| |
|
Dietary Supplementation
With the Tribomechanically
Activated Zeolite Clinoptilolite
in Immunodeficiency: Effects
on the Immune System
|
| |
Slavko Ivkovic, MD
Zagreb, Croatia
Ulrich Deutsch, MD
Negast, Germany
Angelika Silberbach, MD
Richtenberg, Germany
Erwin Walraph, MD
Laboratory for Immunology
Neubrandenburg, Germany
Marcus Mannel, MD
Ad libitum Medical Services
Berlin, Germany
|
ABSTRACT
Natural zeolites are crystalline aluminosilicates with unique adsorption, cationexchange,
and catalytic properties that have multiple uses in industry and
agriculture. TMAZ®, a natural zeolite clinoptilolite with enhanced physicochemical
properties, is the basis of the dietary supplements Megamin® and
Lycopenomin®, which have demonstrated antioxidant activity in humans. The
aim of this prospective, open, and controlled parallel-group study was to investigate
the effects of supplementation with TMAZ on the cellular immune system
in patients undergoing treatment for immunodeficiency disorder. A total of
61 patients were administered daily TMAZ doses of 1.2 g (Lycopenomin) and
3.6 g (Megamin) for 6 to 8 weeks, during which the patients' primary medical
therapy was continued unchanged. Blood and lymphocyte counts were performed
at baseline and at the end of the study. Blood count parameters were not
relevantly affected in either of the two treatment groups. Megamin administration
resulted in significantly increased CD4+, CD19+, and HLA-DR+ lymphocyte
counts and a significantly decreased CD56+ cell count. Lycopenomin was
associated with an increased CD3+ cell count and a decreased CD56+ lymphocyte count.
No adverse reactions to the treatments were observed.
Keywords: | |
zeolites; clinoptilolite; TMAZ; dietary supplements; clinical trial;
immunologic deficiency syndromes; immunomodulators;
immunotherapies; superantigens; antioxidants
|
INTRODUCTION
Zeolites are natural minerals of volcanic origin that can be characterized as crystalline
hydrated aluminosilicates of alkali and alkaline earth cations having an infinite
and open three-dimensional structure (Fig 1). The ability of zeolites to lose and gain
water reversibly and to exchange extra-framework cations, both without change to the
crystalline structure, is the basis of their unique properties as "molecular sieves."
Zeolites exhibit versatile adsorptive, cation-exchanging, dehydrating-rehydrating,
and catalytic properties that make them suitable for multiple uses in industry and
agriculture. Specifically, they are used to dry acid gases; separate oxygen from air;
remove NH3 from drinking water and municipal wastewater; extract cesium and
strontium from nuclear wastes; deodorize animal litter, household items, and clothing;
serve as soilless zeoponic substrates for greenhouses and space missions; and supplement
swine and poultry feed.1
Fig 1. Crystal structure of the zeolite clinoptilolite with its 8-ring and 10-ring channels.
When ingested, powdered zeolites, like almost all silicates, are inert and therefore
do not react chemically with food or body fluids or their metabolites. The risk of any
associated adverse effects is therefore insignificant. In toxicology studies involving
mice and rats, the administration of the zeolite clinoptilolite during a period
between 6 and 12 months caused no changes that could be considered a toxic effect
of treatment.2
Zeolites have also been investigated in a broad spectrum of medical uses. Several
of these applications take advantage of the adsorption and ion exchange properties
of zeolites. A urease-zeolite preparation is administered in oral microcapsules, for
example, to remove urea from the blood in patients with uremia.3 Zeolites are also
used as a filter medium for exchanging NH4
+ during hemodialysis and hemoperfusion.4,5
They are also used as an antidiarrheic drug.6 Among the zeolites that have
shown promise in medical applications, Na2CO3-clinoptilolite has
proved to be an
effective and safe antacid for patients with ulcer disease,1,2 and gadolinium zeolite
has proved useful as a contrast medium that enhances the imaging of the gastrointestinal
tract during magnetic resonance imaging.7 In vitro studies of the synthetic
zeolite A revealed the mineral induces the proliferation and differentiation of
osteoblast cells and the activation of osteoblast cell function, findings that suggest
zeolites may have therapeutic properties in the treatment of osteoporosis.8 Recently,
two clinical studies involving healthy volunteers and patients suffering from malignant
disease and diabetes demonstrated that orally administered natural clinoptilolite
is a potent antioxidant.9, 10 When applied externally in powder form, zeolite has
also been found to quicken the healing of wounds and surgical incisions; in Cuba,
clinoptilolite is commonly used to treat topical wounds in horses and livestock.1
As proven bactericides and fungicides, zeolites have been used to control urinary
tract infection and dental plaque formation.11-13 It is well known that silica particles
prevent almost completely the onset of spontaneous diabetes in young BB rats and
the destruction of β cells in nonobese mice given cyclophosphamide.14, 15 In mice
with alloxan-induced diabetes, natural clinoptilolite has been shown to avert or
diminish some late sequelae of the disorder, such as polyneuropathy.2
Accumulating evidence has suggested that zeolites may significantly affect the regulation
of the immune system. Ueki et al have reported that silica, silicates, and aluminosilicates
may act as nonspecific immunostimulators in a manner similar to that of
the superantigens (SAgs),16, 17 a class of powerful, immunostimulatory bacterial and
viral toxins that are able to cause a number of diseases characterized by fever and
shock. Unlike conventional antigens, SAgs bind as unprocessed proteins to particular
motifs of the variable region of the β chain (Vβ) of the T-cell receptor (TcR) outside the
antigen-binding groove and to invariant regions of major histocompatibility complex
(MHC) class II molecules on the surface of antigen-presenting cells (APCs). As a consequence,
SAgs, in nanogram to picogram concentrations, stimulate up to 10% to 30%
of the host T-cell repertoire, whereas in conventional antigenic peptide-TcR binding,
only 1 in 105 to 106 T cells (0.01%-0.0001%) is activated.18 In accordance with this theory,
proinflammatory macrophages, which belong to MHC class II APCs, are activated
by fibrogenic silicate particles,19, 20 and the removal of MHC class II DP/DR+ cells
results in a lack of macrophage stimulation by the silicate chrysotile.16
More recently, Pavelic et al have demonstrated that the lymphocytes from lymph
nodes of mice that were fed for 28 days with micronized zeolite clinoptilolite provoked
a significantly higher allogeneic graft-versus-host reaction than did lymphocytes
in control mice. After the mice were administered clinoptilolite intraperitoneally,
the number of peritoneal macrophages increased significantly, as did their
superoxide anion production.21
The significant immunostimulatory properties of natural zeolites, as described in
these in vitro and animal studies, suggest that zeolite may provide clinical benefits
as an oral dietary supplement. This study is the first to evaluate the impact of
dietary supplements containing the natural zeolite clinoptilolite on the immune system
of patients who demonstrate immunodeficiency.
MATERIALS AND METHODS
Study Population
Adult outpatients suffering from primary or secondary immunodeficiency were
eligible for participation in this prospective, open, and controlled parallel-group
observational study. Nine primary care physicians in the greater Neubrandenburg
area in Germany participated as investigators and recruited patients frequenting
their private practice for the treatment of known immunodeficiency, determined in
each case on the basis of clinical symptomatology (such as recurrent infections and
autoimmune disorders) and pathologic lymphocyte counts.
Interventions
The dietary supplements administered in this study consisted of Megamin® 500 mg
and Lycopenomin® 500 mg (both manufactured by Tribomin d.o.o., Osijek, Croatia),
which were provided by Megamin GmbH, Berlin, Germany. The primary ingredient
in both products is TMAZ® (Tribomin d.o.o.), a tribomechanically activated version of
the natural zeolite clinoptilolite (Table 1). Each 500-mg Megamin capsule also contains
87 mg of dolomite (CaMg(CO3)2), and each 500-mg Lycopenomin capsule contains
several antioxidants, including 75 mg of vitamin C, 50 mg of natural tomato-derived
lycopene, 50 mg of tomato powder, 25 mg of grape seed extract, and 2 mg of plantderived
magnesium stearate.
During a 6- to 8-week period, eligible patients received, depending on the severity
of their immunodeficiency, either 4 Megamin capsules or 2 Lycopenomin capsules
three times a day. Patients with more severe immunodeficiency were given
Lycopenomin, since this product was anticipated to be the more powerful antioxidant.
All other medical therapies intended to treat the immunodeficiency disorder
were to be continued unchanged throughout the study.
Table 1. Composition and Physicochemical Properties of the Tribomechanically
Activated Zeolite Clinoptilolite (TMAZ®)*
|
Chemical composition |
SiO2, 65.0-71.3%; Al2O3, 11.5-13.1%; CaO 2.7-5.2%; K2O,
2.2-3.4%; Fe2O3, 0.7-1.9%; MgO, 0.6-1.2%; Na2O, 0.2-1.3%;
TiO2, 0.1-0.3%; Si/Al ratio, 4.8-5.4 |
Empirical formula |
(Ca,K2,Na2,Mg)4Al8Si40O9696 × 24H2O
|
Physicomechanical properties |
Specific mass, 2.2-2.5 g/cm3; porosity, 32-40%; effective pore
diameter, 0.4 nm
|
Ion-exchanging capacity |
Total exchange capacity, 1.2-1.5 mol/kg; Ca2+, 0.64-0.98 mol/kg;
Mg2+, 0.06-0.19 mol/kg; K+, 0.22-0.45 mol/kg; Na+,
0.01-0.19 mol/kg
|
Ion-exchanging selectivity |
Cs>NH4
+>Pb2+>K+>Na+>Mg2+>Ba2+>Cu2+>Zn2+
|
Chemicals absorbed |
NH3, hydrocarbons C1-C4, CO2, H2S, SO2, NOx, aldehydes |
Toxicity |
Toxicity Nontoxic; generally recognized as safe (GRAS) according
to US Code of Federal Regulations (21 CFR 182, Subpart C)
|
|
*Analysis by ISEGA Forschungs- und Untersuchungsgesellschaft mbH, Aschaffenburg, Germany
Laboratory Measurements
To evaluate changes in the status of the immune system, blood and lymphocyte
counts were obtained at baseline and after about 6 weeks of supplementation therapy,
each time within the framework of routine laboratory assessments. Routine visits took
place about twice monthly. All laboratory assessments were established in accordance
with the Guidelines of the German National Medical Council (Bundesärztekammer) at
the Laboratory for Immunology, Neubrandenburg, Germany. Blood samples were
obtained routinely with an EDTAS-Monovette® 2.7 mL (Sarstedt AG & Co., Nümbrecht,
Germany) between 12 and 1 PM to avoid variation due to circadian rhythm. Blood
counts were performed with an automated blood counting machine (Sysmex
Corporation, Kobe, Japan). Monoclonal antibodies (Beckman Coulter, Inc., Fullerton,
California) in conjunction with flow cytometry (FACScanIM Becton, Dickinson and
Co., San Jose, California) were used for the quantitative analysis of several lymphocyte
subsets in erythrocyte-lysed whole blood, including mature B lymphocytes (CD19+),
mature T lymphocytes (CD3+), T-helper cells (CD3+/CD4+), T-suppressor/cytotoxic
cells (CD3+/CD8+), activated T lymphocytes (CD3+/HLA-DR+), and natural killer
(NK) cells (CD56+).
Statistical Analysis
Owing to the explorative character of the study and because multiple testing was
performed without adjustment for type 1 error, all statistics reported in this study are
interpreted descriptively. The statistical significance was set to P<.01 for treatment
effects within groups. In addition to the standard methods used for reporting descriptive
statistics, nonparametric tests such as the ÷2 test, Wilcoxon test, and Mann-
Whitney-U test were applied to assess treatment effects within groups and differences
between groups. Between-group comparisons were based on the change from baseline
values of variables to adjust for potential baseline differences between groups.
RESULTS
A total of 65 patients with a diagnosis of immunodeficiency participated in the
trial. Four patients withdrew prematurely and were not included in the analysis.
Thus, 61 subjects formed the primary analysis sample, 31 of whom received Megamin
and 30 Lycopenomin.
Both groups had similar baseline characteristics (Table 2) except for the white blood
cell count, which was lower in patients given Lycopenomin; this was expected, as
these patients had the more severe immunodeficiency disorders (Tables 3 and 4).
Table 2. Baseline Data of the Treatment Groups
|
| Megamin | Lycopenomin | Total | |
| (n=31) | (n=30) | (n=61) | P value*
|
Sex | | | | |
Male | 9 (29.0) | 7 (23.3) | 16 (26.2) | |
Female | 22 (71.0) | 23 (76.7) | 45 (73.8) | .77 |
Age, mean yr ± SD | 56±14 | 60±13 | 58±14 | .29 |
Duration of treatment, mean days ± SD | 57±16 | 49±6 | 53±13 | .06 |
Disorder | | | | .12 |
Unspecified immunodeficiency | 26 (83.9) | 18 (60.0) | 44 (72.1) | |
Cancer | 3 (9.7) | 7 (23.3) | 10 (16.4) | |
Type I allergy | 1 (3.2) | 3 (10.0) | 4 (6.6) | |
Rheumatoid arthritis | 0 | 1 (3.3) | 1 (1.6) | |
Furuncles | 1 (3.2) | 0 | 1 (1.6) | |
Viral infection | 0 | 1 (3.3) | 1 (1.6) | |
|
Values are expressed as number (%) unless otherwise noted.
*χ2 test for binomial data, and Mann-Whitney-U test for continuous data.
Table 3. Blood Counts Before and After Supplementation With Megamin® and Lycopenomin®
|
| Normal | Megamin (n=31) | Lycopenomin (n=30) | Change Between |
Blood Count* | Range | Baseline | Final | P value* | Baseline | Final | P value* | Groups, P value* |
|
|
|
|
|
|
|
|
|
Hb, mmol/L | 7-10 | 8.4 | 8.4 | .62 | 8.3 | 8.2 | .46 | .70 |
| | (7.8-8.9) | (7.7-9.1) | | (7.3-8.7) | (7.5-8.9) | | |
Hc, % | 35-50 | 40 | 41 | .09 | 40 | 40 | .31 | .54 |
| | (39-43) | (38-44) | | (37-42) | (36-43) | | |
WBC, Gpt/L | 4-10 | 6.60 | 6.30 | .11 | 5.70 | 5.35 | .03 | .70 |
| | (5.60-7.50) | (5.25-7.20) | | (4.80-7.10) | (4.13-6.25) | | |
PLT, Gpt/L | 100-350 | 234 | 243 | .33 | 222 | 209 | .99 | .53 |
| | (197-264) | (197-262) | | (176-258) | (190-259) | | |
RBC,Tpt/L | 4-5 | 4.50 | 4.60 | .26 | 4.35 | 4.35 | .89 | .52 |
| | (4.25-4.85) | (4.25-4.80) | | (4.13-4.70) | (4.03-4.68) | | |
MCH, fmol/L | 1.6-1.9 | 1.90 | 1.90 | .73 | 1.80 | 1.90 | .48 | .29 |
| | (1.80-1.90) | (1.80-1.90) | | (1.80-1.90) | (1.80-1.90) | | |
MCHC, mmol/L | 20.0-22.5 | 20.6 | 20.4 | .08 | 20.5 | 20.5 | .20 | .87 |
| | (20.4-21.0) | (20.0-20.9) | | (19.9-21.0) | (19.9-20.9) | | |
MCV, fL | 85-95 | 90.0 | 91.0 | .09 | 91.0 | 91.0 | .004 | .46 |
| | (86.5-93.5) | (87.5-93.5) | | (87.3-93.0) | (88.3-93.0) | | |
|
Values are given as medians (percentiles 25-75). Between-group comparisons analyzed baseline-final differences.
*Within group comparisons: Wilcoxon test; between groups comparisons: Mann-Whitney-U test
Hb=hemoglobin; Hc=hematocrit; WBC=white blood cells; PLT==platelets; RBC=red blood cells; MCH=mean corpuscular Hb;
MCHC=mean corpuscular Hb concentration; MCV==mean corpuscular volume.
Table 4. Relative and Absolute Lymphocyte Counts Before and After Supplementation with Megamin® and Lycopenomin®
|
Lymphocyte |
Normal |
Megamin (n=31) |
Lycopenomin (n=30) |
Change Between |
Count* |
Range |
Baseline |
Final |
P value* |
Baseline |
Final |
P value* |
Groups, P value* |
|
|
|
|
|
|
|
|
|
Total,Gpt/L |
1.0-3.6 |
1.73 (1.57-2.02) |
1.78 (1.39-2.17) |
.74 |
1.11 (0.85-1.54) |
1.13 (0.95-1.43) |
.59 |
.45 |
CD3+, % |
62-86 |
67.0 (60.5-72.5) |
69.0 (61.0-75.0) |
.03 |
65.0 (56.3-72.5) |
65.5 (613-77.8) |
.005 |
.62 |
CD19+, % |
7-23 |
10.0 (8.0-14.0) |
12.0 (10.0-14.0) |
.009 |
10.0 (7.0-14.0) |
10.0 (8.0-14.8) |
.27 |
.17 |
CD4+, % |
31-59 |
41.0 (35.0-52.0) |
44.0 (39.5-52.0) |
.008 |
41.5 (35.0- 49.0) |
43.5 (38.3-50.0) |
.02 |
.99 |
CD8+, % |
19- 48 |
23.0 (18.5-31 .5) |
24.0 (18.5-31.5) |
.32 |
22.0 (17.0-33.5) |
21.0 (17.3-33.0) |
.23 |
.94 |
CD4+/CD8+ |
0.9- 1 .8 |
1.60 (1.20-2.85) |
1.70 (1.40- 2.75) |
.37 |
2.10 (1.20-2.80) |
2.0 (1.13-2.75) |
.48 |
.82 |
HLA-DR+, % |
9-16 |
9.0 (8.0- 13.0) |
10.0 (8.0-15.5) |
.002 |
12.0 (8.0-1 7.8) |
10.0 (8.3-16.0) |
.64 |
.02 |
CD56+, % |
5-26 |
25.0 (19.0-31.5) |
22.0 (22.0-43.0) |
.008 |
27.5 (16.8-35.3) |
20.5 (16.5-28.3) |
.005 |
.42 |
CD3+/ cells/μl |
1200-1790 |
1343 (1074-1590) |
1383 (1252-1700) |
.06 |
871 (683-1108) |
974 (789-1177) |
.13 |
.84 |
CD19+, cells/μl |
150-480 |
227 (124-304) |
243 (172-359) |
.005 |
134 (80-249) |
156 (100-266) |
.24 |
.14 |
CD4+, cells/μl |
590-1200 |
825 (682-1072) |
950 (740-1099) |
.05 |
543 (410-836) |
589 (500-812) |
.03 |
.78 |
CD8+, cells/μl |
400-1010 |
450 (361-602) |
446 (383-638) |
.09 |
329 (223-400) |
359 (268-419) |
.63 |
.39 |
HLA-DR+, cells/μl |
40-300 |
209 (163-243) |
222 (171-322) |
.01 |
179 (137-206) |
163 (116-234) |
.77 |
.02 |
CD56+, cells/μl |
110-550 |
512 (390- 599) |
430 (337-615) |
.08 |
363 (263-546) |
354 (188-504) |
.005 |
.55 |
|
Values are given as medians (percentiles 25-75). Between-group comparisons analyzed baseline-final differences.
*Within group comparisons: Wilcoxon test; between groups comparisons: Mann-Whitney-U-test.
CD=Clusters of Differentition; HLA=Human Leukocyte Antigen
Six to 8 weeks of supplementation therapy did not relevantly affect the blood
counts in either of the 2 treatment groups (Table 3). Among patients given Megamin,
the CD4+, CD19+, and HLA-DR+ lymphocyte counts were significantly increased
over baseline values, whereas the CD56+ cell count was significantly decreased.
Among those given Lycopenomin, the CD3+ cell count was significantly increased
over baseline and the CD56+ lymphocyte count was also significantly decreased. In
general, the relative lymphocyte counts corresponded with the absolute cell counts
(Table 4).
No adverse reactions to treatments were observed.
DISCUSSION
To our knowledge, this is the first prospective clinical study of the effects of oral
supplementation with the natural zeolite clinoptilolite on the immune system of
patients with an immunodeficiency disorder. In this population, 6 to 8 weeks of therapy
did not cause relevant changes in blood counts. This finding is in accordance
with data from a toxicology study in which mice had been fed a clinoptilolite-rich
diet for 6 months.22 Indeed, clinoptilolite supplementation produced significant and
relevant increases in the B lymphocyte (CD19+), T-helper cell (CD4+), activated
T lymphocyte (HLA-DR+), and, to a lesser extent, total T lymphocyte (CD3+) counts
and decreases in the NK cell (CD56+) count. The clinical relevance of these findings
is supported by the improved well being reported by the patients (data not shown)
who underwent clinoptilolite supplementation therapy. The effects of supplementation,
particularly on the activated T lymphocyte count, were more pronounced in
the Megamin group than in the Lycopenomin group.
Patients given Lycopenomin exhibited significantly lower total lymphocyte counts
at baseline than did patients given Megamin, which is why they were assigned the
more powerful antioxidant. The TMAZ doses administered with Megamin were three
times higher than those taken with Lycopenomin (3.6 vs 1.2 g daily). Hence, the more
pronounced effects in the Megamin group may be attributed to a dose-response relationship
of the zeolite, although the results are not adjusted for baseline differences in
severity of illness between groups. In addition, the contribution of Lycopenomin's
other antioxidants to the net effects was not addressed or examined. Moreover,
it remains unclear whether 6 to 8 weeks of treatment is sufficient to achieve the maximal
effect. The results of other studies that have investigated drug-induced
immunomodulation suggest that more-significant effects may be realized beyond two
months of treatment.23 Thus, future studies should include a 4- to 6-month treatment
period and employ repeated measurements.
In this study, because the patient population did not alter their primary therapy
for the treatment of their immunodeficiency disorder, the observed treatment effects
can likely be attributed to the Megamin and Lycopenomin supplements. Although
no adjustments were made for type 1 error, the number of statistically significant test
results suggests these effects are beyond chance. Obviously, these effects must be
examined further in a suitably sized, randomized placebo-controlled trial.
Although an immunomodulatory effect of natural zeolite has been clinically
demonstrated, its mode of action must still be elucidated. After ingestion, clinoptilolite
is resistant to degradation by gastric and intestinal juices, and its major constitutive
elements are not significantly absorbed from the gut into systemic circulation. No
traces of silicon have been detected in the serum of Wistar rats or CBA mice fed with
clinoptilolite. Zeolite particles, however, have been found in the first and second layers
of duodenal cells.2 The interaction of orally administered zeolite particles with
mucosal associated intestinal lymphoid tissue may trigger an immune response similar
to the one observed after the intraperitoneal administration of micronized zeolite.
In both cases, the number of peritoneal macrophages, as well as their superoxide
anion (O2-) production, is increased, while NO production is
decreased.21 Resident
macrophages in the airways and alveolar spaces have also been observed to release
reactive oxygen species, such as O2-, after phagocytosis of inhaled silica particles.
Reactive oxygen species have been found to be important second messengers for
signal transduction in general,24 and alterations in the redox
homeostasis of cells may
play an important role in modulating immune functions. For example, transmembrane
redox signaling activates nuclear factor kappa B (NFκB) in macrophages and
T lymphocytes.25,26 NFκB is involved in the activation of a large number of genes in
response to inflammation, viral and bacterial infections, and other stressful conditions
that necessitate rapid reprogramming of gene expression.
In addition, direct interactions of silicate particles with alveolar cells have been
observed that may enhance the understanding of the immunostimulation provided
by orally administrated zeolite. It seems that mineral particles can trigger alterations
in gene expression by initiating signaling events upstream of gene transactivation.27
The exposure of alveolar macrophages to silicate particles can also activate mitogenactivated
protein kinases, stress-activated protein kinase, and protein kinase C.28
Important transcription factors such as activator protein 1 and NFκB are also activated,
and the expression of proinflammatory cytokines such as interleukin 1α,
interleukin 6, and TNF-α is enhanced.29
Macrophage activation and the subsequent initiation of intracellular signaling pathways,
together with the polyclonal human T-lymphocyte activation observed in vitro,
have led to the hypothesis that silicate particles act as SAgs.16
If this hypothesis can be
confirmed, dietary supplementation with natural zeolites holds promise in the treatment
of autoimmune disorders and infectious and malignant diseases, the pathogenesis
of which is linked to the action of SAgs.30-32 Zeolite supplementation therapy has
demonstrated other antitumor effects in in vitro and animal studies and may prove
beneficial as an adjunct to cancer therapy.33,34
CONCLUSION
Accumulating evidence from preclinical studies and the first human trials suggests
oral zeolite supplementation therapy is associated with significant
immunomodulatory effects that can enhance the primary treatment of a variety of
immunodeficiency disorders. Further research is necessary to clarify the proposed
mechanisms of action of the zeolite compounds and to confirm the promising results
observed in this pilot study.
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