but I'm tired of the needles. If there are 300,000 of us using MS drugs, I would venture to say that at least half of us are ready to toss the syringe and get in line for an MS pill as soon as one has been proven safe and effective. Knowing this, the drug manufacturers are sprinting towards an oral therapy with all of their might.
Joining us on the phone to talk about this is Dr. Patricia O'Looney, Ph.D., the vice president of biomedical research for the National MS Society. Dr. O'Looney, welcome back to HealthTalk.
Dr. Patricia O'Looney:
Oh, good evening, Trevis. Nice being here.
Trevis:
It's nice to have you here. And also joining us is Dr. Rhonda Voskuhl. Dr. Voskuhl is a neurologist and the director of the multiple sclerosis research and treatment program at the UCLA Medical Center in Los Angeles, California. Dr. Voskuhl is widely recognized as an expert in the study of immunology of MS. Dr. Voskuhl, welcome to HealthTalk.
Dr. Rhonda Voskuhl:
Thank you. Glad to be here.
Well, let's jump right into this with a question for Dr. O'Looney. What type of MS drugs right now are being studied for oral administration?
Dr. O'Looney:
Probably as your listeners know, we do know multiple sclerosis is an immune-mediated disease, and so I think it's no surprise that many of the drugs that are under experimental investigation right now are directed towards the immune response, that is trying to control inflammation. We do know now in the past several years that to the extent we can control inflammation we can perhaps control the progression of the disease. So our goal here is to control the immune system. The good news for your listeners is that there are many oral drugs now under investigation for treatment with MS, and at least to my knowledge, there are about five of them that are in their stage III trial, that is their last stage before submitting data to the FDA.
I heard you say something at the very beginning of that answer about an immune-mitigated disease or something like that?
Immune-mediated disease, in which the immune system is up-regulated. It's gone awry. For some reason in multiple sclerosis the immune system has been up-regulated, has been turned on, causing inflammation. And so the belief is that if we can control that immune system, we can control progression of the disease.
And how is this term that you are using different than autoimmune?
Everything is as we believe it to be. We believe MS to be an autoimmune disease itself, but it really hasn't been proven. An autoimmune disease is when the immune system attacks part of one's own body, in this case myelin or oligodendrocytes, which are the cells that make myelin. But there is a school of thought that believes that maybe MS is not autoimmune but just an immunological disease in which the immune system is up-regulated and it then just begins to destroy certain components, but many people believe that MS is also an autoimmune disease.
I appreciate that clarification.
On behalf of our listeners, let's get this first question on the table right away: All things going well, no snags in the process from here until the end of the process, how long before the first of the oral disease-modifying drugs for MS are submitted to the FDA, that's the Food and Drug Administration, for approval? And then, well, how long?
It's always a difficult question to answer when you start talking about how long something will take because you don't want to build false expectations of the individuals with the disease and your listeners. The path that a drug travels from the lab to your medicine cabinet is usually very long, and every drug takes a unique route. The oral medications are in that last stage, the large clinical trials. Most of them have just begun their clinical studies in the past year, and most of them are two years in duration. So to be realistic and to be conservative, I would probably estimate probably another three years before the data is submitted to the FDA, and then the FDA has another 10 months to 12 months to review that data.
And once the data is reviewed, and they take that 10 months or so, from the starting gun at that point when the FDA approves, how long before the therapy is ready for prescriptions?
That can vary as well. If the drug is already on the market and being used for other diseases, then the drug is available and could be available for people with MS very quickly. If it's a drug that's being manufactured particularly for this treatment for people with MS, then often pharmaceutical companies will not make enough - and why would they unless they make sure that it's being approved for MS? So they just make enough drugs to complete the clinical trials. So in other words, once it's approved then you have to go to a manufacturing stage, and also the FDA also has to inspect the facilities of the company, so that may vary as well. So it could be up to another year [although it is usually only a matter of one or two months].
But if the drug is available for another purpose, it may be already on the market. It just has to be repositioned for MS.
And why has it taken so long to create an orally active disease-modifying drug for MS? And the current MS therapies - why must they be infused or injected?
First of all I would like to say that it's not that we haven't tried. So over the past ten years there have been a couple of oral drugs, oral therapies, that have been tested to help people with MS. Oral Copaxone, for example - most of your listeners may know Copaxone (glatiramer acetate) as an injectable drug now - but in the late 90s, I believe it was, it was tested by the company to see if it could be helpful in an oral fashion, and it was found not to be. It wasn't successful as an oral medication. And there have been other attempts as well. So, first, I didn't want your listeners to think that this is our first attempt. There have been attempts but failures.
So why are the current therapies primarily injectable or infused? It kind of goes back to how drugs are created or developed in the pharmaceutical world. A lot of these drugs are large molecules. For example, Tysabri (natalizumab) is a large molecule, and they can't necessarily be given orally, so they are often being given by injections and infusions. And also oral drugs sometimes take longer to work, and so therefore given by injection or infusion, you get a much quicker response.
We, the National MS Society, are actually supporting a trial to see just simply, can you give oral steroids as effectively as the IV methylprednisolone everyone gets in the hospital? So we don't even have a clear-cut answer with regards to that as well.
And, Dr. Voskuhl, we will get to you, but I have got a couple of more questions for Dr. O'Looney here. I think it's important that we make a clarification: There are a number of our listeners who are aware of or use LDN, low-dose naltrexone (Vivitrol, Revia), for their MS, and this is an oral med, but it's been approved by the FDA, but not for MS if I understand that correctly. Do you know how widely it is being used and what the results are that are being seen? And is that being submitted to the FDA for MS approval?
Low-dose naltrexone has been approved by the FDA for drug and alcohol addiction. It has not been approved for multiple sclerosis. I am sure many of your listeners probably know it recently got its interest probably about 20 years ago now when LDN, low-dose naltrexone, was given to help HIV patients or AIDS patients. And it's been interesting to look at in terms of multiple sclerosis, particularly in terms of pain, cognitive function, mental health, and improving alertness of their mental abilities and also fatigue, perhaps, and bladder control. So you also have to keep in mind that naltrexone also up-regulates the immune system, so here's the reason why of course one does have to do clinical studies, because you have to be careful not to give a drug or medication to someone whose immune system, as I mentioned earlier, is already up-regulated, so the last thing you want to do is to increase it even more.
So there is a need to do clinical studies, and there are a couple of investigators. There is one at the University of California San Francisco, and also a group in Italy who recently reported just last month at the American Academy of Neurology meeting two separate studies looking at the use of LDN in multiple sclerosis. It was a small study, very interesting results primarily looking at the improvement of cognitive function or mental alertness in people with MS. So we are not quite there yet in terms of submitting any data to the FDA, that's for sure, but I would certainly encourage any physician who might be listening by chance or any patient who wants to talk to their doctor to do more studies on LDN. We really need the investigators to take the initiative in order to get the answers.
I actually tried to get on a couple of the clinical trials for the oral MS drugs, but the entry criteria was really strict for these trials, and the required testing can be quite extensive. One of the trials I remember required like constant observation for a few hours after each dose of the drug and a battery of tests that made initial diagnosis tests for MS seem like a routine check-up. Why are the pharmaceutical companies being so rigorous as they undertake these studies?
Well, primarily for the patient's safety, Trevis, and obviously when we do clinical trials, it's to test an unknown. It's to test of use of a drug for people with MS. And even though the drug may be used for other diseases, we don't know how it will be in multiple sclerosis, so it's really to protect the patient, protect the human in a clinical trial.
It's also important that when we do a clinical study and we test a new drug, that you get interpretable results. So for example if you are going to do a study with 1,000 patients over two years, you want to make sure that you do it right, that you are not wasting anyone's time, you are surely not wasting money, but particularly that you are not wasting the time of the people who are in the studies - the true volunteers in research are the people who give their time to be a part of a clinical study. So all of those rigorous details and follow-ups and following the patients is really just to make sure that everyone is safe. There is a safety factor in the trial, but also that we have something at the end of the trial that's interpretable.
Now to Dr. Voskuhl. Can you explain to us please the difference between the phases of these clinical drug tests, Phase I through Phase III of the studies? What do they involve? How long do each one of these take? Dr. O'Looney spoke to them a little bit, but you can maybe get inside those a little bit more for us, Doctor.
Dr. Voskuhl:
Sure. Phase I is generally a small study that's given to less than 100 patients, often in the range of 30 to 60 patients, so it will be relatively few. Because this will be a Phase I meaning that it's really being given for the first time in MS patients. Again, it could have been given in other diseases, but this is the first time in MS. These are the patients that have to be watched most closely, and not only will it be given to a small number of patients, it will be given for a very short period of time. So in these studies, they will often use what I will call biomarkers for disease. So the end point won't be relapse rate or it won't be a disability in MS. It will be something like MRI changes or maybe changes in the immune response in the blood. So they will look for biomarkers of disease activity. Because fortunately MS is a very slow disease, which we are all thankful for, and you wouldn't get an impact on these disease-related clinical outcomes if you were to treat for such a short term.
So the bottom line is Phase I is going to be something that is generally about 60 to 30 patients, and it will be treatment for a very short time, on the order of anywhere from four to 12 months, and generally will be able to be done at one site, maybe two sites.
Now, when we go to Phase II, that's going to be done because of the results of the Phase I. The Phase I had to have shown something in these small numbers of patients that looked very promising with respect to these biomarkers. So for example, the MRI got better or the immune system changed in a favorable way, and based on that people are now willing to spend more money on a Phase II trial. How big is a Phase II? It will range anywhere from around 150 to I would say 300 patients. And the treatment time course for that will be somewhere around one to two years. Now, the purpose of this is to get data with regards to these very important clinical outcome measures, namely relapse rate or disability accumulation.
So again based on the biomarkers initially in a small number, now we are going to go and we are going to treat for a longer period of time in a larger number of patients, and it's going to involve more sites, somewhere around the order of five to ten sites, and we are going to try to get some data on how robust the treatment is with respect to, for example, lowering relapse rates.
Now, once we have that information - assuming that it's positive; again, you could have had promising Phase I that basically the Phase II is negative - but let's say the phase II now is positive. By positive, I mean there is a trend, for example, a reduction in relapse rate. It doesn't reach significance because we still have a relatively small group, and that's when you design the Phase III trial.
So the Phase III trial uses those numbers of the effect of the drug on relapse rate, and they say, based on these numbers on relapse rate that were derived from a group of patients that was only about a 100 or 200, we now know that if we enroll for example a thousand, we will be able to achieve statistical significance between the drug and the placebo. So leading into the Phase III trial as inferred, these generally involve about 1,000 patients, and they will be done in many, many centers, anywhere from 70 to 90 centers, and they can even be involved in multiple countries to get these numbers of patients. It's a very large numbers of patients.
And the treatment time minimum will be two years again, because so far I believe all of the drugs for MS have been approved based on reducing the relapse rate. And fortunately since the relapse rate is only about once every two years on average - it's highly variable between individuals - but since it's about once every two years, you have to treat for a minimum of two years if your primary outcome measure is relapse rate reduction. So, again, Phase III will be on the order of 1,000 patients, and they will be treated for a minimum of two years, looking for a definitive effect on relapse rate reduction.
I might add a little bit to what was said before, the FDA and what it will take for approval. Dr. O'Looney is absolutely correct that these Phase III trials are the closest that we have got going so far, and there are approximately five. It's hard for us to say, though, what the FDA will require. You never really know because sometimes they will want two phase III trials, two pivotal trials. We don't know. Or maybe they will say one is good enough. If they want two, then you can see that leads to more of a time delay. That's why she is trying to be so conservative. It's hard to predict what the FDA will want.
You mentioned something else as you were describing that process - you said "design the study." So it's not as if once the 12 months of Phase II is done that you begin recruiting on January first and start that trial with the next group. How long does that take to design and recruit for a study in Phase III typically?
Typically, Phase II will end, and you need to have time to look at all the data, interpret the data, and then you need to have time to see where the biggest effect was and then design the next one to maximize that effect. So I think drug companies, because they have money in hand, they are the best at doing this, and they could probably turn something around in a year. For the academic community, it's actually never been done, because that would [require], of course applying for more grants and so forth. But if you had money in hand like the drug companies do, then I think it could be turned around in about a year.
And the drugs that are in Phase III are obviously the ones that are closest to approval. And earlier when I did ask Dr. O'Looney to make that guess, that was best-case scenario of drug development. What could go wrong, if you will, at this point in a Phase III that would delay [the process]?
Well, as she said, sometimes the oral drugs don't work the way the IV or the IM or the subcutaneous injections work. She gave many reasons why that's the case. Another reason is that sometimes when things go through the gut, they are altered a little bit by the absorption, and they have a first-pass liver effect. So the drug gets changed a little bit when it goes from inside the gut to the bloodstream, and that can unfortunately sometimes change its ability to be effective. And as she said, it's harder to deliver higher doses when you give them orally.
Another thing that comes up often in a Phase III trial is - particularly in all these drugs that are very immunomodulatory, that means, as she said, affecting the immune system to shift it or suppress it or at least change it a little bit away from the MS attacking sort of situation - the problem is you can have susceptibility to infection because we need an immune system to fight infections. So oftentimes there will be toxicities and safety issues, which again goes back to why she was saying that we need such rigorous safety standards when we start to give these drugs to thousands of patients at a time. We need to know, are they going to cause toxicities such that, for example, the immune system has been changed and now people are getting infections? This of course came up very notoriously with the drug Tysabri, where some very serious brain infections came up. So we are sensitized very much that we need to be very careful.
Not to mention the FDA will require this. The FDA is not going to let something on the market merely because efficacy has been shown. The FDA is going to want to know about safety as well. It's just as important, if not more important, to have safety.
Dr. O'Looney, you referred earlier to the real hero of a clinical trial as the volunteer, and I know that many in the MS HealthTalk community would like to know how they could get involved in one of these clinical trials, oral meds or another clinical trial for MS really. What is the best way for people to find out about ongoing trials?
Well, the best way, I think, is go to the National MS Society's Web site - so the www.nationalmssociety.org - and often there we have alerts for the community that there is a clinical trial that's underway that's actively recruiting. In fact, Dr. Voskuhl herself is the primary investigator of one of those oral clinical trials, estriol [also known as oestriol, an estrogen], that's taking place at seven sites I guess. Right, Dr. Voskuhl?
Yes. Seven sites around the United States, and we would love to recruit for that trial. It's estriol. It's a hormone of pregnancy that we think could potentially be both anti-inflammatory and neuroprotective, which would be very distinguishing from the other drugs that are principally only anti-inflammatory.
Just a quick question about that, Dr. Voskuhl. Is that men and women that you are putting through this test?
No. Right now that drug is for women only because it's based on the effect of pregnancy, and when you are pregnant, this estrogen called estriol goes very high. And as some MS patients will know, pregnancy is a situation whereby the disease remits quite a bit. There is actually an 80 percent reduction in relapse rate. That's as compared to about 33 percent with all of the IV shots and IM. All the shots we have are about 33 percent. Tysabri is one of best, which is about 50 percent reduction. The pregnancy reduces relapses by 80 percent, and we have evidence in various systems that estriol may be one of the pregnancy hormones responsible for that improvement during pregnancy.
And so we have funding. Also quite atypically our study is funded by the National MS Society and the NIH, as opposed to all the others which are funded by pharmaceutical companies. And the reason for that is because estriol is going to be a generic drug that will not be patent-protected. But we are very enthusiastic about it being both potentially anti-inflammatory and neuroprotective because the MS community in general is starting to see that MS clearly is an inflammatory autoimmune disease. There is no question.
But the issue is that it's probably also got a neurodegenerative component, and the reason we believe that is because very good drugs, such as Rebif (interferon beta-1a) for example, the high-dose interferon, people take those, and they take them religiously. There is nothing wrong with the way they take them. There is nothing wrong with the drug. It's a very good high-dose interferon, and despite that people still progress on the high-dose interferons. And so reducing relapses by one-third and having only a modest effect on progression, some, but modest - I mean, clearly they should take the drug because it does slow down relapses, but we think we should do better. And I think the MS community at large feels the way to do better would perhaps be to combine an anti-inflammatory with a neuroprotective drug. There is no neuroprotective drug however for MS. And we do have reason to believe that estrogen in general could be neuroprotective using other disease models as well as the MS model.
Dr. O'Looney, one of the drawbacks of the currently available injected and infused MS therapies are side effects. What are some of the common side effects that they are seeing in our current treatments?
Most of the side effects in the six FDA-approved current therapies, which is there are three interferons - the Betaseron (interferon-1b), Rebif (interferon beta-1a), and Avonex (interferon beta-1a) - the Copaxone (glatiramer acetate), then mitoxantrone (Novantrone) and Tysabri. Obviously, they have all been approved for use with MS since their benefits outweigh the side effects. So there are certainly side effects to the therapies, but certainly they are tolerable in the people who are taking the drugs. The most common ones of course with the interferons are the flu-like symptoms, inflammation around the injection site. Liver enzymes have to be monitored. The Copaxone sometimes is also a transient reaction of flushing or a chest tightness. But most of these side effects are usually within the first two or three months of treatment and eventually subside.
Dr. Voskuhl, of the oral treatments that are testing now, are you aware of some of the common side effects that the researchers are reporting?
I think most of the side effects - for example the ones that are in Phase III trials right now, most of these are immunomodulatory, and some of them are forms of chemotherapy - so I think susceptibility to infection is going to be the biggest issue that will need to be followed.
Are any of these oral drugs that are being studied now for the progressive or the worsening forms of MS, such as primary-progressive or secondary-progressive courses of disease, Dr. Voskuhl?
Well, generally no, and the reason for that is because what's interesting and also challenging about MS is that the bulk of the patients have either relapse-remitting or secondary-progressive MS. There are a minority that have primary-progressive MS, but to speak to the majority or about 90 percent, it's thought that the relapsing-remitting phase is a very inflammatory phase because we know that the lesions in the brain are enhancing [on MRI]. They are very inflammatory.
But interestingly, you know, after 10 or 15 or 20 years go by and patients transition into more of the secondary-progressive phase, interestingly the inflammation subsides somewhat. There aren't as many enhancing lesions on MRI, but instead there is some brain atrophy, and that's where you go into more of the neurodegenerative phase. And primary-progressive is also somewhat similar in that there are not very many enhancing or inflammatory lesions as much as more of this degenerative phenomenon.
So logically speaking, when you are treating with all of the drugs that are in Phase III right now, which are all immunomodulatory, it makes sense to try them in the relapse-remitting phase, since this is the most inflammatory phase of type of MS, to see if they work there. If they don't work there, then it's unlikely they are going to work in the secondary-progressive or primary-progressive MS where it clearly has less of an inflammatory component and more of a degenerative component. So the answer, to my knowledge, is no. There will be no phase III trials giving immunomodulatories to secondary or primary-progressive MS.
I do believe, Dr. O'Looney, you can correct me, there was a study of Copaxone in primary-progressive MS. It was a small trial.
That is correct. Yeah. And of course we just recently heard some disappointing results from Rituxan (rituximab) used also in primary-progressive MS.
I think one of the reasons is because it's just not as inflammatory of a disease, and so to use anti-inflammatories don't make quite as much sense.
Dr. Voskuhl mentioned a few minutes ago biomarkers in MS and measuring relapses. That's one of the most important areas of research in MS today and what we [have] need for. What we mean by biomarkers, or any marker, is disease activity. So when we do a clinical trial for two years, three years, one of the reasons it has to be so long is, how do you measure the effect of a drug? Right now all we have is measuring relapses, the clinical symptom or exacerbation, or changes on MRI. But can you imagine what a benefit it would be if we could measure something in the blood or something in the urine, perhaps, that would be a direct correlation to disease activity, and then we would be able to shorten the duration of these trials and just have a better handle on the connection between the efficacy of a drug and its impact on disease activity. And so that's one of the challenges in designing clinical trials and finding new treatments for people with MS.
Thank you very much for that. And are any of these oral drug therapies being thought of for the newly diagnosed patients, Dr. Voskuhl? I mean, a lot of us remember that when Tysabri came back on the market, it was only after you failed another drug could you go on that. Is that the case with these oral drugs?
I think the new oral drugs are being tested in the early forms of MS, and they clearly need to be checked at least in the relapse-remitting group. But I do think they want the early cases because they are the most inflammatory.
The hesitation to [testing] them in the patients that have been just diagnosed is there is somewhat of a hesitation for a patient to enroll in a Phase III [trial]. Like Tysabri - the reason we didn't really want to use it in people who had been initially diagnosed is because these people might do very well on one of the standard interferons or Copaxone, and like Dr. O'Looney said, these drugs have very little side effects. They do have some, but those tend to be transient, and a lot of patients do quite well. And so one would say, "Well, why would I go to something that could give me a serious brain infection like Tysabri when I might be really well controlled on something that's been given to thousands of people and been shown to be extremely safe?" So it's kind of a question of what kind of risk do you want to take when you have been newly diagnosed?
Dr. O'Looney, to your knowledge, will people with MS need to be weaned off their current injectable drugs like we have had to with Tysabri before we take these new pills?
I guess that's an unknown right now, Trevis. It depends upon what the current drug is the patient is taking right now and what kind of drug the oral therapy is. What you are talking about I am sure is just regular daily management of the disease, not a clinical trial. Obviously as we talked about earlier, when you join a clinical trial, then you do have to be weaned off your current medication, and it varies depending upon what drug a person is on from six months to twelve months. And that primary reason is because you don't want the efficacy of the drug that you are currently taking to blind the impact of the new drug that you are going to be tested on in the clinical trial.
But in everyday life and not a clinical trial, it's hard to know at this point how long they would have to take their current drug. I would imagine that it would vary, depending on whether one is taking [for example] Betaseron versus Tysabri. I would think there would be quite a difference.
I suppose since you are talking about efficacy there, we are only going to be able to really compare efficacy of the oral drugs to the injectables after the studies. But I guess the question is, if a person is doing relatively well on their current drug therapy, is the convenience of a pill in-and-of itself a valid enough reason to switch to an oral drug?
Well, yes, but I am going to say that with some hesitation. Obviously when you talk about the convenience, you are talking about a patients' adherence to the medication, also their quality of life. So very few of these clinical trials are going to be a head-to-head comparison. It's really if the clinical trial shows that the oral drug has equal efficacy to another clinical trial - and you always have to hesitate to compare one clinical trial to another. But nonetheless, if the oral drug shows efficacy - say like a reduction of a third of relapses which is similar to the interferon Copaxone - that is generally good news, and I think worthy enough for a patient to consider switching to the oral medication. Because when you say convenience, that certainly is important, but what's most important is the adherence to the medication, that when the patient or the individual agrees to take a medication, we do know now that it's really for a lifetime, that it's important that we continue to reduce that inflammation. So one has to continue to take that medication, and that's what's most important.
Dr. Voskuhl, is there anything that you would like to add to that?
I totally agree with that. I mean, I think it depends on the individual. I think there are a lot of individual differences in people's tolerance levels for being able to inject themselves every day and every week, and I think even within an individual, it changes as time goes by. Sometimes they can do it, and they can do it for a long time, and then I have had patients who just wake up one morning and say, "I can't do it anymore. I just can't inject myself anymore."
So she is right. There is an adherence to the regimen, and that's key because really everyone in the United States where these drugs are available should be taking them, and if people wake up one day and they just can't do it for a lot of reasons, then these oral treatments are going to be just fantastic.
Dr. Voskuhl, just one follow-up here: Several of us have often wondered why is it that a 6-2, 250-pound guy and a 130-pound woman are taking the same dose of injectable drugs, interferons, etcetera. I know that the chemotherapies are a little bit different in their dosing. Will the oral drugs be one-dose-fits-all, or will there be different dosages for different-sized people?
I wondered about that myself, and my only answer is probably based on the fact I think this is practically the way it has to be. What's often been done back in the Phase II is they have done a dose-finding study where they have taken very extreme differences, for example 1.5 mg versus 5 mg, over a threefold difference. So they will have anywhere from two- to fivefold differences in the dose - so very high, relatively low, or placebo - that will often be the case in a Phase II. And they will pick the dose that is out of these two possibilities, the high one or the low one, the one that seems to get efficacy but doesn't have any safety concerns with it.
Now, that's really a financial issue because you can't - when you talk about somebody who weighs 100 pounds versus 150 pounds, you are talking about very little difference. You are not talking about a three- to fivefold change. And so to parse through those really minimal variations in weight or dose adjustment related to weight, you really couldn't logistically have large enough studies that you would have to have so many doses to parse out whether there were any differences. I just don't think it's possible, and the current Phase IIIs that are designed are the same sort of a thing. They picked one dose, and it's been based on generally two to maximum three doses in those earlier studies that are over a very broad range. So I think one size, relatively, does fit all in the scheme of things.
It would certainly be easier to change doses in a pill form than it would be a prepackaged syringe.
Now we open the program to your questions, the questions from our audience. The first question is an e-mail from Leesburg, Georgia, and it says, "My doctor mentioned there may be an issue with macular degeneration and one of the oral medications. Are you aware of any cases of this?"
I have heard of that, and I can't remember which one [oral medication] is. But the patient is right, or the doctor is right. Both of them are right. And I cannot remember which one it is. Yes. I have heard that.
But I suspect that that's going to be something that will come up in the FDA? That will come up in the FDA findings, and if it's bad enough of a side effect, would that stop the drug from being market approved?
Well, it could. Again, you are absolutely right: It depends on how bad it is, and what percentage of patients it affects, if it's one out of 1,000 versus one out of 100. And is it reversible? Is it not reversible? Again, that's why we have such rigorous testing during the trial - to pick up on those things and follow them.
The next question is an e-mail from Kevin in Princeton, West Virginia, and I was thinking about this myself. "The injectable drugs, although having been around for years, have never had a generic equivalent, so the cost has remained incredibly high. With the oral drugs, is it a possibility that one day there might be generic versions of the drug, making it affordable for those of us without insurance?"
Dr. O'Looney, I am going to let you speak to the biologic issue and the congressional issues behind that, as well as the possibility of a pill becoming generic.
I will do my best, and then certainly Dr. Voskuhl can chime in.
I know of two general ways of describing drugs, pharmaceuticals versus biologics. And there are many different types of biologics. Some of them are given intravenously. Some are given orally. And pharmaceutical are more synthesized chemically, versus a biologic, which is a medicine that's made from a living source. And it kind of goes back to what we talked about earlier where the difference here is also the size. Biologics are usually larger in size, which is why they are often given intravenously or by infusion. It's kind of the difference between an antibody versus a small aspirin which is a small medication.
So the question is, how soon can these generic versions of these biologics come about? It's hard to tell. The FDA has certain requirements. They are called, if I remember correctly, therapeutic equivalents, and so when a generic comes along, they have to show that they have a pharmaceutical equivalence to the original drug, so there is kind of like a similarity in the molecule, but they also have a biological equivalence, which is how the drug behaves in the patient or in controlling disease. There are so many different steps when a generic actually becomes available, and they have to follow certain rules and regulations before that actually comes to the market, so we are not quite there yet.
The phones are literally lighting up, and we are going to take a phone call from Sandy in Ohio. Sandy, welcome to HealthTalk. Your question, Sandy?
My doctor here at Ohio State at the MS place, he told me about a drug, fampridine, and it's in its final, third stage and should be completed in June. I want to know if the doctors know anything about this drug.
All right. Thank you very much for your call, Sandy.
Dr. Voskuhl, would you like to address that?
I believe I did read about that one, and I believe it is another of the immunomodulatory treatments.
Dr. O'Looney, are you aware of that being done around June of this year? I was under the impression that it would be June of next year before any of them would be done with their Phase III.
Yes. I must say I am not that familiar with the status in which the clinical trial is taking place.
Our next e-mail comes from New York, New York, a city so nice they named it twice. "Do you think that the side effects monitoring will hinder physicians ordering oral therapies to their patients?"
Dr. Voskuhl, as a doctor who sees MS patients, do you think that doctors are going to be less willing to prescribe a drug because they are going to have to monitor the side effects of their patients?
The oral drugs won't be any different than the shots that we currently have. Each drug, when it is approved in the next few years, will have its own set of potential side effects, and the clinicians will follow those. They are going to watch closely with respect to what was discovered in the Phase III trials, and it will be no different than the injectables. It won't be prohibitive by any means, actually less so because they will realize and appreciate the convenience of the oral drugs and weigh that versus these side effects, which again are also important, and they differ by individual in how important the side effects are.
The other thing is, when clinicians give the drugs in general practice, they generally don't have quite as many tests and ancillary studies, if you may, that are involved in these formal Phase II and Phase III trials. They have basically at that point collected quite a bit of data on what the possible side effects would be, and they kind of focus the clinicians only on those potential worrisome spots for monitoring, so there won't be any high-level monitoring. If a really high level were required, it probably won't be approved in the first place, so they will be relatively safe if the FDA approves them. The clinicians will be given a very straightforward and simplified regimen to follow for safety.
Jacqueline has sent us an e-mail from Upper Marlboro, Maryland, and I suspect that it's because she may be allergic to one of compounds that may be in these drugs. "Do any of these drugs, the oral therapies, contain human albumin?"
I don't know the composition. Do you know, Dr. Voskuhl?
No, I have no idea.
Well, Cathy in Eau Claire, Wisconsin is sending another question. "Will these new pills be easier to swallow than several of the other drugs, Flomax (tamsulosin hydrochloride) for osteoporosis, etcetera. I have lots of heartburn, and the size of the pills are difficult."
Several people with MS have swallowing issues, so do either of you know about the size of the pills and the ease of taking them? Are they timed release? Can we crush them up? Anything along that line?
I don't know, but I can imagine it would be highly variable from drug to drug whether it would even be a tablet or a capsule. It will be variable. Each formulation will probably be different, so I don't think you could generalize.
You can certainly speak to estriol. That's a small, little tablet, isn't it, Dr. Voskuhl?
Yes. The estrogens are generally quite small. That shouldn't be a problem with estriol, but I don't know about these ones in Phase III.
When you get into the FTY720, the fingolimod, I'm not that familiar with how they are manufactured.
Yes. But the swallowing difficulties, that will often affect some of the later phases [stages if MS], not as much the relapse-remitting group, so that's another consideration actually. When you start thinking about taking some of these drugs from the relapsing-remitting to secondary-progressive, if there are conditions that are unique to the secondary-progressives, then we need to consider those such as swallowing difficulties when we start to design trial. So that's a good point.
All you'd have to do is ask those of us who are living with the disease. Berbette in Tulsa, Oklahoma has sent us an e-mail, and this is for you, Dr. Voskuhl. "Would a postmenopausal woman be able to take the estriol drug? If so, would there be any concerns about breast cancer as there is with estrogen in HRT (hormone replacement therapy)?"
That's a great question, and I am originally from Oklahoma, so I appreciate that question. Anyway, estriol has been given widely in Europe and Asia for menopause and specifically to prevent hot flashes. Unfortunately it does not prevent osteoporosis, and so it is not given here. It's generally also given in a 2 mg dose, not an 8 mg dose. We are trying to give a very high dose to [replicate] pregnancy. And so can menopausal women take it? They can. Of course they take 2 mg tablets quite often for hot flashes in other countries. Estriol is not currently available though of course in the Tulsa Rite Aid or CVS pharmacies - they're unavailable. So it is going to take the trial that we are doing to get it readily available in the United States for people to take it as an indication from the FDA, and we are of course going for the MS indication.
Andy from Lancaster, Pennsylvania is sending us an e-mail, and we were talking earlier, Dr. O'Looney, about the stringent criteria to get into the clinical trials. "Why are people that are over 50 or 55 not included in these trials? We suffer from MS as well she says."
Well, then you get into I guess the duration that you once had a disease, because usually one has been diagnosed with MS in their 20s or 30s, and so you have had a disease a little bit longer, perhaps as long as 25, 30 years. Dr. Voskuhl mentioned earlier, most of these drugs are immunomodulatory drugs so they are trying to control inflammation in the immune system. And when one has had the disease for 25, 30 years, at least research seems to indicate that the disease is probably less inflammatory at that point and more maybe loss of tissue. And so if you really want to test these drugs and try and get the most interpretable results in a two-year period, you are trying to choose a part of the population in which the inflammation is at its peak. And so then you get someone who has had that disease within that first ten-year period.
We have another phone call from Peggy in Florida. Peggy, welcome. You are on HealthTalk.
Hi. My question is if you can't tolerate the side effects of the shots, and I have tried all the shots except Tysabri. I get like delirious. I get a really high fever. I get really bad with it, and even over a period of a year. What do the doctors suggest?
Dr. O'Looney, as a neurologist if you had a patient, and we have to speak generally here, Peggy, obviously, but if you had a patient who is continuing to have flushing and chronic side effects that are just too uncomfortable to keep them taking the drugs, what do you recommend?
Well, I am going to pass this to Dr. Voskuhl, if you don't mind. She is probably a little more closely treating patients than I am.
I think that you probably go back to drugs such as Imuran (azathioprine) or Cytoxan (cyclophosphamide), there are drugs that were chemotherapeutic agents. They have been around forever. They are immunomodulatory. They are immunosuppressants. They have never really, unfortunately, gone through some of the testing that's going to happen with these Phase IIIs, and I think primarily because they are now a generic, and they are not going to be big money-makers. But there were some data showing that Imuran and some of these other chemotherapeutic drugs from a long, long time ago, that these could have some of the same possible effects. So some people can be managed with those. But again, these drugs haven't been, they haven't undergone large Phase IIIs. They haven't been shown to be effective. But theoretically since they are immunomodulatory and there is anecdotal data that they may work, those can be tried.
An e-mail from Rockford, Michigan, "What protection is there out there for my stomach? What research has been done on these side effects?"
Dr. O'Looney, as you take a look at the drug trials that are coming across, I know oral prednisone can be difficult for people to take. If we are talking about oral chemotherapy drugs, what protections are there going to be for the stomach?
I guess it's the level of what one can tolerate. So I guess it goes back to the question of what we were talking about with difficulty swallowing. If someone has difficulty with stomach irritation because of the oral drugs, then I guess this is the good news in multiple sclerosis as opposed to 15 years ago - we are getting a more and more drugs on the shelf that we can choose from, so if one of these oral therapies do become available and the person can't tolerate it, the good news is that we will try something different. I am not sure if that answers the question.
I think it does.
Yeah. And I think with the oral steroids, antacids are often useful. And if it's a big enough problem in enough people, I think the companies at some point probably try to change the formulation to where it would be more tolerable if it was widespread enough, this gastric irritation.
Would they then have to go all the way back into Phase I then II then III? Or is something like that - a modification of the drug - something that could be done in between Phase II and III?
I think the FDA would want to see efficacy again with the modification unless the modification was very minimal, and it had no effect on absorption and dose level that you get in the blood. It would have to be very minimal before the FDA would assume that it would be equivalent.
I suppose it's not something like buffering aspirin or something like that? Probably more difficult than that.
An e-mail from Nicole, who doesn't tell us where she is, but that's all right. Nicole would like to know, "Is it known just how often an oral MS med will have to be taken? And could there ever be a liquid version of the medicine?"
Most of the doses in the Phase III trials right now are daily, so once a day. But I don't know that any of them, maybe Dr. O'Looney does, about whether they are being tried in liquid form. I don't know of any in liquid form, but I do know that most of them are once a day I think.
Yeah, I don't know of any that's in a liquid form either.
To your knowledge, just in general chemistry, is there a reason that a pill-form drug could not be made into a liquid-form even if it was something that had to be done at the pharmacy?
I think that depends on the formulation. I think it depends on the chemistry.
An e-mail from Hancock, Michigan. "If we are coming this close to an oral therapy, does it mean that we are closer to understanding MS?"
Well, we are always getting closer to understanding MS. Our knowledge has grown tremendously in just these 15, 20 years, so that certainly is true. But I think as we talked about earlier, one of the great mysteries is the progression of the disease. So even though we are doing a very good job, and we keep improving on how to control the immune system and to control inflammation, which is what we have been talking about for much of tonight, there still is that great mystery about the progression of the disease, and how do we control that? How do we improve and help those individuals who are listening tonight that is in that latter part of the disease? That's all I could think of with Andy earlier, that we need more treatments for them as well. So our knowledge is growing. We are not quite there yet, but certainly all the scientists are asking all the right questions, and so there is great hope out there.
An e-mail question from Silver Springs, Maryland says, "What kind of trials have been conducted on these new therapies? Is there a site where the trials are listed for our review?"
Dr. Voskuhl, is there a place where we can go and we can read up on all of the Phase II data?
Yeah. The MS Society has their site, but also www.clinicaltrials.gov. It's actually a requirement now that everyone post their Web sites for their drug on that site. It's really easy to go to because it's got key words. So for mine for example, you do estriol, and then another one is MS, and it will come up immediately. So I think the clinicaltrials.gov is probably one of the most encompassing Web sites that there is.
And Dr. O'Looney, do you want to give us the National MS Society website one more time?
The www.nationalmssociety.org.
One more question e-mailed from Nick in Pleasant Valley, New York. "With the oral drug so close to approval, is it worth the risk of changing from Avonex to Tysabri today?"
Dr. Voskuhl?
You will have to ask your doctor about that because it really depends on the individual. Generally people, just very generally speaking, I will just say people who would change from Avonex to Tysabri would do it because they are in some measure failing Avonex, and by that I would mean having frequent relapses or deteriorating in some form on Avonex. Avonex is a relatively low-dose interferon, and it's of course taken once a week, not three times a week. And there have been some head-to-head studies showing that Avonex may not be quite as efficacious as the Rebif or beta interferon. And it's fine for a lot of patients who have relatively less aggressive MS, but for those patients who have quite aggressive relapsing-remitting MS, meaning they have quite frequent relapses, oftentimes people will be moved up from an Avonex to a high-dose interferon. If they would, quote-unquote, fail the high-dose interferon, meaning continuing to have relapses, then it would be reasonable to try Tysabri. But I think there needs to be a gradation upwards towards more inconvenience and more frequent shots and more potential for serious side effects, and that's based on how serious the MS is, although I am certainly not against people starting the high-dose interferons right out of the block, right upon diagnosis, because they are relatively safe. Tysabri has some safety issues, and I can't see jumping to that unless you've failed a high-dose interferon, but that's just my opinion.
We appreciate that opinion, and that's going to have to be our last question from our audience on this important topic. But before we go I would like to give our guests a chance to leave us with any final thoughts. And, Dr. O'Looney, we will start with you.
Well, thank you again Trevis for having me, and I have enjoyed sharing this hour with Dr. Voskuhl as well. I think, very quickly, Nick has brought that point up - I don't want people to think that since oral therapy is on the horizon so quickly that they should delay therapy. It's very important when one is diagnosed with MS that they do get on one of the approved therapies, and then we can have the excitement of being on one of the oral therapies when it becomes available.
Also there are so many clinical trials in MS. There are probably about 120 clinical trials, and some of them are focused on maybe an injectable every six months or having an injection once a year. So oral therapies are what we want, but there is a lot of great excitement out there as well.
I thank you for allowing me to be part of this conversation tonight.
Thank you, Dr. O'Looney.
Dr. Voskuhl, anything that you would like to leave our audience with?
I guess I would have two points. One would be, I think when you are looking for a trial and the drug, I think you should ask how it is supposed to work. The big categories would be, is it anti-inflammatory? Two, is it neuroprotective, of which there aren't very many? And those would both be disease-modifying. The last category would be, is it a symptomatic treatment? For example, is it to treat depression or fatigue or other symptoms, not really to modify the disease course, but is it to treat symptoms? Because that's a big category.
And lastly I think people should all be on these shots that are available, and one should think hard before they enter a trial that's got a placebo arm only where you don't get any drug at all.
Thank you, Doctor. I thank you both for your expertise and thank you for all you do for the community. And a big thank you to our listeners who submitted thoughtful questions.
From all of us at the Seattle, Washington studios of HealthTalk, I am Trevis Gleason. Cheers.
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Oh, How I Hate Multiple Sclerosis
Most of the time I get on with life as best I can. But sometimes this disease evokes a primal scream of rage.
Who Is Getting Highly Effective MS Treatments? And When?
A study presented at the 2019 American Academy of Neurology annual meeting shows there's no consensus on when to prescribe higher-efficacy drugs.
Ibudilast's Effect on Brain Atrophy Presents More Questions Than Answers
A study analysis suggests the drug is more effective in PPMS than in SPMS, but researchers say that conclusion is premature.
The Chronic Illness Triangle: Time, Energy, and Recovery
Finding the right balance with multiple sclerosis is a tricky endeavor.
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MS Medications
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Thank you for visiting and welcome to my website! Tara Draper Photography is based out of Wisconsin Dells, in South-central Wisconsin, but I shoot weddings all over Wisconsin and the Midwest area, and I love to travel! Here you will find a collection of my work, tips on how to make your session the best it can be, and a sense of my photography style. I feel honored to be able to share the emotion and beauty that can be captured in a photograph and I am extremely passionate at what I do.
Please take a look around and if you think I'd be the right fit for you, that's awesome. Just fill out the contact form or send me an email at taradraperphoto@yahoo.com. I am always up for an adventure and look forward to creating beautiful photos that you and those closest to you will cherish forever.


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Vandals damage Banstead golf course and steal flags
SELFISH vandals caused damage to a golf course in Banstead and stole around £300 worth of flags and tee blocks from the course.
A group of six teenage boys were seen throwing tee markers around the 11th hole of Banstead Downs golf course at 5pm on Monday.
The group left when approached by a member of staff who put everything back in order, but on Tuesday morning flags from the ninth, tenth, 11th and 12th greens had been stolen along with four tee blocks from the 11th tee and bicycle tyre marks had been left across the course.
PC Sue Roe of Surrey Police said the estimated value of the stolen items is around £300.
"This was a selfish and mindless act of criminal damage and theft of items that would likely be of little or no use to the person or persons who stole them," she said.
"I am appealing for anyone who may have seen a group of teenage boys in the area at the time or who may know the current whereabouts of these unusual items to please come forward so we can return them to their rightful owners and bring those responsible to justice."
Anyone with information should contact Surrey Police on 0845 125 2222, quoting reference number RB/09/7523.


Mexican Food Round-up for Cinco de Mayo: It's no secret that I love Mexican food. I could eat it every day. I am, after all, from Southern California where much of the food around me is influenced by Mexican cooking.
So, with Cinco de Mayo coming up, I thought I'd round up some of my Mexican dishes and share them. From breakfast, to appetizers, to mains, I've got 'em all here.
So, dig in on Cinco de Mayo or any day! Mexican food should be enjoyed year-round!
Homemade tortillas encase fillings like Seasoned Black Bean Mash, Verde Queso Fun-dito, and Homemade Guacamole.
What an incredible collection of Cinco de Mayo dishes Debi…well done! Will be sharing and pinning!
I love all of these great Vegetarian options!
Great collection, Debi! My mouth is watering!
this is a great round up of mouth watering Mexican food!
What a wonderful collection of Mexican recipes!
A round up of all my favorite foods!
I am from San Diego and love Mexican food too! I can't believe all the delicious Mexican recipes you have on your site and am so excited to check them out!
What a great round-up! These all look fantastic!
What a great list, Mexican food is one of my favorites as well!
This a a wonderful roundup!
Nice! I am soooo behind on meal planning for tonight's dinner. I have a bag of avocados and no idea what to do with them. Thanks for the roundup! Very helpful 🙂 I'm thinking about butternut squash tacos -I love the flavour combo in that dish.
Thanks so much Debi for joining our #theWeekendSocia. Hope to see you again next week!


text:
exports.index = function (req, res) {

	var pjson = require('../package.json');
	res.json({ version: pjson.version });

};

redpajama_set_name: RedPajamaGithub


text:
Lucius Marcius Sabula (vollständige Namensform Lucius Marcius Luci filius Romilia Sabula) war ein im 2. Jahrhundert n. Chr. lebender Angehöriger des römischen Ritterstandes (Eques).

Durch ein Militärdiplom, das auf den 25. September 111 datiert ist, ist belegt, dass Sabula 111 Kommandeur der Ala II Hispanorum et Aravacorum war, die zu diesem Zeitpunkt in der Provinz Moesia inferior stationiert war; die Leitung dieser Einheit dürfte sein drittes militärisches Kommando innerhalb der Tres militiae gewesen sein. Sabula war in der Tribus Romilia eingeschrieben.

Einzelnachweise

Eques
Militärperson (Römische Kaiserzeit)
Römer
Mann
Geboren im 1. Jahrhundert
Gestorben im 2. Jahrhundert

redpajama_set_name: RedPajamaWikipedia


We are committed to active involvement in our philanthropic endeavors. Our goal is to make a difference in a heartfelt way, through gestures of caring and compassion, giving of our time and unique talents.
Ginger Bay is committed to making a difference in the community in which we serve. Each year, Ginger Bay donates over $15,000 to area charitable organizations through trivia nights, galas and a variety of fundraisers. Our annual Spa-tacular event is a highly anticipated event which benefits one very deserving charity. During the past 13 years, Ginger Bay has donated over $90,000 to Spa-tacular recipients such as Friends of Kids with Cancer, Our Little Haven, The MS Society, AMC Cancer Research, Annie's Hope, Habitat for Humanity, Equine Assisted Therapy, St. Louis Stray Rescue and Breakdown St. Louis.
Ginger Bay is committed to environmental stewardship. We reuse, repurpose and recycle as much as possible. We donate our used electronics to a local shelter which provides work for individuals with physical challenges. Ginger Bay recycles over 4 tons of paper, plastic, glass and aluminum per year. We donate all of our gently used linens to local womens shelters and animal rescue centers and the mannequin heads we use for training are donated to local law enforcement agencies to support their training. Our printed materials are also produced on post-consumer recycled content using soy-ink.


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Jeff Lorber Fusion June 18, 2012
BB King Blues Club & Grill
237 W 42nd St
By the late 1970s, keyboardist and composer Jeff Lorber had become a prominent figure in the new movement known as jazz fusion - a marriage of traditional jazz with elements of rock, R&B, funk and other electrified sounds. Lorber and his band, the Jeff Lorber Fusion, first honed their craft in the Portland, Oregon, club scene and rapidly expanded their reach to a national and international audience via a combination of complex harmonies, unconventional time signatures and compelling rhythms. In subsequent years, Lorber dropped the term "fusion" from his billing as the movement evolved into what is currently known as contemporary jazz. Still, he continued to explore the innovative, improvisational potential of grafting other musical forms to the jazz idiom. More than three decades after his earliest recordings, Lorber has come full circle. His new recording, 'Now Is The Time,' delves back into his early catalog and reinvents some of the most compelling compositions from the Jeff Lorber Fusion heyday.
Official Website: http://www.songkick.com/concerts/12342353-jeff-lorber-fusion-at-bb-kings-blues-club?utm_source=1126&utm_medium=partner
Added by Upcoming Robot on June 8, 2012


Forside » Apple » Grib idéen… Stopmotion og påsken og en lille video mere!
Her kan i se hvordan en klasse har arbejdet med stopmotion over emnet påsken i kristendomsundervisningen.
I denne her kanal kan du se de andre lign. historier som klassen lavede, og du kan se hvordan man opbygger et Ipad stativ, så man fiksere Ipaden. IStopmotion er et super program til at lave stopmotion med Ipaden.
Herunder kan du se en stopmotion film hvor undervisningsforløbet i en 2-3 klasse har arbejdet med filmiske virkemidler.
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Random Acts of Poetry by Brett Starr
01/27/2021 01/27/2021 LibrarianLaura1 Comment
Brett Starr's Random Acts of Poetry is a lovely compilation of poetry across nine subject areas, including philosophy, humor, science and math, religion, politics, family, death, temptation, and mental illness. The topics and poems in each are timely, but also timeless in how they speak to readers. Most of the poetry is written in free… Continue reading Random Acts of Poetry by Brett Starr
The Dog Ate My Homework by Aaron James
Children's Book Review · Children's Picture Book · Children's Poetry
Recently released for purchase is The Dog Ate My Homework (And Other Poems for Children) by Aaron James and published by Clink Street Publishing. The paperback children's book contains five school-themed poems which have rhyming texts. Each poem tells a humorous tale involving traditional school routines/activities. The illustrations are fitting to the stories being told… Continue reading The Dog Ate My Homework by Aaron James
The Railwayman's Wife by Ashley Hay
The Railwayman's Wife will be published April 5, 2016. The story takes place in the town of Thirroul, in 1948, on the coast of New South Wales. The author's vivid descriptions of the water, the library, the train station, and the beach really help the atmosphere of the book, allowing readers to imagine such beauty. Anikka (Ani) Lachlan, wife… Continue reading The Railwayman's Wife by Ashley Hay


Gissberg Ponds, or more formerly known as Gissberg Twin Lakes County Park, is located just off of Interstate 5 in Smokey Point, Wa. With two good sized lakes and walking paths all around I felt an instant escape from the outside world upon arriving here.
I parked right at the bank of the Southern lake and immediately took off on foot toward the path dividing the two fishing holes. The sun was out and so were the the fisherman with rubber boots and carrying tackle boxes, the little old lady with the floppy sun hat enjoying a book at the base of an ancient tree in the cedar grove, and the two darling ducks gliding across the quieter north pond. Seeing others out enjoying nature and being in their element helped put me right into the mood as well.
It turns out that both of the Gissberg Ponds were man-made back in the 1970's. They hold annual fishing derby's here and are amply stocked with rainbow trout and channel catfish every May. The North Pond is only open to juvenile fisherman. It's also a nice spot for a picnic or walking the pooch. Much more than what you would expect from the side of the freeway!


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General Motors issues the second recall after some cars erupted into flames
July 25, 2021 Dave Barr
General Motors on Friday gave the second review in under a year for its 2017-2019 Chevy Bolt EVs after a portion of the cars that had effectively been fixed still emitted into flames.
Officials with GM and LG, which supplies the electric car's battery cells, have distinguished a second "uncommon assembling imperfection" that expands the danger of a fire, the Detroit-based automaker said.
The review covers around 69,000 cars globally, incorporating very nearly 51,000 in the US.
GM said it will supplant the imperfect battery in the reviewed cars at no expense for customers.
The company asked that proprietors put a 90 percent condition of charge limit on the cars until the review fix can be executed.
The declaration comes seven days after GM and federal regulators asked proprietors to park the Chevy Bolts outside and away from their home because of the danger of fire.
The National Highway Traffic Safety Administration said last week that the battery cell packs in the 2017-2019 Bolt EVs "can possibly smoke and ignite internally."
The fire could then spread to the remainder of the vehicle and cause a design fire if the vehicle is parked inside a carport or close to a house, the NHTSA cautioned.
The federal regulator opened an examination concerning the matter in October and gave a review for the 51,000 influenced cars in the US in November.
In any case, the agency recognized last week that it's currently mindful of two separate episodes of flames in the electric cars that had effectively "got the review cure."
One of the flames happened while the car was charging at the home of a Vermont state legislator recently, media announced.
Posted in Business, News


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Una lengua controlada es una forma especial de comunicación basada en una lengua natural (una lengua utilizada espontáneamente por un grupo) de la cual se utiliza un vocabulario restringido y construcciones gramaticales consideradas simples.

El uso principal de lenguas controladas es la difusión de material y contenidos a grandes audiencias que no tienen un conocimiento avanzado de la lengua base. Por ejemplo en compañías multinacionales para la redacción de manuales, o en la divulgación de actividades comunitarias en grupos de inmigrantes.

Véase también
 Lengua construida
 Basic English, Simple English y Special English.
 Idioma filipino

Lenguas


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Dan O'Hanlon named 'Judge of the Year'
By The West Virginia Record | Sep 19, 2007
Judge O'Hanlon
Photo courtesy of Huntington Herald-Dispatch
CHARLESTON – Judge Dan O'Hanlon, chief judge of the Cabell County Circuit Court, was named Judge of the Year by the West Virginia Association for Justice.
Judge O'Hanlon was nominated for the award by Huntington attorneys Bert Ketchum and Paul T. Farrell, Jr. The award was presented at the WVAJ annual conference in June by WVAJ president Teresa Toriseva.
"Judge O'Hanlon is a dynamic, energetic and gifted jurist for the people who elected him in Cabell County and every West Virginian. He is someone who has worked hard every day that he has been on the bench to be fair and thoughtful in the administration of justice. I was honored to present him with this award," said Toriseva.
In their nomination for Judge O'Hanlon, Ketchum and Farrell wrote, "Judge O'Hanlon has earned the respect of (1) the West Virginia State Bar from which he receives high marks on its judicial rankings; (2) the business community which regularly asks him to sit on various boards and advise business leaders; (3) labor for which he is a former union member; (4) the medical community which asks him to speak at events; and (5) the voters which have made him the top vote getter in Cabell County."
In a 1998 interview with Huntington Quarterly magazine, O'Hanlon shared his thoughts on both the legal system and being a good judge.
"If you advocate for due process of law, things workout in the end and the result will be fair. The system is right a lot more often than it is wrong. A judge who's being a good judge in my view doesn't do it by virtue of individual personality, he does it by continuing to uphold the rules and traditions that have worked for 700 years in our society. The Hatfields and McCoys - that's what's waiting for people without our court system."
Judge O'Hanlon has served as a Cabell County Circuit Court judge since 1985. At that time, he was the youngest circuit court judge elected in West Virginia history.
He came to Huntington in 1978 as the director of the Marshall University Community College's paralegal program; from 1982 – 1984, he was the chairman of Marshall University's Criminal Justice department.
During that time, he also served as an assistant prosecuting attorney for Cabell County as well as a municipal judge for the City of Huntington.
Judge O'Hanlon has served as the chairman of the technology committee for the West Virginia Supreme Court of Appeals since 1993.
Through his work with that committee, Judge O'Hanlon has made West Virginia a national leader in the use of videoconferencing technology in the courtroom, and has helped the state obtain nearly $7 million in grants to assist with that effort.
Originally from Chicago, O'Hanlon received his bachelor's degree from Marquette University in 1970. In 1973, he received his J.D. with honors from the Arizona State University College of Law. O'Hanlon is a member of MENSA, an international society whose members' IQs are in the top two percent.
The West Virginia Association for Justice, formerly the West Virginia Trial Lawyers Association, is a professional association representing more than 600 plaintiffs' attorneys throughout West Virginia and in surrounding states.
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Former Cabell County staffer claims she faced hostile work environment over disability, Facebook post
Charleston, firefighters reach $1.7 million agreement to correct longtime back-pay issue
Both sides confident after Supreme Court hears right-to-work law oral arguments
Former Thomas Health System Rehab patient alleges he was sexually harassed by male employee
Democratic lawmakers – including Manchin – criticize Morrisey healthcare proposal, but AG stands behind bill
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