The problem with traditional research

[IDW2BB]

Thanks for the lymphatic study info, I will go through these over the weekend. At first glance they seem to fit with my thinking on the immunology effect, that I consider very important in female susceptibility to autoimmune disease.

I think with a topical, it would be more effective to use a 5ARI type 2 inhibitor in this application. Any androgen blocker would according to this mechanism, need to reach the deeper lymphatic's of the face and neck. I think a topical would have a problem here. Reducing the amount of DHT produced in the surface structures by a topical would be easier I think, and a type 2 inhibitor alone should be enough as this produces two thirds of local DHT.

We just need to target the large follicles of the scalp and beard area.

Yes I think the principle is the same in Macaques, also related to the action of androgens. Remember the principles of this growth adjustment mechanism, are natural tissue resistance modified by changing local fluid pressures. This explains the differences In patterns and susceptibility in primates , and modern human hairlessness as I argue in my paper.

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Yes I do think the Galea does have an effect for the following reason.

Any increase in local tissue fluid pressure, has a natural dispersal to surrounding lower pressure areas This is the basic physics of pressure differences. The Galea is a membrane that hinders this equalisation of pressure from the male pattern baldness area. I see it as another factor that is not causal, but adds to the retention of excess fluid in male pattern baldness.

Armando, you say eyelash hair is different, in what way? In this mechanism, what is important is not the make up of the hair fibre, but the follicle structure. If its a pocket and the production area protrudes into its base, the physics of this mechanism still apply.

Talking about lymphatic layouts, I would love to see the surface lymphatic layout of lions. I am willing to bet this tells a story about the androgen induced male lions mane.

I will read the posted studies, and post again over the weekend.

Look forward to your input. Might want to check this out as well:



http://www.google.com/patents/EP2153836A1?cl=en


It is a patent on a topical Finasteride formulation that seems to reduce systemic effects while also inhibiting 5ar type 1 to a greater extent than the oral form of finasteride.

What is crazy about the potential of this topical if the research bears out, is that it should be perfect for what you suggest. Using it on the "donor" area and the face.

 

[S Foote.]

I think it is interesting that in the studies about inflammation and lymphatic function, one can influence the other and vice versa. This study about induced lymphedema, demonstrates the downstream immune sensitivity, fibrosis, and oxidative stress (something else also known in the male pattern baldness scalp).

http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030254

For us the important thing is trying to make sense of the cause and effect pathways in male pattern baldness. Lets consider the options here, based on the principles of the scientific method described here.

http://physics.ucr.edu/~wudka/Physics7/Notes_www/node10.html#SECTION02125000000000000000

Some claim that DHT creates an immune response that growth restricts the follicles in male pattern baldness. But that cannot explain the other related factors. For example, what is the reverse immune action of DHT that increases hair growth in other areas? Another mechanism has to be added. Likewise with the significant opposite sweating changes in androgen induced hair loss/growth. There is no physical change in the sweat glands, so it is not a cell growth related issue as in hair follicles. So how can the immunology effect the sweat glands? You need yet another add on mechanism. There is no sensible cause and effect relationship in any direct influence of immunology in male pattern baldness. Also when it comes to biological mechanisms, you have to consider whats the point in evolution? In this case there is no point or advantage to any direct control of hair growth by immunology.

If you consider DHT induced scalp edema as the cause of male pattern baldness, its a different story. DHT induced changes in lymphatic efficiency, easily explain hair growth/loss through the local changes in tissue fluid pressures/levels. The known sweating changes are also explained by these local changes in tissue fluid pressures/levels. The scalp edema also causes the observed immunology changes in male pattern baldness, already a recognised downstream effect of edema. There are no unnecessary add on mechanisms required in this explanation.The point of a fluid pressure/level control of hair growth in evolution, is important advantages as described in my paper.

I want to go on the record here.

The only way we are going to move on from this never ending cycle of hope then dissapointment in treatments, is to sort out the real cause and effect pathway in male pattern baldness. Apart from anything else the recent immune deficient mouse study referenced in my paper, clearly refutes the old notion of significant direct actions of androgens in male pattern baldness.

There is a down side to my proposal. If i am right about this hair growth mechanism, it means many professional scientists have been on the wrong track for a long time. Any professional scientist has a vested interest in their own ideas, and research. Even academic scientists have tenure and grants based on researching a particular pathway. If evidence demonstrates their work is on the wrong track, it threatens their personal position.

I have no axe to grind with professional scientists here. Both before and since my paper was publised, i have been asking scientists in the fields it involves for their comments and critisms of this. Many of these scientists are familiar names to people on hair loss forums, and are regarded as leading experts. If there are any flaws in the evidence for the mechanism i suggest, or they have reasons to think i am a crank or an idiot, i want them to say so.

When i first contact these scientists i make it clear this comes from my systems engineering experience, and interpretation of the evidence. The response is always "sure send it and i will get back to you". Once they read it i don't hear from them again, and any further requests for comments are ignored. There was one occasion when i emailed the link to my paper to the chairman of a leading hair research organisation late at night. The following day i found he had replied within an hour. He was very enthusiastic claiming the members would be very interestd in this, and could i give a lecture about it at an up comming meeting. He must have slept on this and realised it's implications, because my further messages were ignored.

So where's my peer review? I am pretty sure at this point that any weakness in my proposal, would have been willingly pointed out by now. I remain open to any critisms by any professional scientists who are prepared to go on the record, and i will post any such responses here.

There is also the issues this mechanism raises, about the basis upon which some male pattern baldness treatments are being sold to vunerable people. If the hair loss treatment industry is not prepared to address these issues themselves, i am sure the regulatory aurthorities would.

 

[Armando Jose]

You have so much value and many operations in your own hair.
I wish you luck
[h=2]Ockham's Razor is important the simplest theory will be correct[/h]

 

[IDW2BB]

Thanks for the explanations S Foote.

A couple of questions come to mind regarding lymph edema and male pattern baldness.

- Why do some men bald and others don't? Every macaque goes bald (if I'm not mistaken, even the females go bald,). So why doesn't every man go bald?

- What is the reason for the different balding levels? Some men get a bald spot on the top of the head while others just get a receding hairline? Some men only have diffuse hairloss (like women) while others keep a dense amount of hair except in the areas they are actually balding?

- Does lymph edema also have an effect on the nervous system in your theory?


Also, just my opinion, on 5 alpha reductase inhibitors, I don't think a 100% safe one can be made. If a person is sensitive to the medication, even a topical will cause them problems. A topical will still go systemic.

 

[S Foote.]

Thanks for the explanations S Foote.

A couple of questions come to mind regarding lymph edema and male pattern baldness.

- Why do some men bald and others don't? Every macaque goes bald (if I'm not mistaken, even the females go bald,). So why doesn't every man go bald?

- What is the reason for the different balding levels? Some men get a bald spot on the top of the head while others just get a receding hairline? Some men only have diffuse hairloss (like women) while others keep a dense amount of hair except in the areas they are actually balding?

- Does lymph edema also have an effect on the nervous system in your theory?


Also, just my opinion, on 5 alpha reductase inhibitors, I don't think a 100% safe one can be made. If a person is sensitive to the medication, even a topical will cause them problems. A topical will still go systemic.

I think the primary reason some men go bald when others don't for a given level of DHT, is because of the feed side of the equation as I referred to before. I think this is the link that has been recently demonstrated with coronary heart disease.

I think the principles of this evolved mechanism also explain the variations of thinning, and hair loss patterns in the individual. Our scalp follicles vary in depth in the dermis, and in the phase of the hair cycle they are in. Any slight differences in the tissue toughness in local areas of the scalp, or at the different depths of follicles would make a difference in follicle response to increasing fluid levels pressures. Then of course the increases in the fluid aspect, can take time to develop and can effect some scalp areas before others. I suggest the temple area is the most vulnerable area after puberty to increased fluid level/pressure/ accounting for early temple recession.

To give an example the physics involved as I describe in my paper, make shorter larger scalp follicles more resistant to increasing fluid. Longer follicles next to these will produce a finer shorter hair as they are distorted, or if longer still the hair can be shed. Given the length of the anagen phase of human scalp hair of years, individual hairs can remain for a long period in the process.

Once one of these long lasting follicles goes into the resting phase, it gives up its space in the dermis. Then on trying to re-enlarge again it has a harder time because of the increased resistance, and the new follicle is smaller.

I think its all about combinations of these factors in the individual. According to this mechanism, DHT is helping to grow hair, male pattern baldness is caused by too much of a good thing. The male pattern baldness area represents the point where the fluid dynamics of too much local DHT create the reverse effect. I don't think it is all to do with androgens in women, other hormonal or other factors are involved. I think this is why women suffer a more widespread diffuse pattern of loss. We have to remember that women's hair loss is on the increase, whilst in general androgen levels in both sexes are reducing.

Likewise in Macaques, I think it is combinations of all the factors relating to this mechanism that lead to the pattern/rate of loss.

I think its interesting to consider the alternative explanation of the traditional assumptions.

According to this some follicles are directly shrunken by androgens, some are enlarged, and some are not affected at all. The follicles directly affected by androgens each have their own 'genetic clock'. This determines how long it is after androgen exposure, before the follicle actually responds to androgens. The follicles that start to increase hair growth from the ears and nostrils of middle aged men, are really lazy here taking 20 years or so to realize they are androgen dependant!

Taken to its logical conclusion the whole notion becomes ridiculous, and goes against what we know about hormone reactive cells. On top of this, such a pointless in evolution hair growth mechanism, cannot even begin to explain the other accepted factors of immunology, fibrosis, sweating etc.

DHT may well have an effect on the nervous system, but I don't think lymphedema itself does.

I think the trick would be to develop a topical 5ARI that can do the business in follicles then degrade before any significant systematic effects.

 

[DoneWithIt]

I've always thought that there are still pieces of the male pattern baldness puzzle missing.

Of course there are, or we'd have a cure by now...

 

[IDW2BB]

I think the primary reason some men go bald when others don't for a given level of DHT, is because of the feed side of the equation as I referred to before. I think this is the link that has been recently demonstrated with coronary heart disease.

I think the principles of this evolved mechanism also explain the variations of thinning, and hair loss patterns in the individual. Our scalp follicles vary in depth in the dermis, and in the phase of the hair cycle they are in. Any slight differences in the tissue toughness in local areas of the scalp, or at the different depths of follicles would make a difference in follicle response to increasing fluid levels pressures. Then of course the increases in the fluid aspect, can take time to develop and can effect some scalp areas before others. I suggest the temple area is the most vulnerable area after puberty to increased fluid level/pressure/ accounting for early temple recession.

To give an example the physics involved as I describe in my paper, make shorter larger scalp follicles more resistant to increasing fluid. Longer follicles next to these will produce a finer shorter hair as they are distorted, or if longer still the hair can be shed. Given the length of the anagen phase of human scalp hair of years, individual hairs can remain for a long period in the process.

Once one of these long lasting follicles goes into the resting phase, it gives up its space in the dermis. Then on trying to re-enlarge again it has a harder time because of the increased resistance, and the new follicle is smaller.

I think its all about combinations of these factors in the individual. According to this mechanism, DHT is helping to grow hair, male pattern baldness is caused by too much of a good thing. The male pattern baldness area represents the point where the fluid dynamics of too much local DHT create the reverse effect. I don't think it is all to do with androgens in women, other hormonal or other factors are involved. I think this is why women suffer a more widespread diffuse pattern of loss. We have to remember that women's hair loss is on the increase, whilst in general androgen levels in both sexes are reducing.

Likewise in Macaques, I think it is combinations of all the factors relating to this mechanism that lead to the pattern/rate of loss.

I think its interesting to consider the alternative explanation of the traditional assumptions.

According to this some follicles are directly shrunken by androgens, some are enlarged, and some are not affected at all. The follicles directly affected by androgens each have their own 'genetic clock'. This determines how long it is after androgen exposure, before the follicle actually responds to androgens. The follicles that start to increase hair growth from the ears and nostrils of middle aged men, are really lazy here taking 20 years or so to realize they are androgen dependant!

Taken to its logical conclusion the whole notion becomes ridiculous, and goes against what we know about hormone reactive cells. On top of this, such a pointless in evolution hair growth mechanism, cannot even begin to explain the other accepted factors of immunology, fibrosis, sweating etc.

DHT may well have an effect on the nervous system, but I don't think lymphedema itself does.

I think the trick would be to develop a topical 5ARI that can do the business in follicles then degrade before any significant systematic effects.

Searching around you tube in order to understand edema better and found this video. Is this a good visual to help understand the concepts of your theory?



[video=youtube;KuZKQ7Eb_eA]http://www.youtube.com/watch?v=KuZKQ7Eb_eA[/video]

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I was also wondering the impact of this discovery on your theory if any:
http://www.sciencedaily.com/releases/2013/06/130627142402.htm



That the brain waste dumps into the neck lymphatics seems to bring the whole hydraulics together? Any thoughts on this plumbing issue? Associations to male pattern baldness?

 

[S Foote.]

Searching around you tube in order to understand edema better and found this video. Is this a good visual to help understand the concepts of your theory?



[video=youtube;KuZKQ7Eb_eA]http://www.youtube.com/watch?v=KuZKQ7Eb_eA[/video]

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I was also wondering the impact of this discovery on your theory if any:
http://www.sciencedaily.com/releases/2013/06/130627142402.htm



That the brain waste dumps into the neck lymphatics seems to bring the whole hydraulics together? Any thoughts on this plumbing issue? Associations to male pattern baldness?

A very interesting couple of links, thanks.

Yes I think the primer on blood feed/lymph drainage, is a good descriptive article of the basics. From this we can see that a proportion of the fluid transferred into the tissue by the blood supply, has to be returned by the lymphatic's. So the higher the blood supply pressure, the more leakage into the tissue, the greater the amount of fluid required to be drained by the lymphatic's.

This fits the suggestion that DHT induced reduced scalp lymph drainage, is more relevant to male pattern baldness in those with higher blood feed pressure. I suggest this is the recently demonstrated connection with male pattern baldness and CHD.

I think this video also indicates why a male hormone (DHT) should increase lymph drainage over the larger part of the body in terms of evolution. To increase male tissue growth and performance, you have to increase tissue nutrient supply and waste removal. To do this by increasing blood pressure would just lead to edema, and the known problems this causes in tissue.

Increasing lymph drainage would 'suck' increased amounts of nutrients and waste products through the tissue, a much better way of doing it. I think a good analogy is in engine performance tuning. DHT creates the higher performance exhaust system necessary to get the maximum benefits from the other performance related modifications. Body builders who use Finasteride, often complain of reduced tissue growth effects and increased fatigue when training.

The brain 'glymphatic' discovery is interesting. I don't think this is directly relevant to us, as the lymphatic connection is claimed to be lower down the spine. I think it is generally the frontal head/face/neck vessels that generate back pressure in the male pattern baldness area.

I think what this article does add support to, is the 'plumbing' complexity of the modern human head associated with the evolution of the human brain. I think the evidence points to this complexity being at the centre of human male pattern baldness.

 

[IDW2BB]

What do you think about this story? As you can see, hair is present where the bone is and balding where the edema is.


http://pakistan.onepakistan.com.pk/...-surgeons-reconstruct-babys-swollen-head.html







adding this pic. for perspective:


http://weber.ucsd.edu/~dkjordan/resources/clarifications/clarpict/PelvisFetalSkull.gif

 

[S Foote.]

What do you think about this story? As you can see, hair is present where the bone is and balding where the edema is.


http://pakistan.onepakistan.com.pk/...-surgeons-reconstruct-babys-swollen-head.html



View attachment 21851



adding this pic. for perspective:


http://weber.ucsd.edu/~dkjordan/resources/clarifications/clarpict/PelvisFetalSkull.gif

Ouch, that's nasty. I do think if you study hair loss, the common factor of local edema caused for whatever reason is present.

Here are a few links to studies of the rare condition of Lipedematous Alopecia.

http://www.ncbi.nlm.nih.gov/pubmed/10660132

http://www.ncbi.nlm.nih.gov/pubmed/16638399

http://www.ncbi.nlm.nih.gov/pubmed/18477157

http://www.ncbi.nlm.nih.gov/pubmed/17903063

In general these show that the effected tissue can be localised and at different levels of the scalp. I think the last link is of particular interest to us, because of the following quote:

"The presence of ecstatic lymphatic vessels with hair loss was particularly emphasized. Our findings suggest a lessened role of racial factors but confirm the sex implications and significance of lymphangiectatic vessels in development of alopecia in this condition."

 

[today]

A very interesting couple of links, thanks.

Yes I think the primer on blood feed/lymph drainage, is a good descriptive article of the basics. From this we can see that a proportion of the fluid transferred into the tissue by the blood supply, has to be returned by the lymphatic's. So the higher the blood supply pressure, the more leakage into the tissue, the greater the amount of fluid required to be drained by the lymphatic's.

This fits the suggestion that DHT induced reduced scalp lymph drainage, is more relevant to male pattern baldness in those with higher blood feed pressure. I suggest this is the recently demonstrated connection with male pattern baldness and CHD.

I think this video also indicates why a male hormone (DHT) should increase lymph drainage over the larger part of the body in terms of evolution. To increase male tissue growth and performance, you have to increase tissue nutrient supply and waste removal. To do this by increasing blood pressure would just lead to edema, and the known problems this causes in tissue.

Increasing lymph drainage would 'suck' increased amounts of nutrients and waste products through the tissue, a much better way of doing it. I think a good analogy is in engine performance tuning. DHT creates the higher performance exhaust system necessary to get the maximum benefits from the other performance related modifications. Body builders who use Finasteride, often complain of reduced tissue growth effects and increased fatigue when training.

The brain 'glymphatic' discovery is interesting. I don't think this is directly relevant to us, as the lymphatic connection is claimed to be lower down the spine. I think it is generally the frontal head/face/neck vessels that generate back pressure in the male pattern baldness area.

I think what this article does add support to, is the 'plumbing' complexity of the modern human head associated with the evolution of the human brain. I think the evidence points to this complexity being at the centre of human male pattern baldness.

This topic has fascinated me. I done my second scalp peel last week 25% TCA left on for 30 minutes then rinsed with baking soda. Anyway cause i am acne prone I think i would get some extra benefit from using a dht blocking topical for the face and neck area considering thats where i get most my acne spots.
I have dutasteride powder stored away in the freezer and i have pure ethanol. Even though the ethanol is 195% proof it still contains a tiny % of water and therefore is giving me solubility issues with the dutasteride powder. Is there any oils that dutasteride powder is soluble in? You see i was thinking of dissolving 30mgs of dutasteride in ethanol and then mixing the ethanol with a carrier oil i have at home fractionated coconut oil but then i would say ethanol and oil might not mix together well without the oil rising to the top of the mixture. Any suggestions? I don't want to use a pure alcohol based vehicle as my skin is very sensitive.

 

[Armando Jose]

you can try to use a small quantitie of detergent to mix better ethanol and oil

 

[today]

Telogen Effluvium=Armando Jose;1141904]you can try to use a small quantitie of detergent to mix better ethanol and oil[/QUOTE]

I just mixed 5mls of ethanol to 36mgs of dutasteride powder and then i added 45mgs of fractionated coconut oil to it and mixed it together. It seems to work out alright.
I was able to apply 1.7mgs of the solution all over my face and the front/back of the neck, which was about 1mg of dutasteride.
Do you think that will work? I didn't have enough solution to apply over the sides and back of the donor hair, maybe if i had of used the 1.7mg solution a bit more sparingly i would have. But i did cover all of my face, nose forehead and neck front and back.

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I am going to switch the coconut oil for aloe vera gel because the oil didn't completely absorb into my skin 3 hours later an i could still feel the grease of the oil on the surface of the skin. Its just mixing up the ethanol/dutasteride evenly in the aloe vera is going to be the challenge. On another note maybe this is why the guy that did the double AA experiement touted full regrowth after less than a year of using it.

He was using 40gms of aloe vera gel mixed with 1 avodart gel cap per application. He used it in the shower. What he did was dampened his scalp when in the shower, mixed the avodart gel cap in the 40gms of aloe vera in a shot glass using just his finger, completely covered his scalp with the double A for 3 minutes and then shampooed it out right after. He claimed within 8 months complete reversal of hairloss, back to his teenage hairline. I think because he was in the shower he may have been inadvertently got some of the double A on his face definitely with out a doubt the back and sides of his head. An he only needed to apply it for 3 minutes and wash off.

 

[Armando Jose]

http://www.ncbi.nlm.nih.gov/pubmed/21513483
[h=1]Development and characterization of dutasteride bearing liposomal systems for topical use.[/h]Sharma P, Jain D, Maithani M, Mishra SK, Khare P, Jain V, Singh R.
[h=3]Source[/h]School of Pharmaceutical Sciences, Shobhit University, Meerut, Uttar Pradesh, India.

[h=3]Abstract[/h]Dutasteride loaded liposomal system were developed for topical application in order to avoid the side effects associated with the oral administration of the drug. Drug-loaded multilamellar liposomes were prepared using thin-film hydration method followed by sonication and optimized with respect to entrapment efficiency, drug payload, size and lamellarity. The vesicular systems consisting of egg phosphatidylcholine (100 mg), cholesterol (50 mg), and dutasteride (5 mg) showed highest drug entrapment efficiency (94.6%) and drug payload (31.5 µg/mg of total lipids). Mean vesicle size of these liposomes was noted to be 1.82 ± 0.15 µm. Significantly higher skin permeation of dutasteride through excised abdominal mouse skin was achieved via the developed liposomal formulations as compared to hydro-alcoholic solution and conventional gels. The formulation exhibited about seven fold higher deposition of drug in skin. Stability studies indicated that the liposomal formulations were quite stable in the refrigerated conditions for 10 weeks with negligible drug leakage or vesicle size alteration. Results of the current studies exhibited improved and localized drug action in the skin and thus could be formulated as a better option to cure androgenetic alopecia.

But, please open a new thread, about this issue, This one is about the problem with traditional research

 

[today]

http://www.ncbi.nlm.nih.gov/pubmed/21513483
Development and characterization of dutasteride bearing liposomal systems for topical use.

Sharma P, Jain D, Maithani M, Mishra SK, Khare P, Jain V, Singh R.
Source

School of Pharmaceutical Sciences, Shobhit University, Meerut, Uttar Pradesh, India.

Abstract

Dutasteride loaded liposomal system were developed for topical application in order to avoid the side effects associated with the oral administration of the drug. Drug-loaded multilamellar liposomes were prepared using thin-film hydration method followed by sonication and optimized with respect to entrapment efficiency, drug payload, size and lamellarity. The vesicular systems consisting of egg phosphatidylcholine (100 mg), cholesterol (50 mg), and dutasteride (5 mg) showed highest drug entrapment efficiency (94.6%) and drug payload (31.5 µg/mg of total lipids). Mean vesicle size of these liposomes was noted to be 1.82 ± 0.15 µm. Significantly higher skin permeation of dutasteride through excised abdominal mouse skin was achieved via the developed liposomal formulations as compared to hydro-alcoholic solution and conventional gels. The formulation exhibited about seven fold higher deposition of drug in skin. Stability studies indicated that the liposomal formulations were quite stable in the refrigerated conditions for 10 weeks with negligible drug leakage or vesicle size alteration. Results of the current studies exhibited improved and localized drug action in the skin and thus could be formulated as a better option to cure androgenetic alopecia.

But, please open a new thread, about this issue, This one is about the problem with traditional research

Wow man, making a vehicle like that is way above my pay grade. I think i will have to settle for the double AA, i think if i mix 10mls of ethanol with 30mgs of dutasteride powder and draw out 0.3mls of ethanol/dutasteride an mix it with 5grams of aloe vera in a shot glass and apply all over my face, neck and donor area that should work well?

 

[IDW2BB]

Just reading these two together makes me wonder if we baldies are also losing lymph vessels. the pub med link is a free article and the 2nd study I found was posted by Dr. Nigam on a different forum.




http://www.ncbi.nlm.nih.gov/pubmed/18849330

TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair.

Clavin Norwood, Avraham T, Fernandez J, Daluvoy SV, Soares MA, Chaudhry A, Mehrara BJ.


Source

Division of Plastic and Reconstructive Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Abstract

Although clinical studies have identified scarring/fibrosis as significant risk factors for lymphedema, the mechanisms by which lymphatic repair is impaired remain unknown. Transforming growth factor -beta1 (TGF-beta1) is a critical regulator of tissue fibrosis/scarring and may therefore also play a role in the regulation of lymphatic regeneration. The purpose of this study was therefore to assess the role of TGF-beta1 on scarring/fibrosis and lymphatic regeneration in a mouse tail model. Acute lymphedema was induced in mouse tails by full-thickness skin excision and lymphatic ligation. TGF-beta1 expression and scarring were modulated by repairing the wounds with or without a topical collagen gel. Lymphatic function and histological analyses were performed at various time points. Finally, the effects of TGF-beta1 on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-beta1, decreased scarring/fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-beta1 to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-beta1 inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-beta1 caused a dose-dependent significant decrease in cellular proliferation and tubule formation of isolated LECs without changes in the expression of VEGF-C/D. Finally, the increased expression of TGF-beta1 during wound repair resulted in lymphatic fibrosis and the coexpression of alpha-smooth muscle actin and lymphatic vessel endothelial receptor-1 in regenerated lymphatics. In conclusion, the inhibition of TGF-beta1 expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-beta1 expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-beta1 expression may be useful in promoting more rapid lymphatic regeneration.

Involvement of the immune response in regeneration of experimentally amputated whisker follicles in vivo and in a novel culture model of regeneration using newborn follicles
S-W Li1,2, C Higgins3, K Sorensen2, AM Christiano3 and CA Jahoda2 1College of Life Science, Tarim University, Alar, China; 2School of Biological and Biomedical Sciences, Durham University, Durham, UK and 3Department of Dermatology, Columbia University, New York, USA

Follicles have a unique capacity to regenerate a functional end bulb after experimental amputation. Previous work suggests that regeneration entails an initial phase resembling skin wound healing, followed by specific remodeling of the bulb involving epithelialmesenchymal interactions. A key feature of the phenomenon is that the mesenchymal (dermal) components of the follicle (the dermal papilla and dermal sheath) reconstitute without scarring (fibrosis). Macrophages, as well as TGFβ family members, have been strongly linked with fibrosis; therefore one hypothesis is that lower follicle regeneration involves a reduced or modified immune response. This study aimed to investigate this question and to develop a novel culture model of follicle regeneration. For in vivo studies mouse and rat whisker follicles were experimentally amputated and follicles recovered between 24 hours and 3 weeks postoperatively. For in vitro work, follicles were isolated from newborn mice, bases amputated, and the follicles cultured on filters for up to 4 days. All specimens were cryofrozen or wax processed for immunohistochemistry/immunofluorescence. Early changes to the epithelium mirrored that of skin wound healing with migration of the follicle epithelium to fill the inner follicle silo, upregulation of cytokeratin15 near the follicle base, and strong expression of fibronectin. The in vitro model was able to undergo this first phase of regeneration. Labeling of in vivo specimens with a CD68 antibody (rat) and CD11b, F4/80 antibodies (mouse) identified highest concentrations of macrophages around the site of amputation at 48 hours, these cells being lost by 7 days. Interestingly, macrophages were also detected in the culture model. TGFβ1 was strongly expressed in follicle dermis, although, interestingly, not at the immediate site of dermal papilla regeneration. We suggest that lack of scarring in regenerated follicles cannot be attributed to lack of an immune response, although subtleties involving macrophage subpopulations are currently being investigated.

 

[S Foote.]

Just reading these two together makes me wonder if we baldies are also losing lymph vessels. the pub med link is a free article and the 2nd study I found was posted by Dr. Nigam on a different forum.




http://www.ncbi.nlm.nih.gov/pubmed/18849330






Involvement of the immune response in regeneration of experimentally amputated whisker follicles in vivo and in a novel culture model of regeneration using newborn follicles
S-W Li1,2, C Higgins3, K Sorensen2, AM Christiano3 and CA Jahoda2 1College of Life Science, Tarim University, Alar, China; 2School of Biological and Biomedical Sciences, Durham University, Durham, UK and 3Department of Dermatology, Columbia University, New York, USA

Yes I think this complicated downstream cascade of events, all add to the problem in male pattern baldness. We already know that the longer male pattern baldness goes on, the harder it is to reverse.

 

[IDW2BB]

S Foote, what are your thoughts on lymphangiogenesis in the scalp to help with the edema?

I was reading this:

http://www.ncbi.nlm.nih.gov/pubmed/24052499

Not advocating Adiponectin in particular but more inquiring about your thoughts regarding lymphangiogenesis as an avenue to help with hairloss based on your theory!

Thanks!

 

[S Foote.]

S Foote, what are your thoughts on lymphangiogenesis in the scalp to help with the edema?

I was reading this:

http://www.ncbi.nlm.nih.gov/pubmed/24052499

Not advocating Adiponectin in particular but more inquiring about your thoughts regarding lymphangiogenesis as an avenue to help with hairloss based on your theory!

Thanks!

According to the theory, I don't think lymphangiogenesis would help if the restriction is downstream. I think it could possibly be a aid to speed scalp recovery, as long as the other factors we talked about are being addressed.

I should add that laser therapy is believed to aid lymphangiogenesis, as part of its effect upon lymphedema.

http://www.ncbi.nlm.nih.gov/pubmed/9664272

http://www.cancer.gov/cancertopics/pdq/supportivecare/lymphedema/healthprofessional/page2#Section_68

 

[IDW2BB]

Thanks S Foote for your reply! It makes sense. I'm just pondering some of the research I have read regarding crosstalk between what goes on "in" the follicle and the surrounding tissue. Could your theory have an impact on that signaling? Does edema effect signaling?

Also ran across this commentary:

http://www.nature.com/ki/journal/v84/n5/full/ki2013287a.html

excerpt:

For maintenance of interstitial fluid homeostasis, the net flux of filtered plasma is balanced by lymph fluid formation into the initial lymphatic vessels. Three mechanisms for the uptake of interstitial fluid into initial lymphatics have been suggested: vesicular transport, osmotic pressure gradients, or fluid pressure gradients.8 It is generally accepted that interstitial fluid pressure is the main determinant of initial lymph filling and lymph flow.2 Unidirectional flow may be ensured by a primary valve system at the level of the interstitium, which prevents reverse outflow of lymph fluid and is then actively pumped out of the periphery by passive and active contraction of secondary lymph vessels. Identification of molecular mechanisms of lymphangiogenesis by vascular endothelial growth factors9 has opened insights into interstitial fluid physiology that go beyond the classical model. We now learn that immune function is modulated by lymph capillary function, regulatory growth factors, interstitial electrolyte concentration, and interstitial pressure, which suddenly become components determining the resolution of inflammatory responses, immunological tolerance and tumor growth,10 autoimmunity, and systemic blood pressure.

We do not know whether or not the increases in interstitial fluid content and fluid pressure observed in CDK patients trigger similar immune responses in the human interstitium. Ebah and colleagues have provided clinical news from a ‘black box’, which has been named the ‘interstitium’. Evidence suggests that a more critical look into the inner workings of this black box provides promising and novel information.