Who else? Jeremy Berg strikes again.

OER’s Division of Information Services has now analyzed 32,608 applications (including research project grant, research center and SBIR/STTR applications) that were discussed and received overall impact scores during the October, January and May Council rounds in Fiscal Year 2010. Here are the results by institute and center:

Mephedrone, or 4-methylmethcathinone, is a recreational drug that got very popular in the UK in recent years, no doubt due to it being legal to sell and possess up until April of this year. There is not a tremendous amount known about the pharmacology of this drug at present, however we can deduce quite a bit about where we should start looking from user experiences. I am currently intrigued by the fact that if you look at online user forums you can get Ecstasy fans describing mephedrone as being sortof like Ecstasy…only not as good, or not quite the same. In addition, a recent paper which surveyed a certain subset of users found that many of them report intranasal mephedrone to be as good or better than intranasal cocaine. You will recall, of course, that I have a great deal of blog interest in discussing MDMA-related fatalities.
ResearchBlogging.orgA Case Report that recently appeared in the Lancet helps us to connect up some dots. Sammler and colleagues report on the case of a 15 year old girl who presented to their emergency department one afternoon with “altered mental status, vomiting and nausea”. She had been out drinking the night before and had also consumed a “white powdery substance”. The clinical workup contained a few interesting clues:

-the cerebrospinal fluid (CSF) opening pressure during lumbar puncture in the lateral decubitus position was raised at 350 mm of water.
-Blood tests showed profound hyponatraemia at 118 mmol/L.
-Serum osmolality was low at 256 mmol/kg, whereas urine osmolality was high at 742 mmol/kg.

Well, well, well. Hyponatraemia is frequently reported in cases of MDMA-related medical emergency and death. This is very likely related to an effect on vasopressin / antidiuretic hormone release that would cause the kidneys to retain water, perhaps in combination with induced polydipsia (urge to drink) or intentional (albeit misguided) prophylactic strategies. This is likely driven by the serotonin transporter inhibition properties of MDMA, this indirect agonist effect perhaps working through the serotonin 3, 2C, 4 and/or 7 receptor subtypes to induce vasopressin release.

I have no good stats but there is a distinct impression from reading MDMA case reports that young women may be particularly liable to hyponatremia following MDMA. This is something I need to take up at some point- is there evidence for increased sensitivity of adolescent women to fluid balance dysregulation?

Returning to the topic at hand, is this just a case of MDMA-induced hyponatraemia?

Fortunately, the doctors ran the tox panels:

We suspected drug intoxication and did gas chromatography-mass spectroscopy of the patient’s urine; this was unequivocally positive for mephedrone metabolites, but was negative for opioids, methadone, barbiturates, cocaine, cannabinoids, alcohol, benzodiazepines, and amphetamines including ecstasy. Analysis of the white powder was consistent with mephedrone.

Interesting. This suggests to me, as it did to the authors, that there is a MDMA-like component to this mephedrone stuff. It may be a dopamine transporter inhibitor and/or dopamine releaser like cocaine, amphetamine, methamphetamine but the hyponatraemia suggests an additional (significant) serotonergic component of the pharmacological response to mephedrone. This would be consistent with those users who report it as being at least somewhat like Ecstasy.

As I discussed before, one prior paper reported on the subjective effects of several cathinone analog compounds using the drug-discrimination assay. The cathinone structure if very similar to amphetamine and supports parallel modifications. The question becomes whether the same modifications of the cathinone and amphetamine core structures convey similar changes in the pharmacology.

In very brief overview of the drug-discrimination procedure, you train rats to tell you if the drug you have just given it is similar to a reference drug such as amphetamine or MDMA. The prior paper found that methylenedioxycathinone (MDC) and methylenedioxymethcathinone (MDMC) fully substituted for MDMA at reasonably similar doses. MDMC also fully substituted for amphetamine whereas MDC did not; in both cases the potency was much lower-higher doses had to be employed for comparable effect to the reference amphetamine.

This is complicated, because if anything MDA is closer in subjective and behavioral effect to amphetamine than is MDMA. And if there are any data on the 4-Methylmeth modification of amphetamine, I am unaware of them. Nevertheless it provides some clue that we are not totally out of line to suspect that the 4-Methylmeth modification to cathinone adds on a serotonergic agonist component, very likely mediated by blockade of the serotonin transporter (with perhaps some releasing effect)…just like one sees with the methylenedioxymeth modification of amphetamine in the case of MDMA.

Final note: The 15 year old girl in this Case Report made a full recovery. That’s a very good thing.
Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, & O’Riordan JI (2010). A harmless high? Lancet, 376 (9742) PMID: 20801405

Donors Choose Challenge 2010

September 30, 2010

It is my favorite time of year for blog-related group action activities.
Welcome back to the science blogosphere’s efforts to raise money to support classroom projects with Donor’s Choose.

As always, the key consideration is that every little bit counts. If prior years are any judge, the grad students in my readership are unbelievably generous, given their limited incomes. Just sayin, PIs, just sayin.
Also, I’ve selected a bunch of projects for your consideration that caught my eye for undoubtedly random and personal reasons. If you don’t see anything that catches your fancy, take a look through other bloggers’ lists or search for yourself at the Donor’s Choose site. No matter what you choose to support, kids win. And that means we all win.
Now, I must confess that I blew it this year. I was distracted working on some grant or other and blasted up my Donor’s Choose challenge page (Science up the Schools 2010!) ahead of the official launch date for the competition between blog collectives/interests. My total bad. but then The Gam launched….and our new MortalBlogEnemies launched…and what was I gonna do? Now PZ has thrown down with his 8 billion pound commentariat.
Sorry Janet. I’m not having a good few weeks here….

My feed for writedit’s comments keeps being populated with impatient applicants who have managed to land a decent-looking score on a NIH grant proposal. See this one.

The September council met on the 21st, and I have heard nothing. My R01 was scored at the 12th percentile and I am an ESI. I haven’t heard a thing yet, and my Commons status is “Council Review Completed.”

or this one:

The council meeting was over on September 1, and 3rd, mt erA commons sais `council review completed’. It still says the same. My PO is unreachable (has gone back to India until October 1st week). Does this mean I did not get the grant?

for the type.
This is understandable, given the importance of each grant award to the PI in question. But still, this is not mysterious stuff here folks. The timeline for getting a grant awarded is pretty clear.
Let’s take the current Fall Council rounds as an example. The applicants submitted their proposals back in Feb-Mar in most cases- with continuing submission, HIV-related grants and the odd RFA-related study sections, anywhere from January to mid April. These proposals were reviewed for the most part in Jun-Jul with the applicants receiving their scores about a week after the meeting and the summary statements several weeks later.
So they’ve been waiting a long time already. A borderline score makes things extra important when it comes to information about likely funding. Will the proposal sneak under the wire after all funds are accounted for in the IC? Will it really have zero chance, no matter the theoretical nonzero chance? Should, in point of fact, the applicant busy herself with revising the proposal for November or working on a new one for October? Or start planning preliminary studies for a Feb/Mar submission?
But folks, this part of the process is readily understandable.
Even if you have a 1%ile grant, NIH is not going to tell you it is funded until the Notice of Award is actually prepared. And that takes place in the week or two just before the first possible funding date. In this scenario, December 1. So no, you will not hear anything definitive until late November at the very earliest. Stop driving yourself crazy asking over at writedit’s place if the Commons status line will tell you anything. It won’t.
Now the bad news is that this particular round for funding has an extra-special annoying caveat. It is the first one of the new US federal fiscal year. That means that the ICs can’t commit to new awards until Congress passes the appropriations bill funding the NIH for the next year.
They never seem to get that passed on time and it often waits until Congress returns from vacation in late Jan/early Feb.
Sorry about that but you just have to chill.

As my disclaimer, I am one of those that reminds new (and not so new) applicants to the NIH for research funding to talk to the Program Officer. Early and often, just like voting. In the pre-submission phase you want to identify the line POs down in the Division and Branch structure of one of the funding Institutes or Centers of NIH who might be interested in your work. After review, the PO who was actually assigned to your application can give you invaluable feedback about how the review of your application went down. So I recommend calling this person.

Take their comments, however, in context. They don’t know everything. Even if they are sitting in the room, paying attention to the discussion of grants, this does not always mean they truly understand what is going down.

One of the times I get really frustrated with POs is when they are so fixated on the objective truth of peer review. They often act as though they believe that the review process really does work nearly perfectly. Most often when it comes to newbies. Consequently if you are coming up short on your proposals, in their worldview they think you are “not writing well enough”. Or need to (somehow without funding) provide more/better preliminary data.

So this advice gets reflected back on the poor applicant who 1) drives herself crazy trying to “improve” her writing (which is just fine already) or 2) goes back to the lab to find that perfect figure which which will guarantee this grant gets funded (no such thing).

Disastrously, this prevents said newbie from doing what she really needs to be doing which is to submit multiple good-enough grants. In the face of budgets which allow the funding of only a subset (a third? quarter?) of the grants which are excellent and interesting and impactful and all that jazz, review becomes variable. Meaning the difference between making it into a fundable score and just missing a fundable score takes on the appearance of chance. The only way to beat such odds is to give yourself more chances at the game. This means writing and submitting multiple applications (on different topics, of course).

Don’t mistake me. There IS a learning process for grant writing and it remains good advice for the new (and not so new) investigator to seek feedback from peers prior to submitting a grant and when doing the post-mortem after receiving the summary statement. But this can’t be taken too far. At some point, you are just driving yourself crazy with conflicting (good) advice from people who are in different situations from yourself or each other. And anyway, you can apply the stylistic and structural advice you have received to new application just as well as to the revision of your existing application, right?

If you are in a position that Journal of Neuroscience is to be sneered at for an insufficiently high IF, you are a GlamourMag scientist. Topic is irrelevant at that point.

Once I get a fair number of responses I’ll put my real thoughts in the comments…