Complex hardware systems of nuclear resonance diagnosis for medical use

Laws of thermal radiation

The body, which has the absorption coefficient α = 1 is called a blackbody.

 Figure. 1. Model blackbody.

 

“Gray” is called the body, the absorption coefficient of which is less than 1. For the human body, .

According to Kirchhoff's law, the ratio of the spectral power density of luminosity to monochromatic absorption coefficient for all bodies at a given temperature is constant, which is equal to the spectral energy density of blackbody luminosity:

 

(1)

 

From equation (1):

(2)

 

From (2) it follows that the more body radiates energy, the more energy this body will absorbs.

Relationship between energy luminosity of a blackbody and its absolute temperature sets the Stefan-Boltzmann law:

 

(3)

Where  – Stefan-Boltzmann constant, .

 

Energy luminosity of a blackbody is proportional to the fourth power of its temperature.
         If the radiating body is not black, then  , where , an emissivity constant that is equal to the product of the Stefan-Boltzmann constant by a factor , that is less than one.
Figure 2 shows the dependence of the spectral energy density of blackbody luminosity versus wavelength for different temperatures.

 

Figure 2 shows the dependence of the spectral energy density of blackbody luminosity versus wavelength for different temperatures.
                                   
Figure. 2. The dependence of the spectral energy density of the luminosity of a blackbody on temperature (Planck distribution).

 

Wavelength, which accounts for maximum energy luminosity is determined by Wien's displacement law:

 

(4)

where – Wien’s constant ,

 

From (4) it follows that with increasing temperature the maximum energy luminosity shifts towards shorter wavelengths. For the discovery of the laws of thermal radiation Wien was awarded the Nobel Prize in 1911.
At the end of the XIX century several attempts were made to obtain a formula that expresses the energy density of the luminosity of a blackbody as a function of wavelength and absolute temperature T:

 

.

(5)

 

The formula, which describes well the spectral density of blackbody radiation for large wavelengths, was proposed by Rayleigh and Jeans:

In classical physics, radiation and absorption of energy were considered as continuous processes. Max Planck concluded that these basic provisions do not give a proper relationship . It is conjectured that the black body emits and absorbs energy not continuously, but in discrete portions - quanta.
Considering the body that radiates energy as a collection of oscillators whose energy can be changed only by an amount fold  ,

 

(6)

 

Figure. 3. Comparison of the distribution of energy wavelengths.

 

Max Planck obtained an expression for the energy density of blackbody luminosity, correctly describes the emissivity of a blackbody at all wavelengths:

 

, or

(7)

where - Planck's constant, - wavelength, - the absolute temperature, - speed of light in a vacuum, - the Boltzmann constant, - frequency radiation (absorption).
From (7) it is possible to obtain the Stefan - Boltzmann and Wien Laws.

 

The use of ultraviolet and infrared radiation in medicine

      More than 120 years ago, N. Finzen organized treatment of smallpox in rooms with red lights, it was possible to prevent the formation of scars on the skin. It had been attempts to treat skin tuberculosis with concentrated sunlight. With this treatment skin got burnt, but on the skin a scar was formed.
Finzen was the first one to treat patients with ultraviolet rays, which have a bactericidal effect. Under natural conditions, patients are exposed to sunlight; the treatment in the rooms was done using electric arc. In this case, there were no burns, and TB bacteria were killed by ultraviolet radiation.
 For their study N. Finzen was awarded the Nobel Prize in Physiology and Medicine.

Ultraviolet radiation covers the area (gaps) of wavelengths from 380 nm (the limit of visible light) and 10 nm ( limit of X-rays ). It is divided into the high beam (200-10 nm) and low beam  (380-200 nm).

Ultraviolet radiation (UV) is absorbed by the glass, but at a wavelength of 200 nm passes through quartz, rock salt and a special glass. At wavelengths <200 nm radiation is absorbed by a thin layer of arbitrary matter, even air.
In tissues UV penetrates to 0.1-1 mm and is thus a strong biological response that manifests as erythema.

Called erythema, it is an intense redness that appears 6-12 hours after exposure, and later it becomes light brown pigmentation - tan.
There are three areas of UV :

1. Zone A – anti- rachitis

Wavelength from 400 to 315 nm and has a strengthening effect on human body. It is used in hygiene and preventive medicine.
2. Zone B - erythema . Wavelength from 315 to 280 nm, which is characterized by erythema action that is most pronounced at a wavelength of 296,7 nm. Used for therapeutic purposes.
3. Zone C - bactericidal . Wavelength from 280 to 200 nm, which is different bactericidal action that is most pronounced at a wavelength of 253,7 nm. Used for disinfection.
         Among other biological effects of UV radiation should be noted the formation of vitamin D, which promotes absorption from the intestine and absorption of calcium , which is part of the bone and has a number of essential physiological functions. If there is insufficiency in vitamin D, calcium from the food is not absorbed, and body needs to restore calcium from bones, leading to rickets. Vitamin D is found in meat and animal fat, but it can formed in the organism under the influence of UV wavelengths from 280 to 315 nm.
The death of staphylococci occurs at wavelengths of ~ 265 nm.
Law of Stefan - Boltzmann and Wien's displacement law form the basis of medical thermography, which allowed us to measure body temperature without physical contact with it and determines the temperature of its various parts within a few tenths of a Kelvin.

         Thermography - a method for detecting radiation from different parts of the surface of the body to determine the location of the pathological regions.
Thermography - a harmless and non-invasive method of beam diagnostics, recording infrared (thermal) radiation from the surface of the body. In human skin, which completely absorbs infrared radiation and, according to Kirchhoff's law , it emits at . Wavelength emitted by human skin is determined according to formula (4):

.

 

Physiological basis of thermography is to measure the intensity of thermal radiation from the pathological regions due to increased blood flow in them and metabolic processes. Reducing the intensity of blood circulation in the tissues and organs is shown as "decrease" of their thermal field.

Contact thermography is conducted using thin plastic film located on the basis of liquid crystals, which can change its color depending on the temperature. Each thermoindicator has a color- temperature characteristics for which it is possible to study the temperature distribution on the surface of the patient's body.
Contactless (remote) infrared thermography records from the skin using a mirror, which directs heat to the detector. Crystal detector is up to 0,5x0,5 mm, which when heated generates electric signals that are amplified and reproduced as an image on the screen or printed on paper.

Different regions of human skin have certain temperatures. Those which are symmetrically located areas should be almost identical, with the difference that is less than a tenth of a degree. Change (increase or decrease) of the intensity of infrared radiation of the spot can be caused by pathological changes (increase or decrease), the intensity of metabolism, and regional blood flow in it.
If using conventional thermography (in micron range) for investigation of the surface temperature of the body, in the millimeter and decimeter infrared emission spectrum, a doctor can assess the condition of the person.

Figure. 4. Thermographic image.

 

This survey is noninvasive. Information obtained by using traditional thermography can be significantly enhanced through the use of dynamic infrared thermocarding. This significantly increases the diagnostic possibilities of the method, especially in the early stages of the disease.
Scope: oncology, gastroenterology, neurosurgery, orthopedics, dermatology, orthopedics, rheumatology, traumatology, ENT pathology, pulmonology, angiology, endocrinology, psychology and psychiatry, inflammation, local tumors, circulatory disorders, trauma, wound healing processes, mental processes.
No contraindications, the study can be repeated many times. As an independent diagnostic method is rarely used, the data are analyzed with comparison of clinical and radiographic examination of the patient.
Advantages of thermography as a method of diagnosis are technical versatility, remotability, speed, high performance and safety.

 

Figure . 5. Thromboangiitis obliterans . (a) arteriography. Obstruction left thigh and popliteal arteries. (b) Thermography . Normal ventral thermogram right and moderate hypothermia lower left leg .

 

Instruments for thermography and thermal imaging.  What is used today in thermographic diagnosis is scanning equipment, consisting of a mirror that focuses the infrared rays from the surface of the body in a sensitive receiver (photoresistence of indium antimony activated germanium, germanium, with the addition of zinc, gold and mercury). This receiver requires cooling (using liquid nitrogen, liquid hydrogen, neon), which provides high sensitivity. The thermal radiation is sequentially converted into an electrical signal that is amplified and recorded as a grayscale image.

The human body is a source of infrared radiation. The maximum radiation energy corresponds to a wavelength of 9,6 microns. In a healthy person the temperature distribution through the body and infrared emission values are standard. Inflammation, tumors can change the temperature of certain parts of the body, due to which the intensity of the infrared radiation from these regions changes. Therefore, detection of thermal emission from different parts of the human body is used as a diagnostic method.

 

Modern thermal imagers.

Thermal TKVr-IFS Svit. This thermographic camera is a third generation, which works in real time. Sensor is a focal element photodetector array composed of semiconductor capacitors based on indium arsenide (InAs) (Fig. 1). Camera is designed for temperature measurement and analysis of static and variable in time thermal pictures of objects. Thermal images of objects are formed with a special infrared lens and recorded by focal matrix installed in the focal plane of the lens. Photosensitive matrix registers radiation of human skin.

 

Figure. 6. The structure of the photonic receiver.

Wavelength, micrometers

 

Figure 7. The dependence of the flux density of quanta emitted by a black body at two temperatures, versus the wavelength.

 

Elements of focal matrices convert photons of light into electrical charges which are read by silicon multiplexer, amplified, pre-processed via electronic circuit and transmitted to the computer (Fig.9). As a result, we obtain thermo-vision screen image of the object (thermogram).

 

Figure 9. Block diagram of the thermal imaging camera.
1 - Lens 2 - device calibration, 3 - cold aperture, 4 - matrix FPU, 5 - vacuum cryostat with enlightened box, 6 - generator control pulse and DC voltage, 7 - amplifier with differential output, 8 - temperature meter and FPU automatic inclusion of substrate bias voltage InAs, 9,14 - power control and synchronization, 10 - ADC 11 - summator, 12 - memory manager, 13,16 - memory banks, 15 - unit communication with a personal computer, 17 - Computer - PC

 

Technically, one of the advantages of thermal imaging device "Svit" is that the imager is based on matrix IR detector. This is an advantage compared to the imager, which uses internal scanning system, and a lot of the world market is filled with older versions. In connection with the use of the principle of accumulation of information signal matrix imagers, other things being equal benefit of scanning systems to set parameters such as reliability, sensitivity, speed, and spatial resolution.

 

Fig.10 . General view of thermal imaging camera.
1 - section of the cryostat cooled focal matrix , 2 - bay lens and calibration unit , 3 - compartment electronics 4 - neck for pouring liquid nitrogen , 5 - stand , 6 - position connector for standard cable high speed USB 2.0 A / B Cable (DUB-C5AB).

 

SUMMARY OF QUANTUM MECHANICS
1. Wave properties of particles. de Broglie’s hypothesis. Physics of atoms, molecules, atomic nuclei and elementary particles is studied in quantum mechanics. Objects microcosm of the studied quantum mechanics are linear dimensions of the order. At the essence, the quantum mechanics is based on the following idea:
1. In 1900 Max Planck ( Nobel laureate 1919 ), studying blackbody radiation, concluded that the energy emitted by the body by certain portions (quanta of energy).
2. In 1905, Einstein (Nobel laureate 1922), studying the mechanism of the photoelectric effect, proposed to consider radiation as a stream of material particles -  ‘quantum radiation’ or ‘photons’.

3. In 1913, Niels Bohr ( Nobel laureate 1922), using the planetary model of the atom, introduced the concept of energy levels of the atom explaining the laws of linear spectra. Bohr suggested that the values ​​that characterize the microcosm have to be discrete, that they can not take any value, and only certain discrete values ​​multiples of Planck's constant. Thus, the laws of the microcosm are quantum laws. At the time these laws have not yet been established by science. As Bohr based his theory postulates formulated as follows:

     I. An atom can exist only in certain stationary states of the corresponding energies. In the stationary state of the atom does not emit any energy.

II. The transition of an atom from one stationary state to the other is accompanied by emission or absorption of quanta, the energy of which is given by: , where  i – integer numbers (stationary states numbers),  – Planck’s constant .

     ІІІ. Radii of stationary states (orbitals) , where electron with mass m moves around with velocity , should satisfy the following equation:    where .

Bohr's postulates helped to explain the origin of the linear emission and absorption spectra of hydrogen, calculate the frequency of the spectral lines of the hydrogen atom.
      Stationary states of the hydrogen atom (energy levels) are defined as follows:

,                                                                      (8)

where m - the mass of the electron,  - its charge - dielectric constant.
Based on Bohr's second postulate, we can find frequency radiation of the hydrogen atom:

,                                             (9)

where n and k - the relevant energy levels of the atom.

State of atom with n=1 is called the principal. In the principal state of the hydrogen atom can stay indefinitely (provided that the external effects are absent). Conditions with n>1 known as excited. In Fig.13. is shown the system transitions in the hydrogen atom.

A. Compton (Nobel laureate 1927) in 1923, studying the scattering of X-rays by the atoms of matter, found that it is subject to the laws of elastic impact, and hence the photon pulse has a certain value. Thus, it was found that in addition to the wave, photon also has particle properties.

Figure. 11. The spectrum of the hydrogen atom.

Compton experiments showed that the wavelength of the scattered radiation is greater than the wavelength of the incident radiation , the difference  depends on the scattering angle:

 

,

(10)

where  – Compton’s constant,  – angle between initial and scattered directions of photons.

 

At the heart of quantum mechanics is the assumption that the wave-corpuscular dualism set for light has a universal character. The idea that all the particles that have some momentum, have wave properties, and their movement is accompanied by some wave process, was expressed by a French physicist Louis de Broglie (Nobel laureate 1929) in 1924.
The formula for photon momentum:

 

(11)

 

was used for other particles mass m, moving with speed v

 

,
From where ,	(12)

where  – Planck’s constant (J·sec).

 

Those waves are called the de Broglie waves.
An electron moving with a speed of 40 m/s, will have a wavelength

 

,

 

which can be confirmed by experiment.

De Broglie formula was experimentally confirmed by experiments of K. Davison and L. Germer (1927), who observed electron scattering of monocrystals of nickel. Subsequently G. Thompson and S. Tartakovsky observed diffraction of electrons on metallic foil (thickness  cm) (polycrystalline body) (Fig. 12).


 
Figure. 12. Diffraction created by electrons.

 

The wave properties of electrons can be used not only for diffraction structural analysis, but also for enlarged image objects (electron microscope).
Separation distance (resolution, or resolving power) of optical microscope:

 

,

(13)

where  the wavelength, - Refractive index - aperture angle.

 

It follows from (10), the distance resolution of optical microscopy is limited to wavelengths in the visible spectrum (400 - 700 nm) and does not exceed 0.5.
For electron microscope:

 

(14)

where - acceleration voltage, and separation distance (resolving power) equals

 

(15)

 

The wavelength of an electron is accelerated, accelerated difference for 150V is 0.1 nm, which almost coincides with a resolving power of an electron microscope.

Types of Electron Microscopes

1. Translucent (transmission) electron microscope - a device in which the electron beam passes through object of the study (Figure 13 (a)).
2. Scanning electron microscope is used to study the surface of the object using electron beam ejected secondary electrons (Fig.14.).
3. Reflex electron microscope, with that of detecting X-rays are used to study the chemical composition of the object of study (Fig. 15).
The structure and appearance of the electron microscope are shown in Fig. 15.

Fig 13. Schematic structure (a) and general view (b) of transmission electron microscope.

 

The camera of the microscope is equipped with vessel with liquid nitrogen, creating a high vacuum (10^-6 Pa) to eliminate the interaction of electrons with molecules of air. Beam accelerated by the potential difference of the order of 200 kV (for biological objects), the system is operated by electro-magnetic lenses that focus beam on the object. Those electrons which are not dissipated, are passed through the diaphragm, creating on-screen or on-film enlarged image of the object. Electron microscopes can magnify images by 2 million times.

Figure 14 Scanning Microscope: a) general view, b) schematic representation.

Figure. 15. General view of the microscope REMMA-102.
The wave properties are manifested in macroscopic bodies. De Broglie wavelengths for these bodies are so small that they can not be identified.

2. Wave function and its physical meaning. Uncertainty relation.
Since microparticles are compared with the wave process that corresponds to its motion, the state of a particle in quantum mechanics is described by the wave function dependent on the coordinates and time: .
The intensity of the de Broglie waves is determined by the square modulus of the wave function.

In experiments on electron diffraction, it was shown that the intensity of the waves in a given point in space determines the number of electrons trapped in this point in 1 s. This became the basis for probabilistic interpretation of de Broglie waves described by the function. The probability that the particle is in the volume , is proportional to  and volume .

 

(16)

The value  is the probability density and sets the probability of a particle being at a given point in space.

 

(17)

 

In quantum mechanics, there are limitations in the capabilities of simultaneous determination of the coordinates of the particles and the magnitude of their momentum. These restrictions are due to the wave-particle dualism of the microparticles. Heisenberg (Nobel laureate 1933) showed that more accurately identified one of the two variables that determine the state of microparticles, those with less accuracy can be determined by the second one and vice versa. The multiplication of errors, which are determined by these values, ​​can not be less than

Planck's constant.

 

For example, if the coordinate of a particle that moves along the x-axis is defined with an error , the particle momentum is determined with an error, according to the uncertainty principle:

 

(18)

 

The meaning of (8) is not only that there is a definite limit to the accuracy of measurement, but also in the fact that with decreasing particle localization in space increases uncertainty in determining its momentum.
Other value uncertainty establishes is a relationship between energy and time:

 

.

(19)

 

The greater accuracy is achieved in the measurement of time, the accuracy will be lower than in the estimation of energy.
The fundamental principle of Heisenberg uncertainty at the time in the Soviet Union was declared contrary to dialectical materialism and it was forbidden to publicly mention the principle in the papers.

In quantum mechanics effect on objects during the measurement can not be considered small or insignificant - the state of the object during the measurement can change. For example, to determine the position of an electron it is necessary to "light up" it up with the flow of photons. As a result of collision of electron and photon, electron momentum changes by an amount .

 

6.1.3. Schrödinger equation and its solution for the hydrogen atom. Quantum numbers.

After discovery of the Heisenberg uncertainty relation in 1927, there was the creation of the quantum theory of particles, as was the impossibility to describe the movement of particles through the notion of trajectory. State of the microparticles can be set by -function - a function that is defined by the Schrödinger equation (Nobel laureate 1933), which plays in quantum mechanics the same role as the equations of Newton in classical mechanics. Figuratively speaking, the Schrödinger brought the concept of classical mechanics into the language of quantum theory. Using the Schrödinger wave equation can describe the evolution of - function, if it is known at some point in time. E. Schrödinger - author of "What is life from the point of view physics" (1943).

 

If -function is independent of time (), it satisfies the stationary Schrödinger equation, which for one-dimensional case has the form:

 

(20)

where m - the mass of the particle, and and – its full and potential energy.
Functions that satisfy the Schrödinger equation for a given form are called personal functions. They exist only for certain values ​​of energy.

        

Description of atoms and molecules with Schrödinger equation is rather complicated task. The easiest way is solved for a single electron in the field of the nucleus.

Solution Schrödinger equation (6.10) is found in a product of three functions, each of which depends on a single variable:

 

(21)

 

The general solution of Schrödinger equation is discrete, ie, each function has a set (array) of solutions, each of which corresponds to the appropriate quantum number. The first of these principal quantum number  ... . It determines the energy levels of the atom

 

(22)

 

The second quantum number  - orbital, which for a given value of n can take . This number describes the orbital angular momentum of the electron relative to the nucleus:

 

(23)

 

The third quantum number  - magnetic which takes the value  at the given values ​at ​only of  total of values.
This number determines the projection of the orbital angular momentum of an electron at randomly chosen direction:

 

(24)

 

The fourth quantum number – spin number . It can take only two values  ​​.

Spin angular momentum of the electron

 

.

(25)

 

The projection of the spin angular momentum of the electron in the direction of the external magnetic field, which coincides with the axis Z

 

.

(26)

 

The number  is called the magnetic spin quantum number.
Spin magnetic moment of the electron and its projection on the direction of the external magnetic field, which coincides with the axis

 

,

(27)

where - the Bohr magneton.

An electron moving in an orbit around the atomic nucleus has an orbital angular momentum , own spin moment as well as full momentum , which is determined by the vector sum of these points:

.

(28)

 

The value of total angular momentum is given by:

 

.

(29)

 

Quantum number of total angular momentum can take values

 or.

 

Stationary quantum state of an electron in an atom is characterized by a complete set of four quantum numbers: principal , orbital , magnetic  and spin .

 

For elementary particle with spin equal to  (electrons, protons, neutrons, etc.), Pauli principle (Nobel laureate 1945) is true: in any system of particles with spin  can not be more than one particle is in steady state which is determined by this set of four quantum numbers.

If is a number of electrons in an atom that are found in the states, defined this set of four quantum numbers, then

 

 or 1.

 

The largest number  of electrons in an atom, which are in a state defined by a set of three quantum numbers :

 

The largest number of electrons in an atom, which are in a state defined by a set of two quantum numbers   :

 

 

The largest number of electrons  in an atom that are in states that are determined by the value of the principal quantum number n:

 

 

State of correspond to states with 4 orbitals: = (2, 0, 0), (2, 1, 1), (2, 1, 0) or (2, 1, 1). Thus, the state of  can contain 8 electrons, which confirms the formula (6.20.)

Full orbital moment of the atom

 

,

(31)

where - total orbital quantum number which takes only integer positive values :

 

 

For example, for two electrons with  and   we will get: .

 Full spin moment of the atom:

 

,

(32)

 

Where - total spin quantum number.

In the case of an even number of electrons, when the electron spins of different pairs are compensated , and   - for a system with an odd number of electron spins where all electrons except one are pairwise compensated. Thus, for two, three, four, etc. electrons can take the values​​:

 and so on.

Full angular momentum of the atom:

 

,

(33)

where - total internal quantum number, which for the  given  і  can take the following values:

 

.

 

While describing energy of each electron, spectroscopic symbols are used, consisting of uppercase letters that correspond to different values ​​of the quantum numbers:

Value of	0	1	2	3	4	5	…..
Symbol	S	Р	D	F	G	H	…..

 

4. Absorption and emission energy by atoms and molecules.

Spectra of atoms.
Usually, atoms exhibit a tendency to remain in the ground state E0 with minimal energy. The transition from the ground level E0 to the excited level E1 corresponds to the absorption of a photon hv (Fig. 17, a), the transition from level E1 to level E0 is a radiation emmission of a hv photon (Fig. 17, b). Transitions are accompanied by a sharp change in the absorption (or emission) when changing frequency of optical radiation (Fig. 17, c) or wavelength (Fig. 17, d), that is characterized by the appearance of spectral narrow absorption lines (or radiation).

Figure. 16. Spectral properties of the atom: a - absorption of a photon by an atom b - emission of a photon by an atom, c - spectral line absorption (or emission) d - the same with the scale of the wavelength

 

Spectra of molecules

Spectra of molecules are characterized by somewhat more complex structure than the spectra of atoms. This is due primarily to the participation of the molecule as a dynamical system (consisting of atoms), with three types of movements: electron (motion of electrons around the nucleus), oscillation (oscillation around the equilibrium positions of nuclei) and rotation (rotation of the molecules as a whole in space). Thus, the energy of a molecule can be represented as:

 

E = E_ел + E_кол + E_об                                          (34)

Fig. 17. Energy levels of molecules

 

According to Bohr's postulates, a molecule can exist only in certain discrete energy states. The total energy E of the molecule is characterized by a set of electron, vibrational and rotational levels. Between-levels molecular transitions accompanied by the formation of electron-vibrational-rotational spectra. Electronic spectra are located in the ultraviolet and visible parts of the spectrum, vibrational - in the infrared, rotational - in the far infrared and microwave parts of the spectrum. Energy diagram of the molecule is shown in Fig. 17. Spectra of molecules are more complex than the spectra of atoms, due to a set of individual spectral lines that overlap. Therefore, absorption spectra of molecules characterized by wide bands (Fig. 18). After absorption of a photon and the transition of the molecule in the excited state it is involved in the transitions between sublevels. Therefore, absorption peak is always located in the region of higher frequencies (or shorter wavelength) than the peak emission.

 

 

Figure. 18. Energy levels (a) and absorption band (b)


                          The phenomenon of luminescence

Body luminescence in a specific spectral region is called the excess radiation, which has a duration of more than s, which exceeds the period (c) light waves.

Luminescence can be caused by body electron bombardment, by passing an electric current through a substance or an electric field, by illumination with visible light, by X-rays and gamma-rays and by some chemical reactions in the material. Depending on how the excitation of fluorescent glow is caused, respectively, we can distinguish cathodoluminescence, electroluminescence, photoluminescence, x-ray luminescence, chemiluminescence.

Luminescence with decay time of an order of  sec is usually called fluorescence. Such decay is common for liquids and gases. Luminescence that persists long after the termination of the excitation source is called phosphorescence. Such prolonged flashings are emitted by solids.

 

Figure . 19. Typical energy diagram of chlorophyll

 

Electron shell of the molecule that is in the ground state is in the singlet state S0. When molecules absorb photons of light, the electrons move to the outer membranes of higher energy levels SK ( k = 1,2, 3 ...). Transition of electrons from the excited levels of SK to the main S0 always starts with transitions from the upper excited levels to the lowest not-excited level. This transition S2 → S1, S3 → S2 (Fig.21 ) at which photons are not emitted and electronic energy is converted into heat. The next step is to move the electrons from the lower excited state S1 to the primary S0. This will be done with emittion of luminescence quantum. Luminescence, which is accompanied by transition of electrons from the triplet level T1 is called phosphorescence. Since the triplet level T1 is below the excited singlet level S1, then the wavelength of light that is emitted in phosphorescence is greater than that which is emitted in fluorescence.

Consider the phenomenon of photoluminescence, which is excited by electromagnetic radiation of visible or ultraviolet range. D. Stokes studied the photoluminescence, who found that photo-luminescent substance emits usually light that has a longer wavelength than the radiation, which causes luminescence.

This rule is explained in quantum optics.
Indeed, a photon of light, which causes the photoluminescence, has energy hν, which, according to the law of conservation of energy, partly spent on creating fluorescent photon radiation with energy, and various non-optical processes:

 

,

(35)

 

where – energy, spent on various processes besides photoluminescence. Usually, і , which means , that is true to the Stokes theory.

In some cases, photo-luminescent radiation has a wavelength, less than the wavelength of the excitation light (called anti-Stokes radiation). This phenomenon is explained by the fact that the excitation energy of a quantum of radiation energy is added to the thermal motion of atoms (molecules or ions) luminescent substances:

 

,

(36)

 

where  - coefficient depending on the nature of the luminescent material, - the Boltzmann constant, - absolute temperature.

Ant-Stokes radiation is shown more clearly with increasing temperature.
Luminescent analysis is based on the phenomenon of luminescence, the principle of which is as follows: substance on its own or after the relevant action gives the characteristic fluorescent glow. The nature of this luminescence based on the intensity of the lines in the spectrum, can be used to determine not only qualitative, but also quantitative value of the substance. Fluorescent analysis reveals the presence of impurities in the order of g in 1 g of the substance. It is used in medicine to diagnose diseases. In malignant diseases luminescence of the affected tissues, such as blood and urine, usually is brighter than in healthy people. A number of biologically functional molecules, such molecules are membrane proteins, can cause fluorescense. Fluorescent molecules alter the structure of their environment that allows us to study chemical transformations and intermolecular interactions.
If through the cell with a solution of fluorescent substance monochromatic light passes with intensity , the amount of absorbed energy  and dissipation energy are related:

 

                                                         (37)

 

Luminescence intensity  is proportional to the intensity of the scattered light, fluorescence quantum yield  and coefficient , which depends on the solid angle within which there is a fluorescent light:

 

                                                             (38)

 

Substituting formula Bouguer-Beer in formulas (1) - (2) we obtain:

 

                                                      (39)

Expanding (3) in series and assuming that , we find photoluminescent intensity of radiation:

 

                                                       (40)

 

Thus, at low optical density of the solution , the intensity of the fluorescent radiation depends on the concentration of fluorescent material.

Fluorescent microscopic analysis of objects carried by special fluorescent microscopy, in which instead of conventional light sources mercury lamps are used with high pressure (150-400 mm Hg) and with ultrahigh (above atmospheric ) pressure, which have two filters. One is located in front of condenser, highlights that part of the spectrum of the light source, which causes luminescence object. The other is located between the objective and eyepiece, provides light of luminescence.

 

Fig 20. The appearance and structure of fluorescence microscope.

 

The principle of fluorescence microscope

 

The process of energy absorption of photons by organic and inorganic substances, with the subsequent emission of rays of greater wavelength, is a phenomenon known as fluorescence (luminescence). Light emission after irradiation with shorter wave radiation appears simultaneously with the onset of absorption of exciting radiation. This radiation has a greater wavelength than the exciting radiation. If the luminescence time after the cessation of the exciting radiation lasts more than a microsecond, the process is called phosphorescence.
This phenomenon was first discovered and described by Englishman George G. Stokes in 1852. He noted that the mineral fluorite began to glow reddish light if illuminated with ultraviolet rays. Further investigation showed that many of the objects: organic and inorganic materials, crystals, resins, oils, chlorophyll, vitamins, etc. can fluoresce if illuminated with ultraviolet light. Only since 1930 scientists began using fluorescence phenomena in biological research. They studied elements (tissues, bacteria, pathogens, etc.) for their identification after those elements were treated with fluorescent dyes. This led to the creation of fluorescence microscopy.

The basic principle of the fluorescence microscope is that irradiated with UV light sample fluoresces. In perfectly-functioning microscope, only the light from the object excited by fluorescence reaches the eyes of the researcher or the detector so that the resulting fluorescent structures are seen at a high contrast with black background. They literally glow in the dark. The problem is that the excitation light is usually hundreds of thousands, and sometimes millions of times brighter than the light emitted by fluorescence. The figure below shows a diagram of a modern fluorescent microscope for research, using transmitted and reflected light.
Schematic diagram of the fluorescent microscope consists of a source of ultraviolet radiation, excitation and closing filters, thermal (heat-resistant) filter and special fluorescent lens/objective. The light source emits waves in the ultraviolet region of the spectrum that pass through the filter, which cuts off spectral range of other wavelengths. Ultraviolet rays fall on the object of the study cause its luminescence. Luminescence light passes through the locking filter that does not pass the excitation light (ultraviolet waves) and then forms an image through the lenses.
It should be noted that the fluorescence is the only way in optical microscopy, in which a sample after the illumination, itself emits light. This light is emitted spherically in all directions, regardless of the direction of the excitation light source.

Luminescence that caused by exothermic (with heat) and chemical processes in the material, called chemiluminescence.  Another case is biochemiluminescence - luminescence accompanying chemical reactions of biological objects (glow of the rotten trees, fireflies, etc.). Biochemiluminescence occurs during recombination of free radical peroxidation of lipids: excited chemical molecules + quantum of biochemiluminescence. Biochemiluminescence intensity varies considerably with the introduction into the system of salts of divalent iron. For example, if you submit ferrous iron salts in the blood plasma of a patient having appendicitis and cholecystitis, the glow in the former case is much weaker. So biohemiluminescence can be used as a diagnostic method. When irradiated with ultraviolet, serum biochemiluminescence increases if the serum is derived from healthy people and decreases in case of cancer patients.

5. Electron paramagnetic resonance

If an atom with a magnetic moment different from zero, placed in a magnetic field, each energy level of an atom is split.
With the splitting of energy levels in a magnetic field, caused by the presence of electrons and nuclear particles in the magnetic moments associated magnetic resonance phenomenon, which plays an important role in modern methods of studying the structure and properties of matter.
Magnetic resonance is called selective absorption of energy of alternating electromagnetic fields by the substance that is placed in a constant magnetic field. An important special case of resonant absorption is electron paramagnetic resonance, discovered in 1944, by E. K. Zavoyskyy.
The phenomenon of electron paramagnetic resonance (EPR) is a paramagnetic substance absorption of microwave radio emission by transitions between sublevels. The splitting of energy levels is due to the action of a constant magnetic field on the magnetic moments of the particles of matter.

 

Figure. 21. The splitting of energy levels.

Bohr magneton  is a unit of measurement of electron magnetic moments:

 

,

(41)

 

where - charge, - electron mass, - the Planck constant. Similarly, the value determines the energy splitting of the energy levels of electrons in atoms, that are in a magnetic field. Here - Lande factor; there is a dimensionless coefficient  if spin moment of the atom , and , if the orbital moment of the atom , and the total angular momentum of the atom is equal to spin moment of the atom .

When considering EPR, only the spin magnetic moment of the atom is considered. The splitting of energy levels leads to the splitting of spectral lines of atoms, which are placed in a magnetic field. This phenomenon is called the Zeeman effect. The distance between adjacent sublevels is given by:

 

(42)

 

The splitting of energy levels due to the action of a constant magnetic field on the magnetic moments of electrons that determine the paramagnetic properties of substances. There is a preferred orientation of the magnetic moments of atoms along the direction of the magnetic field corresponding to the magnetized state of paramagnetic substances. When applying the alternating magnetic field to the substance with a frequency

 

,

(43)

 

which coincides with the frequency of the transition between the Zeeman splitting sublevels,  then resonance absorption of electromagnetic waves happens.
It is due to the predominance of the number of transitions from more populated lower energy levels to less populated upper levels. The absorption is proportional to the number of absorbing atoms per unit volume of material. With induction B = 10³ mT, resonant frequencyHz, corresponding to the scale electromagnetic radio waves (l= 3 cm ).

Graph of power absorbed electromagnetic energy from the magnetic field B is called the EPR spectrum (Fig. 24).

Figure. 24. EPR spectra.

 

During EPR, along with the absorption of energy, a reverse process is present as well. The ongoing transition of atoms to lower energy levels, and their energy is transferred to the crystal lattice. This process is called spin-lattice interaction and is characterized by the relaxation time . Thus, resonance absorption occurs in some interval  (Fig. 22). The less time of lattice spin relaxation, the greater line width (in Fig. 22).
Block diagram of the EPR - spectrometer is shown in Figure 23.

 

Figure . 23 Block diagram EPR - spectrometer.

where 1 – electromagnet, 2 - generator of electromagnetic waves, 3 - cavity resonator, which concentrates the incident energy on the sample 5, 4 ​​- Receiver, 6 - recording device.

 

In biomedical research EPR is used to detect and study free radicals, photochemical processes, including photosynthesis, some carcinogenic substances. If the objects under study have diamagnetic properties, then researchers use paramagnetic labels/tags (oxygen radicals) that bind to the molecules of the object. Using EPR spectra, we can find locations of the tags in the molecule. This way you can identify the location of different groups of atoms, their interaction and movement. Also used spin probes - paramagnetic particles that are covalently bound molecules. Changing EPR - range spin probe provides information about the state of the surrounding molecules. The main parameters of the EPR spectrum are the integrated intensity, half-width lines, and- factor.

The integrated intensity of the signal - is the area under the curve of absorption. It is a measure of the number of unpaired electrons (free radicals) that are in the sample.

The location of the absorption lines in the spectrum is determined by g - factor and it allows to identify the particle.

The half-width lines determine the splitting of energy levels. Expanding the resonant band may be due to the spin-spin and spin-lattice interactions. One of the features of these interactions is the relaxation time. Expanding bands due to spin- spin interaction is proportional to the distance between the paramagnetic particles, so you can find the band half-width allocation paramagnetic centers in the sample, as well as the structure of paramagnetic molecules.

 

6. Resonance methods of quantum mechanics. Nuclear magnetic resonance. MRI - scan.

The basis of the technique of nuclear magnetic resonance ( NMR) is collective absorption of electromagnetic energy by matter, due to quantum transitions between atomic nuclei energy states with different spin orientations I (own momentum) of the atomic nucleus. The NMR is observed when two mutually perpendicular magnetic field: B0 intense, and weak radiofrequency (RF) B1 ( 10-10 Hz) are applied to the sample. It is known that the nuclei of all elements have an electrical charge that is positive and equal to the absolute value of the sum of the charges of atomic electrons. Due to the spin during rotation, nucleus acts as an elementary magnet ( Fig. 24). Thus, the nucleus is characterized by magnetic moment, whose value depends on the nature of the atom nucleus. Nuclei with an even number of protons and an even number of neutrons do not have spin and magnetic moment, whereas the nucleus of an even number of protons and odd number of neutrons has spin and dipole magnetic moment. If the sample is placed in an intense homogeneous magnetic field B0, all dipoles begin precessing around the direction of the magnetic field.

 

Figure. 24. The nucleus during rotation as an elementary magnet

 

Moreover, one group of dipoles shows the total orientation along the magnetic field, while the second – against the field (Fig. 27). It should be noted that in the equilibrium number of dipoles oriented along the field exceeds the number of oppositely oriented dipoles. This can be explained that in the main energy state when the magnetic dipoles oriented along the magnetic field, the energy of the nucleus is less than excited for which inherent orientation is opposite to the magnetic field.

 

Figure. 25. The behavior of the magnetic moments of nuclei: a – case of absence of an external magnetic field, b – case of presence of an external magnetic field B0

Due to the precession of the magnetic moment, variable magnetic moment is produced  (Fig. 26), which rotates in a plane perpendicular to B0. Field B1, rotating in the same plane with frequency o, interacts with the moment of μ; this interaction becomes noticeable if ω ~ ω0, and the direction of rotation of μ and B1 are the same. The selection rules determine a definite orientation relative to the direction of the magnetic moment field B0: for spin 1 the number of allowed orientations is 2І + 1, which are namely I, (I - 1 ), ... - (I - 1 ) -I. Thus, for isotopes 1H and 13C, which have spin I = 1/2, allowed orientation that corresponds to values 1/2 and -1/2. For isotopes of spin I = 2, the number of allowed energy levels is calculated as 2І + 1 = 5. The energy difference ΔE between the levels is proportional to magnetic induction (Fig. 29): ΔE = γћV0 .

Figure 26. Formation due to the precession of the variable magnetic moment, which rotates in a plane perpendicular Bo.

 

The magnetic moments of nuclei are the sum of the magnetic moments of nucleons. The unit of measurement of magnetic moments of nucleons is the nuclear magneton

 

,

(44)

 

where  and  - the charge and mass of the proton, which is 1836 times greater than the mass of the electron. Therefore, nuclear magneton is 1836 times smaller than the Bohr magneton.

In the presence of an external magnetic field with induction in the projection on the z axis, magnetic dipole moments of the proton and neutron are respectively equal:

 

The negative sign of the projection of the magnetic moment of the neutron indicates that it is directed against the direction of the angular momentum.
The magnetic moment of the nucleus in a constant magnetic field can take only discrete orientation. NMR occurs on nuclei having spin 1/2. They are oriented towards the field or against it. This means that the energy of the nucleus will be corresponding to the sublevel energy distance between them, depending on the magnetic field.

 

(45)

 

where  – nuclear factor of Lande.

 

Figure. 27. Energy diagram of nuclear spins: the energy difference ΔE between the levels is proportional to the magnetic induction.

 

If we influence the nucleus with electromagnetic field, it is possible to induce transitions between sublevels. To make these transitions and energy absorption of the electromagnetic field, it is necessary that its frequency satisfies the condition:

 

(46)

 

Similarly to the conditions for EPR (36).

NMR can be observed when the condition (36) is true only for the free atomic nuclei. Experimental values ​​of  in nuclei of atoms and molecules do not follow (36). One must consider the local magnetic field surrounding nuclei. Therefore, the full effective magnetic field acting on the nucleus, is characterized by function:

 

(47)

 

where - was the screening that is equal in order of magnitude of , depending on the electronic environment of the nuclei. Thus, for this type of nuclei from different environments, resonance is observed at different frequencies, which determines the chemical shift. If the nucleus in the molecule shielded differently, they occupy chemically non-equivalent positions.

NMR spectrum of such molecule has so many resonance lines as chemically non-equivalent groups of nuclei of this type are in the molecule. The intensity of each line is proportional to the number of cores in the group. Spectra of solids have a greater width than spectra of liquid.

According to the number and position of spectral lines we can define the structure of molecules.

Scheme of NMR spectrometer is shown in Fig. 28. The sensitivity with which NMR signal is perceived depends on the nature of the isotope and difference populations between ground and excited levels. NMR technique is used to measure water cell interaction with membranes or macromolecules.

Figure. 28. Scheme of NMR spectrometer

 

The generator creates a field with induction , while a  perpendicular field  is created by the permanent magnet. When , there is a resonance absorption, resulting in the circuit voltage drop. It is recorded by voltage detector, amplified and fed to the oscilloscope. Field  is chosen the way that it is changed by Tl at a frequency of 50 Hz to 1 kHz, and the same is a horizontal scanning frequency of the oscilloscope. Therefore, absorption band is seen on the screen.

 

Magnetic resonance imaging ( MRI)

The nuclei of phosphorus, fluorine, hydrogen and other elements present in the human body, are similar to the "whirlgig ", which rotate on its axis. If you put them in a constant magnetic field, the axis of "those whirlgigs " are oriented toward the induction field lines: one along the field, while others - against it. If you perpendicularly apply variable high-frequency signal (radiowaves), the "nuclear whirlgigs" receive energy while revolving around the magnetic field lines at a well defined resonant frequency (hence the name - nuclear magnetic resonance).
After switching off the current, nuclei will continue the precession for some time due to inertia. Gradually this movement is weakened, but we can say that there is a spin echo. Based on value and speed of its decline we can judge the properties of matter: the greater the density, the faster echo vanishes.
Let the object be in a magnetic field with certain form and induction. After changing the "nuclear whirlgigs", we will register their spin echo. Processed by computer, we can obtain the spatial distribution of the concentration of nuclei, as well as the time during which spin echo diminishes - NMR scan.
Water is the main component of biological objects, therefore, the studied signal during MRI is usually a proton magnetic resonance of water molecules.
NMR frequency is proportional to the induction of an external magnetic field and, therefore, creating a gradient field in the tissue, we obtain NMR spectrum in which the intensity of the signal at a certain frequency will characterize the relative water content in a part of tissue that is mentioned in a magnetic field.
The tested biological object can be seen from different angles in a magnetic field. According to projections obtained using a computer, we can get a picture. There will be different amplitude of the NMR signal in different parts of the sample, and it enables you to investigate each point/location of a biological object. This way you can identify the size and position of tumors in the body. Tumor is characterized by large magnetization, as water NMR signal saturation in tumors occurs more easily than normal tissue signal. This research method can be used to produce images of the inside of the chest and certain areas in the region of the skull. There are studies of not only proton resonance in biological studies using NMR spectroscopy, but also other nuclei are studied, such as .

If NMR scanner is set at a specific radio frequency and induction field, the specific nuclei will react, such as hydrogen, phosphorus. Thus, MRI makes it possible to explore the subtle chemical processes in the human biotissues. MRI not only has great diagnostic potential, but also ensures complete safety for the patient. This method of imaging has precise measurement of internal structures of complex objects without destroying them.

In modern MRI, predominantly the frequency of alternating magnetic field is determined for hydrogen atoms, therefore, the more hydrogen atoms will be present in a tissue, the stronger MR signal we get. Anatomical areas with low density of hydrogen, such as air and bone, will induce very weak MRI signal and the computer image is dark. Areas with a high density of water are brighter. Moving tissues do not generate the MRI signal, so the vessels and chambers of the heart are dark.

Thus, magnetic resonance imaging - a study of the morphology of tissue layers, where the brightness of the image depends on the type of tissue. On MRI images the resolution of distinguished area has a size of 2-4 mm.

Figure. 29. Conducting tomographic examination.

 

MRI can visualize the structure of the various internal organs of the human body as a set of images of individual slices (cross-sections) with their contrast in proton density, using T1 (time of spin-lattice relaxation) and T2 (time of the spin-spin relaxation), providing a differential diagnosis of pathologies of various internal structures ( Fig. 31). The user has the opportunity to manage the MRI scanner by changing number, relative position, and orientation of slices, contrast settings etc. These images are stored in a database and can be analyzed on screen or displayed on print using paper or transparencies.

 

Figure. 31. Images of human tissues and organs by NMR .

 

The system uses a permanent magnet with a cylindrical hole, built-in gradient coil and the magnetic field of about 0.15 Tesla.
Magnet is a major part of MP- tomography, which creates a strong steady magnetic field. Most modern magnets produced by different manufacturers are superconducting.

Inside the magnet, gradient coils are designed to create a controlled change of the main magnetic field B0 along the axes X, Y and Z and for spatial localization signal. Gradient coil due to its configuration creates controlled, uniform and linear change of the field in a particular direction, with high efficiency, low inductance and resistance.

Gradient coils are of different sizes, configurations, and come in the following types:

a) coil in the form of "8" ;

b) Golay coil that creates a magnetic field gradients perpendicular to the main field;
c) Helmholtz coil - a pair of coils with a current that creates a uniform magnetic field in the center between them;

d) Maxwell coil that creates a field gradients in the direction of the main magnetic field;
d) double saddle-like coil, which creates a gradient in axes X and Y.

 

 

Figure 32. Scheme of superconducting magnet

 

For the chosen spatial excitation volume using three orthogonal coils which are connected, creating the necessary gradient fields that are added to the main field (B0). For example, when coding the signal to create a gradient in the Z axis, one can use a pair of Helmholtz and Maxwell coils, and for the axes X and Y - paired saddle coils. Several methods for rapid mapping gradients are used to generate reverse pulse.

The use of these coils can reduce the number of signal averaging with a high signal/noise ratio and resolution, thereby reducing the time of the scan.
Saddle coil consists of two loops of wire to wrap the opposite side of the cylinder, and is used when a static magnetic field is coaxial to the longitudinal (along the body) axis of the coil.

Phase-sensitive detector is a device that consists of two converters, two filters, two amplificators, and a 90°- phase transformer. It has two inputs and two outputs. The inputs provide frequencies ν and ν0 and the output values are transverse magnetizations Mx and Mu. Analog-to-digital converter converts the MP signal into digital signal, which is processed using Fourier transformations and displayed as an image on the monitor.

The computer that controls all the components of the imager contains unit of data transfer and storage, image reconstruction, storage and RAM, and peripherals, which include power device and input/output. Computer program manages gradients that determine the type and amplitude of each of the three gradient fields required for data acquisition and data processing for displaying images (Fig. 33). Gradient amplifier increases the power of the gradient pulses to a level sufficient to control the gradient coils. Source of RF pulses and pulse programmer are RF components that are controlled by a computer. RF amplifier increases the power pulses from milliwatt to kilowatts. Selection and modification of the sequence that reflects input into the computer performed via the control unit.

 

Figure . 33. Computer program manages gradients

 

 

Formation of stimulus signals, providing imaging, in tomograph "UNITOM" is done using digital methods. The processed NMR signal in the receiver of the digital path which uses computational resources specialized digital integrated circuits a high degree of integration, signal processor and CPU IBM- compatible PCs .

 

Figure . 34. Magnetic resonance system Aperto 0,4 T.

Diagnostic capabilities of magnetic resonance imaging :
• MR imaging of the brain ;
• MR imaging of the spine and spinal cord;
• MR imaging of joints;
• MR imaging of the heart and its chambers;
• MR imaging of the abdomen and its environment;
• MR imaging of the pelvic organs (gynecology , urology);
• MR imaging of the orbits ;
• MR imaging of the sinuses;
• MR-angiography imaging of blood vessels: brain , carotid and vertebral arteries, the thoracic and abdominal aorta, renal arteries, the arteries of the lower extremities;
• MR-tomography venography ( phlebography ) of the brain and lower genital vein.

THE ROLE OF INFRARED IMAGING IN THE DETECTION OF CANCER

 

    In order to evaluate the value of thermography, two viewpoints must be considered: first, the sensitivity of thermograms taken preoperatively in patients with known breast carcinoma, and second, the incidence of normal and abnormal thermograms in asymptomatic populations (specificity) and the presence or absence of carcinoma in each of these groups.

    In 1965, Gershon-Cohen, a radiologist and researcher from the Albert Einstein Medical Center, introduced infrared imaging to the United States. Using a Barnes thermograph, he reported on 4,000 cases with a sensitivity of 94% and a false-positive rate of 6%. This data was included in a review of the then current status of infrared imaging published in 1968 in CA - A Cancer Journal for Physicians.

    In prospective studies, Hoffman first reported on thermography in a gynecologic practice. He detected 23 carcinomas in 1,924 patients (a detection rate of 12.5 per 1,000), with an 8.4% false-negative (91.6% sensitivity) and a 7.4% false-positive (92.6% specificity) rate. 

    Stark and Way screened 4,621 asymptomatic women, 35% of whom were under 35 years of age, and detected 24 cancers (detection rate of 7.6 per 1,000), with a sensitivity and specificity of 98.3% and 93.5% respectively.

    In a mobile unit examination of rural Wisconsin, Hobbins screened 37,506 women using thermography. He reported the detection of 5.7 cancers per 1,000 women screened with a 12% false-negative and 14% false-positive rate. His findings also corroborated with others that thermography is the sole early initial signal in 10% of breast cancers.

    Reporting his Radiology division's experience with 10,000 thermographic studies done concomitantly with mammography over a 3 year period, Isard reiterated a number of important concepts including the remarkable thermal and vascular stability of the infrared image from year to year in the otherwise healthy patient and the importance of recognizing any significant change. In his experience, combining these modalities increased the sensitivity rate of detection by approximately 10%; thus, underlining the complementarity of these procedures since each one did not always suspect the same lesion. It was Isard's conclusion that, had there been a preliminary selection of his group of 4,393 asymptomatic patients by infrared imaging, mammographic examination would have been restricted to the 1,028 patients with abnormal infrared imaging, or 23% of this cohort. This would have resulted in a cancer detection rate of 24.1 per 1000 combined infrared and mammographic examinations as contrasted to the expected 7 per 1000 by mammographic screening alone. He concluded that since infrared imaging is an innocuous examination, it could be utilized to focus attention upon asymptomatic women who should be examined more intensely. Isard emphasized that, like mammography and other breast imaging techniques, infrared imaging does not diagnose cancer, but merely indicates the presence of an abnormality. 

    Spitalier and associates screened 61,000 women using thermography over a 10 year period. The false-negative and positive rate was found to be 11% (89% sensitivity and specificity). 91% of the nonpalpable cancers (T0 rating) were detected by thermography. Of all the patients with cancer, thermography alone was the first alarm in 60% of the cases. The authors also noted that "in patients having no clinical or radiographic suspicion of malignancy, a persistently abnormal breast thermogram represents the highest known risk factor for the future development of breast cancer" [28].

    Two small-scale studies by Moskowitz (150 patients) and Treatt (515 patients) reported on the sensitivity and reliability of infrared imaging. Both used unknown "experts" to review the images of breast cancer patients. While Moskowitz excluded unreadable images, data from Threatt's study indicated that less than 30% of the images produced were considered good, the rest being substandard. Both of these studies produced poor results; however, this could be expected from the fact alone that both used such a small patient base. However, the greatest error in these studies is found in the methods used to analyze the images. The type of image analysis consisted of the sole use of abnormal vascular pattern recognition. At the time these studies were performed, the most recognized method of infrared image analysis used a combination of abnormal vascular patterns with a quantitative analysis of temperature variations across the breasts. Consequently, the data obtained from these studies is highly questionable. Their findings were also inconsistent with numerous previous large-scale multi-center trials. The authors suggested that for infrared imaging to be truly effective as a screening tool, there needed to be a more objective means of interpretation and proposed that this would be facilitated by computerized evaluation. This statement is interesting considering that the use of recognized quantitative and qualitative reading protocols (including computer analysis) was available at the time.

    In a unique study comprising 39,802 women screened over a 3 year period, Haberman and associates used thermography and physical examination to determine if mammography was recommended. They reported an 85% sensitivity and 70% specificity for thermography. Haberman cautioned that the findings of thermographic specificity could not be extrapolated from this study as it was well documented that long term observation (8-10 years or more) is necessary to determine a true false-positive rate. The authors noted that 30% of the cancers found would not have been detected if it were not for thermography.

    Gros and Gautherie reported on 85,000 patients screened with a resultant 90% sensitivity and 88% specificity. In order to investigate a method of increasing the sensitivity of the test, 10,834 patients were examined with the addition of a cold-challenge (two types: fan and ice water) in order to elicit an autonomic response. This form of dynamic thermography decreased the false-positive rate to 3.5% (96.5% sensitivity). 

 

    In a large scale multi-center review of nearly 70,000 women screened, Jones reported a false-negative and false-positive rate of 13% (87% sensitivity) and 15% (85% sensitivity) respectively for thermography [36]. 

    In a study performed in 1986, Usuki reported on the relation of thermographic findings in breast cancer diagnosis. He noted an 88% sensitivity for thermography in the detection of breast cancers.

    In a study comparing clinical examination, mammography, and thermography in the diagnosis of breast cancer, three groups of patients were used: 4,716 patients with confirmed carcinoma, 3,305 patients with histologically diagnosed benign breast disease, and 8,757 general patients (16,778 total participants). This paper also compared clinical examination and mammography to other well known studies in the literature including the NCI-sponsored Breast Cancer Detection Demonstration Projects. In this study, clinical examination had an average sensitivity of 75% in detecting all tumors and 50% in cancers less than 2 cm in size. This rate is exceptionally good when compared to many other studies at between 35-66% sensitivity. Mammography was found to have an average 80% sensitivity and 73% specificity. Thermography had an average sensitivity of 88% (85% in tumors less than 1 cm in size) and a specificity of 85%. An abnormal thermogram was found to have a 94% predictive value. From the findings in this study, the authors suggested that "none of the techniques available for screening for breast carcinoma and evaluating patients with breast related symptoms is sufficiently accurate to be used alone. For the best results, a multimodal approach should be used" [38].

    In a series of 4,000 confirmed breast cancers, Thomassin and associates observed 130 sub-clinical carcinomas ranging in diameter of 3-5 mm. Both mammography and thermography were used alone and in combination. Of the 130 cancers, 10% were detected by mammography only, 50% by thermography alone, and 40% by both techniques. Thus, there was a thermal alarm in 90% of the patients and the only sign in 50% of the cases. 

    In a study by Gautherie and associates, the effectiveness of thermography in terms of survival benefit was discussed. The authors analyzed the survival rates of 106 patients in whom the diagnosis of breast cancer was established as a result of the follow-up of thermographic abnormalities found on the initial examination when the breasts were apparently healthy (negative physical and mammographic findings). The control group consisted of 372 breast cancer patients. The patients in both groups were subjected to identical treatment and followed for 5 years. A 61% increase in survival was noted in the patients who were followed-up due to initial thermographic abnormalities. The authors summarized the study by stating that "the findings clearly establish that the early identification of women at high risk of breast cancer based on the objective thermal assessment of breast health results in a dramatic survival benefit".

    In a simple review of over 15 studies from 1967 - 1998, breast thermography has showed an average sensitivity and specificity of 90%. With continued technological advances in infrared imaging in the past decade, some studies are showing even higher sensitivity and specificity values. However, until further large scale studies are performed, these findings remain in question.

 

BREAST CANCER DETECTION AND DEMONSTRATION PROJECTS

 

    The Breast Cancer Detection and Demonstration Project (BCDDP) is the most frequently quoted reason for the decreased use of infrared imaging. The BCDDP was a large-scale study performed from 1973 through 1979 which collected data from many centers around the United States. Three methods of breast cancer detection were studied: physical examination, mammography, and infrared imaging (breast thermography).

 

Inflated Expectations -- Just before the onset of the BCDDP, two important papers appeared in the literature. In 1972, Gerald D. Dodd of the University of Texas Department of Diagnostic Radiology presented an update on infrared imaging in breast cancer diagnosis at the 7th National Cancer Conference sponsored by the National Cancer Society and the National Cancer Institute. In his presentation, he suggested that infrared imaging would be best employed as a screening agent for mammography. He proposed that in any general survey of the female population age 40 and over, 15 to 20% of these subjects would have positive infrared imaging and would require mammograms. Of these, approximately 5% would be recommended for biopsy. He concluded that infrared imaging would serve to eliminate 80 to 85% of the potential mammograms. Dodd also reiterated that the procedure was not competitive with mammography and, reporting the Texas Medical School's experience with infrared imaging, noted that it was capable of detecting approximately 85% of all breast cancers. Dodd's ideas would later help to fuel the premise and attitudes incorporated into the BCDDP. Three years later, J.D. Wallace presented to another Cancer Conference, sponsored by the American College of Radiology, the American Cancer Society and the Cancer Control Program of the National Cancer Institute, an update on infrared imaging of the breast. The author’s analysis suggested that the incidence of breast cancer detection per 1000 patients screened could increase from 2.72 when using mammography to 19 when using infrared imaging. He then underlined that infrared imaging poses no radiation burden on the patient, requires no physical contact and, being an innocuous technique, could concentrate the sought population by a significant factor selecting those patients that required further investigation. He concluded that, "the resulting infrared image contains only a small amount of information as compared to the mammogram, so that the reading of the infrared image is a substantially simpler task".     

 

Faulty Premise -- Unfortunately, this rather simplistic and cavalier attitude toward the generation and interpretation of infrared imaging was prevalent when it was hastily added and then prematurely dismissed from the BCDDP which was just getting underway. Exaggerated expectations led to the ill-founded premise that infrared imaging might replace mammography rather than complement it. A detailed review of the Report of the Working Group of the BCDDP, published in 1979, is essential to understand the subsequent evolution of infrared imaging [44]. The work scope of this project was issued by the NCI on the 26th of March 1973 with six objectives, the second being to determine if a negative infrared image was sufficient to preclude the use of clinical examination and mammography in the detection of breast cancer. The Working Group, reporting on results of the first four years of this project, gave a short history regarding infrared imaging in breast cancer detection. They wrote that as of the sixties, there was intense interest in determining the suitability of infrared imaging for large-scale applications, and mass screening was one possibility. The need for technological improvement was recognized and the authors stated that efforts had been made to refine the technique. One of the important objectives behind these efforts had been to achieve a sufficiently high sensitivity and specificity for infrared imaging under screening conditions to make it useful as a pre-screening device in selecting patients for referral for mammographic examination. It was thought that if successful, this technology would result in a relatively small proportion of women having mammography (a technique that had caused concern at that time because of the carcinogenic effects of radiation). The Working Group indicated that the sensitivity and specificity of infrared imaging readings, with clinical data emanating from inter-institutional studies, were close to the corresponding results for physical examination and mammography. They noted that these three modalities selected different sub-groups of breast cancers, and for this reason further evaluation of infrared imaging as a screening device in a controlled clinical trial was recommended.

 

Poor Study Design -- While this report describes in detail the importance of quality control of mammography, the entire protocol for infrared imaging was summarized in one paragraph and simply indicated that infrared imaging was conducted by a BCDDP trained technician. The detailed extensive results from this report, consisting of over 50 tables, included only one that referred to infrared imaging showing that it had detected only 41% of the breast cancers during the first screening while the residual were either normal or unknown. There is no breakdown as far as these two latter groups were concerned. Since 28% of the first screening and 32% of the second screening were picked up by mammography alone, infrared imaging was dropped from any further evaluation and consideration. The report stated that it was impossible to determine whether abnormal infrared imaging could be predictive of interval cancers (cancers developing between screenings) since they did not collect this data. By the same token, the Working Group was unable to conclude, with their limited experience, whether the findings were related to the then available technology of infrared imaging or with its application. They did, however, conclude that the decision to dismiss infrared imaging should not be taken as a determination of the future of this technique, rather that the procedure continued to be of interest because it does not entail the risk of radiation exposure. In the Working Group's final recommendation, they state that "infrared imaging does not appear to be suitable as a substitute for mammography for routine screening in the BCDDP." The report admitted that several individual programs of the BCDDP had results that were more favorable than what was reported for the BCDDP as a whole. They encouraged investment in the development and testing of infrared imaging under carefully controlled study conditions and suggested that high priority be given to these studies. They noted that a few suitable sites appeared to be available within the BCDDP participants and proposed that developmental studies should be solicited from sites with sufficient experience.

 

Untrained Personnel and Protocol Violations – JoAnn Haberman, who was a participant in this project, provided further insight into the relatively simplistic regard assigned to infrared imaging during this program. The author reiterated that expertise in mammography was an absolute requirement for the awarding of a contract to establish a Screening Center. However, the situation was just the opposite with regard to infrared imaging – no experience was required at all. When the 27 demonstration project centers opened their doors, only 5 had any pre-existing expertise in infrared imaging. Of the remaining screening centers, there was no experience at all in this technology. Finally, more than 18 months after the project had begun, the NCI established centers where radiologists and their technicians could obtain sufficient training in infrared imaging. Unfortunately, only 11 of the demonstration project directors considered this training of sufficient importance to send their technologists to learn proper infrared technique. The imaging sites also disregarded environmental controls. Many of the project sites were mobile imaging vans which had poor heating and cooling capabilities and often kept their doors open in the front and rear to permit an easy flow of patients. This, combined with a lack of pre-imaging patient acclimation, lead to unreadable images.    

 

In summary, with regard to thermography, the BCDDP was plagued with problems and seriously flawed in four critical areas: (1) Completely untrained technicians were used to perform the scans, (2) The study used radiologists who had no experience or knowledge in reading infrared images, (3) Proper laboratory environmental controls were completely ignored. In fact, many of the research sites were mobile trailers with extreme variations in internal temperatures, (4) No standardized reading protocol had yet been established for infrared imaging. The BCDDP was also initiated with an incorrect premise that thermography might replace mammography. From a purely scientific point, an anatomical imaging procedure (mammography) cannot be replaced by a physiological one. Last of all, and of considerable concern, was the reading of the images. It wasn’t until the early 1980’s that established and standardized reading protocols were introduced. Considering these facts, the BCDDP could not have properly evaluated infrared imaging. With the advent of known laboratory environmental controls, established reading protocols, and state-of-the-art infrared technology, a poorly performed 20-year-old study cannot be used to determine the appropriateness of thermography.

 

THERMOGRAPHY AS A RISK INDICATOR

 

    As early as 1976, at the Third International Symposium on Detection and Prevention of Cancer in New York, thermography was established by consensus as the highest risk marker for the possibility of the presence of an undetected breast cancer. It had also been shown to predict such a subsequent occurrence. The Wisconsin Breast Cancer Detection Foundation presented a summary of its findings in this area, which has remained undisputed. This, combined with other reports, has confirmed that thermography is the highest risk indicator for the future development of breast cancer and is 10 times as significant as a first order family history of the disease.

 

    In a study of 10,000 women screened, Gautherie found that, when applied to asymptomatic women, thermography was very useful in assessing the risk of cancer by dividing patients into low- and high-risk categories. This was based on an objective evaluation of each patient's thermograms using an improved reading protocol that incorporated 20 thermopathological factors.  

 

    From a patient base of 58,000 women screened with thermography, Gros and associates followed 1,527 patients with initially healthy breasts and abnormal thermograms for 12 years. Of this group, 40% developed malignancies within 5 years. The study concluded that "an abnormal thermogram is the single most important marker of high risk for the future development of breast cancer" .  

 

    Spitalier and associates followed 1,416 patients with isolated abnormal breast thermograms. It was found that a persistently abnormal thermogram, as an isolated phenomenon, is associated with an actuarial breast cancer risk of 26% at 5 years. Within this study, 165 patients with non-palpable cancers were observed. In 53% of these patients, thermography was the only test which was positive at the time of initial evaluation. It was concluded that: (1) A persistently abnormal thermogram, even in the absence of any other sign of malignancy, is associated with a high risk of developing cancer, (2) This isolated abnormal also carries with it a high risk of developing interval cancer, and as such the patient should be examined more frequently than the customary 12 months, (3) Most patients diagnosed as having minimal breast cancer have abnormal thermograms as the first warning sign .