4th Thursday Update

February 25, 2016

The temperature this afternoon was 79 degrees F (that's 26 degrees C, for those living in the civilized world).

It's nice to have such pleasant, sunny weather for outdoor exercise in February. If 79 sounds too warm for running, bear in mind that this is California, so humidity is quite low. 79 degrees in humid weather would make running an exhausting chore, but when the air is dry, it's quite comfortable.


The big picture

When we look at a painting, our natural inclination is to lean in close and look at the details. However, it can be misleading to focus intensely on a small part of the picture. For example, what is your impression if you look at this close-up detail from a larger picture?

Seen up close like this, it reads as a picture of two cute little girls and their puppy. It's a very innocent image -- nothing dark or creepy about it.

However, what does it look like if you stand back from the picture, and take in all of it? Is there perhaps a sinister aspect of this image which people will miss if they don't stand back from it?

Sad to say, a lot of what goes on -- or at least is publicly reported -- in the world of medical research is a misleading fragment of the big picture, impossible to interpret correctly if you don't (or can't) step back from it to see the situation as a whole.

Whenever I read about a study which seems to show that this or that prescription drug has additional health benefits no one had suspected before (it doesn't just alleviate arthritis, it also prevents Alzheimer's!), I wonder if we are really being shown the entire picture here. Taking a close look at one published study is bound to be misleading, if there were other studies on the same subject which never saw the light of day. We need to be able to stand back from a study, and consider it in the context of all the research that has been done on the subject. Did the pharmaceutical company that stands to benefit from this research sponsor six studies, not one, and make a cynical decision to publish the one study that seemed to show a benefit while hiding the five studies that didn't?

A lot of that sort of thing goes on, it seems. One sign of it is that researchers are surprisingly slow to release their findings publicly, and fairly often fail to release them at all.

An examination of this issue in BMJ found that the results of medical research -- research which is supposed to be reported by way of ClinicalTrials.gov -- are mysteriously slow to appear, if they appear at all. Two thirds of studies still haven't had their results disclosed after two years. More than a third of studies are never published at all.

The authors of this article make clear that this situation is not acceptable: "We found noticeable variation and poor performance across leading academic medical centers in the dissemination of clinical trial results. The lack of timely reporting and publication fundamentally impairs the research enterprise, violates the commitment made by investigators to patients and funders, squanders precious time and resources, and threatens to compromise evidence based clinical decision making."

And furthermore: "Despite ethical obligations to participants, the values espoused by academic centers, and in some instances statutory requirements, there is no effective enforcement mechanism and no repercussions to academic institutions or individual investigators for failing to meet them."

This is a gentle way of saying that the system as currently set up encourages unbridled corruption.

Imagine that your city government had a stated policy to the effect that armed robbery was wrong and should be discouraged -- but they hadn't outlawed it, and the police never arrested anyone for it. What would the crime rate in your neighborhood be, under such a setup?

If you run several clinical trials (especially if they're small), random variation will be enough to make the results of one study look different from the other studies. If that difference yields results which are worth big money to a pharmaceutical company (one which funds research), then scientists will be under pressure to publish the results of that trial and not others. Could that be the reason the results of so many trials never see the light of day?

Studies keep popping up, claiming that this or that costly diabetes drug is worth the extra money, because it doesn't just control your blood glucose, it also prevents heart disease or some other dreaded problem. Call me cynical, but if I worked in the marketing department of a pharmaceutical company, and I saw that our high-priced diabetes drug wasn't selling because metformin did the same thing for less money, I'd be searching day and night for an opportunity to convincee doctors that the drug solves further health problems which meformin doesn't. And I might not care all that much whether this was actually true.


When mice don't floss!

A "murine study" has provided further confirmation that periodontal disease (chronic inflammation of the gums) degrades insulin sensitivity, and therefore promotes Type 2 diabetes.

I had to look up "murine" -- it turns out to mean "mouse-related" in the same way that "bovine" means "cow-related". The word comes from the name of a sub-family of rodents known as Murinae.

Anyway, the researchers managed to give a bunch of mice periodontitis, and showed that this resulted in insulin resistance.

I thought this had already been established beyond a reasonable doubt -- it's assumed to be the reason periodontal disease and diabetes so often go together. However, I guess that was established only by studying correlations in human patients. Giving mice gum disease on purpose is apparently a new one. Well, it yielded the results we would have expected.

So: if you have diabetes (or want to avoid having it), look after your gums. Flossing might not be easy, but it's easier than most things we have to do to keep blood sugar under control.


3rd Thursday Update

February 18, 2016

The warm, sunny weather we've been having (more like May than February) has faltered for a few days. My long run today, which began during a dry interlude, ended just as it was starting to rain again. But May is supposed to return by Saturday. The outdoor-exercise season is definitely back!


Re-inventing sugar

A lot of chemical engineers have been working for many years on the problem of devising an alternative to sugar which tastes just like it but doesn't have such problematic effects on the body.

Artificial sweeteners which contain no actual sugar, and don't elevate blood glucose, might seem to be the obvious solution, but it's amazingly hard to produce one which tastes convincingly like sugar and doesn't have a strange after-taste. Also, some of the more natural-tasting ones have been suspected of causing health problems.

Sugar alcohols (a chemical family of "polyols") are sugar-derived substances, altered in such a way as to make them less readily absorbed by the human digestive system than normal sugars. They have a lower calorie count and carbohydrate count than normal sugars. However, they still have the capacity to elevate blood glucose, so they aren't comparable to zero-calorie artificial sweeteners. They are often misleadingly described as "sugar-free", and diabetes patients must be cautions with them for that reason.

Another option, which I hadn't heard of until recently, is called isomaltulose. I can't really call it a sugar alternative, since it is very much a sugar. However, it's an unusual form of sugar, with interesting properties which are potentially useful to diabetes patients.

Isomaltulose was discovered in 1950; it is made by using an enzyme to alter the structure of sucrose ("table sugar"). Sucrose consists of a pair of simple sugars (glucose and fructose) linked together. What's altered by the enzyme which transforms this stuff into isomaltulose is the nature of the linkage between those two simple sugars. In sucrose, the linkage is 1-alpha-2, and in isomaltulose it's 1-alpha-6. It sounds trivial, but the altered linkage joins the sugars at a different angle, thus giving the resulting assemblage a very different shape. And in biochemistry, shape counts for a lot. Molecules work the way they do within the human body because of the way they are shaped.

Once sucrose has been transformed into the isomaltulose shape, some of its properties change. Unlike sucrose, isomaltulose does not promote tooth decay, because the bacteria in the mouth are not able to use it in the same way. Although it still tastes sweet, isomaltulose is only about half as sweet as sucrose. Isomaltulose is less hygroscopic (that is, it doesn't readily absorb water), and it is digested more slowly. (Although it is still digested and absorbed in the small intestine, isomaltulose is digested further along the intestine than sucrose would be, and this change in the digestion site results in a difference in the gut hormones that are released as a result.)

Probably the most intriguing difference between isomaltulose and sucrose, from the point of view of a diabetes patient, is that digestion of it takes longer, and the delay in digestion results in a difference in gut hormones released. Could these things add up to a health advantage for diabetes patients?

Researchers from the DZD (a German diabetes research center, the Deutsches Zentrum fur Diabetesforschung), think that isomaltulose does indeed show promise as a better sugar for diabetes patients than sucrose. (Not that any sugar is good for diabetes patients -- we're talking about mitigating the harm from the sugar consumption which, given human nature, we know is going to occur anyway.)

The researchers compared the effects of 50 g of sucrose with 50 g of isomaltulose, and found that the resulting gain in blood glucose levels was 20% lower in the case of the isomaltulose; the resulting gain in insulin secretion was 50% lower. Also, changes in the gut hormones released were thought to be more favorable to health in the case of the isomaltulose, particularly in terms of stabilizing blood sugar overall.

I must admit that I was a little disappointed that the blood-glucose spike was only 20% lower with isomaltulose; I had been hoping to hear something a little more dramatic than that. It's especially disappointing in light of the fact that isomaltulose is only half as sweet as sucrose, so people will probably use more of it, perhaps obliterating the comparatively small advantage that isomaltulose provides.

Another discouraging factor: because of the way isomaltulose is made, it's more expensive than sucrose. It is typically sold under the trade name Palatinose, and here's the price I found for 1 kilogram of it:

If you haven't heard of this stuff (I hadn't either), the reason may be that it hasn't been commercially available for very long -- it wasn't approved for sale in the USA until 2006 -- and so far it has mainly been used as an ingredient in processed foods for which it provides some practical advantage. (It is often used in powdered sports drinks, because it doesn't get lumpy.) Most consumers are not aware of it as a product to be bought. That could change, as researchers give the sellers of the stuff an excuse to promote its health advantages.

Those advantages seem to be genuine -- but they also seem to be small, and we need to keep that fact in mind. People have a tendency to hear that something is more healthful than sugar and immediately assume it is harmless at any dosage. If it's only 20% more healthful than sugar, don't go too crazy with it.

But hey -- at least it won't rot your teeth!

Re-inventing insulin

If slowing the breakdown of sugar has advantages for diabetes patients, slowing the breakdown of insulin could provide even greater advantages.

Injections of insulin are meant to substitute for the normally slow, gradual release of insulin by the pancreas. By injecting the insulin into subcutaneous fat, diabetes patients try to create a situation in which the insulin-saturated fat secretes insulin gradually, as if the fat were a normally functioning pancreas. It doesn't work all that well in practice; Type 1 patients who take frequent injections are constantly oscillating between episodes in which the bloodstream contains too much insulin, then too little, then too much.

Danish researchers have been trying to address this problem, by delivering the insulin in the form of self-assembling nanonparticles which place themselves in "hexameres" -- honeycombs of six-sided shapes. This mimics a grid in which natural insulin tends to assemble itself:

The Danish researchers were able to induce injectable insulin to form up in this way:

The idea is that, by inducing an insulin medication to assemble itself in a hexamere structure, the researchers can influence its properties -- and find ways to cause it to be released more gradually into the bloodstream, so that patients can have a stable insulin supply rather than a radically fluctuating one, and suffer fewer episodes of extremely low and high blood glucose.

It sounds as if this research is some distance away from making a medication available, and I suspect that any medication which needs that much chemical engineering to produce will turn out to be outrageously expensive. Still, it sounds like a field worth investigating.


2nd Thursday Update

February 11, 2016


February, California-style

It hit 74 degrees today. This is not winter as most people understand it, but I'm not complaining: outdoor exercise is getting a lot easier. Today's run was definitely a sweaty workout.


Captain Barley to the rescue!

I've been reading some pretty dramatic claims for barley as the miracle-food that will halt the diabetes epidemic. I've grown wary of such claims, but it's always possible there could some substance to them, so I do make an effort to check them out.

The current excitement is the result of a study from Lund University in Sweden, which found that bread made mostly from Barley kernels (with very little wheat flour) has a positive effect on various health indicators -- and has that effect within a remarkably short time period.

The researchers point to an unusual combination of fiber varieties in barley -- a combination which promotes the growth of the beneficial bacteria Prevotella copri in the gut. Apparently barley also suppresses growth of the undesirable bacteria known as Bacterioides. As a result (apparently!) of these changes in the intestinal environment, the people in the study experienced a reduction of blood sugar, a boost in insulin sensitivity, and a reduction in appetite. Also, there were favorable hormonal changes which are thought to reduce chronic inflammation. All these effects are considered helpful in preventing diabetes and heart disease.

Although making bread from barley is an old tradition in England, barley dough doesn't hold together as well as wheat dough, and some wheat is usually included just to keep the barley loaf from falling apart. The photo below shows one of the researchers slicing the barley bread that was used in the study; it was 85% barley and 15% wheat, and although she's putting a brave face on the situation, I'm not surprised that there was no picture of her popping that stuff into the toaster. Not that this makes the bread inedible, but it does hint at why barley bread has not achieved market dominance in our time.

If you would like to experiment at home, barley can be bought in bulk readily enough. It is offered in two varieties: "pearl" (or "pearled") and "hulled".

Hulled barley (sometimes called barley groats) has had only its indigestible outermost layer removed, and is considered a "whole grain". It's chewier than pearl barley, and takes longer to cook (about an hour). Pearl barley has been processed further, to remove one more layer below the hull. This makes it softer and quicker-cooking (about 40 minutes), but also less rich in fiber and other nutrients. Most recipes using barley assume you will be using pearl barley; you can usually substitute the hulled variety if you're willing to cook it longer. The barley dough used in the study was made by boiling barley kernels, grinding them up, and mixing them with a little wheat flour.

I should mention three important facts about the Swedish study:

  • It was a very small, very brief study; it followed just 20 people, and for only a few days.
  • The people participating in the study were middle-aged but apparently not diabetic. It could be that the study's findings are potentially of value to people hoping to avoid diabetes, but not necessarily helpful to people who already have it.
  • The positive effects of the barley were attributed to changes in gut bacterial populations; it's hard to know how reliably (or for how long) barley would help in this way. The researchers themselves noted that individuals who began the study with unusually low concentrations of Prevotella copri received less benefit from the barley, and it's not known if prolonged barley consumption would change that.

I am inclined to take a practical approach to all this. It's nice to know that barley seems to reduce blood sugar in people who don't have diabetes, but how does it affect people who do?

In looking into barley's nutritional specifics, I decided to compare barley with rice. This seemed fair to me: barley looks more like rice than most grains so, and in culinary terms it is used more like rice than most grains are. Like rice, barley is often encountered as a starchy addition to soups. So, anyway, here's the data on barley:

And here's the equivalent data on rice:

Looking on the bright side, barley comes out way ahead on fiber content (6 grams instead of 1 gram). However, the good news seems to end there. In terms of starch content the two grains are virtually identical. Both provide 90% of their calories as starch. Because barley has more fiber, it is considered a lesser glycemic load than rice. But still! Does it seem probable that very many diabetes patients could take in 44 grams of carbohydrate and expect their glucose level to go down? I'm not sure "eat more barley" is going to turn out to be the best maxim for most Type 2 patients to live by.

However, to be fair, I'm focusing here on the immediate, short-term impact of barley in a meal on post-prandial glucose. If the researchers are right in their interpretation of their results, eating barley could cause a brief spike in the short term, but make up for it over the course of the day by bringing average blood sugar down.

I might very well experiment, cautiously, with barley to see if I can find evidence of any such beneficial impact on me. But having been told more or less the same story several times before about other foodstuffs, I'm not going to be astonished if it turns out barley doesn't do for me what the Swedish researchers claim it does for their study participants.

Incidentally: if the researchers received any financial backing from the Swedish Barley Advisory Board or whatever, I can't find any disclosure of it.


More science news...

Astronomers have discovered a giant pig's snout hovering near the galactic core!

No, wait. What they actually discovered was the first observational evidence of the "gravitational waves" which Einstein predicted 100 years ago. As with anything predicted to exist on theoretical grounds, but not so far observed, a lot of scientists have bet their Nobel prize chances on a mission to show whether or not gravitational waves are real. It turns out they are, or at least there is finally some strong evidence that they are.

The reason the detection of gravitational waves is such an impressive achievement is that gravitational waves are incredibly weak and hard to detect. It takes a really grand, cataclysmic event to generate gravity waves strong enough for us to detect them with even the most sophisticated measurement devices.

The cataclysm which figures in the new discovery is believed to have been the violent coming-together of two massive black holes, which spun about one another faster and faster during the final seconds before they collided. That black-hole death-spiral, not a pig's snout, is what the picture above illustrates.

It has been argued that advanced alien civilizations would use gravitational waves as a communication medium, just as we use radio waves. The advantage of this approach is that gravitational waves can't be blocked or interfered with; they pass right through a planet with ease. The down side is that they don't travel any faster than light, so you'd be waiting a long time for Alpha Centauri to get back to you. (Another disadvantage is that making gravitational waves by banging black holes around would take a lot more energy than charging an iPhone.)

Just a few years ago the Higgs boson was finally discovered after decades of searching, and now gravitation waves have been discovered, too. Some people are worrying that science is running out of Big Questions to answer, but I don't buy it. Until someone can give me a much more convincing explanation than I've received so far, of why dropping a soda can causes a foam explosion when you open it shortly thereafter, science will still have work to do. And then, of course, there's the whole barley thing to sort out. I expect scientists will be kept busy for a while yet!

1st Thursday Update

February 4, 2016


A correlation! What does it mean?

Because I'm always reading reports on diabetes research, I'm always having to remind myself of the important distinction between correlation and causation. Correlation simply means that one statistical trend is associated with another. For example, a researcher studying gout might find a higher rate of the disease among people who play golf.

Okay, but what does it mean that you've found more gout among those who play golf? It doesn't necessarily mean that playing golf causes gout. It doesn't necessarily mean that having gout makes you want to play golf. It may not mean anything at all. Or... it may mean that gout and golf are both associated with some third thing, a thing not yet identified. (I made up that golf/gout correlation, by the way, just as an example.)

We need to keep this sort of uncertainty in mind whenever a study finds that some disease (or absence of disease) is associated with a particular food, behavior, or other factor. It's necessary to use caution in interpreting such correlations, because we might easily misunderstand the connection between the two correlated things (even if we're right in assuming there is a connection). It's especially important to be cautious in cases where the correlation seems to tell a story which confirms our preconceptions. The more you'd like to believe it, the more careful you need to be in evaluating it.

Here's a correlation that I didn't make up: according to a new study conducted by two economics professors at Emory University, the more you spend on your wedding, the likelier you are to get divorced. The lowest divorce rate is among those who spent under $1,000 on their wedding, and the divorce risk climbs steadily as the cost of the wedding increases. (Not many people get married of under $1,000, by the way: the average American wedding these days costs $30,000.)

I need to be careful about making too much of this research, or even believing it, because it appeals to me too much. It seems to confirm all my prejudices about people who have (or at least spend) too much money. "Of course they get divorced!" I thought, as soon as I'd read the report. "If they're spending that much, then they're probably spoiled brats!"

Maybe so, although it's likely that a lot of people who are not spoiled brats end up being manipulated, coerced, shamed, and swindled into spending far more on a wedding than they thought they were going to. I've spoken to some shell-shocked people who went into the wedding-planning process with quite modest plans, and soon found that they had become the helpless captives of the wedding industry mafia, powerless to do anything but hand over money. (Maybe Martin Scorsese should make a movie about that industry.)

It could be that couples who overspend on weddings collapse under the strain of paying off their mountain of wedding debt (or the strain of fighting over whose fault it is that things got so far out of control). At any rate, we can't simply assume that overspending on a wedding proves the couple had defective personalities from the start.

I should add some cautionary information here. I was not able to get access to the original research paper; that graph above comes from an article in The Atlantic, and it's their reading of what must have been a very hard-to-interpret data set in the original paper. Other news outlets covering the story have reported different numbers. In one summary I read, the added divorce risk for those spending over $20,000 was 50%, not 46%, while another source made it out to be a gargantuan 350%. I have no idea who's right about the actual numbers, although the claim that divorce risk rises as wedding costs rise seems to be consistent across all journalistic summaries of the research.

Another thing that's been consistent across all summaries of the research is the assumption that the findings mean you can reduce your divorce risk by having a cheaper wedding. That might not be the case at all. If the reason that people get divorced after a lavish wedding is that there is something wrong with them, that thing will still be wrong with them even if, on their wedding day, they restrain their natural impulse toward excess. And suppose that the reason for the low divorce rate following cheap weddings is that such weddings are likelier to involve immigrants whose families come from a culture extremely intolerant of divorce. If that is the case, then saving money like they do -- without adopting their culture -- will not protect you.

The research on wedding costs appeals to me greatly, because it seems to confirm all sorts of things I would like to believe anyway -- but that's when you have to be especially careful not to read too much meaning into a correlation which might not mean what you think it does.

For example, two new studies just came out (one at the end of January, and the other at the beginning of February) both find that obesity and diabetes in mothers correlates with an increased incidence of autism in their children. How much of an increase? The studies disagree; the first study found that the autism rate was increased by a factor of 1.5, but the other found the rate was increased by a factor of more than 3. That seems like quite a disparity. The study which found the larger risk factor was a much smaller study, and was presumably more affected by random variation within a comparatively small sample size. I have to assume the more modest risk factor of 1.5 is more accurate. Which means that, in absolute terms, the incidence of autism in diabetic mothers is 3.3%, versus 2.2% for non-diabetic mothers. (The news sounds a little less alarming when you put it that way, doesn't it?)

Now, autism has become a very complicated issue to study, because the terms of diagnosis have been greatly broadened. Once upon a time, only children who were severely disabled in terms of communication and human interaction were called autistic; now doctors use the term "autism spectrum disorder", and much less severe cases are recognized and included in the health statistics. This changing view (and changing definition) of autism makes it a very tricky business to correlate anything at all with autism incidence.

These days, because of the statistical confusion on the subject, people imagine that there is an "autism epidemic" going on, and they're looking for something to blame it on. So far they've been blaming it on vaccinations -- are they going to blame it on the mothers now, for gaining too much weight and becoming diabetic? If 96.7% of obese, diabetic women have non-autistic children, it doesn't seem as if it would be fair to demonize them, and I hope we're not heading in that direction. Also, the autism risk is increased even in women who weren't diabetic until pregnancy drove them into gestational diabetes -- and plenty of women develop that during pregnancy, whether they are obese or not; so there's another reason not to blame the mothers.

Maybe that's the real danger of correlations: they make people think they've found the perfect excuse to blame somebody they wanted to blame anyway.


Another correlation: diabetes and tendon pain

Tendinopathy means injury or illness of a tendon; it is a slightly less specific term than tendinitis (short-term tendon injury with inflammation) or tendinosis (chronic degeneration of tendon tissue, without inflammation). Tendinopathy encompasses both of those kinds of tendon injury. And both are apparently correlated with diabetes.

Incautious people will jump to the conclusion that this means diabetes causes tendinopathy. Apparently diabetes can cause tendinopathy (because of some kind of harmful effect of excess blood sugar on the tissues involved), but it's also possible for the tendinopathy to cause diabetes (often tendinopathy involves inflammation, and inflammation promotes diabetes by degrading insulin sensitivity). People who already have diabetes are likelier to develop tendinopathy, but the reverse is also true: people who already have tendinopathy are likelier to develop diabetes.

So the answer to the great correlation question (does A cause B, or does B cause A?) is, in this case, "yes".

One implication of this finding is that, for a lot of diabetes patients, tendon pain will get in the way of their doing the exercise that's needed to stay healthy with the disease. Fortunately, I haven't been blocked in that way, except for the occasional short-term sports injury. But for a lot of people, it's a big issue.


Inner cannabis and diabetes

Most drugs (the ones used for entertainment, I mean) operate by imitating -- and greatly exaggerating -- the biochemical effect of naturally-occurring substances in the body. Opiates, for example, happen to be able to stimulate our cellular receptors for endorphins. However, because opiates aren't real endorphins, the endorphin receptors can't disable the opiates as soon as they've delivered their chemical message. The opiates latch onto the receptor for a long time and overstimulate it, hence the narcotic effect they have on us.

The word endorphin means "inner morphine", by the way -- the morphine-like compounds which our bodies produce naturally. It is a curious fact of medical history that these internally-generated substances tend to be discovered long after scientists have discovered the drugs that mimic them. You might not think that we have any inner cannabis to speak of, but in fact we do. The human body uses "endocannabinoids" as signalling molecules, and the cannabinoids in marijuana function as more potent and persistent versions of them.

Well, it turns out that one of the things our bodies use endocannabinoids for is to exchange signals between the alpha cells and beta cells in the pancreas, and coordinate their actions.

Coordinating the alpha and beta cells is important to blood sugar control, because the cells secrete hormones with opposing effects. Alpha cells secrete glucagon, which elevates blood sugar. Beta cells secrete insulin, which reduces blood sugar. The body fine-tunes blood glucose by adjusting the balance between these two opposing hormones. Endocannabinoids exchanged between the alpha and beta cells help keep the two in balance. They also seem to operate during fetal development to determine how stem cells differentiate into alpha and beta cells. It seems likely that fetal endocannabinoid levels play a role in determining whether the baby will be born with a propensity to become diabetic.

So what are the implications in terms of the impact of recreational marijuana use on diabetes, or diabetes risk?

The researchers say it is too early to draw any conclusions about whether marijuana is a risk factor -- or potential treatment -- for Type 2 diabetes. But it seems clear that there's a cannabis connection of some kind here, and we'd best find out what it is.


Stop me before I eat sugar again!

Here's the latest from XKCD:

A Reuters poll found that 58% of Americans say they are trying to reduce their sugar intake. But people are having a hard time doing it, because such large amounts of it are being added to various processed foods.

You have to become pretty good (and consistent) at reading nutritional labels, if you want to avoid taking in lots of hidden sugar in foods you don't think of as desserts.

That stuff is everywhere!


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