Medical Device

The present invention provides a medical device to analyze the composition of interstitial fluid in a human body and to provide a modelling of the human body. More specifically the device measures bio-impedance in interstitial fluid and enables a modelling of the human body and some parameters of the interstitial fluid to be deduced.

Bioelectric impedance measurements are used in a wide range of old and new noninvasive technologies and methods where a very small electric current is applied to the body via one or more surface electrodes and the resultant electricity pulse passing through the body is detected at other surface electrodes placed elsewhere on the body. A drop in voltage occurs as the current encounters impedance or resistance inherent in the fluids and tissues it passes through as it courses through the various physiological "compartments" of the body. These compartments include the bloodstream, the intracellular space, the lymphatic system, the interstitial space, and others. This drop in voltage provides indirect information about the physical and chemical properties of the compartments that the current passes through.

The most familiar form of bioelectric impedance measuring uses alternating current (A.C.). There are dozens of readily available commercial and custom-built A.C. Bioelectrical Impedance Analysis (BIA) systems differing widely in design and complexity. Most systems are used to indirectly estimate the fat content of the body by measuring total body water. These systems typically employ A.C. electricity with a wide range of currents, frequencies, and intensities. The amount of electricity delivered to the body is usually imperceptible and far below the level that would cause cellular or tissue damage. Studies of A.C. BIA systems operating at 50 KHz or higher, have revealed that these frequency A.C. electric currents flow non-selectively through both intracellular and extra cellular spaces, and thus provide relatively non-specific information regarding the physical properties and chemical composition of specific body compartments.

Unlike A.C. bioelectric impedance, the electric current produced by D.C. bioelectric impedance methods specifically passes through the interstitial fluid compartment. The interstitial fluid compartment represents approximately 16% of the body's total water.

Interstitial fluid is extra cellular water and solutes surrounding cells, but outside of the bloodstream and lymphatic system. Interstitial fluid forms the microscopic interface between cells and capillaries.

No direct methods for sampling interstitial fluid are currently available. The composition of interstitial fluid, which constitutes the environment of the cells and is regulated by the cells activity and ionic distribution, has previously been measured by the suction blister or liquid paraffin techniques or by implantation of a perforated capsule or wick. The results have varied, depending on the sampling technique and animal species investigated.

In one study, the ionic distribution between vascular and interstitial compartments agreed with the Donnan equilibrium; in others, the concentrations of sodium and potassium were higher in interstitial fluid than in plasma However, the studies did establish the following elements: Interstitial fluid differs from whole blood by the absence of red blood cells, and it differs from blood plasma in that there are far fewer proteins. The absence of haemoglobin and poor level of proteins which are the main buffers of the blood system explain the more acidic interstitial pH and more importantly, that the acid base regulation is made by cell activity.

Any substance passing between cells and the bloodstream must traverse the interstitial space. These substances include oxygen, carbon dioxide, glucose, as well as thousands of other compounds.

The interstitial fluid's role as a metabolic conduit and its proximity to the collective intracellular space of nearby cells suggests that the chemical composition of the interstitial fluid may reflect the physiology and pathophysiology of the nearby cells.

The volume of the interstitial fluid is closely related to the containing sodium pool.

The exchanges between the vascular sector and the interstitial fluid are complex. The distribution of the electrolytes on each side of the membrane is regulated by "the Donnan equilibrium."

The results of biochemical interstitial values and laboratory tests (blood) can be completely different for 4 reasons: S The interstitial fluid is stagnant

S Each compartment of the human body presents different concentrations of biochemical values. These differences come from the Donnan equilibrium S The absence of haemoglobin and poor level of proteins which are the main buffers of the blood system explains a more acid interstitial pH •f The measurement of the biochemical interstitial values represent the pool of the substance because the interstitial fluid is at least 4 times higher in volume than the vascular system and therefore less sensible to the water variation Cell activity and ionic equilibrium are complex and the following are described in more detail in academic and other publications. In particular:

Niels Fogh-Andersen, Burton M. Altura, Bella T. Altura, and Ole Siggaard-Andersen

CLIN. CHEM.41/10, 1522-1525 (1995)

Gilanyi M, Dcrenyi C, Fekete J, Bαrenyi K, Kovach AGB. Ion concentrations in subcutaneous interstitial fluid: measured versus expected values. Am J Physiol 1988;

255:F513-9

Laurence Hue, Lydie Sparfel, Mary Rissel, Marie-Therese Dimanche-Boitrel, Andre

Guillouzo, Olivier Fardel, and Dominique Lagadic-Gossmann INSERM, Identification of

Na+/H+ exchange as a new target for toxic polycyclic aromatic hydrocarbons in liver cells, The FASEB Journal express article 10.1096/fj .03-0316fje. Published online

December 4, 2003.

S.GRINSTEIN, J.D.GOETZ, and A.ROTHSTEIN Na+/H+ Exchange Through an

Amiloride-insensitive Pathway From the Department of Cell Biology, Research Institute,

The Hospital for Sick Children, and the Department of Biochemistry, University of

Toronto, Ontario M5GlX8,Canada

C.TERMINELLA.K.TOLLEFSOHJ.KROCZYNSKIJ.PELLI.ANDM.CUTAIA

Inhibition of apoptosis in pulmonary endothelial cells by altered pH, mitochondrial function, and ATP supply Pulmonary Disease Division, Department of Medicine, State

University of New York/ Down state Health Sciences Center; and Department of

Veterans Affairs Medical Center, Brooklyn, New York 11209 Received 3 July 2001 ; accepted in 8 August 2002 Am J Physiol Lung Cell MoI Physio 1283: L1291-

L1302,2002;10.1152

R M Leach, D F Treacher ABC of oxygen. Oxygen transportTissue hypoxia BMJ. 1998

November 14; 317(7169): 1370-1373.

Figure 1 shows a schematic process of the cell activity and ionic equilibrium in healthy subject When the sodium concentration decreases in the interstitial fluid, the sodium moves inside the cell and affects the tissue(s) as follows:

1. Cellular volume increases

2. Mitochondrial activity decreases and ATP production decreases

3. Oxygen consumption decreases

4. Intracellular exit of K+ and Na+/ H+ exchange or antiporter cause an exit of H+ to the interstitial fluid causing an interstitial acidosis.

5. An interstitial Chlorine retention and a corresponding retention of intracellular bicarbonate

6. CO2 increases interstitially resulting in an increase in the blood pressure of CO2

7. Interstitial fluid volume decreases, the oncotic pressure is higher than the hydrostatic pressure (Starling equilibrium)

8. Blood microcirculation: vasodilation and blood viscosity decreases (Increased of blood CO2 concentration)

Similarly Figure 2 shows a schematic process of cell activity and under the opposite circumstances in a healthy subject

When the sodium concentration increases in the interstitial fluid, the sodium moves outside of the cell and affects the tissue(s) as follows:

1. Cellular volume decreases

2. Mitochondria activity increase and ATP production increases

3. Oxygen consumption increases and Oxygen delivery decreases

4. Interstitial K+ ions move into the cell and intracellular income of H+ causing an interstitial alkalosis

5. Interstitial Chlorine moves to intracellular space, and a corresponding exit of bicarbonate

6. Interstitial CO2 decreases and a corresponding decrease in the blood of CO2

7. Interstitial fluid volume increases, the hydrostatic pressure is higher that the oncotic pressure (Starling equilibrium)

8. Blood microcirculation, vasoconstriction and blood viscosity increases Knowledge of the composition of interstitial fluid can be very informative regarding the physiological parameters and function of the cells and hence the tissues and organs in the vicinity the interstitial fluid.

As direct current passes primarily through interstitial fluid it is proposed that an abnormality in the chemical composition of interstitial fluid could be detected with an adequately sensitive direct current bioelectric impedance device.

It is therefore an aim of the present invention to provide a reliable non-invasive method to measure the composition of interstitial fluid.

According to the present invention there is provided a method to analyze interstitial fluid the method comprising the steps of measuring bio impedance between at least two electrodes positioned on an individual's body and calculating the volume of interstitial fluid for that individual and deducing the concentration of certain metabolites in the interstitial fluid.

The invention provides a non-invasive method to analyze interstitial fluid in a body, the method comprising the steps of measuring bio impedance between at least two electrodes positioned on an individual's body and calculating the volume of interstitial fluid for that individual and deducing levels of conductivity within the interstitial fluid throughout the body and/or deducing the concentration of certain metabolites in the interstitial fluid.

In one embodiment a black box sends via cables and electrodes a continuous tension of 1.28V to at least 6 zones of the skin and returns in numerical form by the intermediary of a USB port to a computer the intensity of the traversed zones between pairs of electrodes to a data-processing software.

The mothod provides a modeling of the body based on conductivity readings in interstitial fluid. The method may further comprise the step of comparing the levels of conductivity measured with algorithnms from data bases and extrapolating the results based these algorithms and the individual's age, height, weight and sex.

The invention also provides pparatus to carry out the method, the apparatus comprising electrodes to be placed symmetrically on the right and on the left on the level of the face, the hands and the feet, a black box, cables connecting the electrodes to the black box and a USB cable connecting the black box to a computer wherein the computer comprises software to enable a scan to be driven and results to be stored and analysed.

The apparatus may further comprise other monitoring equipment and software to cross analyse the results.

The invention also provides the use of a method or apparatus as described herein to monitor a treatment.

The treatment being monitored may be chosen from the group consisting of thyroid treatment, hypo tensor treatment with converting enzyme inhibitor or beta blockers, antidepressant treatment with SSRI, and anticoagulant treatment for atherosclerosis.

The method described may also be used in the adjuct diagnosis of ADHD children

In a particular embodiment the apparatus can be used to evaluate the conductivity of 22 parts of the human body in bipolar mode between six tactile electrodes using a direct current and a range of frequencies to provide information relating to Interstitial Na+/K+ ATPase pump activity, estimation of tissue pCO2 related with hypoxia, microcirculation blood flow, sympathetic system activity, modeling of the human body and/or estimation of body composition parameters including total body water, fat free mass and fat mass. By comparing the concentration of measured metabolites to certain standards further deductions can be made.

The present inventor devised an interstitial scan system to enable the composition of interstitial fluid to be measured throughout the body. The system called EIS (Electro Interstitial Scan) is available from LD Technology LLC in Miami Florida.

This one non-limiting embodiment illustrates one way to carry out the invention. The device according to the invention named "Electro Interstitial Scan" ("E.I.S") comprises a black box which sends via cables and electrodes a continuous tension of 1.28V to 6 zones of the skin; the black box returns in numerical form by the intermediary of a USB port to the computer the intensity of the traversed zones between 2 electrodes to an expert data- processing software.

According to this one particular embodiment of the invention: electrodes are placed symmetrically on the right and on the left on the level of the face, the hands and the feet.

The apparatus allows measurements to be taken which can be used to provide calculations of certain constants within the interstitial fluid and which also allow modeling of the human body.

The modelling is based on the Maxwell equation which has previously been used with imaging. This is applied together with the Venn Diagram calculation and the bioimpedance measurements to localize body systems.

The constants in the interstitial fluid are calculated by applying the Cottrell equation and Ohm's Law to the bioimpedance measurements.

The invention is exemplified with reference to the following non-limiting description and with reference to the drawings wherein Figure 1 shows a schematic process of the cell activity and ionic equilibrium in healthy subject

Figure 2 shows a schematic process of cell activity and under the opposite circumstances in a healthy subject

Figure 3 shows this arrangement of electrodes and the series of reading that are taken to analyze the interstitial fluid through out the body.

Figure 4 a histogram of the number of values N of each body part, the software removes the extreme values for keep the more frequent mean values for R.

Figure 5 is called the ESG for absolute values Example of ESG (scale 100/-100) is shown as Figure 6.

The boundary value problem to be solved is a time harmonic quasi-static electric field in the steady state taking into account both, the specific electric conductivity σ and the electric permittivity ε is represented in Figure 7

Graphic of the EIS conductivity values of the thyroid in scale -100/+100 is shown as Figure 8

Graphic of the TSH values in laboratory tests is shown as Figure 9 Volumes 2+14+15+17 of the ESG Graph are shown in Figure 10 Blood pressure readings (diastolic) are shown in Figure 11 Volumes 6+8+19+21 of the ESG Graph are shown as Figure 12 Blood pressure readings (diastolic) are shown as Figure 13 Volumes 6+13+19 of the ESG Graph are shown in Figure 14 Prothrombin Time is shown as Figure 15 Volumes 6+13+19 of the ESG Graph are shown as Figure 16

The 22 parts of the ESG graph are shown on Figure 17 for a group of supposedly healthy children who were not diagnosed as ADHD children

The 22 parts of the ESG graph are shown as Figure 18 for a group of children diagnosed as ADHD according to existing conventional methods Volumes 9 and 10 of the ESG graph are shown in Figure 19 Categorized histograms by group: Volume 9 in Figure 20 Categorized histograms by group: Volume 10 is shown in Figure 21

The EIS System is a programmable electro medical system (PEMS) including:

USB plug and play hardware device including black box, 6 tactile electrodes and cables and software installed on a computer..

The six electrodes are placed on the skin as described above

To take a measurement, through the 6 tactile electrodes, a direct current (tension 1.28V) is sent alternatively and records the resistance of 22 parts of the human body in bipolar mode.

Figure 3 shows this arrangement of electrodes and the series of reading that are taken to analyze the interstitial fluid through out the body.

The measurement is runs a number of times in N parameters.

N is a normalized reading taking into account the sex and age of the subject. The coefficient has been determined following studies on more than 20000 subjects of a ranges of ages and both sexes.

Item for the measurement N is determined by the formula of the TWB and an empirically-derived coefficient related to the age, height, weight, and the gender of the subject.

The formula of the calculation of TWB (total body water) v =p Ht 2/R => R= p v/ Ht2

Calculation of

Analysis of the measurement managed According to the Ohm' law

All substances have resistance to the flow of an electric direct current (DC). R = E/I Where:

R = resistance (ohms) E = applied voltage drop (volts) I = current (amperes)

E= 1.28V

The hardware by the microprocessor and the set of resistances transmits the Intensity of each body parts measured to the software via the USB port.

The software by the Ohm' law application, make the calculation of the resistance of each body part according to the formula:

R= E (1.28V)/ 1 (provides by the hardware)

As shown in Figure 4 a histogram of the number of values N of each body part, the software removes the extreme values to keep the more frequent mean values for R.

Then, the software makes the calculation of the conductivity C of each body part C=I /R and then transforms this value in a numeric scale 0-100 The minimum 0= conductivity 0 S.m

The maximum 100= conductivity 140 10-6 S.m-i

The numeric values of the 22 body parts are integrated in a graph with a scale 0- 100: This graph shown as Figure 5 is called the ESG for absolute values

Then, these absolute values for conductivity are converted to the +100 to -100 ESG scale

Item for the measurement A is determined by the arithmetic average of measurements of absolute values.

According to the mathematical formula:

Z - value of the EIS scale

X — numeric value for the system [0. 100]

Z - value scale EIS [- 100. +100]

Z = A * X + B Norms = 66 (+/- 8) for N

Calculation of A

If (X > Norm) A = 100/ (100 - Norm) B - - A * Norm

If(X <= Norm) A = 100/Norm B = - A * Norm

All measurements are carried out according to an optimal delta allowing the recording

Delta automat = absolute value (max - Min) * 1.5

Max - >max value of all volumes

Min - >minimum value of all volumes Example of ESG (scale 100/-100) is shown as Figure 6.

Modeling of the body and localisation of the body system is carried out on the EIS measurements of bioimpedance using Maxwell's equation and the Venn Diagram Calculation. Maxwell has been applied for imaging before using many electrodes but the present invention is the first application of this equation for modelling using a very small number of electrodes (6 in the case of the EIS taking 22 measurements).

Maxwell 'equation

Quasi-static electric field problem

The boundary value problem to be solved is a time harmonic quasi-static electric field in the steady state taking into account both, the specific electric conductivity σ and the electric permittivity ε represented in Figure 7. Only linear material properties are considered. Therefore, the complex formalism can be advantageously exploited.

The Maxwell's equations describing the field observed in Ωc are

Vx E = O (1 )

where denotes the electric field intensity, the conduction current density, D the electric displacement, ω the angular frequency andj the imaginary unit. The surrounding non-conducting region Ωn hasn't been considered because the displacement currents in air are negligible small compared to the conduction and displacement currents in the conducting region. The relation (1) enables to introduce the electric scalar potential V as: E = -VV . (3) Considering the constitutive laws

J = σE (4)

D = ^rE , (5)

Where σ and ε are assumed to be constant, yields the partial differential equation (6) for V.

₊ v([σ + yβiff]vκ) = o (6)

)

On the boundary of Ω either homogeneous tangential components of the electric field intensity

E ^χ n = 0 (7)

on FD , describing electrodes, or homogenous normal components of the total current density

J (J + ./YuD) -Ii = O (8)

On FN will be prescribed. This yields the Dirichlet boundary conditions for the electric scalar potential V in (9) on T

V = V D ₁ (9) The boundary value problem (6), (9) and (10) will be solved by the finite element Galerkin technique using nodal tetrahedral finite elements of second order [4]. To this end the electric scalar potential V will be approximated by a linear combination of nodal shape functions as δ

VK . ^' K.JV, . ( 1 1 )

J A=I

In (11) nn means the number of nodes in the finite element mesh. Introducing (11) in (6) and applying the finite element Galerkin technique yields

Ω

= J N,div([σ + jωε]gradV ^M )dΩ = 0 ( 12) n O ₁ ,

in Ωc with i= 1....n , whereby stands for the number of unknowns. Exploiting the vector identity div (aU) grad (a).U + adiv U, where a means a scalar field and U a vector field, and considering the boundary conditions (9) and (10) results

J gradN, - ([σ + jωε] gradV ^{u )} ) dΩ = 0. ( 13)

The weighting functions N, in (13) in nodes on ID are assumed to be N ₁ = 0 . ( 14)

Carrying out the integral (13) a linear algebraic equation system will be obtained. The known nodal potentials VD yield the right hand side of the system.

Venn Diagram calculation

The EIS modeling choose a set Rn of necklace representatives, one from each necklace, so that the supposed of β (x) induced by Rn has symmetric chain decomposition.

Define the block code β (JC) of a binary string x as follows. If x starts with 0 or ends with l, then β (JC) = (oo). As an example, the block codes of the string 1110101100010 and all its rotations are shown below

Estimated Biochemical values and oxygen delivery

The calculation of the various physiological values is obtained in the following way:

The chronoamperometry and the Cottrell equation is used in laboratory tests devices for the measurement of weak concentration of biochemical values.

In chronoamperometry, the working electrode potential is suddenly stepped from an initial potential to a final potential, and the step usually crosses the formal potential of the analyte. The solution is not stirred. The initial potential is chosen so that no current flows (i.e., the electrode is held at a potential that neither oxidizes nor reduces the predominant form of the analyte). Then, the potential is stepped to a potential that either oxidizes or reduces the analyte, and a current begins to flow at the electrode. This current is quite large at first, but it rapidly decays as the analyte near the electrode is consumed, and a transient signal is observed.

If the point in time when the potential is stepped is taken as time zero, then the Cottrell equation describes the how the current, I, decays as a function of time, t:

The Cottrell equation

F = Faraday constant (96500 C/mole)

A= Electrode area (cm2)

Co = Ionic concentration (mol/ cm3) n =number of electrons per molecule

D= Diffusion coefficient (cm2/ s) t= Measurement time in seconds

Although the current decay may appear to be exponential (in the case of adsorbed redox species), it actually decays as the reciprocal of the square root of time. This dependence on the square root of time reflects the fact that physical diffusion is responsible for transport of the analyte to the electrode surface.

The calculation of the biochemical values is obtained from the following manner: Adaptation of the formula of Cottrell

Co = ionic concentration (mol/ cm3)

F = Faraday constant 96500 (C/mole)

A = surface of electrode (cm2) n= number of electrons per molecule (periodic table) (sodium, H+, potassium or TSH hormone) D= coefficient of diffusion (cm2/s) of sodium, hydrogen ions , potassium or TSH hormone t= time of measurement per body segment (1 second)

i is determined by Ohm's Law i = RU

U = 1.28 V

R is different according to the interstitial fluid resistance and the measured part body:

Concerning the sodium concentration: R is calculated by average of the physical readings 5 and 7 of the ESG providing by the EIS device

Concerning the H+ concentration: R is calculated by average of the physical readings 5 and 7 of the ESG providing by the EIS device

Concerning the concentration of Potassium: R is calculated by average of the physical readings 13 and 14 of the ESG providing by the EIS device

The interstitial oxygen delivery is based on the calculation of the volume of the interstitial fluid.

Formula using for the estimated interstitial fluid volume

Between 5 and 19 years: 0.60 (Ht2/R) - 0.50

Ht represents the height of the subject

R is the calculated resistance at the level of the volume 7 of the ESG providing by the

EIS device

Between 20 and 80 years: 0.372 (Ht2 /R) + 3.05 (sex) + 0.142Wt - 0.069 age

Ht represents the height of the subject

R is the calculated resistance at the level of the volume 7 of the ESG providing by the

EIS device

Sex = 0 for men, 1 for women

Wt = Weight in Kg Age= age in year

The volume of the interstitial fluid measured, is compared with an average equal to 16% total weight. The percentage (volume of the interstitial fluid measured) in comparison with (16% of the total weight) next is applied to the normal values of the delivery of oxygen.

Concerning the concentration of TSH hormone, the level is related to the resistance calculated by average of the physical readings 11 and 12 of the ESG providing by the EIS device

The oxygen delivery level, is proportional to the volume of the interstitial fluid Calculations of the biochemical values (Na+, K+, H+ ) are obtained by application of the formula of Cottrell (as above) and calculated according to the estimated volume of the interstitial fluid , and the TSH level is proportional to the resistance of the reading 11 and 12 of the ESG Graph .

The invention and its embodiment in the EIS system is now further exemplified with reference to the following description and drawings

The EIS System is a programmable electro medical system (PEMS) including USB plug and play hardware device including black box, 6 tactile electrodes and cables.

These six electrodes are placed on the skin, 2 on the forehead, 2 in contact with the palms of the hands and 2 in contact with the soles of the feet.

The electrodes of the hands and the feet comprise stainless steel, preferably of rank ASI 340. The electrodes of the face are gelled on the whole of their surface.

The EIS software is installed on a computer. Through the 6 tactile electrodes, a direct current 1.28 V (ZO) is sent alternatively and records 22 parts of the human body in bipolar mode. These measured parts represent the interstitial fluid resistance.

The measuring accuracy of conductivity depends on: Sending imposed voltage and resistances included in the electronic card The precision of the sending imposed voltage is 1.28V +/- 0.04 thus possible errors +/- 3.1%. The precision of resistances is +/- 5 Ohms for the resistances spread out between 11 KOhms and 390 KOhms thus maximum possible error +/- 0.4%. The precision is thus of the order: of +/- 3.5 % to the maximum Accuracy of the estimated volume of the interstitial fluid volume 5-19 yr SEE 1.69 liters 20-80 yr SEE 1.69 liters

Of the locations of the body systems according to the Maxwell's equation and Venn diagram calculations

Specificity of localization of 89% and a specificity of 84% (CI 95% realized with STATISTICA version 7.0)

The E.I .S system uses the Bioelectrical Impedance technique in DC current in bipolar mode for monitoring some treatments of diseases , screening the ADHD children and estimates some physiological and biochemical values in interstitial fluid.

The EIS system design based upon:

• The general principles of bioelectrical impedance

• physiology of the interstitial Fluid

• Cell activity and ionic equilibrium

• Tissue Oxygen and interstitial Fluid volume

• Modeling of the human body

• Neuronal excitability and interstitial pH and cerebral oxygen delivery

• The Chronoamperometry and CottrelFs Equation

• Ohm's law

• Clinical investigations • Statistical analysis Performances of the device

The performances of the EIS system are allowing its intended uses Measurement of the following interstitial fluid parameters:

• Intensity in μA (Ohm law)

• Resistance in Ω (Ohm law)

• Conductivity in S.m-1 (Ohm law)

• Volume of the interstitial fluid

• Interstitial sodium concentration

• Interstitial potassium concentration

• Interstitial H+ concentration

• Interstitial TSH concentration

• Interstitial oxygen delivery

Purpose and function of the device

The hardware will have as a function to record of:

The resistance of the interstitial fluid following the sending of a D.C current and an imposed weak tension (1.28V)

These resistances will be transmitted via USB port from the black box to the computer

(software).

The software will have a function to:

• To control the hardware operational tests:

> Test of the power supply

> Test of the channels

> Test of laterality and correspondence of volumes.

> Test of the cables and calibration

> The sequence and measuring time of the 22 body parts

• To analyze the transmitted data's:

> To convert the resistance in intensity

> To incorporate the 22 body parts' values in a graph (ESG)

> Estimated the volume of the interstitial fluid > Estimated the concentration of Na+, K+,H+,TSH and oxygen delivery

> To model the human body according to the conductivity of the 22 body parts by using the mathematical calculations of:

• The Maxwell's equation

• The Venn diagram

> To compare the results of 2 or all the visits of the same client on different dates for monitoring.

> To screening the ADHD children profile

Language of the program

• Language C++ Compilers:

• Borland C++ 5.0

• Microsoft Visual C++ (Visual Studio 2003). External program used:

• 3D design program: AutoDesk Inc. 3D Studio MAX 7.0 For modeling

• Microsoft Word for the status Report

Undesirable side effects

No side effects or adverse reactions are known to date.

Contraindications

Patients undergoing external fibrillation

Dermatological lesions in contact with the electrodes or excessive perspiration

This device should not be used in association with or presence of cardiac pacemakers, patients connected to electronic life support devices, or any implanted electronic device.

People unable to be held seated

Metal pins or prostheses on the level of the extremities or the joints

This device should not be used on pregnant women. The effects on the fetus, as well as accuracy of readings are unknown.

An absence of one or more limbs.

The site of the system:

Temperature > 28 C/80 F

The ground in synthetic material

Relative humidity < 30%

Presence of MRI or MR or CT scan.

Clinical investigations: Clinical investigation Botkin hospital 2006

This study was conducted to validate the monitoring of the treatment of 4 diseases

Clinical investigation Dr.Caudal Frederique ADHD children 2007

This study was conducted to validate that the EIS could be used as a screening device for

ADHD in children

Statistical Analysis:

For the EIS system, the data were analyzed using the statistical methods Statistics are computed with STATISTICA™ software (version 7.0). The impedance and clinical data will be transferred from their respective Microsoft Excel databases into the STATISTICA program database. The first step will be to run the STATISTICA version of the Shapiro- WiIk W test to examine whether the impedance data has a normal (Gaussian) distribution. Skewed (non-Gaussian) data will be analyzed with nonparametric methods and data with a normal

(Gaussian) will be analyzed with parametric methods. Choice of Statistical Tests for the EIS system

The statistical analysis from the databases of pre studies, clinical trial and users' databases (> 20.000 measurements) allowed:

• The specificity and sensibility of the localization of the body system on the modeling (P< 0005)

• The calculation of the norms of conductivities for age, gender, weight and height (P< 0005)

EIS system evidence bases:

The results from Botkin 2006 and the pre-study of Caudal 2007 have been confirmed the physiopathology and the clinical applications of these results and the evidence for the monitoring of some treatments and for the specificity and sensitivity of the cerebral measurement in ADHD children

Clinical investigation Botkin 2006

1. Follow-up of thyroid substitute treatment

Clinical trial: population of 52 patients all diagnosed with hypothyroidism

Graphic of the EIS conductivity values of the thyroid in scale -100/+100 is shown as Figure 8

Graphic of the TSH values in laboratory tests is shown as Figure 9

2. Follow-up of hypo tensor treatment with beta-blockers

Clinical trial: population of 37 patients all diagnosed with High blood pressure

Volumes 2+14+15+17 of the ESG Graph are shown in Figure 10

Blood pressure readings (diastolic) are shown in Figure 11

Follow-up of hypo tensor treatment with converting enzyme inhibitor (CEI)

Clinical trial: population of 20 patients all diagnosed with High blood pressure

Volumes 6+8+19+21 of the ESG Graph are shown as Figure 12 Blood pressure readings (diastolic) are shown as Figure 13

3. Follow-up of anticoagulant treatment (vitamin K antagonists oral mode) Clinical trial: population of 49 patients all diagnosed with atherosclerosis

Volumes 6+13+19 of the ESG Graph are shown in Figure 14

Prothrombin Time is shown as Figure 15

4. Follow-up of antidepressant treatment (SSRJ )

Clinical trial: population of 57 patients all diagnosed with uni polar depression

Volumes 6+13+19 of the ESG Graph are shown as Figure 16

USE OF THE EIS AS ADJUNCT TO CONVENTIONAL DIAGNOSIS OF ADHD

CHILDREN

Clinical investigation Caudal 2007 Data from 59 ADHD children diagnosed conventionally and not undergoing treatment were recorded with the EIS System. This database was compared with another control group database of 60 non-ADHD children also recorded with the same EIS System.

RESULTS

• Trial statistics: For all the 22 volumes of the ESG graph

• Mean Plot: Whisker: Mean + 0.95 Confidence interval

1. A group of supposedly healthy children who were not diagnosed as ADHD children The 22 parts of the ESG graph are shown on Figure 17

A group of children diagnosed as ADHD according to existing conventional methods For all the 22 parts of the ESG graph are shown as Figure 18

Non-parametrics tests: Volumes 9 and 10 of the ESG graph are shown in Figure 19 Comparing two independent samples (groups) 0= healthy children 1= hyperactive children Box and Whisker plot by group (Figure 19):

2. Categorized histograms by group: Volume 9 in Figure 20

3. Categorized histograms by group: Volume 10 is shown in Figure 21

DISCUSSION AND CONCLUSION

From the results obtained on the level of statistical results with non-parametrics

For volumes 9/10 of the ESG graph it seems evident that the measure of intensity at the level of these volumes is a marker of ADHD children. With a specificity result of 95% and a sensitivity result of 93%, both are calculated with a confidence interval of 95%. (P<

0001)

Highlights of modification of parameters of ESG volumes of both groups of children

Parameters 9/10 Healthy children ADHD children

Intensity μA 10.21 135

Resistance KOhm 130 9.50

Conductivity S.m-1 7.6x 10- ⁶ 105.3x IQ- ⁶