ArticlePDF Available

Immune messengers in Neuralgia Inducing Cavitational Osteonecrosis (NICO) in jaw bone and systemic interference

Authors:
  • Clinic for Integrative Dentistry, Munich, Germany for
  • Society for Applied Immunology, Munich, Germany

Abstract and Figures

Aim of the study: In the practice of the author astounding improvements of systemic complaints which accompanied apparently rheumatic, neuralgic and other chronically inflammatory systemic diseases are consistently observed after cleaning pain free, radiographically normal edentulous areas of the jaw. These are marked by fatty-degenerative osteonecrosis of the cancellous bone. Thus far, in dental research there are only few scientifically proven explanations concerning such systemic therapeutic successes. Methods: In order to clarify systemic interrelations, samples of cancellous bone have been extracted from six subjects. The specimens were then analyzed by bead-based multiplex technology and tested for 27 immune messengers. Results: All six specimens concordantly showed highest concentration for IL1-ra (interleukin-1-receptor antagonist) and RANTES. In addition, in all samples FGFbasic and PDGF-bb have been distinctly evidenced. A statistically high concentration on IL1-RA and RANTES is noticeable here. The samples' small distribution and specific concentration on IL1-ra and RANTES, despite the high number of 27 tested mediators, is a striking figure.
Content may be subject to copyright.
This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
http://www.elsevier.com/copyright
Author's personal copy
A
vailable online at www.sciencedirect.com
European Journal of Integrative Medicine 2 (2010) 71–77
Original article
Immune messengers in Neuralgia Inducing Cavitational Osteonecrosis
(NICO) in jaw bone and systemic interference
J. Lechner a,, W. Mayer b,1
aGrünwalder Str. 10A, D-81547 München, Germany
bImmumed – Gesellschaft für angewandte Immunologie, Goethestraße 10, D-80336 München, Germany
Received 7 January 2010; received in revised form 24 March 2010; accepted 31 March 2010
Abstract
Aim of the study: In the practice of the author astounding improvements of systemic complaints which accompanied apparently rheumatic, neuralgic
and other chronically inflammatory systemic diseases are consistently observed after cleaning pain free, radiographically normal edentulous areas
of the jaw. These are marked by fatty-degenerative osteonecrosis of the cancellous bone. Thus far, in dental research there are only few scientifically
proven explanations concerning such systemic therapeutic successes.
Methods: In order to clarify systemic interrelations, samples of cancellous bone have been extracted from six subjects. The specimens were then
analyzed by bead-based multiplex technology and tested for 27 immune messengers.
Results: All six specimens concordantly showed highest concentration for IL1-ra (interleukin-1-receptor antagonist) and RANTES. In addition,
in all samples FGFbasic and PDGF-bb have been distinctly evidenced. A statistically high concentration on IL1-RA and RANTES is noticeable
here. The samples’ small distribution and specific concentration on IL1-ra and RANTES, despite the high number of 27 tested mediators, is a
striking figure.
© 2010 Elsevier GmbH. All rights reserved.
Keywords: NICO; Immune messenger; RANTES; Proinflammatory cytokines; Osteonecrosis; Systemic interference
Introduction
What is NICO (Neuralgia Inducing Cavitational
Osteonecrosis)?
Chronic softenings in the jaw are nothing new in medical
history. Already in 1848 textbooks have been published on
fatty dissolution of the jaw bone, which exists separately from
abscesses or acute inflammation of the teeth. In 1915, G.V. Black
– the father of modern dentistry – describes chronic osteitis of
the jaw as a preceding chronic progress which produces cavi-
tations and necrosis of bone cells. Black was impressed by the
expansions of these medical conditions and suggested surgi-
Corresponding author. Tel.: +49 89 697 00 55; fax: +49 89 692 58 30.
E-mail addresses: drlechner@aol.com (J. Lechner), wm@immumed.de
(W. Mayer).
URL: http://www.dr-lechner.de (J. Lechner).
1Tel.: +49 89 543 21 77 89; fax: +49 89 543 21 77 82.
cal removal of such “dead appearing” jaw bone [1]. In 1930,
these processes have been specified in the USA for the first time
as “cavitations” and “avascular” (lack of inflammation-induced
vascular proliferations) and less “infectious”. American scien-
tist Dr. Fischer from the University of Cincinnati wrote a book in
1940 titled: “Death and Dentistry” in which he describes chronic
osteitis of the jaw as a “metastasis of microorganisms from these
bone necroses” [2]. Professor G. Bouquot, American pathologist
from University of Pennsylvania gave this cavitation producing
osteonecrosis the name NICO (Neuralgia Inducing Cavitational
Osteonecrosis). In an analysis of more than 200 samples from
patients with trigeminal neuralgia, he noted necrosis of the jaw
bone with concomitant irritation of the trigeminal nerve in all
cases [3–5]. At least 800 medical papers report on NICO. More
than 27 studies concerning osteonecrosis/NICO have been pub-
lished in peer reviewed journals since 1979.
The term NICO suggests, however, that neuralgia is the only
consequence of the osteonecrosis. Possible systemic effects of
this osteolysis of the jaw bone on the organism in terms of
chronic strain are not covered by this nomenclature. Neverthe-
1876-3820/$ – see front matter © 2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.eujim.2010.03.004
Author's personal copy
72 J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77
less, we will confine ourselves to the term NICO to describe
these processes in the following. The author published not only
an alleviation of neuralgic complaints of the maxillofacial area,
but also striking improvements of systemic symptoms [6,9]. The
guiding principles of the present analysis are:
Can immune messengers, cytokines and growth factors gen-
erally be found in tissue samples of NICO sites in the jaw?
Do immune messenger based inflammatory processes in the
NICO sites exist?
Which immune messengers appear high in NICO tissue? Can
they possibly be related to systemic diseases?
Problems of radiological diagnosis of NICO
The existence of NICO is largely denied today in main
stream dentistry. The reason is that normal X-ray do not show
the process of bone marrow osteolytic NICO. To answer this
question the author published the following research in sum-
mary [6,9]: healthy parts of the jaw bone (n= 8) and softened
spongial parts (n= 29) were examined in a nuclear absorp-
tion spectrometer to view their mineral contents. The following
mechanisms seem to happen within a NICO regarding the
minerals.
Inside the NICO the hydroxyl apatite of the jaw bone split
with loss of calcium and phosphate. The originally solid bone
structure softens; the clinical image of a rarefying fatty degen-
erate NICO is expected to develop increased permeability for
X-rays and thus a corresponding brightening of the X-ray by
the loss of calcium and phosphate. Spectral analysis shows that,
parallel to the dissolution of the bone, the trace minerals copper,
iron and zinc increase statistically highly significant. Now a fatal
overlapping effect comes up in the NICO area: the increased
tendency to throw a positive radiological picture by loss of
calcium and phosphate is compensated by the increased X-ray-
absorption of accumulation of copper, iron and zinc; this in turn
leads to a balance in the amount of X-ray permeability. The fatal
diagnostic effect: radiological examination of NICO is without
positive results. Thus radiological techniques are not apt for the
exclusive diagnosis of NICO lesions in the jaw bone. The author
documented the extent of this lesions in former publications
[6,9].
Complementary diagnosis of NICO by ultrasound imaging
Obviously low bone density of NICO is difficult to detect
in the maxillofacial bones via radiographic imaging. To give
the practitioner an aid to diagnose the debilitating effects
of bone marrow softening inside NICO lesions a computer-
assisted through-transmission alveolar transmission through
sonography called CAVITAT was developed. CAVITAT pre-
cisely images and identifies cavitational porosity in the jawbone.
To compare radiology with this new ultrasonography technol-
ogy, relative to the ability to identify alveolar bone with NICO
lesions studies show that in 84% of cases the CAVITAT image
changes were more obvious and more readily identified, than
the radiograph for the same site. CAVITAT imaging proved
Fig. 1. Sample of fatty and osteolytic spongial bone of lower jaw.
significantly superior to radiology for the detection of micro-
scopically confirmed osteoporotic and osteopenic NICO bone
[7,8].
Materials and methods
Sampling method of NICO tissue
Following local anesthetics, six subjects underwent intraop-
erative folding back of the gingival flap of the affected part of
the jaw. The overlying cortical bone was removed. All six cases
showed in the spongial area of the jaw bone osteolytic and degen-
erative fatty tissue. This was typical NICO instead of normal jaw
bone. Samples of these osteolytic and fatty-degenerative parts
of cancellous bone were removed. In three subjects, the softened
cancellous bone tissue was extracted from retro molar and third
molar’s areas of the mandible, in cases of the other three from the
corresponding areas of the maxilla. This cancellous bone tissue
could be spooned out in all six cases as fatty-appearing lumps
with a volume up to 1/2 cubic centimeter [10]. The pea-sized
tissue lumps were immediately put into a dry, sterile storage
receptacle (Sarsted Mikro-Tube, Ref. 72.693.005), the screw cap
was sealed airtight und stored at 20 C in the freezer until it
was transported to the laboratory [29].
Macroscopic clinical features of the NICO bone samples
All six samples showed a surprisingly high degree of oste-
olysis of the cancellous bone. The softening is so distinct, that
the marrow space can be sucked and spooned out. Degenera-
tion of the cancellous bone extends in the mandible areas as
far as to the canal of the infraalveolar nerve. Bouquot describes
NICO-induced necrotic, softened cancellous bones as follows:
Hollow cavitations with soft tissue that had undergone fatty
dystrophic changes and demyelination of the bony sheath of
the infraalveolar nerve [3,4]. The six NICO samples present
themselves clinically and macroscopically as fatty lumps of tis-
sue. Fig. 1 shows such a specimen with predominantly fatty
transformation of the jaw bone.
Author's personal copy
J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77 73
Microscopic features of the NICO bone samples
Every sample was examined histopathologically. The
changes of the bone are similar to those seen in osteoporosis.
The trabeculae are thin with a loss of their bony interconnec-
tions. The widened intertrabecular spaces often contain small
necrotic bone fragments. The fatty marrow shows a mucoid
degeneration with an interstitial edema and an accumulation
of acid mucopolysaccharides staining positively using alcian
blue. These chronic degenerative changes are intermingled with
foci of recent areactive adipocyte necrosis with granular dis-
solution of cytoplasma. The amount of fat cells is constantly
strikingly increased: They show “foamy” changes as sign of
an energetic imbalance of micro-metabolism. Small groups of
foamy makrophagocytic cells are to be seen. Fibrosis is restricted
to small amounts of collagen fibers adjacent to the bony trabec-
ulae. Small nerve fibers are a striking feature in most biopsies of
the jawbone. Nerve fibers are situated in close contact to degen-
erated and necrotic fatty tissue. Typical signs of inflammation,
especially of an inflammatory cell response are missing. There
are no significant leukocyte infiltrates, only few lymphocytes
and mast cells. It is rather the fatty degenerative and osteolytic
aspect, which overweighs. Thus all specimen show degenera-
tive changes of fatty marrow and bone tissue due to insufficient
supply, that is a chronic trophic disorder [30].
Laboratory treatment of the bone samples
After unfreezing, the samples were mixed in the Micro-Tube
with 150 l sterile, phosphate buffered saline (Sigma–Aldrich,
Dulbeccos Phosphate Buffered Saline, Lot. 108K2334), 10 s
vortexed and finally centrifuged (1min, 5000rpm, Eppendorf
5415D). 50 l from the protrusion has been put apart for an
analysis of immune messengers.
Measurement of immune messengers
Determination of human messengers (G-CSF, GM-CSF,
IFN-gamma, IL1beta, IL2, IL4, IL5, IL6, IL7, IL8, IL9,
IL10 IL12(p70), IL13, IL15, IL17, IP10, MCP1, MIP-1alpha,
MIP-1beta,TNF-alpha, Eotaxin, FGFbasic, IL1-ra, PDGF-BB,
RANTES, VEGF) was performed via a bead-based assay
(Bio-Plex Human Group I Cytokine Broad Range Panel, Ref.
171-A11127) on a BioRad Luminex System according to
manufacturer’s instructions. Quantification of the messengers
followed standard curves included in the Bioplex software.
Results
Regarding to immune messengers IL1-ra und RANTES, all
six samples show levels exceeding 800 pg/ml. The interleukin 6
level as well averaged clearly above 1000 pg/ml. However, this
is due to one exceptionally high reading in only one of the six
specimens. In the range from 97 to 298 pg/ml FGFbasic could be
evidenced in all samples, MCP-1 and PDGF-BB were present
at an average concentration above 100pg/ml. The concentration
of messengers IL1b, IL2, IL8, Eotaxin, G-CSF, GM-CSF, IFN-
Fig. 2. Readings of 27-parameter of six NICO samples show high levels in
RANTES (CCL5) and FGFbasic.
gamma, IP10, MIP1b and TNF-alpha averaged in the specimens
at levels between 30 and 90 pg/ml. Messengers IL4, IL5, IL7 and
IL9 were hardly detectable, their average readings lying below
15 pg/ml. IL10, IL12(p70) IL13, IL15, IL17, MIP1a, VEGF
were contained as well in very low concentrations (<15 pg/ml).
Fig. 2 shows the results from the 27-parameter luminex mea-
suring in six processed NICO samples. Readings are in pg/ml,
OOR < below detection limit, OOR>above detection limit with
extrapolated reading.
Author's personal copy
74 J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77
Discussion of the immunological results
The present research is the first to analyze immune messen-
gers on a broad level within the scope of a screening of processed
samples of degenerated jaw bone tissue (NICO). There is no
study with similar purpose and extensiveness known to the
authors.
Inflammatory and proinflammatory messengers
Primarily striking are the messengers that showed the highest
concentrations, thus IL1-ra and RANTES, as well as FGFba-
sic and PDGF-BB. In this context it stands out, that except of
RANTES, no other proinflammatory messenger, as interferon-
gamma, interleukin 6, interleukin 8 or TNF-alpha, was detected
in such distinctively elevated levels.
RANTES (CCL-5) signifies “regulated on activation nor-
mal T-cell expressed and secreted” and belongs to the
group of chemotactic cytokines with proinflammatory effects.
RANTES affects leukocytes chemotactically, especially T-cells,
eosinophils and basophil granulocytes. Synthesis of RANTES
in circulating T-cells is induced by TNF-alpha and IL1-alpha.
Increased RANTES concentrations in the serum are described
in a large number of inflammatory diseases, e.g. autoimmune
diseases, cardiovascular diseases, chronic infects etc. [11–14].
RANTES levels up to approximately 20 ng/ml in the serum are
regarded as normal [14]. Proceeding on this assumption, the
concentrations of ca. 1 ng/ml metered in the samples have to be
considered as relatively low. However, RANTES “standard lev-
els” for normal jaw bone specimens are not available yet and can
therefore not be evaluated. A systemic proinflammatory effect
seems unlikely, because the RANTES concentration is relatively
low in relation to the serum level.
Anti-inflammatory messengers
In contrast to RANTES, IL1-ra (interleukin-1-receptor antag-
onist) acts strongly anti-inflammatory by blocking signal
transduction at the interleukin-1 receptor, by inhibiting IL2-
secretion and IL2-receptor expression on the cell surface. IL1-ra
can be generated by a variety of cells, e.g. macrophages, mono-
cytes, neutrophils, fibroblasts and ephitelial cells. Due to strong
immunosuppressive effects of IL1-ra, recombinant human IL1-
ra is used successfully by patients with rheumatoid arthritis (e.g.
Kineret®). In regard to IL1-ra, serum concentrations are noted
up to a maximum of 1000 pg/ml in normal subjects [15], com-
pared to that, the concentrations of up to 21,000 pg/ml detected
in the specimens appear as salient. Growth factors FGFbasic
and PDGF-BB are generated, amongst others, by fibroblasts and
stimulate the migration of osteoblasts and the formation of colla-
gen. Both are assigned an important role in osteogenesis [16,17].
FGF concentration in the specimens can be estimated as rela-
tively high, compared to serum concentration of normal subjects
(FGFbasic ca. <2 pg/ml) [18,19]. On the other hand, PDGF-BB
concentration is distinctively below the expected level of normal
subjects (ca. <1.5 ng/ml) [20].
Conclusion
Concluding, it has to be recorded that the present mes-
senger diagram of the analyzed samples, in comparison to
reference levels in serum, accounts for a growth promot-
ing, anti-inflammatory milieu. That is consistent with the lack
of inflammation at the histopathologic analysis [3,4,6]. The
assumption, that the samples high local IL1-ra levels have a sys-
temic effect in terms of an overweight of immunohomoeostatic
processes with a consequent tendency to chronic inflammation,
has to be substantiated in further researches. It is supposed as
immunological fact that any raised immune messenger is a proof
for inflammatory activity. Inflammation is defined not only by
inflammatory and proinflammatory mediators but also by anti-
inflammatory mediators. In spite of the above limitations of this
research NICO can be defined as sort of inflammatory focus.
A determination of messenger levels, in particular those of
IL1-ra, PDGF-BB, FGF and RANTES, in serums of NICO
affected patients would be appropriate to provide indications
of systemic effects of the local NICO messengers. This research
was only targeting NICO as a possible source of immune mes-
sengers, with the striking outcome of high levels of IL1-ra and
RANTES. Naturally the question comes up: How far are the lev-
els of immune messengers in the fatty degenerated NICO probes
to compare with levels in healthy jaw bone? The NICO probes
are by itself altered tissue which has no corresponding structure
in normal bone; similar to pus where a healthy reference is also
not existent.
Salutogenetical aspects of NICO treatment in
complementary medical practice
The reasons for initiating the present study are systemic
phenomena which have been described repeatedly under the key-
words: “osteitis of the jaw” and “maxillary disturbance fields”.
On the one hand, positive therapeutic outcomes of such interfer-
ence field elimination are well known. On the other hand there
are only few verified explanatory models and validated mecha-
nisms referring to the presumed links between systemic diseases
and NICO. Meridian based relations of organs and teeth; orig-
inating from traditional Chinese acupuncture do exist. In this
research the authors’ purpose is to develop an immunologi-
cal based explanatory model of systemic phenomena caused by
NICO jaw surgery.
Case 1: male patient, age 38
Clinical symptoms
Initial complaints: pain in the right knee joint for 12 months.
Previous diagnosis: rheumatic arthritis. Previous medical treat-
ment: prescription of oral Prednisolon and Metotrexat.
Postsurgical findings after NICO treatment
After NICO treatment in the left part of the upper jaw on
September 8th, 2008, the knee pain ceased promptly. In March
2009 the patient gives the following account:
Author's personal copy
J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77 75
From February to May 2007,the pain in my knee increased to
such an extent that I went to see my family doctor.He referred
to a rheumatologist.Until the appointment in the mid of Juno
2007,the state of my health worsened,so that I had difficul-
ties to get out of bed in the mornings and down the stairs.My
hands became increasingly stiff as well.The rheumatologist
diagnosed rheumatoid arthritis.The treatment consisted of
medication with Prednisolon and Metrotexat.Because of the
adverse effects I would have had to expect and the statement
of the rheumatologist “I would be able to live a relatively
normal life once adjusted to the medication”,I turned to
complementary medicine.I decided to seek alternative treat-
ment besides orthodox medicine.I contacted Dr.L.in March
2008 to have an examination for disturbance fields in the
head area.In March 2008 you diagnosed NICO lesions in all
four wisdom tooth’s regions.After every operation,four in
total,my condition improved.In the beginning of May 2008 I
stopped the intake of Prednisolon and Metrotexat.Today–in
March 2009 - I’m 95% free of pain,especially when getting
up in the mornings.
Histological findings
The histological diagnosis of the NICO area 28/29 on
September 12th, 2008 showed the following result:
Bone tissue consistently vital with preserved osteocytes.The
marrow spaces show exclusively fat tissue,on the one hand
a very small area with a recent fat tissue necrosis which
shows a lack of adipocyte nuclei,individual,immigrated
neutrophil granulocytes,extravasates of erythrocytes.On
the other hand,areas in where the width of the adipocytes
caliber is varying,and a foam cellular or fine fibrillar trans-
formed cytoplasm edge.In the remaining marrow spaces,
here a small area with a more recent fat tissue necrosis,
other areas with varying calibers and partly lipoid degener-
ation of the cytoplasm in the way of a trophic dysfunction.
No hemopoietic bone marrow,no relevant inflammation,no
atypias.Presented findings definitely (provided with concur-
rent clinic and radiology)are described as NICO.
Evaluation of pathologic analysis data
The RANTES level of the NICO bone sample of this par-
ticular case of region 28/29, amounting to 911.39 pg/ml, is
considerable increased in the range of the limit of detection.
Where are the connections between local increased RANTES
levels and joints? RANTES is secreted by human fibroblasts
in the synovia and therefore can be part of a progressing
inflammatory process which accompanies rheumatoid arthri-
tis [21,22]. Synoviocytes produce synovia fluid and secrete
effector molecules, which advance inflammations and joint
destruction [23]. They form part of complex network of
autocrine and paracrine factors. A hypothetic causal relationship
regarding the increased RANTES secretion in NICO reads: Cor-
responding individual set-up provided, a permanently increased
level of NICO-RANTES could exert negative impact in terms
of joint inflammation, articular effusions and rheumatoid
arthritis.
Case 2: male patient, age 39
Clinic symptoms
Initial complaints: massive exercise-induced asthma. Pre-
vious diagnosis: exercise-induced asthma of unknown origin.
Previous treatment: cortisone spray, meaning a medically pre-
scribed lifelong intake.
Postsurgical findings after NICO treatment
After NICO treatment in the right part of the lower jaw
in September 2008 regio 48/49, the pain in the knee ceased
promptly. In January 2009, the patient reports:
I wanted to give a short feedback on my previous state of
health and on how I am now.About four years ago,I suddenly
started having problems cycling.On a longer cycling tour
of about 100 km,including many mountain stages,all of a
sudden there was absolutely no power left in my legs.I did not
recover over three months.I went from one doctor to another
and it was declared that I suffered from massive,exercise-
induced asthma.Since then,I had to inhale cortisone spray
every time before I went on a cycling tour.The doctors could
not tell me why I got this asthma,nor where it came from,but
they did tell me that I had to take this spray for the rest of my
life.I had surgery in the jaw bone.Since the treatment of my
teeth,I never had any problems with my maxillary sinus and
I did not need the asthma spray once in the entire summer.I
hope,that it continues like this for the rest of my life.
Histological findings
The histological findings of the NICO area 48/49 show the
following result:
An excised osseous specimen (regio 48/49)with cancellous
bone which shows partially fibrosed,yellow marrow,which is
situated intertrabecular and has increasingly “meandering”,
vital blood vessels and nerve branches.The yellow marrow
shows distinctive,mucoid degeneration.This mucoid degen-
eration suggests a chronic,trophic disorder and belongs to
those findings that are repeatedly seen in the context of NICO.
No inflammatory infiltrates and no atypias.
Evaluation of pathologic analysis data
The RANTES level of the NICO bone sample of this
particular case of area 48/49, amounting to extrapolated
OOR >20,000 pg/ml, is considerably increased above the
range of detection. Where is the connection between local
increased RANTES levels and allergological-pulmonary dis-
orders? RANTES is chemotactic for T-cells, eosinophils and
basophils and takes an active part in mobilizing leucocytes in
inflammatory changed areas. As a result, it is assumed that a gen-
eral cellular activation is taking place, which can often be linked
with diseases like asthma and allergic rhinitis [24,25]. RANTES
is as well a potent activator of the oxidative metabolism, specific
for eosinophils [26]. RANTES activates basophils and thereby
causes the releasing of histamines. A hypothetic causal relation
of the increased secretion of RANTES in the context of NICO
reads: Given a corresponding, individual set-up, a constantly
Author's personal copy
76 J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77
increased NICO-RANTES level could exert negative influence
by advancing chronic-inflammatory processes in other parts of
the organism.
Pathogenetic aspects of NICO: approach to a
mediator-based hypothesis of systemic-causal relations
Discussion of systemic relations of the RANTES readings
The issue which gave reason to analyzing the immune mes-
sengers in the six NICO samples had risen from complementary
medical experience of “disturbing fields” in the jaw area. Where
is the explanatory link between local, operative removal of NICO
and the undeniable healing successes in “disturbed fields” of
organic symptoms and clinical presentation? Could it be the
chronically elevated RANTES level from NICO sites in the jaw
bone?
The crucial point of a systemic interpretation of the results
lies in the understanding that NICO is an insidious, chronic sub-
liminal effect. Although RANTES level of all six NICO samples
were noticeably high, they appear rather low in comparison to
RANTES readings which can occur with acute arthritis in serum.
These high serum-levels of RANTES in acute stages should not
be admitted to hide the fact that acute stages of arthritis (case 1)
or asthma (case 2) are actually the late or final stage of a chronic,
asymptomatic promoting phase. Factoring chronicity into the
considerations, increased RANTES level in the local NICO area
lead to the conclusion that the cytokine-regulated signaling in
the body in the course of disturbance field processes is a chronic
challenge for the immune system. The RANTES increase in
NICO can persist for years, is usually clinically unnoticed and
causes a displaced increased development of RANTES level.
Where the local complaints manifest themselves – knee joint
(case 1) or in the bronchial tubes (case 2) depends on genetic
and other individual stress factors. As RANTES is found in many
other systemic diseases it is worth to discuss further aspects of
possible pathogenetic effects of NICO lesions:
RANTES and its role in MS
RANTES has been detected in brain lesions of multiple
sclerosis (MS) patients. IP-10 and RANTES CSF levels were
elevated in MS patients compared with controls. Because both
IP-10 and RANTES are potent T-cell chemoattractants, it is rea-
sonable to postulate that the elevated levels of these chemokines
during active episodes of MS induce accumulation of T-cells
into the CNS. RANTES is a chemo attractant for both T-cells
and macrophages and could be a key proinflammatory factor in
the pathogenesis of MS [27].
RANTES and its role in cancer metastasis
The body’s own stem cells stimulate cancer cells to mutate,
to spread and to form tumors in other organs. A particular sort
of stem cells is required for cancer metastasis. Mesenchymal
stem cells from the bone marrow have been suspected for some
time past. Scientists of Whitehead-Institute Cambridge, Mas.,
USA assume that those stem cells with the aid of messengers
transmute tumor cells into metastasizing cells. These scientists
have already found a molecule which stimulates metastasis:
chemokine CCL5, also called RANTES: The breast cancer cells
stimulate de novo secretion of the chemokine CCL5 (also called
RANTES) from mesenchymal stem cells, which then acts in
a paracrine fashion on the cancer cells to enhance their motil-
ity, invasion and metastasis. This enhanced metastatic ability
is reversible and is dependent on CCL5 signaling through the
chemokine receptor CCR5 [28].
Concluding, the presented hypothetic model of systemic
NICO-impacts can be reduced to a challenge- and stimulation
pattern. There is no direct, monocausal relationship between
disturbance field and disturbance. Interesting, though, is the
author’s longtime clinical experience that in dental therapy prac-
tice a removal of the proinflammatory NICO lesion usually leads
to disappearance of various inflammatory clinical presentations
in our patients.
Authors
All research done by the authors.
Financial support
None.
Conflict of interest
No conflict of interest declared.
References
[1] Black GV. A work on special dental pathology. 2nd ed. Chicago: Medico-
Dental Publ. Co.; 1920.
[2] Fischer MH. Death and dentistry. Springfield, IL: Charles C. Thomas Pub.;
1941.
[3] Bouquot JE, Roberts AM, Person P, Christian J. NICO (neuralgia-
inducing cavitational osteonecrosis): osteomyelitis in 224 jawbone samples
from patients with facial neuralgias. Oral Surg Oral Med Oral Pathol
1992;73:307–19.
[4] Bouquot JE. Neuralgia-inducing cavitational osteonecrosis (NICO). Oral
Surg Oral Med Oral Pathol 1992;73:307–19.
[5] Bouquot JE, Christian J. Longterm effects of jawbone curettage on the pain
of facial neuralgia. J Oral Maxillofac Surg 1995;53:387–97.
[6] Lechner J. Störfelder im Trigeminusbereich und Systemerkrankung. VGM
Kötzting; 1999.
[7] Bouquot JE, Martin W, Wrobleski G. Computer-based thru-transmission
sonography (CTS) imaging of ischemic osteonecrosis of the jaws—a pre-
liminary investigation of 6 cadaverjaws and 15 pain patients. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2001;92:550.
[8] Bouquot JE, Shankland WE, Margolis II M. Through-transmission alveolar
ultrasonography (TAU)—new technology for evaluation of bone density
and desiccation. Comparison with radiology of 170 biopsied alveolar sites
of osteoporotic and ischemic disease. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2002;93.
[9] Lechner J. Herd, regulation und information. Heidelberg: Hüthig-Verlag;
1993.
[10] Lechner J. Fakt oder Fiktion—Dokumentation des NICO-Störfelds, Reg-
ulationsMedizin 8. Heft 2003;2.
Author's personal copy
J. Lechner, W. Mayer / European Journal of Integrative Medicine 2 (2010) 71–77 77
[11] Liu C, Papewalis C, Domberg J, Scherbaum WA, Schott M. Chemokines
and autoimmune thyroid diseases. Horm Metab Res 2008;40(June
(6)):361–8 [Epub April 16, 2008].
[12] Kraaijeveld AO, de Jager SC, de Jager WJ, Prakken BJ, McColl SR, Haspels
I, et al. CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine
ligand-18 (CCL18/PARC) are specific markers of refractory unstable
angina pectoris and are transiently raised during severe ischemic symptoms.
Circulation 2007;116(October (17)):1931–41 [Epub October 1, 2007].
[13] Zeremski M, Petrovic LM, Talal AH. The role of chemokines as inflam-
matory mediators in chronic hepatitis C virus infection. J Viral Hepat
2007;14(October (10)):675–87.
[14] Nomura S, Uehata S, Saito S, Osumi K, Ozeki Y, Kimura Y. Enzyme
immunoassay detection of platelet-derived microparticles and RANTES in
acute coronary syndrome. Thromb Haemost 2003;89(March (3)):506–12.
[15] Słotwi´
nski R, Olszewski WL, Paluszkiewicz R, Zieniewicz K, Hevelke P,
Zaleska M, et al. Serum cytokine concentration after liver lobe harvesting
for transplantation. Ann Transpl 2002;7(3):36–9.
[16] Lind M. Growth factor stimulation of bone healing. Effects on
osteoblasts, osteomies, and implants fixation. Acta Orthop Scand Suppl
1998;283(October):2–37.
[17] Lind M, Deleuran B, Thestrup-Pedersen K, Søballe K, Eriksen EF, Bünger
C. Chemotaxis of human osteoblasts. Effects of osteotropic growth factors.
APMIS 1995;103(February (2)):140–6.
[18] Robak E, Wo´
zniacka A, Sysa-Jedrzejowska A, Stepie´
n H, Robak T.
Serum levels of angiogenic cytokines in systemic lupus erythemato-
sus and their correlation with disease activity. Eur Cytokine Netw
2001;12(July–September (3)):445–52.
[19] Urbaska-Rys H, Wierzbowska A, Robak T. Circulating angiogenic
cytokines in multiple myeloma and related disorders. Eur Cytokine Netw
2003;14(January–March (1)):40–51.
[20] Czarkowska-Paczek B, Bartlomiejczyk I, Przybylski J. The serum levels of
growth factors: PDGF, TGF-beta and VEGF are increased after strenuous
physical exercise. J Physiol Pharmacol 2006;57(June (2)):189–97.
[21] Hirano F, Kobayashi A, Hirano Y, Nomura Y, Fukawa E, Makino
I. Thrombin-induced expression of RANTES mRNA through protease
activated receptor-1 in human synovial fibroblasts. Ann Rheum Dis
2002;61(9):834–7.
[22] Rathanaswami P,Hachicha M, Sadick M, Schall TJ, McColl SR. Expression
of the cytokine RANTES in human rheumatoid synovial fibroblasts. Dif-
ferential regulation of RANTES and interleukin-8 genes by inflammatory
cytokines. J Biol Chem 1993;268(8):5834–9.
[23] Chicheportiche Y, Chicheportiche R, Sizing I, Thompson J, Benjamin
CB, Ambrose C, et al. Proinflammatory activity of TWEAK on human
dermal fibroblasts and synoviocytes: blocking and enhancing effects of
anti-TWEAK monoclonal antibodies. Arthritis Res 2002;4(2):126–33.
[24] Conlon K, Lloyd A, Chattopadhyay U, Lukacs N, Kunkel S, Schall T, et
al. CD8+ and CD45RA+ human peripheral blood lymphocytes are potent
sources of macrophage inflammatory protein 1 alpha, interleukin-8 and
RANTES. Europ J Immunol 1995;25(3):751–6.
[25] Kimura Y, Pawankar R, Aoki M, Niimi Y, Kawana S. Mast cells and T cells
in Kimura’s disease express increased levels of interleukin-4, interleukin-5,
eotaxin and RANTES. Clin Exp Allergy 2002;32(12):1787–93.
[26] Staruch MJ, Camacho R, Dumont FJ. Distinctive calcineurin-dependent
(FK506-sensitive) mechanisms regulate the production of the CC
chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta,
and RANTES vs IL2 and TNF-alpha by activated human T cells. Cell
Immunol 1998;190(2):121–31.
[27] Bolin LM, Murray R, Lukacs NW, Strieter RM, Kunkel SL, Schall TJ, et al.
Primary sensory neurons migrate in response to the chemokine RANTES.
J Neuroimmunol 1998;81(1–2):49–57.
[28] Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al.
Nature 2007;449(7162):557–63.
[29] Immumed, Gesellschaft für angewandte Immunologie, Goethestraße 10,
80336 München, Germany.
[30] Gemeinschaftspraxis für Pathologie & Zytologie, Drs. Zwicknagel/Aßmus,
85635 Freising, Germany.
... The clumps of fat found in osteolytic jawbone are extremely biochemically active and produce specific cytokines in high amounts, the most notable of which is the chemokine RANTES (more recently known as CCL5; R/C). This chronic R/C production may influence immunologic patterns and exacerbate systemic immunologic diseases (Lechner and Mayer 2010;Lechner andvon Baehr 2013, 2015;Lechner, Huesker et al. 2017;Lechner, Schuett et al. 2017). The status of cancellous bone in the jaw is of great importance with respect to dental implants and the success of implantology, according to previous publications by other authors (Klein et al. 2008;Lee et al. 2013). ...
... Pre-operative HU attenuation coefficients and corresponding TAU-n attenuation coefficients (Average(log); columns in gray) are compared with postoperatively measured levels of R/C expression from the samples obtained during surgical treatment for BMDJ/FDOJ (columns in blue). MV refers to the medium values obtained in the course of our research, and the final row compares the corresponding values of healthy jawbone found in the literature (HUs; Guglielmi and de Terlizzi 2009;Mah et al. 2010;Komar et al. 2019) and R/C levels (pg/mL; Klein et al. 2008;Lechner and Mayer 2010;Lechner andvon Baehr 2013, 2015;Lechner, Huesker et al. 2017;Lechner, Schuett et al. 2017). filled with water. ...
... Determining BMDJ/FDOJ with R/C expression BMDJ/FDOJ cavitations contain degenerated adipocytes that exhibit a particular expression profile of the chemokine R/C (Lechner and Mayer 2010;Lechner andvon Baehr 2013, 2015;Lechner, Huesker et al. 2017;Lechner, Schuett et al. 2017). Hence, BMDJ/FDOJ samples were also analyzed for expression of the inflammatory immune mediator R/C. ...
Article
Full-text available
The interest in the application of TAU-n lies in the decrease in bone density in BMDJ/FDOJ owing to osteolysis. The upper limit of DVT HU values of interest with respect to BMDJ/FDOJ is +300, as at this point there is a transition to healthy cancellous bone. Values over +300 HUs thus fall outside the necessary detection range of TAU-n. The HU values produced in this study (range: −680 to +150) indicate BMDJ/FDOJ in class 5 cases ( Mah et al., 2010 • Mah P • Reeves TE • McDavid WD. Deriving Hounsfield units using grey levels in cone beam computed tomography.Dentomaxillofac Radiol. 2010; 39: 323-335 • Google Scholar ). The data presented here show that HU values demonstrate osteolysis and correspond to R/C overexpression in BMDJ/FDOJ areas (Lechner et al., 2018 • Lechner J • Rudi T • von Baehr V Osteoimmunology of tumor necrosis factor-alpha, IL-6, and RANTES/CCL5: A review of known and poorly understood inflammatory patterns in osteonecrosis.Clin Cosmet Investig Dent. 2018; 10: 251-262 • Google Scholar ). When the data derived from both methods used to evaluate BMDJ/FDOJ (i.e., HU values and R/C expression) are compared with the TAU-n results, there is a correlation between the attenuation coefficients of HUs and TAU-n. Thus, it may be assumed that TAU-n, which uses ultrasound waves, is able to provide an accurate representation of the degrees of mineralization and bone density in the jawbone area. • •Using the Average(log) values generated with TAU-n, we confirmed a general correspondence between HU values and R/C multiplex analysis in a cohort of 210 people with BMDJ/FDOJ patients. • •Table 1 shows two participants (#53 = 2.29 and #123 = 2.67) with an Average(log) value > 2 from the total of 210 participants. • •Here, HU values and post-operatively measured levels of cytokine expression confirm the reliability of TAU-n measurements with respect to displaying decreased bone density in cases of BMDJ/FDOJ.
... Associations between NICO and other systemic diseases were examined in five studies (Lechner & von Baehr, 2013, 2014Lechner, Huesker, et al., 2017;Lechner & Mayer, 2010;Lechner, Schuett, et al., 2017). Examined study populations with proposed associations varied greatly and encompassed patients with breast cancer (Lechner & von Baehr, 2014), chronic fatigue syndrome (Lechner, Huesker, et al., 2017) as well as mixed study populations with a number of diseases/complaints: one study analysed 31 patients with facial pain (n = 7), rheumatoid arthritis or joint pain (n = 7), chronic fatigue syndrome (n = 4), breast cancer (n = 5), Hashimoto's thyroiditis (n = 3), multiple sclerosis (n = 2), Parkinson's disease (n = 1), asthma (n = 1), leukaemia (n = 1), allergies (n = 1) and amyotrophic lateral sclerosis (n = 1) (multiple counts due to overlapping symptoms) (Lechner & von Baehr, 2013); one study examined 6 patients, of which one had rheumatoid arthritis and one had exercise-induced asthma, and the medical history of the other four patients was not reported (Lechner & Mayer, 2010). ...
... Associations between NICO and other systemic diseases were examined in five studies (Lechner & von Baehr, 2013, 2014Lechner, Huesker, et al., 2017;Lechner & Mayer, 2010;Lechner, Schuett, et al., 2017). Examined study populations with proposed associations varied greatly and encompassed patients with breast cancer (Lechner & von Baehr, 2014), chronic fatigue syndrome (Lechner, Huesker, et al., 2017) as well as mixed study populations with a number of diseases/complaints: one study analysed 31 patients with facial pain (n = 7), rheumatoid arthritis or joint pain (n = 7), chronic fatigue syndrome (n = 4), breast cancer (n = 5), Hashimoto's thyroiditis (n = 3), multiple sclerosis (n = 2), Parkinson's disease (n = 1), asthma (n = 1), leukaemia (n = 1), allergies (n = 1) and amyotrophic lateral sclerosis (n = 1) (multiple counts due to overlapping symptoms) (Lechner & von Baehr, 2013); one study examined 6 patients, of which one had rheumatoid arthritis and one had exercise-induced asthma, and the medical history of the other four patients was not reported (Lechner & Mayer, 2010). The composition of the study population examined by Lechner, Schuett, et al. (2017)) was incomprehensible due to conflict- Results focused on the difference in inflammatory cytokines. ...
... Following surgery, diagnostic methods included microbial and histopathologic analyses, as well as CCL5 tissue levels. The latter were reported to be elevated in the NICO/FDOJ bone samples (Lechner, 2014;Lechner, Aschoff, et al., 2018;Lechner & von Baehr, 2013;Lechner, Huesker, et al., 2017;Lechner & Mayer, 2010;Lechner et al., 2019Lechner et al., , 2020. Four studies reported results from microbial analyses, and 19 studies described histopathological features (see Table S1 in the Appendix S1 for details). ...
Article
Full-text available
Objective: To assess the etiologic factors, proposed diagnostic means and treatment strategies for Neuralgia-inducing cavitational osteonecrosis. Methods: A search of the literature published up to June 2020 was conducted using Medline, the Cochrane Library, PsycINFO, CINAHL, and Web of Science. The scientific quality of the evidence was rated according to NIH Quality Assessment Tools. Results: 4051 articles were found, 59 were reviewed in full text, 29 studies were included. With the exception of hereditary coagulopathies, which were identified as potential risk factors in five studies, suggestions concerning the aetiology varied widely. No gold standard diagnostic mean could be identified. Treatment was most often performed by surgical curettage of the affected bone. Surgical treatment outcomes were equally varied: significant facial pain remission was reported in 66 -100% for periods varying between 2 months to 18 years, whereas no or little relief and recurrences were reported in up to ⅓ of cases. All studies were observational in their design. All investigations were rated as poor quality because of high risk of bias and non-transparent reporting. Conclusions: Evidence concerning the aetiology, diagnosis, and treatment of NICO is poor. Prospective diagnostic and therapeutic studies are needed before the usefulness of invasive therapeutic procedures can be evaluated.
... In the fatty tissue samples obtained from the softened region of the patient's jaw at area 38 and retromolar area 39, the multiplex analysis of the laboratory showed 6218 pg/mL of the proinflammatory chemokine RANTES/CCL5 (R/C), representing a nearly 40-fold overexpression; the normal finding for R/C in healthy medullary maxillary spongial bone is 149.9 pg/mL (average age, 51.4 years; range, 33-72 years; gender (female/male): 10/9) ( Figure 6). 13,14 In a previous case report, we demonstrated the immunological connection between the local overexpression of R/C found in fatty degenerative osteonecrosis of the jawbone (FDOJ) and systemic disease. 15 ...
... With the analysis of RANTES expression in morphologically and histologically conspicuous jawbone samples, we are entering new territory. [13][14][15] Chemokine RANTES/ CCL5 (R/C) is a recognized inflammatory agent in medical research. The progression of chronic inflammatory diseases is often hidden beneath the surface as a result of an immune system that is chronically activated by excess cytokines. ...
... The progression of chronic inflammatory diseases is often hidden beneath the surface as a result of an immune system that is chronically activated by excess cytokines. These chemokines also stimulate other signaling pathways, the expression of which we have identified in BMDJ/FDOJ, [13][14][15] including in the specific case presented here. 16 The striking result arising from the multiplex analysis of the BMDJ/FDOJ area indicated the marked elevation of the chemokine R/C. ...
Article
Full-text available
Purpose: This paper aims to demonstrate the additional benefit of ultrasound in the diagnosis of chronic osteolysis and osteonecrosis (bone marrow defects) of the jaw shown in a clinical case report. Patients and methods: A case of chronic fatigue syndrome (CFS) in a young man presenting the typical, ambiguous symptoms, which were accompanied by headaches and tinnitus. X-ray techniques, namely panoramic radiographs (OPG) and cone beam computed tomography (DVT/CBCT), failed to produce any remarkable findings of bone marrow defects (BMDJ) in the jawbone. However, the measurement of bone density using trans-alveolar ultrasound (TAU) indicated a possible bone marrow defect in the lower left jawbone. Results: Surgery was undertaken at the conspicuous area. Additional to softened, ischemic, fatty tissue, a black area was revealed, which was surprisingly subsequently identified as aspergillosis by histopathological analysis. In addition, the excessive local RANTES/CCL5 expression found in the affected area confirmed the necessity for surgical debridement and additional findings of TAU. Conclusion: In contrast to radiography, complementary TAU imaging of the BMDJ revealed chronic inflammatory signaling RANTES/CCL5 pathways and fungal colonization. This case report supports the need for additional diagnostic techniques beyond radiographic modalities, which can help to elucidate the diagnostic composition and knowledge of the bone manifestations of systemic diseases.
... The current treatment for FDOJ lesions consists of bony cavity curettage. 17,18 To elucidate a possible causative link between FDOJ and VDR-deac at the Munich Clinic for Integrative Dentistry (Munich, Germany), 43 patients with ISDs who were also diagnosed with FDOJ underwent surgery on the affected jaw area. Following the administration of local ...
... The aforementioned effects of VDR-deac may provide a further explanation for the chronic "silent inflammation" in the jaw, here referred to as FDOJ, that we have repeatedly reported. 14,18,37 At the same time, the chemokine R/C is partly responsible for many ISDs -rheumatism, breast cancer, Hashimoto's thyroiditis, melanomas, multiple sclerosis, Amyotrophyic lateral sclerosis and so on; it serves as a key pathogenic element, being overexpressed by up to 35-fold in the affected jaw area. We consider, therefore, the research findings of VDR deactivation in the development of FDOJ to be illuminating. ...
Article
Full-text available
Background Recent research on vitamin D indicates that our current understanding of the factors leading to chronic inflammation should be revised. One of the key mechanisms by which microbial immunosuppression occurs is the suppression of one of the most common endogenous cell nucleus receptors: the vitamin D receptor (VDR). Autoimmune diseases may be correlated with VDR deactivation (VDR-deac) which occurs when the receptor is no longer able to transcribe antimicrobial agents. Excess 1,25-dihydroxyvitamin D (1,25D) is not converted to 25-hydroxyvitamin D (25D); thus, high 1,25D levels may be accompanied by low 25D values. Patients and methods Since 1,25D promotes osteoclast activity and may thereby cause osteoporosis, fatty-degenerative osteolysis of the jaw (FDOJ), as described by our team, may also be associated with VDR-deac. In 43 patients, vitamin D conversion, immune system function and the quality of bone resorption and formation in the jawbone were related factors that may enhance chronic inflammatory processes. Here, we examine the relationship between immunology and bone metabolism among 43 FDOJ patients and those with immune system diseases (ISDs). Results We provide a link between FDOJ, RANTES/CCL5 overexpression and VDR-deac. Conclusion The clinical data demonstrate the interaction between VDR-deac and proinflammatory RANTES/CCL5 overexpression in FDOJ patients.
... It may produce facial pain but can also be present for years as an asymptomatic process. Dramatically increased levels of RANTES and fibroblast growth factor 2 (FGF-2) can be detected in the fatty tissue removed by surgery, but no elevations in cytokines associated with acute inflammation [32,33]. RANTES is increased in the serum of patients with several chronic diseases, including ALS [34]. ...
... RANTES is increased in the serum of patients with several chronic diseases, including ALS [34]. Surgical debridement of the tissue in the cavitations has led in several cases to an improvement of the neuralgic pain in the face [35], and also of immunological complaints, such as rheumatic, allergic, and other inflammatory diseases [33]. The fact that the patient felt immediate relief after treatment of his teeth even before the start of the chelation therapy points to a possible contribution of this treatment to healing. ...
Article
Full-text available
Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. Case report: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. Conclusions: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.
... klinisch-praktische Bedeutung nach Meinung des Autors in der "main-streamdentistry" immer noch vernachl?ssigt wird [8]. ...
... The original solid bone softens and leads to increased permeability for X-rays and a corresponding brightening of X-rays by loss of calcium and phosphate. 16 Glueck et al hypothesized that T-786C mutation of endothelial nitric oxide synthase gene affecting nitric oxide production is associated with NICO and may open therapeutic approaches to treatment of NICO by provision of L-arginine, the amino-acid precursor of nitric oxide. 17 The treatment of NICO is surgical debridement/ curettage. ...
... 11 However, the possible systemic effects and the status of cytokine-triggered immune activation in samples of FDOJ have not been widely assessed. 5 Diagnostic problems of FDOJ lesions in jawbone. The existence of FDOJ is largely neglected today in mainstream dentistry; the reason is that conventional X-ray techniques have limited ability to diagnose the location and extent of FDOJ. ...
Article
Full-text available
Background: Hollow spaces in the jawbone have been defined as fatty degenerative osteonecrosis of jawbone (FDOJ) and have been linked with a dysregulated immune system. Little is known about the underlying relationship. Objectives: Samples of FDOJ were analyzed to assess expression of cytokines which can play a role in the pathogenesis of breast cancer (MaCa). Material and methods: Samples of FDOJ extracted from 23 patients with MaCa and 19 healthy control jawbone samples were analyzed for 7 immune messengers. Results: RANTES was found to be highly overexpressed in disease samples. No change was observed in expression levels of the other immune mediators. Discussion: This data provides a compelling confirmation that FDOJ produces high levels of RANTES, a cytokine implicated in MaCa and metastasis. Levels detected in FDOJ are five-fold higher than that previously reported for MaCa tissue suggesting its role as a cytokine source in MaCa. Conclusion: We thus hypothesize that FDOJ may serve as an expeditor of MaCa progression, through RANTES production.
... 11 However, the possible systemic effects and the status of cytokine-triggered immune activation in samples of FDOJ have not been widely assessed. 5 Diagnostic problems of FDOJ lesions in jawbone. The existence of FDOJ is largely neglected today in mainstream dentistry; the reason is that conventional X-ray techniques have limited ability to diagnose the location and extent of FDOJ. ...
Article
Full-text available
BACKGROUND: Hollow spaces in the jawbone have been defined as fatty degenerative osteonecrosis of jawbone (FDOJ) and have been linked with a dysregulated immune system. Little is known about the underlying relationship. OBJECTIVES: Samples of FDOJ were analyzed to assess expression of cytokines which can play a role in the pathogenesis of breast cancer (MaCa). MATERIAL AND METHODS: Samples of FDOJ extracted from 23 patients with MaCa and 19 healthy control jawbone samples were analyzed for 7 immune messengers. RESULTS: RANTES was found to be highly overexpressed in disease samples. No change was observed in expression levels of the other immune mediators. DISCUSSION: This data provides a compelling confirmation that FDOJ produces high levels of RANTES, a cytokine implicated in MaCa and metasta-sis. Levels detected in FDOJ are five-fold higher than that previously reported for MaCa tissue suggesting its role as a cytokine source in MaCa. CONCLUSION: We thus hypothesize that FDOJ may serve as an expeditor of MaCa progression, through RANTES production.
Article
Die übergeordnete Rolle der Störfelder bzw. Neuromodulativer Trigger im Bereich der Zähne und der Kieferknochen haben großen Einfluss auf Krankheiten und funktionelle Beschwerden bei unseren Patienten. Das Ziel ist es, durch unterschiedliche diagnostische Schritte die Störfelder im Trigeminusbereich zu diagnostizieren und als Neuraltherapeut zur zahnärztlichen Intervention zu begleiten. Eine enge Zusammenarbeit mit einem Zahnarzt/Kieferchirurgen kann unumgänglich werden, vor allem bei chronischen Krankheitsbildern mit fehlender Kompensation der Beschwerden.
Conference Paper
Full-text available
Objectives: To determine whether or not the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production is associated with NICO, since it has been found in a high proportion of idiopathic hip osteonecrosis cases. Gene polymorphism associated with reduced NO production is associated with vasoconstriction, platelet aggregation, thrombosis and regulation of bone turnover ...all important to ischemic bone damage. Methods: Blood was collected from 22 biopsy-proven NICO patients (17 females; 5 years average pain duration; no bisphosphonate, estrogen or corticosteroid use; hot spot in quadrant of pain via technetium-99 MDP scintigraphy scan) and processed for real time PCR analysis of mutations affecting NO production (eNOS T-786C, stromelysin 5A6A). Two race/gender matched normal controls were used per case. Results: Homozygosity for the mutant eNOS allele (TT) was present in 6 of 22 (27%) NICO cases compared to 0 of 44 (0%) of controls; heterozygosity (TC) was present in 8 cases (36%) vs 15 controls (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) vs 29 controls (66%) (p = 0.0008). The mutant eNOS T-786C allele was more common in cases (20/44 [45%]) than in controls (15/88 [17%]), p =0.0005. The specificity of eNOS T-786C genotype (homozygosity vs non-homozygosity) was very high, with all 44 healthy controls (100%) free of eNOS homozygosity. However, the distribution of the stromelysin 5A6A genotype in cases did not differ from controls (p=.13) and specificity was low, only 82%, with 36 of 44 healthy controls free of eNOS homozygosity. Conclusions: While cause-and-effect cannot be proven by our study design, the eNOS T-786C polymorphism affecting NO production is associated with NICO and may, therefore, contribute to the multifactorial pathogenesis of that disease, perhaps allowing medical approaches to treatment through use of L-arginine, the amino-acid precursor of NO.
Article
Full-text available
A somewhat obscure etiologic theory for facial neuralgias presumes a low-grade osteomyelitis of the jaws that produces neural degeneration with subsequent production of inappropriate pain signals. Animal investigations and treatment successes with human patients based on this theory lend it credence. The present study examined 224 tissue samples removed from alveolar bone cavities in 135 patients with trigeminal neuralgia or atypical facial neuralgia. All tissue samples demonstrated clear evidence of chronic intraosseous inflammation. The most common microscopic features included dense marrow fibrosis or "scar" formation, a sprinkling of lymphocytes in a relative absence of other inflammatory cells (especially histiocytes), and smudged, nonresorbing necrotic bone flakes. Very little healing or new bone formation was visible. These lesions were able to burrow several centimeters to initiate distant cavities. The present preliminary investigation cannot prove etiology, but the presence of intraosseous inflammation in every single jawbone specimen in these patients and certain clinical and treatment aspects of these lesions (to be reported later) has led the authors to recommend the term neuralgia-inducing cavitational osteonecrosis or NICO for these lesions.
Article
The in vitro chemotactic response of human osteoblasts was investigated towards the following growth factors: TGF-β, PDGFs, FGFs and IGFs. Human osteoblasts grown from trabecular bone after enzymatic digestion were studied. TGF-β stimulated the migration of human osteoblasts in a dose-dependent manner with a four-fold increase in migrated cells at 100 pg/ml, which was the optimum concentration. PDGF-BB also stimulated migration four-fold in a dose-dependent manner with a maximum response at 10 ng/ml. PDGF-AA, IGF-I and IGF-II stimulated migration two-fold at 100 ng/ml. The results show that TGF-P and PDGF-BB are important regulators of human osteoblast migration, but other growth factors IGF-I, IGF-II and PDGF-AA may also stimulate osteoblast migration. Our results additionally suggest that TGF-P and PDGF-BB may participate in the recruitment of osteoblasts during bone remodeling since both TGF-P and PDGF-BB are found in bone matrix and could be released during osteoclastic bone resorption. They furthermore support a possible use of TGF-P and PDGF-BB in growth factor-induced osteogenesis.
Article
The chemokines macrophage inflammatory protein 1 (MIP 1), interleukin-8 (IL-8) and RANTES are potent regulators of leukocyte trafficking. Examination of chemokine secretion by human peripheral blood lymphocytes after stimulation with anti-CD3 or phorbol 12, 13 myristate acetate and ionomycin showed CD8+ cells were the dominant source of MIP 1 and RANTES. Although production of MIP 1 and IL-8 were similar in pharmacologically stimulated CD4+ CD45RA+, CD4+ CD45RO+, and CD8+ CD45RA+ cells, the largest amounts of MIP 1 and RANTES were secreted by CD8+ CD45RO+ lymphocytes. A parallel pattern of prolonged chemokine mRNA expression for at least 18 h after activation was observed in the T cell subsets. These results confirm that human T lymphocytes have a unique capacity for secretion of these three chemokines. In addition, CD8+ cells have an unrecognized role in recruiting cells to sites of inflammation, and adult human CD45RA+ cells have a physiologically significant secretory capacity.
Article
We examined the potential for the C-C chemokine RANTES to stimulate dorsal root ganglia (DRG) cell migration. Embryonic day 12 (E12.5) mouse DRG cells migrated in response to RANTES, in vitro, differentiating to the nociceptive phenotype within 18 h. In addition, RANTES stimulated intracellular calcium mobilization in DRG cells. RANTES expression was demonstrated by polymerase chain reaction analysis to be present in E10.5 limb bud, E12.5 DRG, Schwann cells, spinal cord and skin. RANTES protein was detected immunohistochemically in E12.5 DRG and the cutaneous layers of the developing hind limb. Thus, RANTES expression is spatially and temporally consistent with an effector molecule in sensory neuropoiesis, potentially expanding the role of this chemokine to include neurotropism.