An excellent blog to follow and read

From Bart's Hospital, UK - lots of short posts, all very interesting!

http://multiple-sclerosis-research.blogspot.com

see what's happening at ECTRIMS

http://drkarenlee.ca

Dr. Karen Lee from the MS Society is blogging from ECTRIMS in Copenhagen.
You can also follow her on Twitter @dr_karenlee
Or researcher Jordan Warford at @jrwarford

Pain and MS, including those with an axe to grind

Oh legs. Legs'o'mine. Couldja leave me alone just for a leetle while?
I still don't get it - why is there so much numbness plus so much pain? Surely they should block one another out?
But no, here I cringe, legs repositioning every few minutes while I struggle to feel my fingers on the keys.
I do wish I understood this disease better. I wish anyone understood it better.
And thanks, CCSVI advocates for once again sending me an unnecessarily long and gruesome post to my CCSVI, the terrible temptations post. Every few months you send me one. It's tedious.It's advertising, pure and simple. Usually I delete the comments, made as they are by some mailing robot that spasms, like my legs, unexpectedly, and shoots out blather.
I've decided to allow this one because we are at the point of doing a study here in Canada that looks like it will be carefully designed enough to actually give us some answer, unlike all the observational studies done before. This study will assign patients with venous "obstructions" to control and experimental groups and do mock procedures on the controls. Everyone involved will be blinded as to who got what procedure. then, a year later, the groups will be switched, so everyone will end up with the procedure (important as it is an invasive experiment) and the same person can be evaluated throughout the experiment for effects. I don't know if they are following the procedures with physical therapy, my own personal thought about how the benefits are accrued from the procedure.
So in two years, we should have some hard research results.
Best thing is that the doc who is leading the study, while one of THOSE( neurologist) types, is also one of the most caring, considerate, and thoughtful neurologists I've happened to meet. I've worked with him on the Canadian MS registry project through CIHI and he is a good man, not given to self-aggrandizement, prone to listening to ideas, and open and easy to speak to. I'm hoping the centre in Montreal is going to be led by my other favourite neurologist, another gem of a doc. I'd mention their names but I don't want them to be swamped with people demanding care to the point they burn out. Nice neurologists are not common out there. tremendously smart and knowledgeable ones, yes, but pleasant and friendly, not so much.
Perhaps, unlike my numbness and pain, niceness and smartness don't normally occur together.

But in some lucky or unlucky instances, they do.

Why all the fury about CCSVI?

Whew. Apparently there will be an announcement about CCSVI made by the NL Health Minister at noon today.

Instantly the chatter lines light up. The CCSVI advocates are hollering again. They yell, they tirade, they do personal attacks on neurologists, the MS Society, the people who work at the MS Society, drug representatives, cardiologists, radiologists, that guy that's walking by the window, anyone who doesn't eat pasta, that annoying mosquito.

It's like as soon as you mention those four initials, you've poured alcohol on a fire.
From my way of thinking, I don't find such ranting persuasive. The pro-CCSVI people are sounding more and more like a cult of late.

We've seen this before, folks. Remember laetrile?

I don't know what will transpire regarding CCSVI and MS. I hate the medications we have to take that we aren't sure will do anything and that cost us a lot in terms of money and side effects (potential and present). I hate the fact that I have to take medications at all. I particularly hate that Copaxone has been fined for overcharging and they, TEVA, just wandered out of the discussion, grinning and patting their fat wallets. While gesturing with their other middle finger.

(But then, I have high cholesterol, too, and pay into Crestor's vast resources while eating potato chips. Thus supporting TWO evil industries. I feel kind of silly grousing about big pharma when I lack the self control to avoid them.)

But interventional radiologists are making money on this, too. They have better press at present, true, and maybe that's because a great many neurologists are, unfortunately, just not nice. Or they are frustrated dealing with a chronic disease for which they have no real hope or answer, despite years of research on it. Brains are, apparently, complicated. Immune systems even more so. Who designed this system, anyway?

In any case, the jury is still out. We're devoting resources to investigating this CCSVI thing, that, unfortunately, doesn't seem to be coming back with positive answers for many.

And any who raise a cautionary hand are being demonized.

This is a confusing disease. It's awful and hopeless and expensive and leads many to suicide. How about stepping back and stopping the attacks, eh, CCSVIers? I, for one, would be more tempted to listen. Right now I wish the whole thing would go away.

Black Holes in my brain...or, do we actually know ANYTHING about MS at all?

The longer I have this disease, the more discouraging it becomes. Not so much because it's a stinky disease and has its hateful bits, but because the more I look at the research, the more I realize we actually have no idea at all about what goes on with it, despite years and years of research.
I just finished reading this report (http://brain.oxfordjournals.org/content/126/8/1782.long)
about the black holes (so termed) that form in our brains over time. I had thought I was told they were permanent, visions of brain death and atrophy.
However, this study talks of how they can revert. Huh? And of course there is no association between the number of them and disease progression except in that overall brain atrophy is linked with physical and cognitive decline. At least I think that is what I understood, given that my brain doesn't seem to be functioning so well today. It's squinting, trying to focus. Brain squinting is an odd sensation. I used to be a hyper-intelligent mega-being with delusions of grandeur. Now I'm just deluded.
So, to summarize what I know about MS:
1. the disease modifying drugs we all take every day don't actually prevent progression of disease, they just modify how it presents itself - i.e. fewer acute attacks - but still the disease goes on ever on in our nervous systems. The drug companies want to tell us they delay progression, but I'm not seeing it in the research. So, after years of injecting myself with this drug, I have absolutely no proof that it's doing anything for me except bettering my injection skills and helping me learn how to needle felt.
2. Cognitive changes and mood changes are very poorly understood and rarely dealt with, as is pain. So we wander about, foggy and groaning until someone takes pity on us and feeds us chocolate.
3. What used to be an indicator, number of brain lesions, is apparently totally unconnected to disease activity and it is really the silent inflammation that causes the problems. Of some part of the brain as yet uncertain. Maybe glial cells. Maybe that bubble gum I inhaled as a child. Who knows.
4. We have no idea what causes the inflammation, what makes it worse, what makes it better, or what causes it to start in the first place.
5. The only way to treat the disease is symptomatically with ever more intrusive treatments, appliances, care, limitations. The thought of a scooter was cool when I didn't see it lurking around the corner. Let's not talk about Depends, shall we, until Victoria's secret makes some?
6. We used to think that MS was unknown in people who get a lot of sun, but now we are finding fresh cases that have had MS for years and who have only just moved north from the equator. So maybe the Vitamin D thing isn't right, either.
7. Practically EVERYONE gets Epstein-Barr virus at some point  (though it's one of those things that is implicated in many diseases) so why do some get this, some get non-Hodgkins lymphoma, etc? Is there an infectious cause? Who knows?
8. CCSVI's hypothesis isn't proven, but some people get benefit from having their veins plunged. No one knows why. No one knows why not. Everyone knows stents are dangerous, but people are still getting them. There is no logic in this disease anywhere, except the logic of the market.
9. Completely killing your bone marrow and starting fresh with a new lot of cells seems to help - but for how long? No one knows.
10. Apparently zapping your brain deep inside can help with cognitive problems, but it also helps with depression, which can lead to cognitive problems. Chicken and egg, people. It's always chicken and egg.
11. The only certain thing, MAYBE, is that we are losing myelination of our nerves. But are we really? Since most of the research is done on mice and cadavers, I'm not so sure even that is true, and as I'm still alive, and not a rodent, I'll never know til too late.

Is it any wonder we get depressed?
Ach, the hell with it. It's obviously time to stop looking at the research. It makes my brain ache, and I know that can't be good.

MS as a lipid disease? Interesting concept...

from i09.com

Have we been looking at Multiple Sclerosis all wrong?

Multiple sclerosis is a confusing disease. Widely regarded as an autoimmune problem, it affects millions of sufferers, and we still don't have a complete grasp of what causes it. Part of this problem is due to the fact that every time we find something that seems to be a factor in how it works, that factor doesn't seem universal.

But now there's a new theory of MS that could lead to a radically different treatment for the disease.

Top image: Random 42 Medical Animation.

A new meta-analysis by Dr. Angélique Corthals proposes that much of the difficulty we have with understanding the causes of MS may be because we're wrong about its basic mechanism. In a publication in The Quarterly Review of Biology, she proposes that rather than an autoimmune disease like previously supposed, MS might in fact be a metabolic one with an immune component.

It's a bold assertion to be sure, and one without original data to back it up (at this point, anyway). With MS, the myelin which protects and insulated the nerve tissue on your brain and spinal cord swells, and then scars, leading to neuronal damage. Corthals' theory gives another framework to approach this damage, and one with links to a disease we do understand — atherosclerosis.

This is where things get a bit dense, so bear with me.

There are certain environmental and genetic factors which can impair PPARs (peroxisome proliferator-activated receptors), which is part of the system that controls the metabolism of fat as well as immune response. When it's running at partial power, the PPARs can't properly control the levels of LDL — the infamous bad cholesterol — which leads to a build up of an oxidized toxic derivative of LDL called oxLDL in the blood. Once these are in the system, Corthals believes the body is "primed" for MS, and it can be triggered by a number of causes, including Epstein-Barr Virus, which is linked to MS in its own right.

Once triggered, an immune system chain reaction starts. The body sends out macrophages to deal with a pathogen, but the macrophages incorrectly gorge themselves on oxLDL. This puts them in a "zombie state", where they don't die and can't empty their contents, instead just building up plaques which damage the myelin sheath, and cause the symptoms of MS.

Edited to clarify: At this point, the disease triggers the immune problems we know of as MS. The theory isn't discarding the immunological side of the disease, just citing metabolism as a root trigger, which leads to the problems of the immune response.

Said Corthals:

Eventually, the toxic macrophages are cleared, leading to the remission part of the RRMS (relapsing-remitting MS) cycle. But this detente holds only until the next trigger comes along. Dysfunction of the PPAR is further implicated in MS because it slows the repair mechanism of the central nervous system to a crawl, preventing the efficient renewal and synthesis of myelin.

It's a novel theory, and while Corthals is working on pulling together some empirical data to back it up, it does answer some of the issues with how MS manifests. The disease has been linked previously to low levels of vitamin D, and is on the uptick in recent decades. Low vitamin D and a diet high in both saturated fat and carbohydrates (which is likewise on the rise) both contribute to the impairment of PPARs.

The mechanism that Corthals suggests is also interesting because it's incredibly similar to that of atherosclerosis. Atherosclerosis is when PPAR failure causes plaque buildup and scarring in arteries, which is the equivalent to what's being described happening to myelin. Also interestingly, men are far more likely to have atherosclerosis and women to have MS, which Corthals suggests may be because of the different way sexes metabolize fats. In the paper, she recommends "multiple sclerosis should be thought of as a metabolic disease, the female equivalent of atherosclerosis, not as a disease of the immune system."

If the raw data bears out this theory, it would mean a radically different approach to the treatment of a major chronic disease. One based on lipid metabolism (and potentially diet) rather than targeting the immune system directly. If it holds up, it would be a major paradigm shift in the way MS is handled — but first we need to see if the data fits the theory.

For further reading, Corthals has been weighing in on this discussion, and if we're lucky, she may even pop up here.

Contact Tim Barribeau:

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Interesting discussion on this blog as well...plus a link to the research article.
http://asknicola.blogspot.com/2011/12/huge-news-multiple-sclerosis-is.html

No wonder I feel dizzy

It makes sense that MS would affect the autonomic nervous system, something we don't talk much about since we usually deal with the muscle problems and cognitive problems and all that other messy stuff. But apparently, according to this study, we may be losing venous pressure while sitting.
Which a lot of us do a lot of.
PS: I think it's hilarious one of the researchers is named Venturi.
I still remember reading the deadly serious warnings on our BBQ about SPIDERS IN THE VENTURI TUBES. Of course when we looked at our BBQ after the long winter, mice had nested in it, and their woven bed made out of our lawn chairs had indeed prevented any spiders from seeking a home. But that's another topic.
Note, CCSVIers, this has nothing to do with blockages, so please don't fill my blog with "Aha! Proof!" rants. It's tiresome. And this is a preliminary study...needs repetition. Still, very interesting. I think we should be aware of the autonomic effects of MS as it may help explain the weakness that we feel and perhaps some of the vertigo.

http://www.msif.org/en/research/ms_research_news/quantitative_col.html

Quantitative Colour Doppler Sonography Evaluation of Cerebral Venous Outflow: A Comparative Study between Patients with Multiple Sclerosis and Controls
		summary: This interesting paper published by a group from Italy reports data from 27 healthy adults and 52 patients with MS. The difference between cerebral venous outflow (CVF) when lying down and CVF in the seated position which they refer to as ΔCVF was found to be negative in 59.6% of patients with MS and positive in 96.3% of healthy subjects. Statistical analysis showed that negative ΔCVF values were significantly associated with MS (p<0.0001). However there was no significant correlation with clinical variables. The authors comment that negative ΔCVF has a hemodynamic significance, since it reflects an increased venous return in the seated position, and suggest that in MS it may be a result of vascular dysregulation from involvement of the autonomous nervous system. authors: Monti L, Menci E, Ulivelli M, Cerase A, Bartalini S, Piu P, Marotti N, Leonini S, Galluzzi P, Romano DG, Casasco AE, Venturi C. source: PLoS One. 2011;6(9):e25012. Epub 2011 Sep 22. weblink: click here category: Imaging related research news: click here glossary:     Cerebral     Multiple sclerosis     Nervous system     Sclerosis     Sign

Reviewing the CCSVI research..

In my role as education person for the local MS Society, I've been called upon to try and figure out a presentation re: CCSVI.  The only problem is that little research has been completed to date.  There are status updates to the research funded by the MS Societies on their pages, but I went wandering through the other research looking for something else that might have been done.
Here are my conclusions:
Anyone associated with Dr.s Zamboni, Haacke, Simka, or their research institute have found that CCSVI has positive results.  Sample sizes are small, and my impression is that the several published papers resulted mainly from the same study set.
Anyone who is a neurologist finds no benefits from the CCSVI procedure. Their study sizes are also small, except for one study that looked for brain ferritin levels (following the iron damage hypothesis) which looked at 1408 patients with brain disorders and normals and found an increased amount of ferritin in people with various forms of MS and brain damage of other sorts.
Interestingly, studies by interventional radiologists also don't find a positive association between CCSVI treatment and MS improvement.
"Improvement" is, as has been said before, stated in terms of fatigue level improvement, some sensory improvement.  As someone who is dead tired all the time and numb from stem to stern, this sounds vaguely appealing, except for the costs. And the transience of the improvement. The study summaries are below.
The small sample sizes are a problem, as so much difference can be explained by random changes, especially in a variable disease like MS.  It's also a problem that most of the studies were unblinded - in other words, the experimenters knew who they were looking at.  This allows for bias and in fact, if you happen to have a vested interest in the results, like the neurologists who have invested years in the autoimmune theory, or the Zamboni group who are currently marketing the only machine capable of detecting the hard to find CCSVI (some conflict of interest there, methinks), bias comes in inevitably.
On the good side, the whole debate has increased interest in MS research.  On the bad side, several people have, for some unknown reason, decided the current researchers are not capable of doing a proper study, and so have stopped sending money to the MS Society.  Instead we should be sending more, and demanding unbiased studies, multisectorial, blinded, and large. We won't know for sure until we get those studies done. Until then, taking a stand is perhaps premature.

Study/date	Blinded?	Number of participants	results
The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011 Feb 4. [Epub ahead of print] Mayer CA, Pfeilschifter W, Lorenz MW, et al	Yes ++	20 MS, 20 controls	No retrograde blood flow Conclusions This triple-blinded extra- and transcranial duplex sonographic assessment of cervical and cerebral veins does not provide supportive evidence for the presence of CCSVI in MS patients. The findings cast serious doubt on the concept of CCSVI in MS.
Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control studyInt Angiol. 2010 Apr;29(2):158-75. Zivadinov R, Schirda C, Dwyer MG, Haacke ME, Zamboni P et al	No	16 RRMS 8 controls	All 16 MS patients fulfilled the diagnosis of CCSVI (median VH=4), compared to none of the HC Iron concentration measures were related to longer disease duration and increased disability as measured by EDSS and MSFC, and to increased MRI lesion burden and decreased brain volume.
CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study. Zamboni P, Menegatti E, Weinstock-Guttman B, , Zivadinov R. et al Int Angiol. 2010 Apr;29(2):140-8.	No	16 MS 8 controls	Vascular Hemodynamic changes occur more frequently in MS patients than controls. Altered VH is associated with abnormal CSF flow dynamics and decreased brain volume.
No Evidence of Chronic Cerebrospinal Venous Insufficiency at Multiple Sclerosis Onset Claudio Baracchini, MD,1 Paola Perini, MD,1,2 Massimiliano Calabrese, MD,1,2 Francesco Causin, MD,3 Francesca Rinaldi, MD,1,2 and Paolo Gallo, MD, PhD1	No	50 MS 60 global amnesia 60 healthy.	Our findings do not support a cause-effect relationship between CCSVI and pMS. Further studies are warranted to clarify whether CCSVI is associated with later disease stages and characterizes the progressive forms of MS.
Intracranial venous pressure is normal in patients with multiple sclerosis. Meyer-Schwickerath R, Haug C, Hacker A, Fink F, Seidel D, Hartung HP, Haupts MR.	No	29 MS 28 Controls 19 patients with increased intracranial pressure	There is no evidence of an increased intracranial venous pressure in MS patients.
Cardiovasc Intervent Radiol. 2011 Feb;34(1):1-2. Epub 2010 Dec 7. Cardiovascular and Interventional Radiological Society of Europe commentary on the treatment of chronic cerebrospinal venous insufficiency. Reekers JA, Lee MJ, Belli AM, Barkhof F.	No	Comment only	Thus far, no trial data are available, and there is currently no randomized controlled trial (RCT) in proress Therefore, the basis for this new treatment rests on anecdotal evidence and successful testimonies by patients on the Internet. CIRSE believes that this is not a sound basis on which to offer a new treatment, which could have possible procedure-related complications, to an often desperate patient population. PMID: 21136256 [PubMed - in process]
Nervenarzt. 2010 Jun;81(6):740-6. ["Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients]. [Article in German] Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R.	No	?	The "venous hypothesis" is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the "chronic cerebrospinal venous insufficiency (CCSVI)" cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive "therapeutic" approaches, especially if they are performed outside of clinical trials.
Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A. Neurology. 2010 Nov 2;75(18):1617-22. Epub 2010 Sep 29.	No	cross-sectional (n = 1,408) longitudinal (n = 29) patients with MS and a range of neurologic disorders.	Pathologic (>12 ng/mL) CSF ferritin levels were observed in 4% of the control patients (median 4 ng/mL), 91% of patients with superficial siderosis (75 ng/mL), 73% of patients with a subarachnoid hemorrhage (59 ng/mL), 10% of patients with relapsing-remitting MS (5 ng/mL), 11% of patients with primary progressive MS (6 ng/mL), 23% of patients with secondary progressive MS (5 ng/mL), and 23% of patients with meningoencephalitis (5 ng/mL). In MS, there was no significant change of CSF ferritin levels over the 3-year follow-up period. CONCLUSION: These data do not support an etiologic role for CCSVI-related parenchymal iron deposition
No cerebrocervical venous congestion in patients with multiple sclerosis. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. Ann Neurol. 2010 Aug;68(2):173-83.	No	56 MS 20 Controls Sonography study, flow analysis, CCSVI criteria	Our results challenge the hypothesis that cerebral venous congestion plays a significant role in the pathogenesis of MS. Future studies should elucidate the difference between patients and healthy subjects in BVF regulation. No MS patient had >1 CCSVI criterion
Int Angiol. 2010 Apr;29(2):189-92. Chronic cerebro-spinal venous insufficiency: report of transcranial magnetic stimulation follow-up study in a patient with multiple sclerosis. Plasmati R, Pastorelli F, Fini N, Salvi F, Galeotti R, Zamboni P.	No	I patient	The demonstration of a modification of the cerebrovenous function with both clinical manifestation and via TMS suggests that the hampered cerebral venous return may contribute to the clinical course of MS.
Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study. Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P. Int Angiol. 2010 Apr;29(2):176-82.	No.	31 fatigue testing 1, 6 and 12 mos post-procedure	The reestablishment of cerebral venous return dramatically reduced CF perception in a group of MS patients with associated CCSVI, suggesting that CF is likely the symptom of CCSVI. Note: Patients were identified as having CCSVI and Chronic Fatigue
Chronic cerebrospinal venous insufficiency and multiple sclerosis Omar Khan MD1,*, Massimo Filippi MD2, Mark S. Freedman MD3, et al ANN NEUROL 2010;67:286–290			In this Point of View, we discuss the recent investigations that led to the description of CCSVI as well as the conceptual and technical shortcomings that challenge the potential relationship of this phenomenon to MS. The need for conducting carefully designed and rigorously controlled studies to investigate CCVSI has been recognized by the scientific bodies engaged in MS research. At present, invasive and potentially dangerous endovascular procedures as therapy for patients with MS should be discouraged until such studies have been completed, analyzed, and debated in the scientific arena.
Venous and cerebrospinal fluid flow in multiple sclerosis: A case-control study .    Peter Sundström MD, PhD1,*, Anders Wåhlin MSc2, Khalid et al	No	21 MS 20 control	We found no differences regarding internal jugular venous outflow, aqueductal cerebrospinal fluid flow, or the presence of internal jugular blood reflux. Three of 21 cases had internal jugular vein stenoses. In conclusion, we found no evidence confirming the suggested vascular multiple sclerosis hypothesis. ANN NEUROL 2010;68:255–259
Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? T Ludyga *, M Kazibudzki *, M Simka * , M Hartel , M wierad *, J Piegza *, P Latacz *, L Sedlak * and M Tochowicz *	No	564 procedures in 331 MS patients with CCSVI	The procedures appeared to be safe and well tolerated by the patients, regardless of the actual impact of the endovascular treatments for venous pathology on the clinical course of multiple sclerosis, which warrants long-term follow-up.
No association of abnormal cranial venous drainage with multiple sclerosis: a magnetic resonance venography and flow-quantification study Mike P Wattjes1, Bob W van Oosten2, Wolter L de Graaf1, Alexandra Seewann2, et al	Yes	20 MS, 20 control MRV studies (magnetic resonance venography)	A completely normal venous anatomy was observed in 10 MS patients and 12 controls. Anomalies of the venous system (venous stenosis/occlusions) were found in 10 MS patients and eight healthy controls. An anomalous venous system in combination with associated alternative venous drainage was observed in six MS patients and five healthy controls. Flow quantification showed no venous backflow in any MS patient or control. Conclusions Findings suggestive of anomalies of the cranial venous outflow anatomy were frequently observed in both MS patients and healthy controls. Given the normal intracranial venous flow quantification results, it is likely that these findings reflect anatomical variants of venous drainage rather than clinically relevant venous outflow obstructions.
Iron and Neurodegeneration in Multiple Sclerosis Michael Khalil,1, 2 Charlotte Teunissen,2 and Christian Langkammer1 Multiple Sclerosis International Volume 2011, Article ID 606807,			In summary, increased iron deposition has been consistently reported to occur in MS, but its role in pathogenetic processes of this disease has not yet been completely clarified. Quantitative MRI and histopathologic analyses of postmortem MS brains should complement these     [9] studies.