New Dermaroller Study; Thoughts, comments?

[squeegee]

It also seems that PGE2 in highly expresses in Thermal Injury.. burn wounds.. which probably answer the results for the BBQ http://www.bmj.com/highwire/filestream/339492/field_highwire_article_pdf/0/1645.2

http://journals.tubitak.gov.tr/medical/issues/sag-04-34-4/sag-34-4-1-0405-1.pdf


Thermal injury alters macrophage responses to prostaglandin E2: contribution to the enhancement of inducible nitric oxide synthase activity.

Schwacha MG, Samy TS, Catania RA, Chaudry IH.
Source

Center for Surgical Research, Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence 02903, USA. MSchwacha@RIHosp.edu

Abstract

Prostaglandin E2 (PGE2) and macrophage (Mphi)-derived reactive nitrogen intermediates (RNI) have been implicated in T cell dysfunction after thermal injury. Normally, Mphi inducible nitric oxide synthase (iNOS) activity can be regulated by PGE2, however, it is unknown whether PGE2 modulates Mphi iNOS activity after thermal injury. Splenic Mphi isolated from mice 7 days after thermal injury produced higher levels of RNI than Mphi from sham mice when stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in combination. PGE2, when added concurrently with LPS, suppressed RNI production by Mphi from sham mice, whereas Mphi from injured mice were unaffected. When Mphi were pretreated with PGE2 before LPS, RNI production was suppressed in both populations. RNI production in response to IFN-gamma or IFN-gamma and TNF-alpha in combination was enhanced by PGE2 in both populations, however, the effect was markedly greater in Mphi from injured mice. The PGE2-mediated changes in RNI production were paralleled by similar changes in iNOS protein expression, suggesting that the effect of PGE2 was at the level of enzyme expression rather than activity. Dibutryl cAMP induced similar effects as PGE2, suggesting the response to PGE2 after thermal injury is independent of potential changes in PGE2-induced adenylate cyclase activity and is cAMP-mediated. The results indicate that Mphi from burned mice display an altered sensitivity to PGE2, resulting in enhanced iNOS activity. Thus, PGE2, which is elevated after thermal injury and can directly suppress T cell function, may also contribute to immune dysfunction through the enhancement of Mphi iNOS activity.

http://www.ncbi.nlm.nih.gov/pubmed/9850155


Mechanism of increased tumor necrosis factor production after thermal injury. Altered sensitivity to PGE2 and immunomodulation with indomethacin.

Molloy RG, O'Riordain M, Holzheimer R, Nestor M, Collins K, Mannick JA, Rodrick ML.
Source

Department of Surgical Immunology, Harvard Medical School, Boston, MA.

Abstract

Altered macrophage function after thermal injury is associated with increased production of PGE2 and TNF. However, it is not clear why synthesis of both cellular products remains elevated, as PGE2 is a potent inhibitor of TNF secretion. We studied the relationship between PGE2 and TNF synthesis in a murine model of thermal injury, and examined the effect of prostaglandin blockade on splenic macrophage secretion of these mediators of inflammation. LPS-stimulated production of PGE2 was significantly elevated in burn groups compared with sham-burned controls (pg/ml mean(SEM); sham 151(32): burn 597(147), p < 0.01). TNF production was similarly increased after thermal injury (pg/ml mean(SEM); sham 62(20): burn 928(316), p < 0.01). In vitro culture of macrophages with indomethacin augmented LPS stimulated TNF production in sham-burned controls but did not affect synthesis in burn groups, suggesting a loss of PGE2-dependent regulation of TNF synthesis after thermal injury. Direct measurement of TNF secretion as a function of exogenous PGE2 confirmed this dissociation between PGE2 and TNF synthesis, as burned animals displayed a 5-fold reduction in sensitivity to PGE2-induced inhibition of TNF, when compared with sham-burned controls (ID50 PGE2 molar; sham 1.26 x 10(-8): burn 6.43 x 10(-8), p < 0.05). In vivo pretreatment of burn groups with indomethacin for 5 days before assay partially restored sensitivity to the prostaglandin, and significantly down-regulated synthesis of both TNF and PGE2. These data show that thermal injury is associated with a loss of PGE2-dependent down-regulation of TNF synthesis, which accounts at least in part for increased TNF in these animals. In vivo cyclooxygenase blockade partially restored sensitivity to the prostaglandin and consequently down-regulated synthesis of TNF. These data further support existing evidence that suggests a potential therapeutic role for cyclooxygenase blockade after major thermal injury and trauma.

http://www.ncbi.nlm.nih.gov/pubmed/8345198

- - - Updated - - -

I've seen that study yesterday..

Nat Med. 2013 Jul;19(7):916-23. doi: 10.1038/nm.3181. Epub 2013 Jun 2.
Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding.

Gay D, Kwon O, Zhang Z, Spata M, Plikus MV, Holler PD, Ito M, Yang Z, Treffeisen E, Kim CD, Nace A, Zhang X, Baratono S, Wang F, Ornitz DM, Millar SE, Cotsarelis G.
Source

Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Abstract

Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by γδ T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound-induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from γδ T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal γδ T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans.


PrincessRambo.. But explain to me the relation with sudden thick hair with acute inflammation from rolling? That FGF9 is released from somewhere.. not my *** LOL.. FGF9 is still released from PGE2? BTW **** mice.. we have a totally different immune system so probably a different reaction to inflammation! I am pretty convinced that others growth factors are involved in hair growth. BTW that gif. is priceless!! hahaha

- - - Updated - - -

I want to known the secret of the BBQ guy!

- - - Updated - - -

SO Acute inflammation= Release of ATP, NO and PGE2 (vasodilation) then hair growth? LOL.. Sounds like a MINOXIDIL.

 

[Agahi]

sunburns must be different because bald guys get sunburned on their heads after losing the hair up there and do not begin growing hair after. Also don't mind me just trying to be constructive, though I can barely follow when you guys start throwing studies out there lol.

 

[DesperateOne]

I am mad, very not happy at all, sorry guys, seems like nobody reads most of the stuff being posted here. The study squeegee and zombie hair are referring I already explained. Please see post #1493 on page 150 :argue: why is this new again? I clearly explained in that post that the amount of PGE2 needed to induce this is border line insane, notably amount of PGE2 needs to be tween 0.1 microM and 10 microM, this an insane amount, in the balding scalp we only have about 3.2 nano gram per ml. We are talking about an amount of PGE2 is this 10000 times greater than that, that is what they used in the PGE2 -> FGF9 study, why is this new again?:ermm: Also

No...

http://www.ncbi.nlm.nih.gov/pubmed/23727932

There need to be a feedback loop between fgf9 and wnt to regenerate new hair, this happens in mice, but humans don't have enough gamma delta t cells to produces enough fgf9 to initiate the feedback loop. And no, PGE2 after wounding would also not produce fgf9 to trigger this, the PGE2 inflammatory response occurs very very early in the process, the fgf9 induction needs to occurs Day 1 through 4 after scab removal as noted in the patent and mentioned in the Cots study, they found this period to be at least 10 days after wounding (at that stage initial PGE2 upshot is already over, ps: even if there were pge2 upshot, it wouldn't be enough, like I explained above). Now, see below

PWD = POST WOUND DATE. See the blue bar above? That is the critical window. The thing is, even if we had fgf9, we don't know how the same window of opportunity will translate to a shallow wound induce by rolling. Why is this new again? We have discussed this before and before that, and before that once again. This thread is so long now that we need to repeat everything over and over again :argue:.

Rambo, I am going to reply to you with an answer that few are willing to admit. Most of us here can't make of half the **** that is written on these patents, we just have an overall view of the science but not really the details. There is about 2-3 guys in this entire forum who understand what in world really happens and if it is even worth attempting, one of them being you.
That is why we needed you back because you are one of the few we can rely on, I know you get frustrated but this is just how it is. This is why it is important in my opinion for you to just start a blog and put your interpretations and recommendations based on the patents in there. Anyways, that is just my opinion, I was also noticing why squeegee kept bringing the fgf9 back when it was discussed in the past.

 

[squeegee]

Rambo, I am going to reply to you with an answer that few are willing to admit. Most of us here can't make of half the **** that is written on these patents, we just have an overall view of the science but not really the details. There is about 2-3 guys in this entire forum who understand what in world really happens and if it is even worth attempting, one of them being you.
That is why we needed you back because you are one of the few we can rely on, I know you get frustrated but this is just how it is. This is why it is important in my opinion for you to just start a blog and put your interpretations and recommendations based on the patents in there. Anyways, that is just my opinion, I was also noticing why squeegee kept bringing the fgf9 back when it was discussed in the past.

What is wrong with that? FGF9 is not the only factor in hair growth. Also mice and humans don't share the same immune system. I am trying to put in perspective/ understand the reason why my frigging hair looks thicker during the post rolling session.

 

[karankaran]

Rambo is right...i do not know why ppl think putting **** ten times in their sentences makes their arguments better!!!

 

[squeegee]

Rambo is right...i do not know why ppl think putting **** ten times in their sentences makes their arguments better!!!

KaranKaran, tell me why Minoxidil induces hair growth in the first place? There is other factors that contributes to hair growth after wounding or in general, sorry If I brought back FGF9 in the picture. Also **** you!

 

[Manoko]

There need to be a feedback loop between fgf9 and wnt to regenerate new hair, this happens in mice, but humans don't have enough gamma delta t cells to produces enough fgf9 to initiate the feedback loop. And no, PGE2 after wounding would also not produce fgf9 to trigger this, the PGE2 inflammatory response occurs very very early in the process, the fgf9 induction needs to occurs Day 1 through 4 after scab removal as noted in the patent and mentioned in the Cots study, they found this period to be at least 10 days after wounding (at that stage initial PGE2 upshot is already over, ps: even if there were pge2 upshot, it wouldn't be enough, like I explained above)

Sorry to make you repeat then, but what's the point of damaging our scalps if wounding in humans can't regenerate hair ?
It's just to maintain the hair we already have, by preventing fibrosis ?

And if so, what's the role of Minoxidil in all this, or semen.

 

[princessRambo]

What is wrong with that? FGF9 is not the only factor in hair growth. Also mice and humans don't share the same immune system. I am trying to put in perspective/ understand the reason why my frigging hair looks thicker during the post rolling session.

You are confusing two things, when you roll, you are inducing some wnt, vegf, and other growth factors, this is helping your existing hair grow, fast and thicker possibly. Fgf9 is for follicle neo genesis. The barbecue guy was a freak accident, one embodiment of the follica patent is actually close to the bbq guy, notably, full removal of all the epidermis, dermis and sub dermis, in other word, they have a patent to remove a huge chunk of flesh up to 7mm deep. You cannot do that with dermarolling, simple as that, and we don't know what mechanism results in such regeneration, I don't think fgf9 alone is even relevant in such case. The dermarolling you are doing is not resulting in fgf9, science says you simply are not a mouse, they tried wounding humans before, it is not that simple. In fact in one of the videos I posted earlier, Cotsarelis specifically said we shouldn't use cheese grater on our scalp, it simply doesn't work on humans that way. Your existing hair are getting thicker because of other growth factors. You are not inducing follicular neo genesis, you don't have enough gamma delta t cells to do this, if we were creating new hair every time we rolled, we would be cured by now, no one will be on this thread even discussing hair loss, in fact, hair loss talk would be out of business.

 

[supermusic]

Impossible, hair cannot suddenly get thick, except due a cosmetic effect...

 

[zombiehair]

@PrincessRambo
Never said the study was new I said "that takes us back to pge2" and I linked the study that showed that Pge2 can induce FGF9 In reply to mj9 s suggestion that follica may have a compound to induce FGF9 and are not
using FGF9 directly.As far as I can remember from all the discussions and studys Ive read In this Thread the PGE2 route Is the only way we are aware of to Induce FGF9.
In your post on page 150 you mention that the pge2 levels in seamen fall within the range of pge2 needed to induce FGF9.

I'm considering a lighter rolling session with a smaller needled roller in between the more aggressive rolls.
My logic for this is not to do deep damage but to increase blood flow and oxygen to the scalp.
thoughts ?

My scalp does feel way more alive after rolling.

 

[princessRambo]

@manoko, you are doing amazingly good things to your scalp by dermarolling, you are helping your existing hair, in fact, since this thread is solely based on the indian researchers findings, here is what they say about rolling, note: no mention of fgf9 or new hair neo genesis, it is for the sole benefit of your existing hair, possibly reducing fibrosis on your scalp:

Mechanisms of hair re-growth induced by Microneedling include: [SUP][5],[6],[12][/SUP]

1. Release of platelet derived growth factor, epidermal growth factors are increased through platelet activation and skin wound regeneration mechanism
2. Activation of stem cells in the hair bulge area under wound healing conditions which is caused by a dermaroller
3. Overexpression of hair growth related genes vascular endothelial growth factor, B catenin, Wnt3a, and Wnt10 b.

Studies on repeated Microneedling stimulation by Jeong et al. [SUP][5][/SUP] and Kim et al. [SUP][6][/SUP] showed the enhanced expression of hair related genes and stimulation of hair in mice.

Kim et al. [SUP][6][/SUP] also noted earlier and faster hair re-growth with more shiny texture of the hair in micro needle treated group than the untreated mice group. The authors also suggested that micro needle roller could be useful to treat hair loss refractory to Minoxidil therapy.

This is why you are using a dermaroller and it is a damn good reason, that said, let's remove the wounding-automatically-induces-pge2-automatically-induces fgf9 broscience out of the picture for now , we wouldn't be talking in this thread if it was that easy
@zombiehair: let's discuss the semen thing in another thread in the future before we get yelled at again

 

[squeegee]

You are confusing two things, when you roll, you are inducing some wnt, vegf, and other growth factors, this is helping your existing hair grow, fast and thicker possibly. Fgf9 is for follicle neo genesis. The barbecue guy was a freak accident, one embodiment of the follica patent is actually close to the bbq guy, notably, full removal of all the epidermis, dermis and sub dermis, in other word, they have a patent to remove a huge chunk of flesh up to 7mm deep. You cannot do that with dermarolling, simple as that, and we don't know what mechanism results in such regeneration, I don't think fgf9 alone is even relevant in such case. The dermarolling you are doing is not resulting in fgf9, science says you simply are not a mouse, they tried wounding humans before, it is not that simple. In fact in one of the videos I posted earlier, Cotsarelis specifically said we shouldn't use cheese grater on our scalp, it simply doesn't work on humans that way. Your existing hair are getting thicker because of other growth factors. You are not inducing follicular neo genesis, you don't have enough gamma delta t cells to do this, if we were creating new hair every time we rolled, we would be cured by now, no one will be on this thread even discussing hair loss, in fact, hair loss talk would be out of business.

Yes, understand all that.. Do you really need the activation of FGF9 to get regrowth? If we can get the progenitor cells back in business.. our dormant follicles will go alive again. Don't forget that study as well done on humans! EPC mobilization= hair!

Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells

http://www.jci.org/articles/view/44478

 

[karankaran]

ok i understand your point now... but i guess FGF9 might come into picture for a complete regeneration of follicles... and derma rolling wounding might come into picture for fibriosis when follicles have not completely died...or something... dat is what i think...i just want to be sure dat what i am doing will work ... coz i am so desperate for a CURE....

 

[squeegee]

Tissue Regeneration, Stem Cells, and Wound Healing

Inhibition of wound-induced hair neogenesis by prostaglandin D2

AM Nelson,[SUP]1[/SUP] DE Loy,[SUP]1[/SUP] JA Lawson,[SUP]2,3[/SUP] AS Katseff,[SUP]1[/SUP] GA FitzGerald[SUP]2,3[/SUP] and LA Garza[SUP]1[/SUP] 1 Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, 2 Pharmacology, University of Pennsylvania, Philadelphia, PA and 3 Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA
Prostaglandins (PGs) are key inflammatory mediators involved in wound healing. Recent evidence also illustrated a role for PGs in skin homeostasis with a specific role in regulating hair growth; however, no study to date has examined their role in skin regeneration after injury. Using the wound-induced hair follicle neogenesis (WIHN) assay, we hypothesized that PGs would impact hair follicle neogenesis, a marker for skin regeneration. We found that in C57Bl/6J mice, the levels of prostaglandin synthases and their products (PGD2, PGE2, PGF2a) were reciprocally expressed during wound healing. PGE2 and PGF2a levels increased during the early phases of wound healing while PGD2 increased during the later stages of wound healing (n>3; p<0.05). The level of hair follicle neogenesis after wounding varied significantly among C57Bl/6J, FVB/N and mixed background strains of mice (n>33; p<0.01). Levels of lipocalin-type prostaglandin D2 synthase (Ptgds) mRNA (n>4; p<0.01) and its product PGD2 (n=6; p<0.05) inversely correlated with regeneration ability. C57Bl/6 mice had the highest level of Ptgds mRNA expression, PGD2 levels and the least follicle neogenesis. Additionally, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with the regeneration phenotype among strains of mice (n=9; p<0.05). Exogenous application of PGD2 decreased WIHN in wild type mice (n=8; p=0.06). Of the two canonical PGD2 receptor null mice, only Gpr44 showed increased WIHN compared to strain-matched control mice (n=31; p<0.05). In all, these findings demonstrate that PGD2 inversely correlates with hair follicle regeneration implying that inhibition of PGD2 production or Gpr44 signaling pathways may promote skin regeneration.

- - - Updated - - -

ok i understand your point now... but i guess FGF9 might come into picture for a complete regeneration of follicles... and derma rolling wounding might come into picture for fibriosis when follicles have not completely died...or something... dat is what i think...i just want to be sure dat what i am doing will work ... coz i am so desperate for a CURE....

We all sick of this male pattern baldness madness! Me first! :bigun2:

 

[princessRambo]

Yes, understand all that.. Do you really need the activation of FGF9 to get regrowth? If we can get the progenitor cells back in business.. our dormant follicles will go alive again. Don't forget that study as well done on humans! EPC mobilization= hair!

Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells

http://www.jci.org/articles/view/44478

Yes we might not need fgf9 for regeneration, fgf9 is for neo genesis, which are completely two different ball games. I made my previous post because it was being suggested that simply wounding on humans could do this. As for regeneration, I do not know if dormant stem cells can be reactivated by dermarolling, I have not seen a single study indicating this, if anyone sees such study, please share. If that was the case, hair loss could still be cured just by dermarolling alone, and the study would be all over the news and hair loss talk would still go out of business

@zombiehair: follica used doxycycline to induce fgf9 in the mice. Before anyone rushes to the pharmacy, they were genetically modified mice to specifically express fgf9 in the presence of doxycycline.

we asked whether increasing levels of Fgf9 in the wound would promote hair follicle neogenesis following wounding. We used a doxycycline-inducible transgenic mouse (K14rtTAx TRE-Fgf9-IRES-eGfp) to inducibly target Fgf9 expression to the epidermis following wound re-epithelialization. Administration of doxcycline from SDl to SD4 increased Fgf9 expression 150-fold

SD stands for Scab Detachment. So SD1 to SD4 is a period of 4 days when scab detachment starts and where they induce fgf9 and magically new hair pops. The first day of scab detachment is where the blue line in my previous post starts, notably 10 days after wounding.

 

[karankaran]

"Adding Fgf9 to wounds increases the regeneration of hair follicles in mice lacking gamma/delta T cells in their skin, similar to human skin." -> and when top layer of the skin is removed, the skin is in embryonic state and if you put PGE2/FGF9 in sufficient quantities, hair follicles will develop. i.e. not necessary to go as deep as 7 mm if one can find a source to apply PGE2/FGF9 in sufficient quantities. also to add to the study of semen, when i do it and i used to do it daily...it used to fall on lower part of my stomach, and there is so much hair in that area...and all over the place... so dermaroller 2.5mm wounding+ topical PGE2/FGF9 (in sufficient concentrations) can help?!!

 

[zombiehair]

Just had a thought.
What are we going to do if all this does lead to a cure.
we will have to find a new hobby.

@princessRambo
maybe thats follicas patent and plan ,To have us all genetically modified into mice

 

[squeegee]

Yes we might not need fgf9 for regeneration, fgf9 is for neo genesis, which are completely two different ball games. I made my previous post because it was being suggested that simply wounding on humans could do this. As for regeneration, I do not know if dormant stem cells can be reactivated by dermarolling, I have not seen a single study indicating this, if anyone sees such study, please share. If that was the case, hair loss could still be cured just by dermarolling alone, and the study would be all over the news and hair loss talk would still go out of business

@zombiehair: follica used doxycycline to induce fgf9 in the mice. Before anyone rushes to the pharmacy, they were genetically modified mice to specifically express fgf9 in the presence of doxycycline.



SD stands for Scab Detachment. So SD1 to SD4 is a period of 4 days when scab detachment starts and where they induce fgf9 and magically new hair pops. The first day of scab detachment is where the blue line in my previous post starts, notably 10 days after wounding.

PrincessRambo Each time you hurt yourself, Endothelial Progenitor cell show up to fix the booboo.. This is why athletes use hyperbaric chamber so they can heal up faster than normal by bringing extra oxygen into the tissues.Helps mobilizing the EPCs.
Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound healing.

Liu ZJ, Velazquez OC.
Source

The DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.

Abstract

Diabetic foot disease is a major health problem, which affects 15% of the 200 million patients with diabetes worldwide. Diminished peripheral blood flow and decreased local neovascularization are critical factors that contribute to the delayed or nonhealing wounds in these patients. The correction of impaired local angiogenesis may be a key component in developing therapeutic protocols for treating chronic wounds of the lower extremity and diabetic foot ulcers. Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal neovascularization and play a central role in wound healing, but their circulating and wound-level numbers are decreased in diabetes, implicating an abnormality in EPC mobilization and homing mechanisms. The deficiency in EPC mobilization is presumably due to impairment of eNOS-NO cascade in bone marrow (BM). Hyperoxia, induced by a clinically relevant hyperbaric oxygen therapy (HBO) protocol, can significantly enhance the mobilization of EPCs from the BM into peripheral blood. However, increased circulating EPCs failed to reach to wound tissues. This is partly a result of downregulated production of SDF-1alpha in local wound lesions with diabetes. Administration of exogenous SDF-1alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, neovascularization, and wound healing.

 

[DesperateOne]

Just had a thought.
What are we going to do if all this does lead to a cure.
we will have to find a new hobby.

@princessRambo
maybe thats follicas patent and plan ,To have us all genetically modified into mice

Easy answer, we would all meet up somewhere to celebrate.

The thread just headed up in the last couple of hours.

 

[squeegee]

Easy answer, we would all meet up somewhere to celebrate.

That sounds like a plan!:agree:

- - - Updated - - -

Endothelial progenitor cells (EPCs) move towards injured endothelium or inflamed tissues and incorporate into foci of neovascularisation, thereby improving blood flow and tissue repair. This is why it is important to bleed during the derma rolling process.

http://www.hindawi.com/journals/bmri/2013/845037/