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Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain

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John Lyftogt at Lyftogtmed ltd
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110 Australasian Musculoskeletal Medicine
Abstract
In 2005, 127 painful knees (74), shoulders (33) and
lateral elbows (20) were treated with subcutaneous
prolotherapy. The mean length of symptoms was 23.9
months and mean length of treatment 7 weeks. The mean
initial visual analogue scale (VAS) of 6.7 reduced at mean
follow up of 21.4 months to VAS 0.76. Patient satisfaction
rates at follow up were 91.7%. The treatment was well
tolerated and safe.
Introduction
The most common presentation in a prolotherapy clinic
is chronic musculoskeletal pain with variable associated
degrees of dysfunction. All patients presenting had refrac-
tory musculoskeletal pain despite prior multiple treatment
modalities from a wide range of health professionals. They
had been thoroughly investigated.
The author had already experienced excellent results
from targeting tender/trigger points (TPs) with a hypertonic
glucose/lignocaine solution in the subcutaneous tissues of
Achilles tendinopathy.1
There is growing international appreciation that most
knee, shoulder, and elbow pain is due to tendinopathy/
tendinosis.2
It was hypothesized that the underlying pathology was
similar to Achilles tendinopathy and that the expected
response to subcutaneous prolotherapy would be compa-
rable. As with the Achilles tendon pilot study, all patients
were prospectively monitored with a Recovergram.3
The observed clinical outcome suggested a similar out-
come as for Achilles tendons and it was decided to sub-
stantiate the results with long-term follow up evaluation.
Methods and results
All patients presenting in 2005 were prospectively moni-
tored with a Recovergram.
The treatment protocol consisted of weekly treatments
where possible. All active TPs were identified by palpation
and injected subcutaneously with 0.5-1 ml of a Glucose
20%/Lignocaine 0.1% solution. The objective at the time of
each treatment was to achieve complete local anesthetic
pain relief. Treatments were continued until VAS 0-1 and/
or after consultation with the patient.
Patients were encouraged to assist the treatment by
resuming some form of modified activity on a daily basis,
emphasizing that a mild degree of pain during activity was
beneficial to repair. Clinical experience had already iden-
tified that rest does not enhance response to subcutane-
Subcutaneous prolotherapy treatment of
refractory knee, shoulder, and lateral
elbow pain
Dr John Lyftogt, Christchurch, New Zealand
ous prolotherapy. This advice is in line with Alfredson and
Ohberg’s4 protocol for Achilles tendinosis eccentric strength
exercises.
All individual Recovergrams were collated into a “Study
Recovergram” with recordings of gender, mean age, mean
length of symptoms, mean length of treatment, mean initial
VAS, mean length of follow up, mean follow up VAS, and
satisfaction rates.
Follow up was conducted by telephone through an
independent party.
No of knees treated 74
Males 42
Females 21
Mean age 43 (15-82)
Mean length of symptoms 33.7 months (1-204)
Mean length of treatment 6.8 weeks (2-15)
Mean initial VAS 6.3 (3-9)
Follow up 73% at mean 21 months
Mean follow up VAS 0.84
Satisfied with treatment 89%
November 2007 111
No of shoulders treated 33
Males 15
Females 18
Mean age 51.3 (19-81)
Mean length of symptoms 12.9 months (1-120)
Mean length of treatment 7.6 weeks (2-14)
Mean initial VAS 7.4 (5-9)
Follow up 75% at mean 24 months
Mean follow up VAS 1.8
Satisfied with treatment 88%
No of elbows treated 20
Males 11
Females 9
Mean age 39 (24-64)
Mean length of symptoms 6 (2-18)
Mean length of treatment 7.2 weeks (3-16)
Mean initial VAS 7.2
Follow up 77% at mean 19 months
Mean follow up VAS 0.4
Satisfied with treatment 100%
Discussion
The author’s clinical experience that response rates to
subcutaneous prolotherapy for refractive musculoskeletal
pain are consistent irrespective of location is worthy of
closer scrutiny.
This clinical study attempts to quantify the treatment
outcome of refractory knee, shoulder and lateral elbow
pain with respect to duration of treatment and duration of
effect. The results are not dissimilar to four years of
subcutaneous treatment of 169 Achilles tendinopathies as
separately reported in this journal.
The combined outcome statistics for the treatment of the
2005 knee, shoulder and lateral elbow pain showed a
mean length of symptoms of 23.9 months and a mean
treatment length of 7 weeks. The mean initial VAS 6.7
reduced at follow up of mean 21.4 months to VAS 0.76. The
combined satisfaction rate at follow up was 91.7%.
These statistics suggest a treatment effect with lasting
benefits.
In a clinical study of this kind it is important to consider the
effect of subcutaneous prolotherapy on individual patients
as statistics cannot do this. Of the 33 patients with shoulder
pain three (12%) did not respond and opted for surgery.
64% were completely pain free from the end of treatment
to follow up. The remaining 23% had a marked reduction
of pain at the end of treatment, which was sustained,
resulting in an overall satisfaction rate of 88%.
One 53-year-old female patient, the owner of a vineyard,
had two years of severe pain (VAS 9, including night pain).
She had prior treatment with two corticosteroid injections
and extensive physiotherapy. She required 14 weeks of
treatment to achieve VAS 0, the same at follow up. She
described the result at telephone follow up as “fantastic”.
At her first consultation large numbers of very active TPs
were identified over the left infraspinatus. Mechanical
stimulation of these TPs increased her associated hand
pain, previously diagnosed as carpal tunnel syndrome.
Numerous TPs were also identified in the mid and anterior
deltoid. The hand pain resolved with one treatment and the
night pain with two. She had full asymptomatic range of
movement (ROM) and normal strength at the end of the
treatment. An ultrasound (US) examination before the
treatment did not identify rotator cuff pathology, although
clinical examination showed a clear painful arc and mark-
edly reduced ROM.
The above statistics, although impressive, are unhelpful
in outlining the specifics of subcutaneous prolotherapy
when treating these incapacitating painful conditions as
each patient has a different pain pattern and a different
distribution of TPs. This is where the skill and “art” in
medicine define outcome.
In the traditional rationale for prolotherapy an irritant
solution (proliferant) is injected in or around painful weak
ligaments and/or entheses, creating an inflammatory re-
sponse. This inflammation is said to initiate a repair re-
sponse resulting in strengthening of the weakened liga-
ment and resolution of pain.5
The understanding of tissue repair has changed since
Hackett first published his theories on prolotherapy in
1956. Inflammation is now seen as a cellular mechanism
to render the tissues immunologically neutral and “effec-
tive repair” is determined by the balance between prolifera-
tion and apoptosis.6,7 The role of the peripheral nervous
system in initiating tendon repair and renewal in a rat model
of Achilles tendon injury has been identified by Ackerman
et al.8 The importance of the peptidergic “noceffectors”
calcitonin gene-related peptide (CGRP) and substance P
(SP) in repair was first described by Kruger et al. in 1989,9
and a review in the British Journal of Pharmacology in
200310 focussed on the evidence that nerves and blood
vessels control each other in a paracrine way. The new role
of vascular endothelial growth factor (VEGF) as a neuro-
trophic factor as well as an angiogenic factor is discussed
in “Vascular endothelial growth factor and the nervous
system”11 and research is now identifying CGRP nerves as
controlling tissue VEGF levels at least in psoriasis.12 VEGF
levels are elevated in tendinosis,13 and in oncology re-
search it is well established that VEGF prevents apoptosis
Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain
112 Australasian Musculoskeletal Medicine
and normal cell senescence, allowing proliferation of
nociceptors and endothelial cells to proceed unhindered.
Inflammation increases pain and this does not fit in with
the clinical experience in subcutaneous prolotherapy of an
immediate reduction in pain often after the first treatment,
and in particular night pain seems to diminish early.
The author hypothesizes that subcutaneous prolotherapy
injections of hypertonic glucose and 0.1% lignocaine in-
duce apoptosis of proliferating peptidergic noceffectors
and neovessels by reducing VEGF levels and restoring
“effective repair” processes, with reduction of pain.
Whatever the rationale is going to be for subcutaneous
prolotherapy, the reported initial results are encouraging,
particularly as one considers the proven safety, speed of
response, the low cost, and the lasting benefit of this
treatment.
References
1. Lyftogt J. Prolotherapy and Achilles tendinopathy: A prospec-
tive pilot study of an old treatment. Australas Musculoskeletal
Med 2005; 10(1): 16-19.
2. Khan KM, Cook JL, Kannus P et al. Time to abandon the
“tendonitis” myth. Br Med J 2002; 324: 626-27.
3. Watson P. The Recovergram. Australas Musculoskeletal
Med 2000; 5 (2): 24-28.
4. Ohberg L, Alfredson H. Effects on neovascularisation behind
the good results with eccentric training in chronic mid-portion
Achilles tendinosis? Knee Surg Traumatol Arthrosc 2004;12 (5):
465-70.
5. Hackett G. Ligamentous and tendon relaxation treated by
prolotherapy. 3rd ed. Springfield; Charles C Thomas, 1958.
6. Huang N F. University of California and University of California
San Francisco Joint Graduate Group in Bioengineering.
Apoptosis in abnormal wound healing.
7. Avocet Polymer Technologies Inc. Facts about Scars. Wound
healing and scarring. www.avocetcorp.com/wound
_healing.html.
8. Ackermann PW, Li J, Lundeberg T, Kreicbergs A. Neuronal
plasticity in relation to nociception and healing of rat Achilles
tendon. J Orthop Res 2002; 21 : 432-41.
9. Kruger L, Silverman JD, Mantyh P W et al. Peripheral patterns
of calcitonin-gene-related peptide general somatic sensory in-
nervation: Cutaneous and deep terminations. J Comp Neurol
1989; l280(2): 291-302.
10. Emanueli C, Schratzberger P, Kirchmair R, Madeddu P.
Paracrine control of vascularization and neurogenesis by
neurotrophins. Br J Pharmacol 2003; 140 (4):614-19.
11. Brockington A, Lewis C, Wharton S, Shaw PJ. Vascular
endothelial growth factor and the nervous system. Neuropathol
Appl Neurobiol 2004; 30: 427-46.
12. Yu X, Li C, Wang K, Dai HY. Calcitonin gene-related peptide
regulates the expression of vascular endothelial growth factor in
human HaCaT keratinocytes by activation of ERK1/2 MAPK.
Regul Pept 2006; 137(3):134-39.
13. Pufe T, Petersen WJ, Mentlein R, Tillmann BN. The role of
vasculature and angiogenesis for the pathogenesis of degen-
erative tendons disease. Scand J Med Sci Sorts 2005: 15: 211-
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Subcutaneous prolotherapy treatment of refractory knee, shoulder, and lateral elbow pain
... Of the 263 remaining studies, 243 were excluded for the following reasons: Review studies (n = 58), preclinical studies in vitro model or animal model (n = 39), studies where dextrose was applied by a route other than the subcutaneous (intra-articular, intramuscular, intratendinous, in tendon and ligaments enthesis, periosteal or perineural hydrodissection) (n = 131), case reports or case series with less than five patients (n = 12), studies published in abstract form (n = 3). Finally, 20 studies [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] were eligible for inclusion in the analysis of this Scoping Review. The flowchart of the systematized search is shown in Figure 1. ...
... Of the 20 studies included, 13 studies had a randomized clinical trials design [25][26][27][29][30][31][32][33][34][35]37,39,41]; one study had a comparative and non-randomized study design [36]; while six studies had an uncontrolled study design (case series type) [23,24,28,38,40,42]. ...
... Regarding the place where the research was performed: six studies were carried out in Africa (Egypt) [23,27,29,32,35,37], eight studies were performed in Asia (Iran and Turkey) [25,26,30,31,33,36,40,42], four studies in Oceania (Australia and New Zealand) [24,28,38,39], one study in America Latina (Mexico) [34] and one study in North America (USA) [41]. No studies from Europe were included. ...
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... Several nonoperative therapeutic options have been proposed to reduce symptoms and improve QoL including prolotherapy [5][6][7]. Prolotherapy with irritant substances such as hyperosmolar dextrose and morrhuate sodium has been used in several chronic musculoskeletal conditions including OA [6,[8][9][10]. Several theories have been proposed for the beneficial effect of these hypertonic solutions, including decreasing the nociceptive pain signaling through the opening of potassium channels hyperpolarizing the nerve ending [11]. ...
... Moreover, at the 24-week assessment, our patients reported less pain with higher functional capacity as reflected by the statistically significant decrease in their VAS and overall WOMAC scores compared to baseline. This is in accordance with the studies by Rabago et al. [24,27], who proposed a regenerative and reconstructive effect of DPT, which results in improvement in knee function [10,24]. ...
... Several studies have suggested the potential mechanisms for DPT, which included stimulation of inflammatory cascades [32], a noninflammatory proliferative effect [33][34][35], and even induction of chondrogenesis [16]. Lyftogt [10] proposed another theory; by stopping the neurogenic inflammation and inhibiting the release of the neuropeptides, substance P, and calcitonin gene-related ...
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Background Knee osteoarthritis (KOA) is a progressive musculoskeletal disease that leads to physical impairment and disability. Several nonoperative therapeutic options have been proposed to reduce symptoms, improve physical function, and prevent disability. One of these therapeutic options is dextrose prolotherapy (DPT). The current study aimed to investigate the efficacy of DPT in the treatment of symptomatic KOA and to evaluate its potential proliferative role as assessed by musculoskeletal ultrasound (MSUS) and magnetic resonance imaging (MRI). Results Seventeen knees (21.25%) dropped out, leaving 63 knees in the final analysis (57 females and 6 males, aged 41–74 years) with KOA. At 24-week follow-up, the visual analogue scale and overall Western Ontario and McMaster Universities scores showed significant improvement ( P < 0.001). Moreover, a highly significant increase in cartilage thickness with a decrease in effusion grade and meniscal extrusion was observed by MSUS ( P < 0.001). By MRI, there was a statistically significant decrease in effusion grade ( P = 0.013) and meniscal extrusion ( P = 0.005) and a highly significant increase in cartilage thickness ( P < 0.001). Logistic analysis showed that lower patients’ body mass index (BMI) at baseline was a significant predictor for clinical improvement following DPT. Conclusion DPT might be considered a relatively safe minimally invasive intervention for the treatment of KOA with high adherence and satisfaction. It may lead to significant clinical and structural improvement in patients with KOA. Furthermore, lower BMI is a predicting factor for better clinical response to DPT. Trial registration The study was registered prospectively in ClinicalTrials.gov: clinical trial registration number NCT04178304 on 21 November 2019, https://register.clinicaltrials.gov/XXX .
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... Similarly, glucose solutions have been reported to block pain by other, not very well-described mechanisms. It has been suggested that subcutaneous prolotherapy injections of hypertonic glucose and 0.1% lignocaine might induce apoptosis of proliferating peptidergic noceffectors and neovessels by reducing VEGF levels and restoring "effective repair" processes, with the final outcome being the reduction in pain [35]. Transient Receptor Potential (TRP) channels have emerged as potential drug targets for the treatment of osteoarthritis, rheumatoid arthritis, and gout. ...
... Prolotherapy is an emerging modality used to treat joint disorders [11][12][13]32,35,[37][38][39][40][41][42][43][44][45][46]. In this regard, the present review qualitatively and quantitatively synthesized the currently available evidence about the application of prolotherapy in the temporomandibular joint. ...
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... Dr. John Lyftogt heeft onlangs vastgesteld dat in ltraties van glucose 5% (G5) rond een pijnlijke zenuw de neuropathische pijn zeer snel doen verdwijnen (18 ...
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... Plus récemment, le Dr John Lyftogt a remarqué que les in ltrations de glucose à 5% (G5) autour d'un nerf douloureux faisaient disparaître la douleur neuropathique très rapidement (18). Dans un premier temps, il a appelé cette méthode neural prolotherapy mais, pour éviter la confusion entre les deux techniques, il a renommé sa technique Perineural Injection erapy (PIT). ...
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... In 2006, Dr. John Lyftogt reported clinical benefit from subcutaneous hypertonic dextrose injection for compartment syndrome 37 and in 2007 for a variety of painful conditions. 38,39 He postulated that dextrose has a favorable effect on unremitting peripheral neurogenic inflammation. 40 The most striking observation by Dr. Lyftogt was the speed of analgesia (within seconds) upon injection of hypertonic dextrose subcutaneously over fascial penetration points of painful sensory nerves and over the course of the nerves themselves. ...
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... PDRN has been reported to have positive therapeutic effects in reducing anti-inflammatory symptoms and pain in numerous clinical [32] and animal model studies [33]. Glucose injection therapy is also used clinically to reduce neuropathic pain [34] and is widely applied in clinical practice [35]. ...
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... PIT targets neurogenic inflammation of the subcutaneous nerves, which potentially causes pain [4,5]. It was further improved by Lyftogt [6] using dextrose injections, which provided significant pain control in a series of 300 cases of Achilles tendinopathy. ...
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Full-text available
  • Jun 2003
Nerve regeneration and the occurrence of three neuropeptides; i.e. substance P (SP), calcitonin gene related peptide (CGRP) and galanin (GAL), were studied during healing of tendon rupture in the rat by semi‐quantitative immunohistochemistry. The neuronal findings were related to nociception as assessed by hindpaw withdrawal latencies at thermal and mechanical tests. Experimental rupture of rat Achilles tendon—normally devoid of nerves—elicited extensive nerve ingrowth into the rupture site in the early phase of healing followed by almost complete fiber disappearance (weeks 12–16). The ingrowth of SP and CGRP positive fibers, seen already at weeks 1–2, was associated with increased nociception. Subsequently, the occurrence of GAL positive fibers at weeks 4–6 was associated with decreased nociception. An even stronger relationship to nociception during healing was observed when the rate of change in neuropeptide expression instead of the expression in absolute terms was considered, according to the „cascade”︁ formula of SP' + CGRP' – GAL'. It may prove that the observed temporal occurrence of different neuropeptides reflects a role of the peripheral nervous system in regulating synchronously nociception and healing. © 2002 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.
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Article
  • Feb 1989
The distribution of calcitonin‐gene‐related peptide (CGRP) immunoreactivity (IR) was studied in peripheral tissues of rats. The ganglionic origin, somatosensory nature, and anatomic relations of this thin‐axon population were evaluated with particular emphasis on possible nociceptive roles. In animals untreated with colchicine, CGRP‐IR is found in a vast proportion of small‐ and medium‐diameter sensory ganglion cells that give rise to numerous thinly myelinated and unmyelinated axons that display CGRP‐IR throughout the body. The integumentary innervation consists, in part, of an extensive subpapillary network largely traced to dermal blood vessels, sweat glands, and “free” nerve endings, some of which are found within regions containing only mast cells, fibroblasts, and collagen. Dermal papillae contain CGRP‐IR axons surrounding each vascular loop; other papillary axons end freely or occasionally surround Meissner corpuscles. Intraepithelial axons enter glabrous epidermal pegs, branching and exhibiting terminals throughout the stratum spinosum. A similar pattern is found in hairy skin with additional innervation entering the base and surrounding the lower third of each hair follicle, but apparently not supplying sebaceous glands and arrector pili muscle. Axons innervating nonkeratinized oral epithelium are similar or greater in number and distribution compared to epidermis, often with more extensive branching. The high density of intraepithelial CGRP‐IR innervation does not appear to correlate with the sensitive mechanoreceptor‐based increase in spatial sensory discriminative capacities in the distal portions of the limb. In deep somatic tissues, CGRP‐IR is principally related to vasculature and motor end plates of striated muscle, but there is an extensive network of thin axons within bone, principally in the periosteum, and focally in joint capsules, but not in relation to muscle spindles or tendon organs. These findings, together with the distribution in cranial tissues described in an accompanying paper (Silverman and Kruger: J. Comp. Neurol. 280: 303–330, '89), are considered in the context of a “noceffector” concept incorporating the efferent role of these sensory axons in various tissues. It is suggested that involvement in tissue maintenance and renewal during normal function, as well as following injury, may predominate over the relatively infrequent nociceptive role of this peptidergic sensory system.
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Paracrine control of vascularization and neurogenesis by neurotrophins
Article
  • Nov 2003
The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies. British Journal of Pharmacology (2003) 140, 614–619. doi:10.1038/sj.bjp.0705458
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Effects on neovascularisatino behind the good results with eccentric training in chronic Achilles tendinosis? Knee Surg Sports Traumatol Arthrosc
Article
  • Oct 2004
The background to the good clinical results reported using painful eccentric calf-muscle training as treatment for chronic painful mid-portion Achilles tendinosis is not known. Recently, using ultrasound and colour Doppler technique, we showed that painful tendinosis was associated with a local neovascularisation. Furthermore, in a pilot study, destroying these neovessels by sclerosing therapy cured the pain in most patients. Dynamic ultrasound and colour Doppler examination has shown that the flow in the neovessels stops during dorsiflexion in the ankle joint. Therefore, it was of interest to study the occurrence of neovascularisation before and after eccentric training. Forty-one tendons in 30 patients (22 men and 8 women, mean age 48 years) with chronic painful mid-portion Achilles tendinosis were examined with ultrasonography and colour Doppler, before and after 12 weeks of eccentric calf-muscle training. Before treatment, there was a local neovascularisation in the area with tendon changes (hypo-echoic areas, irregular fibre structure) in all tendons. At follow-up after treatment (mean 28 months), there was a good clinical result (no tendon pain during activity) in 36/41 tendons, and a poor result in 5/41 tendons. In 34/36 tendons with a good clinical result of treatment there was a more normal tendon structure, and in 32/36 tendons there was no remaining neovascularisation. In 5/5 tendons with a poor clinical result there was a remaining neovascularisation in the tendon, and in 2/5 tendons there were remaining structural abnormalities. In conclusion, in patients with chronic painful mid-portion Achilles tendinosis, a good clinical result after eccentric training seems to be associated with a more normal tendon structure and no remaining neovascularisation. Action on the area with neovessels during the eccentric training regimen might possibly be responsible for the good clinical results.
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Vascular endothelial growth factor and the nervous system
Article
  • Nov 2004
Vascular endothelial growth factor (VEGF) is an angiogenic factor essential for the formation of new blood vessels during embryogenesis and in many pathological conditions. A new role for VEGF as a neurotrophic factor has recently emerged. In the developing nervous system, VEGF plays a pivotal role not only in vascularization, but also in neuronal proliferation, and the growth of coordinated vascular and neuronal networks. After injury to the nervous system, activation of VEGF and its receptors may restore blood supply and promote neuronal survival and repair. There is a growing body of evidence that VEGF is essential for motor neurone survival, and that aberrant regulation of VEGF may play a role in the degeneration of neurones in diseases such as amyotrophic lateral sclerosis.
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The role of vasculature and angiogenesis for pathogenesis of degenerative tendons disease
Article
  • Sep 2005
More than 100 years ago Wilhelm Roux (1895) introduced the term “functional adaptation to anatomy and physiology”. Compared with other organ systems the functional adaptation processes are best identifiable in the locomotor system, like for example in the two types of tendons: traction and gliding tendons. Traction tendons are tendons where the direction of pull is in line with the direction of the muscle (e.g. Achilles tendon). Gliding tendons (e.g. tibialis posterior tendon) change direction by turning around a bony or fibrous hypomochlion. In this region the tendon is subjected to intermittent compressive and shear forces and the extracellular matrix consists of avascular fibrocartilage. Avascularity is considered to be a key factor for the etiology of degenerative tendon disease. The repair capability after repetitive microtrauma is strongly compromised in avascular tissue of gliding tendons. Reduced vascularity is not a specific feature of gliding tendons; several studies have shown that the number and size of blood vessels are largely shortened in the waist of the Achilles tendon. However, histological biopsies from degenerated Achilles tendons and Doppler flow examinations revealed a high blood vessel density in patients with degenerative tendon disease. Angiogenesis is mediated by angiogenic factors and recent studies have shown that the vascular endothelial growth factor (VEGF) is highly expressed in degenerative Achilles tendons, whereas VEGF expression is nearly completely downregulated in healthy tendons. Several factors are able to upregulate VEGF expression in tenocytes: hypoxia, inflammatory cytokines and mechanical load. Since VEGF has the potential to stimulate the expression of matrix metalloproteinases and inhibit the expression of tissue inhibitors of matrix metalloproteinases tissue inhibitor of metalloproteinases (TIMP) in various cell types (e.g. endothelial cells, fibroblasts, chondrocytes), this cytokine might play a significant role for the pathogenetic processes during degenerative tendon disease. An animal experiment in the rabbit has shown that local injection of VEGF reduced the material properties of the Achilles tendon. These experimental findings are in accordance with clinical results that a locally administered (in the area with neovascularization) sclerosing drug (Polidocanol) has a beneficial effect on chronic mid‐portion Achilles tendinosis. In conclusion, decreased and increased vascularity might be involved in the pathogenesis of degenerative Achilles tendon disease.
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Calcitonin gene-related peptide regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes by activation of ERK1/2 MAPK
Article
  • Jan 2007
  • REGUL PEPTIDES
Psoriasis is a chronic disease characterized by abnormal epidermal proliferation, inflammation and angiogenesis. The pathogenetic process resulting in hypervascularity remains to be further investigated. It has been reported that a potent angiogenic factor, vascular endothelial growth factor (VEGF) is overexpressed in psoriatic epidermis and that the level of calcitonin gene-related peptide (CGRP) is elevated in psoriasis lesions and CGRP-containing neuropeptide nerve fibers are denser in the psoriatic epidermis. We hypothesized that CGRP might regulate the expression of VEGF by human keratinocytes. VEGF expression in the CGRP-treated human keratinocytes was investigated and the CGRP signaling pathways were examined with respect to VEGF expression. The mRNA and protein levels of VEGF by CGRP were increased in a concentration-dependent manner. However, this increase was abrogated by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor PD98059. The CGRP-mediated VEGF induction was also effectively inhibited by a pretreatment with the CGRP receptor antagonist CGRP 8-37. In addition, CGRP treatment induced rapid phosphorylation of ERK1/2, PD98059 and CGRP 8-37 were able to inhibit CGRP-induced ERK1/2 phosphorylation. These results suggest that CGRP regulates the expression of VEGF through the CGRP receptor and ERK1/2 MAPK signaling pathway in human HaCaT keratinocytes.
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Ligamentous and tendon relaxation treated by prolotherapy
  • G Hackett
Hackett G. Ligamentous and tendon relaxation treated by prolotherapy. 3rd ed. Springfield;
Prolotherapy and Achilles tendinopathy: A prospective pilot study of an old treatment
  • Jan 2005
  • 16-19
  • J Lyftogt
Lyftogt J. Prolotherapy and Achilles tendinopathy: A prospective pilot study of an old treatment. Australas Musculoskeletal Med 2005; 10(1): 16-19.