are exosomes the Priuses of RNAi transport?

Knocking out insidious genes using RNA-interference (RNAi) has been massively pursued as a therapeutic technique since its discovery.  Specifically, methods of delivering RNAi through the blood stream to target tissues have been of great interest.  Scientists have successfully packaged and delivered RNAi in  lentiviruses, micelles and other nanoparticles.  However, the search for cost-effectiveness, efficiency and target accuracy never sleeps (insert wise crack about the tendency of their funding to hibernate).

In a study recently published in Nature Biotechnology, exosomes are suggested to be a significant improvement over other vehicles.  The scientists used dendritic cells -- derived from bone marrow progenitor cells, and not to be confused with neural somas -- and proceeded to test the efficiency and accuracy of their RNAi packaging and delivery.  They purified the exosomes, tagged them with muscle or brain targeting peptides, loaded them with exogenous cargo (siRNA for GADPH, a housekeeping gene), and tested their delivery both in vitro and in vivo.

Alvarez-Erviti and colleagues achieved a marked knockdown of GADPH in vitro, and an even more impressive knockdown in several peripheral organ and brain region tissues in vivo, suggesting an improved blood brain barrier-transcending capacity compared to other methods.  The exosome delivery method was accurate, and achieved a 60% knockdown of mRNA and a 62% knockdown of protein expression using, allegedly, 10% of the siRNA cargo that other methods have used.

62% efficiency is generally accepted as a pretty high yield in the biomedical sciences.  Whether this exosomal packing and delivery system can be optimized to better penetrate the blood brain barrier remains to be seen.  However, with its cost-effective, accurate and non-invasive methods, the exosome may be the Prius of siRNA delivery.


Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, & Wood MJ (2011). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature biotechnology, 29 (4), 341-5 PMID: 21423189

Saccharomyces boulardii improves migration of new epithelial cells

The lifespan of healthy intestinal epithelia is generally accepted to be about 5 days.  These cells, once departed and sloughed off into the fecal stream, are replaced by newer, younger, healthier cells which proceed through the same life-cycle.  In the case of inflammatory bowel diseases (IBDs), in addition to inflammation/ulceration/tissue injury, the migration process of these new epithelial cells is stunted.  Since the replacement cells have trouble reaching their destination, damage to the intestinal lining is exacerbated.

A recent study -- published in PLoS ONE and open access if anyone wants to take a peek -- investigated the capacity of a nonpathogenic yeast to alleviate this stunted migration of new epithelial cells to the tips of intestinal villi (the fingers of tissue that protrude from the intestinal wall to create surface area for absorption).  Saccharomyces boulardii (Sb) is typically used to treat issues such as diarrhea, the idea being that it stimulates growth factors that help restore homeostasis to the gut.

This nigh-rockstar study strikes me because it is targeting a curative mechanism as opposed to a squelching of symptoms.  To achieve actual remission in IBDs, one has to pwn both inflammatory and repair dysfunctions.  The inflammatory component is predominantly targeted by the entourage of immuno-suppressants with which Crohns are so familiar.  Repair is seldom highlighted as it should be -- excepting methods of balancing gut flora.

The team of scientists in France, lead by one Frederic Andre, looked at the beneficial effects of Sb in both mice and an in vitro wound model (this is a strain of cultured epithelial cells which are attacked gently with a toothpick... rather cute).

The first major finding was that mice who were fed Sb for one week doubled new epithelial cell migration.  Only one downer for me in this study was that the mice were all healthy, with no in vivo IBD model for comparison.  Nonetheless quite encouraging, no?

The second conclusion was that the wounded cell line closed its wound (or, repaired its injury) by roughly 70%.  Their video supplement to this end is quite something.

The scientists conclude that Sb improves new epithelial migration both in vivo and in vitro.  Interestingly, the study suggests that increased migration is due to increased motility of cells and not to increased proliferation (the generation of new cells).  Sb may be stimulating this activity by secreting factors that stimulate  a target signaling pathway FAX/paxillin, which leads to several physiological changes in the intestinal epithelial lining that enable motility of new epithelial cells.

The thing about supplement studies such as this one is that they make me want to stop by the grocery and pick some up on my way home...


Canonici A, Siret C, Pellegrino E, Pontier-Bres R, Pouyet L, Montero MP, Colin C, Czerucka D, Rigot V, & André F (2011). Saccharomyces boulardii Improves Intestinal Cell Restitution through Activation of the α2β1 Integrin Collagen Receptor. PloS one, 6 (3) PMID: 21483797

an instance of misconstrued media reporting: placebos

A most recent example of the media mis-representing scientific findings is the recent NPR report on placebos being equally effective in IBS patients as "the strongest prescription drugs", even when the patients knew that they were being given the placebo.  This coverage was a translation of a study out of Harvard Medical, and published in PLoS ONE.


The study, termed "honest placebo", didn't actually eliminate the deception for which placebo studies are renowned.  In the methodology, the researchers report telling the patients who received placebo treatment that “placebo pills, something like sugar pills, have been shown in rigorous clinical testing to produce significant mind-body self-healing processes.”  By this design, the patients may have received a similar benefit to what they would have experienced if they had expected that they were being given a strong prescription drug.  The patients were given the impression that the placebo would help them.  What would have contributed even greater meaning to this study is an additional group who were told that they were receiving a placebo drug, but not told that it was expected to help them.


As many of the comments on the NPR report echo, a strong component in placebo studies is the idea of holism and self-healing.  Dr. Ted Kaptchuk, a co-investigator in the Harvard study, states in his interview that the healing factor was assumed to be the "self-healing ritual" of dosing oneself twice daily, even with a placebo.  This scientist would suggest that self-healing is as likely to take place due to the belief that a placebo had been reported helpful as it is to be due to the ritual of pill-taking.


The great value of this study's conclusions is lost in the media translation: there is healing potential in having the expectation that your therapy will work. 
 NPR does the courtesy of acknowledging that "placebos don't shrink tumors or stop multiple sclerosis in its tracks".  However, particularly for conditions such as IBS, which have consistently shown to be negatively effected by stress and proactive treatment, this study's findings are important to treatment development.


Ted J. Kaptchuk, Elizabeth Friedlander, John M. Kelley, M. Norma Sanchez, Efi Kokkotou, Joyce P. Singer, Magda Kowalczykowski, Franklin G. Miller, Irving Kirsch, Anthony J. Lembo (2010). Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome PLoS

SfN 2010: Monday

Monday morning's highlight was the Experience-Dependent Synaptic Plasticity and Neurogenesis in the Degenerating and Injured Brain nanosymposia session.


Carl Cotman, professor of neurology at UC Irvine and a potential mentor, spoke about the effects of exercise in mice, canines and humans.  Dr. Cotman specializes in Alzheimer's (AD) research, and presented a collection of studies highlighting the effect of exercise on blood flow, amyloid aggregation and instance of BDNF.  In transgenic mouse models of AD (Tg2576), Cotman discussed reduced amyloid and increased BDNF with exercise.  In humans with AD, increased vessel volume and blood flow was observed with fast walking, corroborative with decreased amyloid reported by Liang et al in the Annals of Neurology this year.


Most notably, Dr. Cotman proposed that the brain "has a memory for exercise."  Exemplifying this statement was his study from 2005 where AD rats exercised on a treadmill for one week, resulting in increased BDNF in the hippocampus.  Some of these rats proceeded without exercise in the following week which resulted in decreased BDNF levels.   These levels increased rapidly when the animals were exercised for an additional week to levels beyond those revealed due to the initial exposure, a phenomenon that typically takes weeks to induce in naive rats.  This "memory for exercise" may prove to be key in designing rehabilitative exercise programs.


Mike Jakowec and Giselle Petzinger, respectively professor and clinician-researcher at USC, represented the recent work of their labs as well as the strong collaborative efforts within USC's Neuroscience labs.  Advocate of exercise in rodent models of Parkinson's disease, Dr. Petzinger presented evidence that exercise may be working through the indirect dopamine pathway (D2) to aide motor recovery.  Mot strikingly to me, their lab has reported that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in dopamine neuron spine loss specific to the D2 pathway via [F]Fallypride radiotracing (PET scan).  Exercise in their MPTP mouse model results in a 98% increase in the striatal D2 receptor.  This research suggests some very interesting targets for intervention.


The David Kopf lecture on Neuroethics was given this year by Hank Greely, professor of law at Stanford, and a professor by courtesy of genetics at the School of Medicine.  Beyond delivering a lecture as eloquently as one will ever hear, the poignant stars of Dr. Greely's talk were copious.


Dr. Greely opened by saying that the "ethical issues of neuroscience are 10 years behind those in genetics," referring to the paradigm sweeps that genetic discoveries have prompted (i.e. eugenics).  He elaborated that the implications of neuroscientific discovery were "more important than [those of] genetics, made so by immediacy and power."  Namely, neurological dysfunction has very present consequences, whereas genetic abnormalities must emerge on the physiological level before they can be acted upon.  For instance, if you were to find yourself predisposed to Alzheimer's through genetic testing, you would be protected from discrimination by the Genetic Information Non-discrimination Act of 2008.  However, there exists no such protection if you are diagnosed via MRI.


Humans as mind-readers, MRI's distinguishing between conscious and unconscious vegetative states, and the responsibility of humanity to discern what is an adverse disease and what is just a condition that makes "us" (the indirectly affected "us") uncomfortable:  these are some of many issues with which neuroscientists can become dangerously dissociated, but the bench does not separate us from the issues produced by our discoveries.  The mindfulness of scientists guides social consequences.


I refer readers to Stanford's Neuroblog and The Neuro Dilettante for more adequate coverage of Greely's lecture.



Liang KY, Mintun MA, Fagan AM, Goate AM, Bugg JM, Holtzman DM, Morris JC, & Head D (2010). Exercise and Alzheimer's disease biomarkers in cognitively normal older adults. Annals of neurology, 68 (3), 311-8 PMID: 20818789


Adlard, P. (2005). Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease Journal of Neuroscience, 25 (17), 4217-4221 DOI: 10.1523/JNEUROSCI.0496-05.2005

Journal Club Follow-Up: Coenzyme Q10

Many Parkinson's patients take Coenzyme Q10 supplements.  As mentioned in the previous post, CoQ10 is part of the Electron Transport Chain -- a very important part, in fact, as it alleviates pressure on our precarious and susceptible-to-aging Complex I.

While many theorize that Complex I is shut down or is deficient in PD (1, 2, 3, 4), others believe that deficient activity of the CoQ10 pool beside Complex I is more to blame (5, 6).  The CoQ10 theory claims that PD causes a deficiency in the CoQ10 pool that carries electrons from Complex I to their next destination without producing ROS.  As a result of low CoQ10, electrons build up in Complex I and get released from the entrance because they cannot leave through the exit.

Some PD patients are able to take CoQ10 supplements and improve their condition (7).

It is my opinion that CoQ10 is a palliative treatment and not a long-term solution.  The Ndi1gene therapy discussed in the previous post is a better option if it makes it to, and proves robust in clinical trials.  My reasoning is that a genetic replacement for Complex I is a more stable therapy than a persistent aid to CoQ10: it is more permanent and a more widespread solution; a large portion of PD patients do not have CoQ10 deficiencies.  Ndi1 would also contribute to the sustaining of the proton gradient in the mitochondria, also vital to creating energy in the ETC.


Greenamyre, J. (2001). Response: Parkinson's disease, pesticides and mitochondrial dysfunction Trends in Neurosciences, 24 (5) DOI: 10.1016/S0166-2236(00)01788-4

Schapira AH (1994). Evidence for mitochondrial dysfunction in Parkinson's disease--a critical appraisal. Movement disorders : official journal of the Movement Disorder Society, 9 (2), 125-38 PMID: 8196673

Morais, V., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., Van Coster, R., Wurst, W., Scorrano, L., & De Strooper, B. (2009). Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function EMBO Molecular Medicine, 1 (2), 99-111 DOI: 10.1002/emmm.200900006

Storch, A., Jost, W., Vieregge, P., Spiegel, J., Greulich, W., Durner, J., Muller, T., Kupsch, A., Henningsen, H., Oertel, W., Fuchs, G., Kuhn, W., Niklowitz, P., Koch, R., Herting, B., Reichmann, H., & , . (2007). Randomized, Double-blind, Placebo-Controlled Trial on Symptomatic Effects of Coenzyme Q10 in Parkinson Disease Archives of Neurology, 64 (7), 938-944 DOI: 10.1001/archneur.64.7.nct60005

Journal Club: RBD and Parkinson's Disease

There is a great deal of research being done regarding the mechanisms of Parkinson's disease (PD) and possible targets for therapeutic cures.  Yet, it is one of many conditions that remains incredibly hard to diagnose.  PD patients are not typically diagnosed until the disease has progressed to 70-90% dopamine cell depletion when symptoms become observable in movement behaviors (Jankovic 2008).

By the time cell loss has progressed this far, it is very difficult to achieve a successful long-term treatment plan.  Pharmaceuticals such as L-Dopa (Jubalt et al 2009) and rasagiline (Olanow et al 2009) are generally effective, but can lose their effect or cause dangerous side effects over time.  Deep brain stimulation has been shown to be very effective behaviorally, but there it is an intense procedure which has occasionally been correlated with subsequent cognitive impairments (York et al 2008).  Exercise therapies have also shown promise in recovery therapy, but have seemed more lasting in the peripheral nervous system than the dopamine system of the CNS (Goodwin et al 2009; Petzinger et al 2007; Muhlack et al 2007).

When it is so important to try to identify markers of PD before it progresses beyond our current ability to treat it in a lasting way, Dr. Ronald Postuma and colleagues out of Montreal, Quebec, Canada have identified REM sleep behavior disorder (RBD) as a possible indication of developing PD.  RBD is the loss of muscle atonia that normally occurs during REM sleep, causing a person to thrash unconsciously.

Their study is a beautiful longitudinal representation of several patients diagnosed with RBD in the 1980s who developed either PD or dementia by 2004.  Of their 17 final RBD patients, 6 (5m/1f) had developed PD and 11 (10m/1f) developed dementia.

The Postuma group suggests that there might be a discrete pathological condition specific to "RBD-then-neurodegeneration"which has different early manifestations than PD alone.  A very interesting concept as RBD, dementia and PD are all distinctive in their Lewy body and ß-amyloid
deposition.  If further study of the evolution of RBD into PD shows a strong correlation, this could be a giant leap forward in terms of PD diagnosis and early treatment.  There may indeed be a distinct pathology to this progression or there may not be.  In any case, this is a very important study in the field of neurodegenerative disorders, and I believe it is expecially important to get longitudinal studies like this one funded.

The staging model of PD developmnt proposed by Braak et al in 2003 proposes that the effects of PD begin in the olfactory area of the brain, spreading to autonomic and sleep-involved regions, and finally to dopamine loss in the nigrostriatal pathway and several downstream cortical pathways (Braak et al 2003).  The Braak model, in conjunction with this new proposal from Postuma et al, leaves me wondering about Restless Leg Syndrome (RLS) as another possible indicator of PD.

The connection between RLS and PD is in dopaminergic transmission, as suggested by Dr. David Rye in 2004.  A study by Tan et al in 2002 found that prevalence of RLS in PD patients was not significantly different from incidence in their healthy population, roughly 15%.  The Tan study was not looking at progression of RLS into PD, however, so it is possible, as suggested in the Postuma study, that RLS-PD may have its own unique pathology. 

To date, I have not found any longitudinal studies of RLS progressing into RBD or PD.

gene patenting

This week's Science Friday focused on gene patenting.  Specifically, a case that has been in court since May of 2009: the American Civil Liberties Union (ACLU) -- along with several cancer patients and organizations of pathologists -- has raised a lawsuit against Myriad Genetics' patenting of the two genes BRCA1 and BRCA2.  Mutations of these genes are indicative of increased risk of breast and ovarian cancer.

The ACLU claims that Myriad's 1994 patent on the genes is illegal, unconstitutional and should be thrown out.  The issue of importance to the cancer patients involved is that Myriad's monopoly on the tests for mutated BRCA1 and 2 prevents patients from getting a second opinion on the results of their tests, and from obtaining a more affordable version of the test.

In my mind, patenting genes is like patenting anything else in medicine.  By invoking a 20-year period of exclusive rights, development of the patented technology or drug is inhibited.  This is the way it has worked with pharmaceuticals for eons: drugs remain produced, distributed and exorbitantly priced by the pharmaceutical companies who patent them, and become eligible for other companies to optimize and distribute generically when that 20-year period is up.

The opposition to this argument is that patenting genes causes more stunting to medical innovation -- and, by default, medical cures -- than does patenting of drugs and other medical technology.  By patenting genes and the single test that has been developed to identify them, patients interested in the risk those genes may pose to them are forced to rely on the interpretation of the patenting company.  In the case of BRCA1 and 2, patients cannot get a second opinion outside of Myriad Genetics; they are forced to rely on the results obtained from Myriad's test and on the interpretation of Myriad's doctors.

My response to this opposition is as follows:

Genes are only a single indication of disease.  It has been reported that  "inherited BRCA1 and BRCA2 mutations account for 5 to 10 percent of breast cancers and 10 to 15 percent of ovarian cancers among white women in the United States" (Campeau et al 2008) -- having the mutations is not a definitive diagnosis of cancer.  It has also been reported that this percentage is even smaller: "[a]pproximately 5-10% of breast carcinomas and 10% of ovarian carcinomas are ascribable to a genetic susceptibility. Of these, about 40% are related to genetic mutations in the genes BRCA1 and BRCA2" (Palma et al 2006).  Take from that statistical discrepancy what you will -- I guarantee there was not a new census taken between 2006 and 2008.

If patenting of genes inhibits patients from getting a second opinion on their genetic tests, it seems that seeking a verification through other diagnostic methods is not only an acceptable option, but a preferable one.  Treatment of breast/ovarian cancers in particular are radically invasive and life-altering; until the BRCA gene identification tests are available "generically", mammograms,  MRI and screenings for other genetic markers of breast/ovarian cancers are not only options but -- in my very humble opinion -- an incredibly good idea before making decisions about radical mastectomy and chemo:

"Clinical testing options for BRCA1 and BRCA2 are limited in the United States. In contrast to genetic testing for BRCA1 and BRCA2, genetic testing for other cancer susceptibility genes (MSH2, MLH1, PTEN, TP53, etc) is available from numerous profit and notfor- profit laboratories, with a range of testing options and prices."

"In addition to DNA sequencing of BRCA1 and BRCA2, genetic testing for other major breast cancer susceptibility genes including CHEK2, PTEN, and TP53 is clinically available in the United States." (Walsh et al 2008)

 Patients at risk for cancer should not limit their diagnosis to the outcome of a single kind of test when there are several out there, and certainly not to a single genetic test which measures only susceptibility.  I do not argue against the legitimacy of a patient's concern, I just don't think that this particular argument is reasonable ground to make illegal the patenting of genes by their discoverers.

I am not sure I agree with the ACLU's argument either:

“What they have really patented,” says Chris Hansen of the ACLU to the New York Times, “is knowledge.” 

Really?  If that is a legitimate statement, then every biomedical patent in the world is a blockade against knowledge, and they should all be overturned.  Patenting is a measure taken to protect and honor the discoveries of researchers.  It gives them the opportunity to make advancements on their own discoveries before the whole world is allowed to take a crack at them.

"Genes are informational. [By] allowing a company to have a patent on the actual sequence you are restricting the free flow of information," Tania Simoncelli, ACLU's science advisor, told Pharmacogenomics Reporter back in May.  Simoncelli's colorful expatiation of this comment can be found here.

THE POINT OF PATENTS IS TO TEMPORARILY RESTRICT THE FLOW OF INFORMATION.  IF YOU WANT TO BRING THE FIRST AMENDMENT INTO THIS, YOU HAVE TO FIGHT ALL PATENTING OF ALL DISCOVERIES EVER.

BIOMEDICAL RESEARCH HAS BEEN PATENTING GENES SINCE THE 1980's AND DOCTORS HAVE BEEN PISSED OFF ABOUT IT SINCE THE 1980's.  IF THE PATENT OFFICE WAS WORRIED ABOUT GENE PATENTING BEING CONTRARY TO THE PUBLIC INTEREST, THEY WOULD NOT ISSUE THEM.

In short, I have yet to find a legitimate argument made by the ACLU against patenting the BRCA1 and 2 genes, much less any gene.  I'm not saying that genes should or should not be patentable; what I'm saying is that the ACLU is making a poor argument, and needs to approach this from more of a patient access angle.

Maybe what needs to happen here is for gene patenting to selectively be restricted to 5 years instead of 20.  Five years is nothing from a scientific standpoint, and wouldn't actually allow researchers the opportunity to make significant headway before the rest of the world chimed in, but it would at least give them a head start without making prospective patients wait an inordinate amount of time for reasonable diagnosis or treatment.  And five years of profit from over-priced tests certainly ain't bad.

Journal Club: on the selective degeneration of dopamine neurons in Parkinson's disease

http://www.ncbi.nlm.nih.gov/pubmed/16299504

The therapeutic application of potassium gated ATP channels (K-ATP) in Parkinson's disease arises from their ubiquitous expression in the basal ganglia.  Regulation of these channels evokes cell hyperpolarization in order to prevent cell excitability.  In the mitrochondria, they play a role in translating the metabolic state of the neuron.  This week's journal club discussed an article suggesting that K-ATP channels are necessary for the selective vulnerability of dopamine neurons in the substantia nigra pars compacta (SNpc) relative to the ventral tegmental area (VTA).   Liss et al demonstrate this theory using mitrochondrial complex I inhibitors rotenone and MPP+, both neurotoxins commonly used in developing Parkinson's disease models in rodents.

Rotenone and MPP+ are known to selectively degenerate dopamine neurons of the SNpc, leaving the VTA dopamine neurons primarily in tact.  Liss et al suggest that this phenomenon is due to differential mitochondrial uncoupling (or, disruption of metabolism).  Extensive uncoupling with the application of FCCP resulted in activation of K-ATP channels in both the SNpc and VTA.  Mild uncoupling with FCCP did not activate K-ATP channels in either region.

"Notably, however, mild uncoupling inverted the response of K-ATP channels to complex I inhibition: in this case, VTA DA neurons, but not SN DA neurons, were hyperpolarized and functionally silenced due to K-ATP channel activation. In the presence of 50 nM FCCP, none of the SN DA neurons was significantly affected by 100 nM rotenone (Fig. 5a,b, left; perforatedpatch recording in 50 nM FCCP: 2.33 ± 0.29 Hz; FCCP + rotenone: 1.92 ± 0.36, n ¼ 6; P ¼ 0.40) or 10 mM MPP+ (data not shown). In contrast, the presence of 50 nM FCCP sensitized K-ATP channels of VTA DA neurons to complex I inhibition (Fig. 5a,b, right; 50 nM FCCP: 2.4 ± 0.55 Hz; FCCP + rotenone: 0 ± 0 Hz, n ¼ 6; P ¼ 0.0075)."

"Stereological analysis of all SN pars compacta neurons in hematoxylin-eosin counterstained sections demonstrated genuineMPTP-induced neuronal death in wildtype mice and confirmed the complete rescue of SN neurons in the Kir6.2-/- mice (Fig. 6d, middle panel; Kir6.2+/+ SN: control, 11,882 ± 222; post MPTP, 8,061 ± 632, P ¼ 0.029; Kir6.2 -/- SN: control, 12,288 ± 231; post-MPTP, 12,619 ± 223; P ¼ 0.36; n ¼ 3 each)." ** Kir6.2 -/- mice are a genetic strain not expressing a unit of the K-ATP channel necessary for activation.  This means that blocking the channel's activity prevented SN DA neurons from being lost.

I want to see some apoptosis markers in these SNpc DA neurons due to K-ATP activity.  The comaprison of SNpc and VTA DA neurons is an invaluable resource for identifying mechanisms of the selective degeneration that marks Parkinson's disease.  Because the VTA DA neuron population is so identifiably unaffected by most neurotoxins from which Parkinson's models are developed, the selectivity of the models and the degree of neural degeneration is not only measurable but comparable to many cellular mechanisms of the disease itself.  Uncoupling of the mitochondria speaks to selective metabolic toxicity, and a new target for neuroprotective therapies.

** This was a very complex article using six different mouse strains/treatment groups and analyzing the cell viability using electrophysiology, histology and RT-PCR -- I am reciting only the briefest summary which does not to justice to the extensive work done (although my critique is long-winded, I was impressed with these studies).

Journal Club: on Vitamin D and Parkinson's disease

Preface:  After a long hiatus during which I have been doing so much research on Crohn's disease that I haven't written a damn thing about neuroscience, I've decided that it's time to return.  I have officially submitted my graduate school applications, and now need to get myself back into regular science-writing mode.

This week's Movement Disorders Journal Club held some lively discussion on the roles that vitamin D might play in the balance deficits of Parkinson's disease patients.  This was based on data presented for a grant application, so the following will have little to do with Dr. P's actual pilot study.

Vitamin D deficiency appears to be prominent in elderly people who frequently experience falls (Bischoff-Ferrari et al 2004).  The mechanisms by which vitamin D is involved with balance, however, are largely unknown.  Dr. P's studies propose to look at how vitamin D levels correlate with falls and posturography in patients with Parkinson's disease (PD) because post-mortem immunolabeling studies have shown that vitamin D receptors are particularly dense in the substantia nigra pars compacta (SNpc)(Eyles et al 2005).

The SNpc is an area of primary pathology in PD; specifically, it is the beginning of the primary dopamine pathway that extends to the basal ganglia and motor cortex, which ultimately make commands of the muscles.  When this pathway is depleted, as in PD, the lack of dopamine signaling from SNpc cells has ramifications through several terminal brain regions which lead to the rigidity, tremor and poor balance that characterize the disease.

One of the important questions to ask, given the high vitamin D receptor density in the SNpc, is what role vitamin D might play in that region of the brain: Is there a central nervous system mechanism by which vitamin D is involved in alleviating behavioral deficits of PD, or is vitamin D helping patients with more general balance deficits through its effect on muscles?

Dr. P is proposing to address this question on both clinical and basic science levels.  Her clinical studies will address the attenuation of several behavioral and motor impairments as correlated with various vitamin D levels.  Her complementary basic science component proposes to speculate vitamin D's activity in the SNpc of a rodent model.  Naturally, this is super exciting to yours truly, so I have offered my services (as an MD, Dr. P needs a collaborative basic science lab in which to conduct the non-human animal component of her studies).  It stunned me, in fact, to learn how little has been studied regarding the role of vitamin D in the SNpc and nigrostriatal pathway, given the clear indication that its receptors are prevalent.

Although this will not begin for several more months, at least, there will be more to come as the publishable results unfurl.  In the meantime, expose yourself to the sunshine! -- you supposedly benefit more from 15min/day sun exposure than from dietary means (Hall et al 2009; Wolpowitz & Gilchrest 2006).  Fanatic Cook elaborates on this beautifully.

catfish

i run on water and thought, but only as it consumes me and not because i am human.

an overwhelming subpopulous of humanity pursues thought as if it were food. not as if it were a delicacy, and not in the way we sought after food when food was/is scarce, but in the same greedy insatiable way that is characteristic of fast food nations... dare i say "brain obesity"... actually no... i'm not going to go there... because then i'd have to talk about omega six and placental malleability and the origins of intelligence and i don't have it in me at the moment. but. why are we so hungry for thought? and not just thought for the sake of wonder; we have conglomerated on this idea that thought is worthless if it doesn't lead to concrete ends. answers. explanations. and this... is extremism. and this... is what intraspecies competition has come to (and you... can think about that one because i'm not going to follow it up just now).

i do not fit in well in the world of medicine for two reasons: patients, and the government.

patients - unless they are of the mindset that i am about to indulge - expect medicine to perform miracles. to be god in a 400 mg tablet of compressed powder. the thing is that medicine doesn't work that way... because your body's biochemistry doesn't work that way. nobody has the same performance of metabolism, digestion or cellular transduction mechanisms. ergo, exogenous chemicals do not affect everyone in the same way (to the same end that diets don't work the same way for everyone and people give up on them because their body didn't respond optimally, which is why being conscious of your active health is the better alternative). for the most part, we're built to perform the same biological functions and a high enough concentration of a drug will do similar things in us all: alleviate the system malfunction it was designed to target. however. because we are not built like appliances, we respond differently. tylenol works for the most part with innocuous residue because its target is so well understood, and happens to be fairly well behaviorally conserved across humans. most biochemical mechanisms are not so simple. yes, there are myriad side effects for every drug. that is because almost any patient who takes that drug will have at least one of those side effects. almost nobody will have all of them, because your reaction depends on the particular idiosyncrasies of your system. to bring about a point, i do not fit in well in the world of medicine because patients do not understand or accept this, and i am totally okay with it. because i understand that if you're going to endogenously assault the body, you had better damn well cater to the specific nature of that body in the best way you can. or, if you're going to take a drug that's on the market but not quite yet understood in its entirety, you had better damn well not expect it to work perfectly in your very particular system. because i think that there is no single answer to any question, and that more often than not the answers end up making the questions more mysterious and any concrete answer more elusive (for the same reason, i could never be a politician, lawyer or historian). point: if we did not so vehemently lust after thought as a provider of perfect answers, we would not have unfathomable expectations of medicine, would not be so disappointed, would not lose confidence in science, and i would fit perfectly in the world of medicine.

the government - on whom i will not get started because the rant is unending - protects the patient, and is not only unyielding to the nature of medicine as a science, but is the propago mater that defines the patient's expectations of medicine... fucking conservative tyrannical government... screwing up what i want to do with my life...

-----

i really don't think this is scheherazade's fault. yes, intelligence is attractive, and helps propagate the species and all that junk (not that we're prized machines to be replicated anymore, but that's another problem). but really, intrigue is always in the invigorating mystery, and being able to speculate without needing to arrive at an end, but enough to shape our tendancies... that should be what our species runs on. r o m a n t i c p r a g m a t i s m.

and so i am a catfish. benthic, beneath the chaos created by the noise of humanity's greedy hunger for this particular kind of knowledge. detritivorous, feeding on the development of thoughts that people discard because they are unrefined and inconclusive. and running on water. i could carry this one even further and say that like the male catfish, i house and nurture eggs of thought with my mouth until they are ready to hatch... but i'm not going to...


really? with the metaphor and the disgusting cliche? yes, yes i did.