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Research Article Open Access
Beneficial effects of a Fermented Papaya Preparation for the
treatment of electrohypersensitivity self-reporting patients: results
of a phase I-II clinical trial with special reference to cerebral
pulsation measurement and oxidative stress analysis
Irigaray Philippe1, Garrel Catherine2, Houssay Carine1, Mantello Pierre3, Belpomme
1European Cancer and Environment Research Institute (ECERI), Brussels, Belgium; 2Pathology
and biology institute, Centre Hospitalier Universitaire, Grenoble, France; 3Osato Research
Institute, Gifu, Japan; 4Paris V University Hospital, France
Corresponding author: Belpomme Dominique, European Cancer and Environment Research
Institute (ECERI), Brussels, Belgium
Submission Date: November 23rd, 2017, Acceptance Date: February 25th, 2018, Publication
Date: February 28th, 2018
Citation: Philippe I., Catherine G., Carine H., Pierre M., Dominique B. Beneficial effects of a
Fermented Papaya Preparation for the treatment of electrohypersensitivity self-reporting patients:
results of a phase I-II clinical trial with special reference to cerebral pulsation measurement and
oxidative stress analysis. Functional Foods in Health and Disease 2018; 8(2):122-144.
Background: Electromagnetic Field Intolerance Syndrome (EMFIS), also termed Idiopathic
Environmental Intolerance (IEI) attributed to Electromagnetic Fields (IEI-EMF) by WHO, is a
newly identified pathological disorder occurring in electrohypersensitivity (EHS) self-reporting
patients. To date, there has been no recognized treatment of this disorder. We have shown that
EHS self-reporting patients experience some degree of oxidative stress, inflammation, and
autoimmune response. Additionally, Fermented Papaya Preparation (FPP) has some antioxidant,
anti-inflammation, and immuno-modulating properties. The objective of this phase I-II clinical
trial was thus to test whether FPP treatment is well tolerated, can improve clinical outcomes, and
can normalize biological abnormalities.
Methods: 32 EMFIS-bearing patients were serially included in this trial, among which 26 and 16
of them were evaluable after 3 and 6 months of FPP treatment, respectively. Clinical assessment
was conducted during a specific face to face interview by using a validated pre-established
questionnaire. Biological assessment consisted of measuring intracerebral tissue pulsometric
index (PI) in the temporal lobes with ultrasonic cerebral tomosphygmography (UCTS), in
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 123 of 144
addition to oxidative stress and inflammation with a battery of oxidative stress and
inflammation-related peripheral blood tests.
Results: Overall, clinical improvement was obtained in 50-60% of the cases, among which 20-
35% presented major improvement that mainly consisted of the regression of cognitive
symptoms such as loss of short term memory, concentration, attention deficiencies, insomnia,
and fatigue. This clinical improvement was objectively supported by a statistically significant
normal recovery of mean PI in the temporal lobes and by a FPP-related antioxidative effect,
evidenced by a statistically significant decrease in malondialdehyde levels in the plasma
(p<0.0001) and increase in the Glutathione peroxidase activity in red blood cells (p<0.01) in
patients experiencing oxidative stress. Moreover, this trial evidenced some degree of FPP-related
anti-inflammatory effects by demonstrating a statistically significant decrease in histamine
(p=0.049) and HSP27/HSP70 chaperone proteins (p=0.007) in the peripheral blood of patients
with initial increased values of these inflammation-related biomarkers.
Conclusion: The results suggest a beneficial clinical and biological therapeutic effect of FPP in
EHS self-reporting patients. However, the precise underlying mechanism has not yet been
Electromagnetic Field Intolerance Syndrome (EMFIS) is a new, emerging clinical disorder that
has also been termed “idiopathic environmental intolerance (IEI) attributed to electromagnetic
fields” (IEI-EMF) by the World Health Organization (WHO) . This new pathological
disorder, which occurs in so called electrohypersensitivity (EHS) self-reporting patients, has
been shown to be associated with clinical symptoms such as headache, tinnitus, hyperacusis,
superficial and/or deep sensibility abnormalities, skin lesions, fibromyalgia, vegetative system
dysfunction, and reduced cognitive capability. All symptoms reported by these patients occur
each time they are exposed to EMFs fields, which may result in chronic insomnia, fatigue,
irritability, and depressive tendencies [2-6].
Recently, we clinically identified and biologically characterized this new disorder by
showing that it is associated with a decrease in intracerebral tissue pulsations in the temporal
lobes. In addition, there were several biological abnormalities in the peripheral blood, reflecting
varying degrees of oxidative stress, inflammation, and autoimmune response. This led us to
hypothesize that these processes may account for blood brain barrier (BBB) opening and
decrease in brain blood flow (BBF) in the temporal lobes of these patients .
Fermented Papaya Preparation (FPP) is a recent biotechnology product resulting from yeast
fermentation of the non-genetically modified medicinal plant Carica Papaya Linn, which was
initially developed by Osato Research Institute in Japan and is currently marketed as a 100%
natural dietary functional health supplement under the brand name Immun’Âge® in Europe,
Asia, and the United States .
FPP has been shown to possess some anti-oxidant, anti-inflammatory, and immune-
modulating properties in several pathological conditions [8-11], including neurodegenerative
disorders . This prompted us to test FPP in EMFIS-bearing patients, (i.e. in so called EHS
self-reporting patients, in the framework of a prospective phase I-II clinical trial to demonstrate
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 124 of 144
whether FPP is well tolerated, can improve clinical outcome, and can normalize biological
abnormalities). In this trial, we paid special attention to the measurement of intracerebral tissue
pulsometric index (PI) in the temporal lobes by using ultrasonic cerebral tomosphygmography
(UCTS) before and after FPP treatment. Additionally, we analyzed the FPP effects on oxidative
stress and inflammation by measuring a series of biomarkers in the peripheral blood of these
MATERIALS AND METHODS
In this study, we clinically defined EMFIS on the basis of five criteria: (1) Absence of known
pathology accounting for the observed clinical symptoms; (2) Reproducibility of symptoms
under the influence of EMFs, regardless of the incriminated source (radio-frequencies and/or
hyper frequencies or low and/or extremely low frequencies); (3) Regression or disappearance of
clinical symptoms in the case of EMF avoidance; (4) Clinical symptoms compatible with those
previously reported in EHS self-reporting patients in the scientific literature; and (5) Chronic
evolution of symptoms [4-7].
Therefore, before inclusion in this study, all patients had a general and neurological clinical
examination and a systematic general biological check-up to exclude any EMFIS-non related
pathology. Thus, to be included in the trial, patients should have a normal carotidian and
vertebral echodoppler, a normal magnetic resonance imaging (MRI) or computed tomography
(CT) scan before inclusion, and normal blood tests that are currently used, in particular
hematologic, hepatic, and renal tests. Moreover, patients should be between 18 and 75 years old,
have a body mass index between 18.5 and 25, normal peripheral blood pressure, normal fasting
glycemia, no gluten and/or lactose/casein intolerance, and no multiple chemical sensitivity
Additionally, all patients should have no history of pathologies such as cancer, Alzheimer
disease, type II diabetes, and/or cardiovascular disease, and should be in a clinical active phase
of EMFIS, (i.e. with grade 2 or 3 clinical symptoms according to the grading scale system we
used - see the section “evaluation”) whether they have been treated or not treated previously.
However, since clinical symptoms in so called EHS patients are mainly subjectively-
expressed, we used two additional biological inclusion criteria to characterize objectively EMFIS
bearing patients: (1) a mean low tissue PI measured in areas of at least one temporal lobe by
using UCTS (since as we have previously reported, in EHS self-reporting patients there is a low
mean tissue PI in several areas of temporal lobes ) and (2) increase of at least one of three
peripheral blood biomarkers we have previously identified as being possibly associated with
EHS : Increased histamine, a mediator of inflammation ; increased protein S100B, a
marker of oxidative stress-related BBB opening [14-15]; and increased chaperone proteins
Hsp27 and/or Hsp70, markers of heat-shock cell stress-associated inflammation and/or immune
response [16-17] (see Table 1).
This study was agreed to by the ECERI Scientific/Ethical advisory committee and was
conducted according to currently accepted ethical guidelines, including informed written consent
approval which was signed by all patients prior to the study. This non-invasive investigation has
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 125 of 144
been also registered in the European Clinical *Trials* Database (*EudraCT*) under the
registration number 2017-003937-27.
FPP Treatment and Study design
FPP was supplied by Osato research institute as sachets containing 4.5 grams of powder, one
sachet being administered twice a day, morning and evening, according to the currently
recommended use of this marketed product. In this study, FPP was administered during a 6-
month period. The FPP components have been previously reported  (see discussion).
The study was an open prospective case-crossover phase I-II trial, each patient serving as its
own control over time. A minimum of one-month washout period between the inclusion time
(Ti) and therapeutic protocol initiation (T0) was used in the case of previously treated patients in
order to avoid any bias due to an eventual backward effects of pre-inclusion treatments.
Additionally, patients were asked to maintain their usual lifestyle in order to avoid any
confounding factors which may have modified their clinical symptoms during the study period.
Their ordinary diet, physical activity, regular living behavior and working activity were
systematically recorded and carefully analyzed during the study quality assurance process.
Accordingly, any eventual modification should have been negligible for each included case to be
Patients were serially investigated clinically and biologically at Ti and T0 and after the 3-month
(T3) and 6-month treatment (T6). Clinical assessment was conducted systematically at T3 and
T6 in comparison with T0 during a specific face to face interview by using a validated pre-
established questionnaire and a complete clinical examination. The evaluation included FPP
tolerance and clinical effects on EMFIS symptoms. Clinical assessment was performed using a
symptomatic grading scale system: Grade 0 -no symptoms; Grade 1 - mild and/or transitory
symptoms; Grade 2 - intensive or permanent symptoms; and Grade 3 - intensive and permanent
symptoms. A shift from Grade 2-3 to Grade 0 was considered a "major" symptomatic
improvement, while a shift from Grade 3 to Grade 2 or from Grade 2 to Grade 1 was categorized
as a "minor" improvement. Overall clinical response at T3 or T6 was assessed in comparison
with T0 by using the following grading system: "Complete response" (CR): disappearance of all
symptoms (i.e. Grade 0); "Partial response" (PR): persistence of Grade 1 symptoms; "Stable" (S):
no change; and "Failure" (F): increase of Grade 2 or 3 symptoms.
A complete biological evaluation was conducted at T3 and/or T6 in comparison with Ti or
T0. This included a new PI measurement at T3 or T6 by UCTS for comparison with that of Ti; at
T3 and T6 a new dosage of EMFIS-associated inflammation-related biomarkers in the peripheral
blood (i.e. histamine, protein S100B, chaperone proteins Hsp27 and Hsp70) for comparison with
Ti; and at T3 and T6 a new dosage of oxidative stress-related biomarkers for comparison with
Ultrasonic cerebral tomosphygmography
After intracranial pulsation measurements were pioneered in the USA , UCTS was
standardized and developed in France [19-20]. In this study, we rehabilitated this former
intracerebral tissue-related ultrasonic technique to measure precise PI in the two temporal lobes
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 126 of 144
because our preliminary clinical data have revealed that patients complaining with EHS most
often have cognitive defects such as loss of short term memory, attention, and concentration
deficiencies, in addition to frequent auditory and olfactory abnormalities. The UCTS technique
has been documented in our previous article . UCTS consists of a non-invasive computerized
technique that enables measurement of mean tissue PI by centimeter-thick sections of the
temporal lobes from the cortex to the middle line of the brain through using the emission of 2
MHz pulsed ultrasonic waves at different intensity levels from a transmitting ultrasonic source
(see Fig 1), in addition to the analysis of the reflection of these ultrasonic waves on the different
neurologic and vascular tissue structures in the temporal lobe, particularly the red blood cells
(RBC) in capillaries of the vascular network of the middle cerebral artery (MCA) .
Figure 1. Schematic diagram showing the different MCA-dependent areas individualized in the
temporal lobes for the measurement of mean PI by using UCTS according to Parini et al. .
The addition of the mean PI value obtained at the 3rd cm from the cutaneous cranial surface to the
mean PI value obtained at the 4th cm corresponds to the cortical/sub-cortical area. The addition
of the mean PI values obtained from the 3rd cm to the 5th cm corresponds to the superficial area
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of the MCA. The addition of the mean PI values obtained from the 5th cm to the 7th cm, to the
deep area of MCA and the mean PI value obtained at the 7th cm, corresponds to the capsulo-
thalamic area. The addition of values obtained from the 3rd cm to the 7th cm corresponds to the
MCA dependent carotidian area. Finally, the addition of values obtained from the 8th cm to the
9th cm corresponds to the vertebro-basilar area.
Mean PI values corresponding to the different temporal lobe territories investigated were
directly recorded by the standard UCTS equipment we used. In fact, it has been previously
shown that the mean physiological PI values determined in the six temporal lobe tissue territories
have been individualized differ from each other (see Fig 1). Since these different tissue territories
were shown to correspond to different brain structures they have been termed respectively from
the temporal lobe cortex to the brain middle line: carotidian, cortical-subcortical, superficial
sylvian (or superficial MCA), deep sylvian (or deep MCA), capsulo-thalamic, and vertebro-
basilar according to the main neurologic or vascular cerebral structure they are associated with,
the so called carotidian territory corresponding to all the measured areas except the vertebro-
As a result, by using UCTS we were able to measure mean PI in each of the different tissue
territories investigated in all patients. In our previous ground-breaking publication, mean PI
values were determined in 727 EHS and/or MCS patients and compared to a series of normal
historical controls that have been used for the determination of the physiological mean PI
reference values in each of the six individualized temporal lobe territories . This allowed us
to demonstrate that in comparison to normal subjects, cerebral pulsatility in patients with self-
reporting EHS decreased or was even completely suppressed in several tissue areas in one or the
two temporal lobes, most often in the capsulo-thalamic area, suggesting that within these
territories BBF may be decreased in EHS and/or MCS patients .
Therefore, in the present study we used UCTS at Ti, T3, and/or T6 to measure PI in the
temporal lobes before and after FPP administration to examine whether FPP is able to restore
Inflammation- and oxidative stress-related biomarkers
One of the objective of this study was to measure inflammation and oxidative stress-related
biomarkers in the peripheral blood of EMFIS-bearing patients before and after FPP treatment to
demonstrate possible FPP anti-inflammatory and anti-oxidative stress effects.
Venous whole blood sampling was performed at Ti, T0, T3, and T6 in laboratory "Labo XV" in
Paris. EHS-related biomarkers were measured in this laboratory on serum, with the exception of
histamine, which was measured on plasma after a whole blood collection on lithium heparinate.
For oxidative stress-related biomarkers, whole blood was also collected on lithium heparinate
and frozen immediately at -80°C before samples were sent to Laboratory Equinox, an academic
research laboratory specialized in oxidative stress measurement and analysis in the University
Hospital of Grenoble (France).
The methods of measurement of the inflammation-related biomarkers we used in this study have
already been published . Tests and methods are indicated in Table 1. For histamine we used an
ELISA specific test (Histamine ELISA RE59221 from IBL International GmbH)  and for
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protein S100B a quantitative automated chemiluminescent immunoassays (Liason S100 from
DiaSorin Deutschland GmbH) ; for the chaperone protein Hsp27 we used a quantitative
sandwich ELISA assay test (Assay Designs™ Hsp27 ELISA kit) , and for the chaperone
protein Hsp70 an Enzyme Immunometric Assay test (Assay Designs™ Hsp70 High Sensitivity
Enzyme Immunometric Assay kit) . All tests were performed using commercially available
reagents, each patient value being compared to the normal reference value obtained from the
commercial companies. Sensitivity, specificity, and reproducibility of the tests were in
agreement with those provided by the companies. All assays were completed according to the
recommended manufacturer’s method.
Table 1. Investigated Inflammation-related biomarkers, and oxidative and antioxidative stress-
Total thiol group
MDA, Malondialdehyde; TBARs, Thiobarbituric acid reactive substances; GSSG, oxidized
glutathione; GSH, Reduced Glutathione; TAS, Total antioxidant status; SOD, Superoxide
dismutase; GR, Glutathione Reductase; GPx, Glutathione Peroxidase; RBC, red blood cells.
Oxidative and antioxidative stress-related biomarkers
We used a battery of tests to measure oxidative stress biomarkers and anti-oxidative non-
enzymatic and enzymatic proteins in plasma and/or RBC before and after FPP treatment (Table
1). Measurements were completed after centrifugation (4000 g, 10 min, 4°C) to separate RBC
from plasma. Normal reference values obtained for each biomarker we used in this study were
pre-determined from the analysis of a series of 123 normal subjects.
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Oxidative stress biomarkers
For oxidative stress assessment we measured the three following markers in the plasma:
malondialdehyde (MDA), all thiobarbituric acid (TBA), reactive substances (TBARS), and total
thiol group proteins.
For measuring MDA, we used its reaction with TBA. The MDA-TBA complex was then
separated from interfering substances and specifically identified by using reverse-phase HPLC
coupled with a UV/visible detection. In fact, MDA was quantified on the basis of its strong light-
absorbing and fluorescing property following its reaction with TBA. Results were expressed in
µmoles per liter (µM) . For the dosage of lipid peroxidation intermediates we measured all
plasma TBARS such as MDA by using a modification of the method of Ohkawa et al. . This
method is based on the reaction of the aldehyde function of TBARS with TBA to form a
TBARS-TBA colored complex which was quantified by fluorometry. Results were expressed in
µM. For the dosage of total thiol (SH) group proteins, we used 5, 5’- dithio-bis(2-nitrobenzoic
acid) (DTNB) as reagent and measured the level of plasmatic SH group spectrophotometrically
at 412 nm. Results were expressed in Unit per liter (U/l) .
Antioxidative non-enzymatic proteins
The dosage of reduced glutathione (GSH) and oxidized glutathione (GSSG) in the plasma was
done according to the method of Akerboom and Sies . Briefly, before centrifugation (400g,
10 min, 4°C), 400 µl of whole blood were collected in 3.6 ml of metaphoric acid. After
centrifugation, total glutathione and GSH were measured enzymatically in the acidic protein-
free-supernatant. The assay of GSSG was performed after having masked GSH by adding 2-
vinylpyridine to the deproteinized extract. As for the total glutathione and GSH GSSG was
measured enzymatically. Results were expressed in µM.
Finally, measurement of the total antioxidant status (TAS) in the plasma was done by a
colorimetric method using a randox kit (Randox Total Antioxidant Status, NX2332, Randox
laboratory). Results were expressed in µM .
Antioxidative enzymatic proteins
Measurement of antioxidative enzymes was done in RBC or both in RBC and plasma. For
measuring Cu-Zn superoxide dismutase (SOD) activity in RBC we used the method described by
Marklund and Marklund , which consists of a simple and rapid test based on the ability of
SOD to inhibit the autoxidation of pyrogallol. Indeed, at pH 7.9 the reaction is inhibited by SOD,
indicating the almost total effect of SOD on the superoxide anion radical, 02°-, in the reaction. In
this method, the rate of pyrogallol auto-oxidation was determined spectrophotometrically from
the increase in absorbance at 420 nm; one unit of SOD activity being defined as the amount of
the enzyme required to inhibit the rate of pyrogallol auto-oxidation by 50%. Results were
expressed in Unit/mg hemoglobin (U/mg Hb). For the dosage of Glutathione reductase (GR), we
used a colorimetric method from a randox kit (GR2368 from Randox laboratory). Results were
expressed in Unit/gram of hemoglobin (U/g Hb) for RBC GR, and Unit per liter (U/l) for
plasmatic GR . Additionally, Glutathione peroxidase (GPx) activity was measured in RBC
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and plasma using a method derived from Gunzler et al. . The GPx assay was based on the
oxidation of NADPH to NADP+, which is accompanied by a decrease in absorbance at 340nm.
The rate of this decrease is directly proportional to the GPx activity in the sample. GPx activity
was then evaluated in nmoles per liter (nM) of NADPH oxidized per min and the results were
expressed in Unit/gram of hemoglobin (U/g Hb) for RBC GPx and in Unit per liter (U/l) for
The design of this study was a case-crossover clinical trial, which consisted of a within group
comparison between the data obtained before and after the treatment.
Clinical assessment before and after FPP treatment was described as the following. Major
and minor symptomatic improvements in addition to the overall response rates were established
according to the clinical criteria previously defined in section “evaluation.”
We used three different statistical tests: (1) the Chi-squared test of independence for
comparison between the percentages of patients for the symptomatic (Tables 2 and 3) and
biomarker assessment (Table 6); (2) the Fisher exact test followed by the two-tailed Student’s t-
test for comparison between the values obtained from two groups under comparison, such as the
mean PI values relative to the mean normal control values (Table 5), or between the values
obtained for the different oxidative stress-related biological parameters obtained from the
patients with or without oxidative stress (Table 8); and (3) the Wilcoxon signed-rank test, as we
hypothesized our data were not in agreement with a normal distribution for a within group
comparison between the different values obtained at time measurement, such as for PI (Table 5)
or biomarker analysis (Tables 7 and 9).
All statistical analysis was conducted using the XLSTAT software.
Of the 32 patients that were included, 26 were evaluable both for clinical symptoms and
biological tests at T3. 5 cases were lost in the follow-up period between Ti and T3 and 1 case
was not evaluable. At T6 18 patients were evaluable, 4 cases being excluded from the protocol at
T3 due to failure and 4 other cases being lost in the follow-up period between T3 and T6.
In this study, all evaluable patients tolerated FPP well. Tables 2, 3, and 4 summarize our clinical
Major symptomatic improvement at T3 was obtained in 20-40% of the cases for loss of short
term memory, impaired concentration/attention, insomnia, and fatigue. In contrast, there was
improvement in only 5-15% of cases for depressive tendencies and for neurologic symptoms,
such as headache, tinnitus, and dysesthesia. However, if we include the minor improvement, the
total symptomatic improvement reaches about 30-60% of the cases, depending on the type of
symptoms analyzed, which persists at T6 for those patients who reached 6 month FPP treatment
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Table 2. Symptomatic evaluation at T3 and T6 in comparison with T0
2/26 (7.7 %)
12/26 (46.2 %)
14/26 (53.9 %)
8/18 (44.4 %)
11/26 (42.3 %)
7/26 (26.9 %)
18/26 (69.2 %)
14/18 (77.8 %)
10/26 (38.5 %)
6/26 (23.1 %)
16/26 (61.5 %)
14/18 (77.8 %)
Loss of short term memory
5/26 (19.2 %)
9/26 (34.6 %)
14/26 (53.8 %)
10/18 (55.6 %)
7/26 (26.9 %)
6/26 (23.1 %)
13/26 (50 %)
11/18 (61.1 %)
2/26 (7.7 %)
7/26 (26.9 %)
9/26 (34.6 %)
7/18 (38.9 %)
5/26 (19.2 %)
7/26 (26.9 %)
12/26 (46.2 %)
7/18 (38.9 %)
3/26 (11.5 %)
7/26 (26.9 %)
10/26 (38.5 %)
14/18 (77.8 %)
2/26 (7.7 %)
8/26 (30.8 %)
10/26 (38.5 %)
11/18 (61.1 %)
This was confirmed in Table 3, which shows the percentages of patients with symptoms at
T3 and T6 in comparison with T0 are statistically significantly decreased for each symptom
analyzed (p < 0.0001).
Table 3. Evolution of the percentage of symptomatic patients at T3 and T6 in comparison with
T0 for each symptom analyzed.
Percent of patients with symptoms
Loss of short term memory
*p values relative to T0 values were calculated using the Chi-square test of independence.
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Finally, a complete or partial clinical response was obtained at T3 in 14 of the 26 evaluable
cases which resulted in an overall response rate of 53.8% (Table 4).
Table 4. Overall clinical response rates after 3 month FPP treatment (T3) in the 26 evaluable
Number of patients
6/32 (18.8 %)
26/32 (81.2 %)
3/26 (11.5 %)
14/26 (53.8 %)
11/26 (42.3 %)
8/26 (30.8 %)
12/26 (46.2 %)
4/26 (15.4 %)
As indicated in Table 5 and Fig 2, we confirmed that by using UCTS at Ti there was a
statistically significant decrease in mean PI in the capsulo-thalamic area of both temporal lobes
and in the deep MCA area and the vertebro-basilar area of the right and left temporal lobe
respectively. On the other hand, there was a statistically significant increase in the cortical-
subcortical and superficial MCA areas in both temporal lobes. At T3/T6, we find a statistically
significant recovery of normal mean PI in comparison to Ti for the capsulo-thalamic area of both
temporal lobes, and for the deep MCA area and the vertebro-basilar area of the right and left
temporal lobe respectively. Accordingly, with the exception of the vertebro-basilar area of the
right temporal lobe which shows no PI recovery, all tissue areas for which there was a decreased
mean PI value at Ti recovered at T3/T6 a statistically significant normal mean PI value after FPP
treatment. In contrast, for all the other explored temporal areas with a normal or increased mean
tissue PI value at Ti, mean PI values at T3/T6 were statistically significantly increased.
Table 5. Mean PI values (+/-SD) measured in the different MCA dependent tissue territories in
the two temporal lobes. Effect of FPP treatment at T3/T6 in comparison with Ti.
11.60 +/- 2.80
22.52 +/- 5.26
1.5 +/- 0.5
4.89 +/- 2.31*
8.61 +/- 3.46
5 +/- 1
6.88 +/- 2.70*
12.86 +/- 4.10
12 +/- 2
6.69 +/- 2.20 **
13.91 +/- 3.10
5 +/- 1
2.02 +/- 0.86 **
5.28 +/- 1.63
9 +/- 1
8.87 +/- 1.59
9.15 +/- 2.37
9 +/- 1
4.79 +/- 2.86**
9.70 +/- 2.79
5 +/- 1
3.46 +/- 1.68**
4.77 +/- 2.03
12 +/- 2
10.12 +/- 2.67
13.42 +/- 3.40
5 +/- 1
8.48 +/- 3.30*
13.16 +/- 3.03
1.5 +/- 0.5
5.18 +/- 2.33*
9.21 +/- 2.25
15.30 +/- 4.00
22.63 +/- 4.40
SD, Standard deviation; Ti, Inclusion time; T3, UCTS assessment after 3 month treatment from the date
of treatment initiation (T0); T6, UCTS assessment after 6 month treatment from T0.
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*Mean PI values at Ti relative to normal reference values are statistically significantly increased using the
Fisher exact test followed by the two-tailed Student’s t-test (p< 0.001) for the superficial MCA and
cortical-subcortical areas of the right and left temporal lobes.
** Mean PI values at Ti relative to normal reference value are statistically significantly decreased using
the Fisher exact test followed by the two-tailed Student’s t-test. The difference is statistically significant
at p<0.0001 for the capsulo-thalamic area and the deep MCA area of the right temporal lobe and for the
vertebro-basilar area of the left temporal lobe, while being p<0.01 for the capsulo-thalamic area of the left
*** D% is calculated according to ((t3/t6 – ti) / ti) x 100, where t3/t6 and ti are mean PI values at T3/T6
and Ti. It corresponds to the percent mean value change between T3/T6 and Ti.
****p values for comparison between mean PI values obtained at T3/T6 and Ti were calculated using the
Wilcoxon signed-rank test.
Figure 2. Mean PI values recorded by UCTS in the different territories of each temporal lobe
investigated at T3/T6 in comparison with Ti.
(A) Right temporal lobe. (B) Left temporal lobe. White columns correspond to mean values +/- standard
error (SE) at Ti and black columns to mean +/- SE at T3/T6.
*Statistically significant values using the Wilcoxon signed-rank test.
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 134 of 144
Tables 6 and 7 depict the results we obtained at T3 and T6 in comparison with Ti for the
inflammation-related biomarkers in EHS-bearing patients presenting with increase in these
biomarkers at Ti.
As indicated in Table 6 there is a statistically significant decrease in the number (and
percentage) of EHS patients with abnormal inflammation-related biomarker values at T3 and T6
in comparison with Ti (p < 0.0001) for histamine, S100B protein, and HSP27/70 chaperone
proteins, suggesting the occurrence of some FPP-related anti-inflammatory effect in the
peripheral blood of EHS patients with initially detectable inflammation. Moreover, as indicated
in Table 7, the FPP-related anti-inflammatory effect was confirmed by comparing the mean+/-
SD values of histamine and Hsp27/Hsp70 chaperone proteins at T3 and T6 with those at Ti, the
decrease in mean values+/-SD being statistically significant at T3 and T6 relative to Ti.
Table 6. Number and percentage of EHS-bearing patients with increased inflammation-related
biomarker values at T3 and T6 in comparison with Ti
values at Ti
values at T3
values at T6
≤ 10 nmol/l
11 (42.3 %)
4 (15.4 %)
3 (16.7 %)
≤ 0.105 μg/l
6 (23.1 %)
3 (11.5 %)
≤ 5 ng/ml
17 (65.4 %)
5 (19.2 %)
2 (11.1 %)
*p values relative to Ti values were calculated using the Chi-square test of independence
Table 7. Mean values (+/- SD) of inflammation-related biomarkers at T3 and T6 in comparison
with Ti in EHS-bearing patients having initial detectable increased inflammation-related
≤ 10 nmol/l
23.22 +/- 9.79
12.03 +/- 11.90
8.73 +/- 8.06
≤ 0.105 μg/l
0.188 +/- 0.104
0.097 +/- 0.002
≤ 5 ng/ml
9.02 +/- 7.41
4.29 +/- 1.76
3.34 +/- 1.98
*Comparison was done using the Wilcoxon signed-rank test.
Oxidative stress and antioxidative stress-related biomarkers
Results are depicted in Tables 8 and 9. A remarkable finding is that 12 of the 26 evaluable
patients (46%) experienced oxidative stress. This was evidenced by the observation that at T0
these patients presented with statistically significant increase in MDA and TBARS in the plasma
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 135 of 144
relative to the normal reference values, while these values differed statistically significantly from
those obtained in the patients with no detectable oxidative stress (p<0.0001). Moreover, the
individualization of the group of patients with oxidative stress from that with no oxidative stress
was further supported by the fact that in comparison with normal reference value, GSSG was
statistically significantly increased in oxidative stress bearing patients (p<0.0001), but not in
patients with no oxidative stress (Table 8).
Table 8. Individualization and characterization of a group of EHS self-reporting patients with
oxidative stress at T0 and comparison between the two groups with or without oxidative stress
with regards to the mean values +/- SD obtained for the different oxidative stress biomarker
1.47 +/- 0.35 µM
2.14 +/- 0.17*
1.53 +/- 0.21
2.5 +/- 0.37 µM
3.16 +/- 0.18*
2.67 +/- 0.23
Total thiol group
6.79 +/- 0.99 µmoles/g
6.56 +/- 0.46
6.51 +/- 0.44
12.40 +/- 6.90 µM
24.08 +/- 12.66*
18.74 +/- 7.37
966 +/- 237 µM
848.38 +/- 160.18
822.12 +/- 149.47
988.50 +/- 239.50 µM
896.58 +/- 175.40
859.60 +/- 148.79
97 +/- 2.90 %
94.75 +/- 1.99
95.54 +/- 1.75
97.55 +/- 57.45 µM/µM
41.20 +/- 15.75
50.35 +/- 23.02
1.50 +/- 0.15 µM
1.46 +/- 0.05
1.47 +/- 0.09
1.34 +/- 0.12 U/mg Hb
1.47 +/- 0.14
1.51 +/- 0.09
54 +/- 21 U/l
65.42 +/- 8.22
60.50 +/- 9.03
8.95 +/- 4.25 U/g Hb
9.83 +/- 1.28
9.18 +/- 2.23
375 +/- 75 U/l
399.00 +/- 33.86
367.45 +/- 58.80
44.15 +/- 16.35 U/g Hb
53.53 +/- 10.80
50.95 +/- 8.18
MDA, Malondialdehyde; TBARs, Thiobarbituric acid reactive substances; GSSG, oxidized
glutathione; GSH, Reduced Glutathione; TAS, Total antioxidant status; SOD, Superoxyde
dismutase; GR, Glutathione Reductase; GPx, Glutathione Peroxidase.
* Mean values +/- SD are statistically significantly higher than the normal reference values by
using the Fisher exact test followed by the two-tailed Student’s t-test (p < 0.0001).
**For comparison between patients with oxidative stress and without oxidative stress, p values
are calculated by using the Fisher exact test followed by the two-tailed Student’s t-test.
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 136 of 144
Table 9. FPP-related antioxidative response at T3 in comparison with T0 in EHS self-reporting
patients with or without oxidative stress
Patients with oxidative stress
Patients without oxidative stress
+/- 10.97 *
+/- 0.08 *
MDA, Malondialdehyde; TBARs, Thiobarbituric acid reactive substances; GSSG, oxidized glutathione;
GSH, Reduced Glutathione; TAS, Total antioxidant status; SOD, Superoxyde dismutase; GR, Glutathione
Reductase; GPx, Glutathione Peroxidase.
* Mean values +/- SD relative to normal reference values are statistically significantly increased at TO for
MDA, TBARs, and GSSG for the patients with oxidative stress and for SOD for the patients without
oxidative stress by using the Fisher’s exact test followed by the two-tailed Student’s t-test (p <0.0001).
**p values were calculated using the Wilcoxon signed-rank test.
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 137 of 144
As indicated in Table 9, an additional observation is that for the group of patients with
oxidative stress at T3 in comparison with T0 there is a statistically significant decrease of MDA
level in the plasma (p<0.0001) and a statistically significant increase in the glutathione
peroxidase activity in RBC (p<0.01). This result suggests that FPP may have some detectable
antioxidative effect in patients with initially detectable oxidative stress. However, in this group
of patients, the evidence for such an effect was not supported for the thiol group marker, whose
normal level did not change at T3 and for TBARS and GSSG, since in comparison with the
normal values the plasmatic values of these two markers were still statistically significantly
increased at T3. In fact, regardless of the group of patients considered (i.e. with or without
oxidative stress) we were unable to detect any statistically significant effect of FPP on the
antioxidative enzymatic or non-enzymatic proteins so far investigated, with the exception of the
increased glutathione peroxidase activity in RBC in the oxidative stress-related group.
To our knowledge, this is the first study to demonstrate some beneficial therapeutic effects in
EHS self-reporting patients. In previous works, EHS or similar environmental pathological
disorders such as MCS were categorized as toxicant-induced loss of tolerance (TILT) disease
 or as sensitivity-related illness (SRI) , to account for the fact that EHS and MCS
patients cannot tolerate weak EMF intensity and weak chemical concentration respectively. More
recently we defined EHS more precisely as a decrease of EMF tolerance threshold and extension
of this decreased threshold to the whole electromagnetic spectrum as disease progresses .
Since we were not able to measure precisely the EMF tolerance threshold in the patients included
in this study and provide the supporting evidence that symptoms may have occurred in the case
of weak EMF intensity, we preferred to use the more general term EMFIS to qualify the clinical
and biological pathological condition these patients were associated with. Although WHO
officially recognized EHS as an adverse health condition , a similar approach was proposed
following the Prague WHO sponsored international workshop on EMF hypersensitivity, as it was
recommended to use the term IEI-EMF  to qualify such pathology because there is still no
proven causality between EMF exposure and EHS genesis.
In the present study, the clinical symptoms we analyzed correspond to those reported in the
scientific literature for EHS self-reporting patients [2-6]. Currently, we have no clear explanation
why after FPP treatment the cognitive symptoms including loss of short term memory and/or
attention/concentration deficiencies were more frequently improved than the neurologic
symptoms, which included headaches, tinnitus, or dysesthesia. From the analysis of Table 2, it
appears that several symptoms such as fatigue, impaired concentration, depression tendencies,
and dysesthesia may have improved at T6 in comparison with T3. Unfortunately, this is likely
not the case because at T6, there were only 18 evaluable cases, 4 cases not being considered at
T6 due to failure at T3 and 4 other cases because of the loss of follow-up and the undetermined
outcome. As a result, such a selection process may have thereby artificially overestimated this
apparently beneficial effect at T6. Due to this limitation, we cannot consider that FPP may have a
permanent beneficial effect. Although we could not eliminate the possibility of some placebo
effect to explain the general beneficial effect we observed, we believe such a placebo effect may
have been relatively modest since the improvement has been observed not only at the standpoint
of subjective clinical symptoms but also objectively through the use of UCTS and biomarker
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 138 of 144
detection. In order to clearly answer this important new clinical research question, a randomized
trial testing the effect of FPP versus a placebo is necessary, a step which we are currently
Since UCTS measure tissue pulsations of centimeter-thick sections corresponding to
intracerebral tissue territories vascularized by MCA but not pulsation of the MCA itself, this
technique must be distinguished from the classical transcranial Doppler ultrasonography (TDU),
which measures cerebral perfusion pressure upon MCA blood flow velocity [35-36].
It is well known that using transcranial ultrasound techniques such as TDU or UCTS factors
that affect cerebral pulsations can be extracranial or intracranial . Among the extracranial
factors there are peripheral vascular changes, such as low systolic arterial pressure. However, in
this study, at Ti all patients had a normal systemic arterial pressure and a normal carotidian and
vertebral echodoppler. This led us to consider that intracranial factors such as local vascular
changes and/or changes in brain tissue metabolism and function may be involved to account for
the low mean PI detected by UCTS in the different temporal lobe areas investigated.
In an ongoing study, by using TDU in association with UCTS we found some decrease in
MCA blood flow velocity in the brain of EHS self-reporting patients for whom we had
simultaneously evidenced a decrease in intracerebral tissue PI in temporal lobes, suggesting the
decreased PI measured by UCTS may be associated in these patients with a decrease in MCA-
related BBF . This finding may confirm other publications which have shown by using other
imaging techniques that the excessive use of mobile phones (i.e. the prolonged exposure to
pulse-modulated radio frequency EMF) can affect regional BBF [37-38]; and that BBF
disruption may consequently disturb sleep and waking EEG . Moreover, it has been clearly
established experimentally that 900 MHz or 2.45 GHz microwave short term or chronic EMF
exposure in rats can trigger neuronal dysfunction and even apoptosis of hippocampal pyramidal
cells [40-42] and cerebellum Purkinje cells [43-44] through oxidative stress induction, and that
EMF-related oxidative stress-induced neuronal pathologic changes may transmit to offspring
The statistically significant decrease in mean PI values evidenced at Ti in the MCA
dependent temporal lobe territories investigated by using UCTS may thus similarly be associated
with brain tissue metabolic changes in the limbic system and the nearby temporal lobe neuronal
structures. Such pathological changes may indeed be related to oxidative stress-induced BBB
opening , and/or to brain hypoxia caused by EMF-induced BBF decrease and/or EMF-
induced hemoglobin deoxygenation [46-47]. Consequently, this may induce metabolic neuronal
dysfunction but not apoptosis. For example, in our study, with the exception of the vertebro-
basilar area of the right temporal lobe, a complete mean PI recovery was observed as soon as 3/6
month FPP treatment was achieved. This is particularly true for the capsulo-thalamic area which
was constantly associated with a decrease in mean tissue PI in one or the two temporal lobes at
Ti and which comprises the limbic system (i.e. the hippocampus and the amygdale) and the
thalamus. We hypothesize this area is particularly critical since it may contain the multisensory
parieto-temporal cortex zone which appears to be connected with the thalamus for integration of
auditory and somatosensory responses, as it was demonstrated in the rat . Regardless of the
mechanisms, dysfunction of the limbic system and the thalamus may account for the cognitive
deficiency and the superficial and/or deep sensibility abnormalities we observed clinically before
FPP treatment. We have also previously reported that similar PI decrease in the capsulo-thalamic
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 139 of 144
area can be evidenced in MCS patients . Since we have shown that MCS is associated with
EHS in many patients, it cannot be excluded that chemicals may also be involved as causal
environmental stressors in EHS genesis.
In the present study, all the included patients for whom a MRI or CT scan could have been
conducted before inclusion had a normal brain MRI or CT scan. Accordingly, abnormalities in
the limbic system and/or in the thalamus could not be detected using these typical imaging
techniques. However, by using more sophisticated imaging techniques such as positron emission
tomography (PET) or functional MRI (fMRI), it has been possible to observe some metabolic
hyperactivity in the limbic amygdale of MCS patients (PET studies)  and some abnormal
default mode network, including decreased BBF and/or metabolic activity within bi-frontal lobes
in the brain of EHS patients (fMRI studies) .
In the present, we have no clear explanation how FPP can restore normal mean PI values
and how it can increase mean tissue PI values in comparison with normal values at T3/T6 in the
superficial MCA, cortical-subcortical and carotidian areas of the left and right temporal lobes
(see Table 5). UCTS related-mean PI decrease in temporal lobes has been shown to be associated
with brain dysfunction [19-20]. There is no data which demonstrates that increased mean tissue
PI is pathologic. In fact, in our study the FPP-related increase in mean tissue PI in these temporal
lobe areas was transitory, as several months after FPP treatment concluded mean PI values were
normal or even decreased.
Analysis of the general composition of FPP has revealed it contains 91.3% of carbohydrates,
<0.1% of lipids, and only 0.3% of proteins for which all amino acids, mainly arginine, leucine,
glutamic acid, and aspartic acid but not cysteine are represented . The precise role of these
plant-derived natural components on health is not known. However, FPP has been shown to
produce some anti-inflammatory and anti-oxidant effects in chronic degenerative disease such as
Alzheimer disease . Similar favorable effects have also been observed for the treatment of
diabetes  and for the prevention of psychological stress-induced acute gastric mucosal lesions
, oxidative stress-induced oral cavity mucosal inflammation , and oxidative stress-
associated occupational burn out .
On the basis of our previous data , we have speculated that BBF decrease and BBB
opening may be caused by EMF and/or chemical-induced inflammatory and oxidative stress
processes in the temporal lobes, thereby avoiding any psychosomatic or nocebo causal effects in
EHS and/or MCS genesis. This hypothesis was supported by the numerous animal experiments
which clearly demonstrate that EMFs can cause oxidative stress [52-53] more particularly in the
brain [42, 54-56], and that in tested animals EMFs causally affect the test group but not the sham
control group [40-42, 55, 57]. Our hypothesis has been recently confirmed in humans within a
carefully-conducted interview-based psycho-clinical study showing EHS patient symptoms
appear a long time before patients start questioning themselves on the EMF’s impact on their
health. An observation inconsistent with the hypothesis that EHS originates from a nocebo
response to perceived EMF exposure .
We have examined whether FPP treatment could bring about some anti-inflammatory and
antioxidant effects. To this end we have used a battery of biomarkers (see Table 1) chosen for
their ability to reflect the general inflammation and redox state in the organism. An important
observation in our study is that FPP can decrease the peripheral blood levels of histamine and
Hsp27/Hsp70 chaperone proteins in patients where levels of these inflammation-related
Functional Foods in Health and Disease 2018; 8(2):122-144 Page 140 of 144
biomarkers were initially elevated, a finding which confirms that FPP can bring about some anti-
inflammatory effect. MDA and TBARS plasmatic values were found at T0 to be statistically
significantly increased in comparison with normal reference values (p<0.0001) in 12 patients.
This allowed us to individualize a group of patients with oxidative stress which represent 46% of
the total number of evaluable patients (Table 8). MDA is one of the most prevalent by-products
of lipid peroxidation during oxidative stress. This is also the case for TBARS, which include
MDA, with both by-products being markers of lipid peroxidation . A further finding which
strengthens our proposed distinction between EHS patients with and without oxidative stress is
that relative to the normal reference value GSSG levels were also found to be statistically
significantly increased in the oxidative stress group (p<0.0001) but not in the group with no
oxidative stress (see Table 8).
Regarding the anti-oxidative effect of FPP, we found a statistically significant decrease in
MDA plasmatic levels and a statistically significant increase in glutathione peroxidase activity in
RBC at T3 in the group of patients with oxidative stress (see Table 9), a finding which confirms
that FPP may have also some systemic antioxidant properties.
In fact, papaya juice has been shown to scavenge free radicals  and it is believed that
polyphenols in FPP may have such an antioxidant effect  by enhancing the total oxidant-
scavenging capacities of human blood by binding to RBC . Another antioxidant mechanism
could be that FPP may act by inhibiting the Fenton reaction  by causing iron chelation 
As we observed some clinical improvement, an UCTS-based tissue PI normalization in temporal
lobes, and some anti-inflammatory and antioxidative stress effects, we conclude that FPP is a
useful treatment for EMFIS-bearing patients, i.e. for so called EHS self-reporting patients.
Acknowledgements and Funding: This work was supported by a specific grant provided by the
Osato Research Institute and by the ARTAC, the Association for Research on Treatment Against
Cancer which is a non-profit private research center. The authors acknowledge Ms. Marie Anne
Barros from the ARTAC for clinical assistance, Dr. Natalio Awaida from Labo XV-Paris for
blood collection and high quality EHS-related blood marker measurement and Dr. Philippe
Lebar for technical assistance in carrying out UCTS. They also thank Tony Tweedale from
R.I.S.K. (Rebutting Industry Science with Knowledge) Consultancy for his careful scientific
review of the manuscript.
Conflict of interest
At the exception of Dr. Pierre Mantello, who is in charge with the marketing and communication
of Immun’Age®, all the authors declare no financial conflict of interest.
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