TISSUE MODIFICATION OF THE LATERAL COMPARTMENT OF THE TIBIO-FEMORAL JOINT FOLLOWING IN VIVO VARUS LOADING IN THE RAT

“This study describes the first application of a varus loading device (VLD) to the rat hind limb to study the role of sustained altered compressive loading and its relationship to the initiation of degenerative changes to the tibio-femoral joint. The VLD applies decreased compressive load to the lateral compartment and increased compressive load to the medial compartment of the tibio-femoral joint in a controlled manner.

Mature rats were randomized into one of three groups: unoperated control, 0% (sham) or 80% body weight (BW). Devices were attached to animal’s leg to deliver altered loads of 0% and 80% BW to the experimental knee for 12 weeks. Compartment-specific material properties of the tibial cartilage and subchondral bone were determined using indentation tests. Articular cartilage, calcified cartilage and subchondral bone thicknesses, articular cartilage cellularity, and degeneration score were determined histologically.

Joint tissues were sensitive to 12 weeks of decreased compressive loading in the lateral compartment with articular cartilage thickness decreased in the peripheral region, subchondral bone thickness increased, and cellularity of the midline region decreased in the 80% BW group as compared to the 0% BW group. The medial compartment revealed trends for diminished cellularity and aggregate modulus with increased loading.

The rat-VLD model provides a new system to evaluate altered quantified levels of chronic in vivo loading without disruption of the joint capsule while maintaining full use of the knee. These results reveal a greater sensitivity of tissue parameters to decreased loading versus increased loading of 80% BW for 12 weeks in the rat. This model will allow future mechanistic studies that focus on the initiation and progression of degenerative changes with increased exposure in both magnitude and time to altered compressive loads.”

” The VLD applies altered loads in addition to the normal loads across the joint without disruption of the joint capsule while maintaining full use and range of motion of the joint.”

The mice were 9-month old sprague dawley.  The rats had the plates attached surgically so it’s not really an exact approximation of LSJL.  And the 0% BW results were drastically different from control so the apparatus definitely had an effect.

“Gross observation of the tibial plateau revealed minimal erosion or fibrillation of the articular cartilage in all experimental groups.”

“The thickness of the articular cartilage in the peripheral region of the lateral compartment decreased 19% in the 80% BW group as compared to the 0% BW group and 26% as compared to the control group. In contrst, the thickness of the subchondral bone increased 38% in the 80% BW group as compared to the 0% BW group”<-So loading increases subchondral bone “thickness” but does this thickness add to height?

Here’s a comparison between sham control(0% BW) and 80% BW.  Loading definitely decreased chondrocyte number but it didn’t seem to decrease articular cartilage height and subchondral bone height seemed to be higher.

Subchondral bone thickness is considered height.

Short and tall stature: a new paradigm emerges.
Full Study->jeffreybaron study

“In the past, the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis was often considered to be the main system that regulated childhood growth and, therefore, determined short stature and tall stature. However, findings have now revealed that the GH-IGF-1 axis is just one of many regulatory systems that control chondrogenesis in the growth plate, which is the biological process that drives height gain. Consequently, normal growth in children depends not only on GH and IGF-1 but also on multiple hormones, paracrine factors, extracellular matrix molecules and intracellular proteins that regulate the activity of growth plate chondrocytes. Mutations in the genes that encode many of these local proteins cause short stature or tall stature. Similarly, genome-wide association studies have revealed that the normal variation in height seems to be largely due to genes outside the GH-IGF-1 axis that affect growth at the growth plate through a wide variety of mechanisms. These findings point to a new conceptual framework for understanding short and tall stature that is centred not on two particular hormones but rather on the growth plate, which is the structure responsible for height gain.”

Note extracellular fluid is listed as a factor and extracellular fluid flow can be modified by LSJL.

This page lists genes that cause mutations to linear growth.  This page lists other mutations and their effects on stature.

“the vast majority of children with short stature do not have a well-substantiated defect in the GH–IGF-1 axis.”

“Many new genes have been identified that, when mutated, result in short stature or tall stature, the majority of which do not participate in the GH–IGF-1 system”

“Estrogen has complex effects on the growth plate, not only altering growth rate, but also accelerating the loss of progenitor cells in the resting zone and thereby speeding up the developmental program of growth plate senescence, which causes early cessation of growth”

“tumour necrosis factor, IL-1β and IL-6 act directly on growth plate cartilage to suppress bone growth”

“fairly low doses of ionizing radiation, such as a single dose of 10 Gy, can impair longitudinal growth. Mechanical compression across the growth plate also impairs the elongation of bones, which is partly due to decreased enlargement of hypertrophic chondrocytes.”<-Chondrocyte hypertrophy size increases due to lsjl.

“FGFR-3 signalling negatively regulates growth by decreasing proliferation in the proliferative zone, decreasing production of the extracellular matrix, accelerating the onset of hypertrophic differentiation and decreasing the size of the hypertrophic chondrocytes”

“~2% of children who present with idiopathic short stature have mutations in NPR2, Conversely, overexpression of CNP or activating mutations in NPR2 result in tall stature.”

” Binding of CNP to NPR2 stimulates the guanylyl cyclase activity of the receptor, thereby increasing synthesis of cGMP, which activates the type II cGMP-dependent protein kinase”

“Of individuals presenting with idiopathic short stature, 2–15% have mutations in SHOX, with the exact percentage depending on the study. Conversely, increased copies of SHOX are associated with tall stature in individuals with Klinefelter syndrome and other types of sex chromosome aneuploidy”

“Sotos syndrome (characterized by tall stature) is associated with decreased activity of the Ras–MAPK pathway.”

“Ras, a small GTPase, signals via MAPK cascades to phosphorylate numerous cytoplasmic and nuclear proteins, regulating cell proliferation and differentiation.”

“heterozygous mutations in DNA methyltransferase 3A (DNMT3A) cause tall stature, a distinctive facial appearance and intellectual disability.”

“heterozygous mutations in EZH2, which encodes an enzyme that specifically methylates lysine residue 27 of histone 3 (H3K27, which is associated with transcriptional repression), are associated with Weaver syndrome (characterized by prenatal and postnatal overgrowth and a markedly advanced bone age).”

There’s a lot more covered in the study than I mentioned here.  The full study is worthwhile to read.

It’s frustrating how much bodybuilding research there is in terms of sets, reps, and all sorts of factors to build up muscle and how little there is in terms of height.  Note that most of this research does not come from science it comes from tons of independent bodybuilders.

With muscle building we know that stressing the muscles in general increases their size.  Bodybuilders don’t wait for calf and pec implants to get bigger muscles.

We don’t know though how to lengthen bone?  We don’t know what stimulus to apply?  Actually we have a pretty good idea.

To induce chondrogenic differentiation(chondrocytes are the basis for the growth plate) one method is to induce a hydrostatic pressure of at least 0.1 MPa.  A blood pressure cuff during a heart beat generates about 120mmHg which is about 0.015MPa an order of magnitude of what we need.  To get 0.1MPa we’d need a blood pressure of about 750mmHg which would probably cause death.  There has to be a way for the body to safely induce hydrostatic pressure of 0.1MPa-10MPa’s to induce chondrogenic differentiation.  HP levels of the articular cartilage can vary between 1-5MPa in response to physiological(occurs normally) stress.  There are two possible ways to make up the difference in the hydrostatic pressure deficit(0.015MPa versus 0.1MPa or ideally higher) fluid flow and bone deformation.

Ultrasound levels of 30–200 mW/cm2, Frequency=1–1.5 MHz are one possibility(you’d target in the epiphysis).  Note I have not tested this so attempt at your own risk!  Muscular contraction can also increase marrow hydrostatic pressure.  You’d probably need to use external electrical stimuli to generate the muscular contraction needed to induce significant hydrostatic pressure.  Again I can not say whether or not this is safe or not!

An increase in hydrostatic pressure also results in an increase in fluid flow which may be the primary inducer of chondrogenic differentiation rather than the HP itself.  Thus you could find ways to induce fluid flow directly and in conjunction with an increase in hydrostatic pressure to get the needed stimulus to induce chondrogenic differentiation.

The growth plate is exposed to high hydrostatic pressure via the bone pressing down on it.  If we create a fibrous layer in a neo-growth plate region maybe the hydrostatic pressure to encourage a growth plate will occur naturally.  Note that LSJL does encourage fibrous tissue differentiation.  If we can create a fibrous tissue layer, the compression force of the bone itself will create the hydrostatic pressure and induce chondroinduction.

Fluid flow induces recruitment of integrins to focal adhesions.  This alteration in cell signaling by fluid flow directly could induce chondrogenic differentiation.

So we know the key to growing taller is to induce a new growth plate in the bone as bone tissue is not mechanically suited for interstitial growth.  We know that this can happen at around 0.1MPa hydrostatic pressure in the bone epiphysis.  It’s possible to make up for a deficit in hydrostatic pressure levels via other factors like fluid flow via dynamic lateral compression.  There’s also the possibility of using ultrasound and electrical muscle stimulation.  Such levels would have to be supranormal as no muscle stimulation of longitudinal bone growth has yet to be reported.  Since it is supranormal all the effects are not known so it would have to be tested somewhat for safety first.

Metformin Hydrochloride is used to treat type II diabetes.  It’s possible that Metformin could increase height via a SIRT1 cellular senescence related mechanism, a mitochondrial related mechanism(chondrocytes are hypoxic so metformin could affect height in that way), or another mechanism.

Evaluating the Effects of Metformin Use on Height in Children and Adolescents: A Meta-analysis of Randomized Clinical Trials.

Full study->poi150054

“Metformin hydrochloride use is increasing in children and adolescents. [There’s] a large variability in the effects of metformin use on body mass index changes but have not considered height changes as a confounder{Height affects BMI, Metforim may affect height}.
To conduct a systematic review and meta-analysis of the effects of metformin use on height in children and adolescents.
Computerized databases, including MEDLINE and EMBASE, were searched up to September 9, 2014, for terms related to metformin and childhood or adolescence.
Randomized clinical trials examining the effects of metformin use on height of participants younger than 19 years were considered eligible. Trials with cointerventions other than lifestyle changes were excluded.
Height, weight, body mass index, age, sex, metformin dosage, and study duration were independently extracted by 2 reviewers. The weighted mean differences for changes in height, weight, and body mass index were compared between the metformin and control groups using random-effects models.
Ten studies were included, with a total of 562 participants, 330 (58.7%) of whom were female. The mean age within the studies ranged from 7.9 to 16.1 years, with a high variability in most studies. The duration of metformin interventions lasted from 3 to 48 months. Overall, height changes were not significantly different between the metformin and control groups. However, stratified analyses according to the cumulative metformin dose (in milligrams per day times the number of days of treatment) showed a greater increase in height with metformin use in the 5 studies providing the largest cumulative metformin doses (weighted mean difference, 1.0; 95% CI, 0.0 to 2.0 cm) but not in the 5 studies providing the lowest doses (weighted mean difference, -0.1; 95% CI, -0.7 to 1.0 cm) compared with the control group.
Preliminary evidence suggests a dose-response relationship between metformin use and increases in height in children and adolescents compared with a control group. While an approximate 1-cm increase in height may appear small, it is likely underestimated given that many studies were of short duration and included older adolescents, potentially after epiphyseal growth plate closure.”

Metforrim may have had an impact on height by up to 2cm in subjects that high doses of metforrim.

“A greater cumulative exposure to metformin may increase height by a mean of approximately 1 cm in children and adolescents compared with a control group.”<-A dedicated study is needed though.

“a 2.8-cm greater increase in height in the metformin group for girls approximately 9 years old”

“metformin administration during puberty could enhance or prolong the normally occurring, puberty induced height change”

Does Metformin Really Increase Height, or Is There Some Problem With the Controls?—Reply

“thank Poulton for the thoughtful letter that stated that the greater increase in height observed in studies from our meta-analysis with the highest cumulative metformin dose was owing to “a combination of inaccurate and abnormally slow growth rates in the control individuals.”

We agree that artifacts could arise from a higher attrition level in the study by Kendall et al, and understand why it is tempting for Dr Poulton to suggest that we should reanalyze without this study. However, we disagree that we should exclude an individual study owing to its attrition level without applying this criterion to all studies (eg, the study by Mauras et al had the highest control group attrition rate but a −0.2-cm change in height in the metformin vs the control group). While the changes in height in the control group from Kendall et al (ie, 1 cm in 6 months; mean baseline age of 13.6 years) may seem “suspiciously slow,” it is not dissimilar from other studies we reviewed that were comparable in terms of duration and participants’ baseline age. This “slower growth than normal in the controls” may therefore be explained by findings that suggest children with obesity have an earlier peak height velocity and onset of puberty, but lower peak height velocity. For these reasons, we believe it would be inappropriate for us to single out and exclude the data from Kendall et al.^“

Early metformin therapy to delay menarche and augment height in girls with precocious pubarche

“At age 8 years, girls were randomly assigned to remain untreated or to receive metformin for 4 years; subsequently, both subgroups were followed without treatment until each girl was postmenarcheal.

I was reading some random study in the field of orthopedics today and someone mentioned the condition SED, or Spondyloepiphyseal dysplasia congenita based Dwarfism, and that made me remember a few things that I had not looked at for a long time.

I remember people telling me about quack-pseudo-scientific ideas on how to treat SED before on other websites, but I wondered whether the Patent databases had anything written about treating it, in a more scientifically legitimate way. So I googled “Spondyloepiphyseal Dysplasia Congenita” into the Google Patent database to see what would come up.

Some of the first few results were obviously crazy, like the following “Drug composition for treating spondyloepiphyseal dysplasia – CN 103142900 A”. This patent apparently was only filed in the China based database, and it is based on a combination of strange vegetables, minerals, and plants. The idea from this ancient formulation I would guess is to reduce the curvature of the spinal or straighten it out, which would obviously give the person a little bit of height increase. However, I would not be willing to put money on an idea based on Traditional Chinese Medicine practices.

It would be the next search result, which really caught my eye. Refer to the patent “Variants of C-Type Natriuretic Peptide – US 20100297021 A1″. This was a patent which I don’t believe I have talked about before, and the name of it would not be an indication to most people searching the Patent Database that it is anything of importance, but this patent is basically a patent for a way to help people become taller.

Tyler and I have in our research throughout the years have seen multiple similar patents working on the similar idea which was also for increasing stature. 

Refer to the Abstract below….

The present disclosure provides variants of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising CNP variants, and methods of making CNP variants. The CNP variants are useful as therapeutic agents for the treatment of diseases responsive to CNP, including but not limited to bone-related disorders, such as skeletal dysplasias (e.g., achondroplasia), and vascular smooth muscle disorders (e.g., restenosis and arteriosclerosis).

The Inventor is a Daniel Wendt from Biomarin Pharmaceutical. If we need to remember, Biomarin was the company which made the BMN 111 compound, which is used to treat childhood achondroplasia. I remember reading about this drug maybe a year ago on a website that focused specifically on how to help cope with a child who has the condition.

As one can see, this patent was filed back in 2010 and it has been filed in the USA, Canada, Europe, China, and the World Patent Database System. If I was to guess, I probably had linked to this patent multiple times before, but never really read the patent thoroughly..

Refer to the sections in the patent which I will highlight below…

“….In contrast, mice engineered to produce elevated levels of CNP display elongated long bones and vertebrae.”

I would learn further that in the growth plate, the proliferative zone expresses a compound called NPR-B while the hypertrophy zone expresses NPR-C. CNP (which stands for C-Type Natriuretic Peptide) is an agonist for the NPR-B. Agonist just means some type of chemical or protein that assists or increases a biochemical process. Further down the chain of chemical processes (which in the chemical/medical industry call downstream), the CNP and NPR-B pathway causes the FGFR3 pathway to be blocked. Remember that Achondroplasia is most often caused by a mutation of the FGFR3 causing it to be overstimulated or extra-sensitive. In the FGFR3 pathway, there is a step in the MAPK section. It seems that the CNP/NPR-B disrupts the pathway at MAPK, causing the FGFR3 to become inhibited, thus removing the stunted height morphology.

Refer to the section below from the patent….

“In humans activating mutations of FGFR-3 are the primary cause of genetic dwarfism. Mice having activated FGFR-3 serve as a model of achondroplasia, the most common form of the skeletal dysplasias, and overexpression of CNP rescues these animals from dwarfism. Accordingly, CNP and functional variants of CNP are potential therapeutics for treatment of the various skeletal dysplasias.”

Something that I would further learn is that the plasma-half life of CNP in the human blood stream is very short, only 2.6 minutes (in-vivo). This means to get this biomedical technique to work out, the CNP would need to be continuously pumped into the subject’s body. Apparently the basic level of CNP in the human body is around 5 picoMolar (5*10^(-9) Molar). The level of CNP must be higher than this concentration.

Refer also to more sections from the patent…

“…In a further embodiment, the CNP variants are useful for increasing the size of the growth plate of a bone (e.g., a limb bone). In another embodiment, the CNP variants are useful for elongating a bone or increasing long bone growth. In still another embodiment, the CNP variants are useful for enhancing matrix production, proliferation and differentiation of chondrocytes.”

Apparently to make the femur longer at the highest rate, you want to use a variant of CNP known as N-terminal PEGylated CNP variant.

“…Ex vivo studies of cultures of mouse bones indicated that CNP37 was delivered to the growth plate and was able to increase chondrocyte cellularity and hypertrophy, which are associated with growth plate expansion and longitudinal bone growth.”

“…These results demonstrate that CNP variants of the disclosure penetrate into the growth plate of wild-type and achondroplastic animals, increase the number and size of chondrocytes, increase the thickness of the proliferating zone and the hypertrophic zone of the growth plate, and increase longitudinal bone growth in treated wild-type and achondroplasic animals. Therefore, the CNP variants are useful for stimulating bone growth in achondroplastic subjects.”

There apparently was even news stories published in the Major Online News Websites talking about this drug/invention. (Note: Yes, I am fully aware that I am assuming that the patent I found is referring to the Vosoritide/BMN 111 chemical compound)

Drug Accelerated Growth in Children With Dwarfism, Pharmaceutical Firm Says – 6/17/2015 – The news reported that children would be growing around 6 cm/year than 4/cm by taking the drug. The other name for BMN 111 is vosoritide. There has been questions about the efficacy of this chemical after the first year of use, and whether after the first year the drug would still be as effective as the first year. In addition, it seems that people who did not suffer from Achondroplasia did not get any type of increased bone longitudinal growth benefit from using it. Since the article was written back in June of just this year, the drug is now in Phase 3 Trials, where around 50-150 children will be subjects for this new treatment.

BioMarin drug boosts growth in children with dwarfism – the source here seems to make a correction on something the previous source said, which is that the 6 cm of increased height is actually from just 6 months of tabulated data, not a full year.

BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study – This source suggest that the efficacy of BMN 111 will continue past the 6 month range in Phase 2 –

• There was a dose-related increase in urinary excretion of cGMP measured over the 6 month duration of the study. cGMP is a biochemical marker that may indicate that BMN 111’s  biological effect will continue beyond 6 months.

Refer to the chart from the source below….

It would seem that National Health Industries and Organizations will not fund for a condition unless it has been diagnosed as a real medical condition or a disability. Short stature is not technically a disability, but having achondroplasia or dwarfism does qualify as a medical condition. This is where biomedical research will go and the funding will flow towards.

If you guys are interested in learning more about this compound, just type in the common name for it, Vosoritide or BMN 111. Biomarin even has itself listed on the Nasdaq under the acronym BMRN.

Note: If you really want to see the video of this unique creature, just scroll down this post to the very bottom. I found quite a few videos of this creature off of the Chinese website tudou.com and soku.com, and the Chinese documentaries and expeditions to find more information about it.

I was made aware today of a very interesting viral video that has been on the Youtube universe for a few years now. So far, it has already gained over 10 Mil views. Apparently there is even more old videos of what appears to be a very tall chinese/asian looking ape-like creature from the Chinese internet sources, which I found.

Just like the North American Bigfoot, the Chinese media also like to bring up this case on occasion to have “experts” discuss this person. Apparently very little information is known about him except maybe 1-2 minutes of reel on him, walking around and squatting in a very primitive fashion.

What I do know for a fact, from a lifetime of being fascinated with the paranormal and supernatural is that maybe half of the cultures in the world have some story about giant primate type animals that lived close to humans.

Bigfoot, Sasquatch, Alma, Yeren, Yeti, Abominable Snowman, etc. these are all labels we have given these animals.

In the video below, we see a human that is clearly very tall. His head size compared to his torso and his arms, legs, limbs is just incredible. The average length ratio of most human’s heads to overall body length is supposed to be 1/8.5, but the head/body ratio seems to be much greater here. Personally, I estimate the size of him to be around 7 feet tall, which is tremendously unusual, similar to the case of Siah Khan, the 8 feet tall Iranian farmer. However, if you look at the way this Chinese giant is walking, he seems to be just fine with no ailments. His ability to cognitively function is obviously not at the level of most humans.

If this person only had that shaped head without his great size, then most people would have written his mother’s story about being raped by a Yeren as fake. However, it is his great height and size that is most striking. We realize that the most likely medical explanation is that this human just suffers from microcephaly similar to the Pinhead from the old Freaks movie. Wikipedia says the name was Schlitzie. However, Schlitzie only stood 4 feet tall. This chinese version of a microcephaly seems to be 7 feet tall, if not more.

Of course, we have to realize that this creature/human’s body would look big compared to most Chinese women in the rural area. When we look up the Wikipedia article on Microcephaly, it states that most babies that have shrunken brains develop dwarfed bodies, not giant sized bodies.

This is not the only thing. Pictures from the videos of this Chinese Yeren shows underneath the hair on his head that he had grooves on his skull, similar to the skull of gorillas. I personally don’t understand the Chinese being spoken in the video but I can guess from the pictures that the researchers are analyzing that they are focusing on the head, to see whether this yeren was really human or some type of bigfoot hybrid.

I am not willing to say that this Chinese giant is the missing link, or a human-bigfoot hybrid. His mothers claims of being raped by a Chinese Yeren is also very suspicious. When you look at the video, obviously you know it is not a man in a suit, like people who do hoax for bigfoot sighting. The creature is nearly completely naked. This is video which seems to have been shot decades ago, so there is probably no video editing or graphics design done. The story is probably real, this human did exist, but most likely dead now.