The Biological Effects Of Ionizing Radiation Biology Essay

The Biological Effects Of Ionizing Radiation Biology Essay The biological effects of ionizing radiation are determined by both the radiation dose and the radiation quality ionization density. To understand the radiation protection concerns associated with different types of ionizing radiation, knowledge of both the extent of exposure and consequent macroscopic dose absorbed gray value, as well as the microscopic dose distribution of the radiation modality is required. The definitions of these variables are discussed below but in general to advance the knowledge of the biological effects of different radiation types one needs to know the dose absorbed, the radiation quality and effectiveness of a particular radiation type to induce biological damage. In this study the biological effect of high energy neutrons is compared to that of a reference radiation type 60Co ÃŽÂ ³-rays for a cohort of donors, mostly radiation workers. Comparisons are made at different dose levels in blood cells from each donor to ascertain the relative biological effectiveness of the test radiation modality against that of a recognized reference radiation (Hall, 2005). Such studies are essential to determine the radiation quality for high energy neutron sources applicable to practises in radiation protection. In some nuclear medicine applications radionuclides are used to treat malignant disease. For this the use of short lived alpha particle emitters or other radiation modalities that deliver high ionization densities in cells, are particularly attractive. This as the cellular response in relation to inherent radiosensitivity of the effected cells is thought to be more consistent compared to the use of radionuclides that emit radiation with a lower ionization density e.g. ÃŽÂ ²-particles. The relative biological effectiveness of the high energy neutrons used in this study is followed as a function of the inherent radiosensitivity of different individuals. This allows the identification of cell populations that are relatively sensitive or relatively resistant to radiation. As such research material is available to investigate cellular response too Auger electrons. The latter is known to induce biological damage akin to that of alpha particles. A short description of the physical and biological variables applicable to this study is summarised below. Ionizing Radiation The term ionizing radiation refers to both charged particles (e.g., electrons or protons) and uncharged particles (e.g., photons or neutrons) that can impart enough energy to atoms and molecules to cause ionizations in that medium, or to initiate nuclear or elementary-particle transformations that in turn result in ionization or the production of ionizing radiation. Ionization produced by particles is the process by which one or more electrons are liberated in collisions of the particles with atoms or molecules (The International Commission on Radiation Units and Measurements [ICRU] Report 85, 2011). Interaction of Ionizing Radiation with Matter Ionizing radiation is not restricted to ionization events alone. Several physical and chemical effects in matter such as: heat generation, atomic displacements, excitation of atoms and molecules, destruction of chemical bonds and nuclear reactions may occur. The effects of ionizing radiation on matter depend on the type and energy of radiation, the target, and the irradiation conditions. Radiation can be categorized in terms of how it induces ionizations: Directly ionizing radiation, consist of charged particles such as electrons, protons and alpha particles. Indirectly ionizing radiation consists of neutral particles and/or electromagnetic radiation such as neutrons and photons (ÃŽÂ ³-rays and X-rays). Ionising radiation interacts with matter by: Interaction with the electron cloud of the atom, or by Interaction with the nucleus of the atom. Types of ionizing radiation linked to this study ÃŽÂ ³-rays Ionizing photons (ÃŽÂ ³- and X-rays) are indirectly ionising radiation. These wave like particles have zero rest mass and carry no electrical charge. Low energy (E>2m0c2) may be absorbed by atomic nuclei and initiate nuclear reactions (Cember, 1969). The charged electrons emitted from the atoms, produce the excitation and ionisation events in the absorbing medium. Neutrons Neutrons, similar to ionizing photons are indirectly ionizing radiations; however, these particles do have a rest mass. There is negligible interaction between neutrons and the electron cloud of atoms since neutrons do not have a net electrical charge (Henry, 1969). The principle interactions occur through direct collisions with atomic nuclei during elastic scattering events. In this process, ionisation is produced by charged particles such as recoil nuclei and nuclear reaction products. The production of secondary ionising photons will result in the release of energetic electrons. In turn these charged particles can deposit energy at a considerable distance from the interaction sites (Pizzarello, 1982). Auger electrons Auger electron emission is an atomic-, not a nuclear process. In this process an electron is ejected from an orbital shell of the atom. A preceding event, e.g. electron capture (EC) or internal conversion (IC) leaves the atom with a vacant state in its electron configuration. An electron from a higher energy shell will drop into the vacant state and the energy difference will be emitted as a characteristic x-ray (Cember, 1969). The energy of the x-ray (Ex-ray) being the difference in energy (E) between the two electron shells L and K. Ex-ray = EL -EK Alternatively, the energy may be transferred to an electron of an outer shell, causing it to be ejected from the atom (Fig. 1). The emitted electron is known as an Auger electron and similarly to the x-ray has an energy: EAuger = EΆ -EB where: EΆ = the energy of inner-shell vacancy energy of outer-shell vacancy EB = binding energy of emitted (Auger) electron Auger emission is favoured for, low-Z materials where electron binding energies are small. Auger electrons have low kinetic energies; hence travel only a very short range in the absorbing medium (Cember, 1969). File:Auger Process.svg Fig. 1: Schematic representation of the Auger electron emission process, where an orbital electron is ejected following an ionization event. Dosimetric Quantities Several dosimetric quantities have been defined to quantify energy deposition in a medium when ionizing radiation passes through it. Radiation fields are well described by physical quantities such as particle fluence or air kerma free in air are used. However these quantities do not relate to the effects of exposure on biological systems (International Commission on Radiological Protection [ICRP] Publication 103, 2007). The absorbed dose, D, is the basic physical quantity used in radiobiology, radiology and radiation protection that quantifies energy deposition by any type of radiation in any absorbing material. The International System of Units (SI) of absorbed dose is joule per kilogram (J.kg-1) and is termed the gray (Gy). Absorbed dose, D, is defined as the quotient of mean energy, dÃŽÂ µ, imparted by ionising radiation in a volume element and the mass, dm, of the matter in that volume (Cember, 1969). The absorbed dose quantifies the energy imparted per unit mass absorbing medium, but does not relate this value to radiation damage induced in cells or tissue. The radiation weighted dose (HT) is used as a measure of the biological effect for a specific radiation quality on cells or tissue. It is calculated from equation where DT,R is the mean absorbed dose in a tissue T due to radiation of type R and wR is the corresponding dimensionless radiation weighting factor. The unit of radiation weighted dose is J.kg-1 and is termed the sievert (Sv). Radiation weighting factors are recommended by the International Commission on Radiological Protection (International Commission on Radiological Protection [ICRP] Publication 103, 2007) and are derived from studies on the effect of the micro-deposition of radiation energy in tissue and on its carcinogenic potential. Linear Energy Transfer (LET) Ionizing radiation deposits energy in the form of ionizations along the track of the ionizing particle. The spatial distribution of these ionization events is related to the radiation type. The term linear energy transfer (LET) relates to the rate at which secondary charged particles deposit energy in the absorbing medium per unit distance (keV/ µm). LET is a realistic measure of radiation quality (Duncan, 1977). The LET (L) of charged particles in a medium is defined as the quotient of dE/dl where dE is the average energy locally imparted to the medium by a charged particle of specified energy in traversing a distance dl (Pizzarello, 1982). For high energy photons (x- and ÃŽÂ ³-rays), fast electrons are ejected when energetic photons interact with the absorbing medium. The primary ionization events along the track of the ionizing particle are well separated. This type of sparsely ionizing radiation is termed low-LET radiation. The LET of a 60Cobalt teletherapy source (1.3325 and 1.1732 MeV) is in the range of 0.24 keV/ µm (Vral et al., 1994). Neutrons cause the emission of recoil protons, alpha particles and heavy nuclear fragments during scattering events. These emitted charged particles interact more readily with the absorbing medium and cause densely spaced ionizing events along its track. The p66(Be) neutron beam used in this study has an ionization density of 20 keV/ µm and hence regarded as high-LET radiation. Auger electrons travel very short distances in the absorbing medium due to their low kinetic energies. All the energy of these particles is liberated in small volumes over short track lengths. Ionization densities are therefore very high, up to 40 keV/ µm this is comparable to high-LET alpha particles (Godu et al., 1994). Relative Biological Effectiveness (RBE) The degree of damage caused by ionizing radiation depends firstly on the absorbed dose and secondly on the ionization density or quality of radiation. Variances in the biological effects of different radiation qualities can be described in terms of the relative biological effectiveness (RBE). RBE defines the magnitude of biological response for a certain radiation quality compared to a distinct reference radiation. It is expressed in terms of the ratio (Quoc, 2009): Megavoltage X-rays or 60Co ÃŽÂ ³-rays are commonly employed as the reference radiation since these are standard therapeutic sources of radiation. Thus for an identical dose neutrons the biological effect observed would be greater, compared to 60Co ÃŽÂ ³-rays. The fundamental difference between these radiation modalities is in the spatial orientation or micro deposition of energy. Furthermore, RBE varies as a function of the dose applied increase in RBE is noted for a decrease in dose. By evaluating dose response curves (Fig 2), it is evident that the shoulder of the neutron curve is much shallower (smaller ÃŽÂ ²-value) compared to the reference radiation curve. Therefore changes in RBE are prominent over low dose ranges (Hall, 2005). Fig 2: Dose response curves based on the linear quadratic model demonstrate differences in RBE as a function of dose. Through evaluation of the biological effect curves it is apparent that the RBE for a specific radiation quality may vary. This is characterized by the type of tissue or cells being investigated, dose and dose rates applied oxygenation status of the tissue, energy of radiation and the phase of the cell cycle and inherent radiosensitivity of cells. The RBE increases with a decrease in dose, to reach a maximum RBE denoted RBEM this is calculated from the ratio of the initial slope of the dose response curves for both radiation modalities. RBE LET relationship For a given absorbed dose, differences in the biological response for several cell lines, exposed to different radiation qualities have been demonstrated (Slabbert et al., 1996). Cells exposed to a specified dose low LET radiation do not exhibit the same biological endpoint than those exposed to same dose high LET radiation. This since with low LET radiation a substantial amount of damage may be repaired because the energy density imparted to each ionization site is relatively low. The predominant mode of interaction for this radiation type is indirect through chemical attack from radiolysis of water. As the LET increases, for a specific dose, fewer sites are damaged but the sites that are located along the track of the ionizing particle are severely damaged because more energy is imparted. Thus the probability of direct interaction between the particle track and the target molecule increases with an increase in LET. The RBE of radiation can be correlated with the estimates of LET values. However, as the LET increases, exceeding 10keV/ µm it is no longer possible to assign a single value for the RBE. Beyond this LET, the shape of the cell survival curve changes markedly in the shoulder region compared to low-LET. Since RBE is a measure of the biological effect produced, comparison of the low-LET and high-LET curves will reveal that RBE increases with decreasing dose (Hall, 2005). The average separation in ionizing events at LET of about 100 keV/ÃŽÂ ¼m is equal to the width of deoxyribonucleic acid (DNA) double strand molecule (Fig. 3). Further increase in LET results in decreased RBE since ionization events occur at smaller intervals than DNA molecule strand separation (Fig. 3) and this energy imparted does not contribute to DNA damage. Fig 3: Average spatial distribution of ionizing events for different LET values in relation to the DNA double helix structure (Hall 2005). Cellular Radiosensitivity Tissue radiosensitivity models In 1906 the radiobiologists Bergonie and Tribondeau established a rule for tissue radiosensitivity. They studied the relative radiosensitivities of cells and from this could predict which type of cells would be more radiosensitive (Hall, 2005). Bergonie and Tribondeau realized that cells were most sensitive to radiation when they are: Rapidly dividing (high mitotic activity). Cells with a long dividing future. Cells of an unspecialised type. The law of Bergonie and Tribondeau was later adapted by Ancel and Vitemberger; they concluded that radiation damage is dependent on two factors: the biological stress on the cell. the conditions to which the cell is exposed pre and post irradiation. Cell division causes biological stress thus cells with a short doubling time express radiation damage at an earlier stage than slowly dividing cells. Undifferentiated rapidly dividing cells therefore are most radiosensitive (Hall, 2005). A comprehensive system of classification was proposed by Rubin and Casarett, cell populations were grouped into 4 categories based on the reproduction kinetics: Vegetative intermitotic cells were defined as rapidly dividing undifferentiated cells. These cells usually have a short life cycle. For example: erythroblasts and intestinal crypt cells and are very radiosensitive. Differentiating intermitotic cells are characterized as actively dividing cells with some level of differentiation. Examples include: meylocytes and midlevel cells in maturing cell lines these cells are radiosensitive. Reverting postmitotic cells are regarded as to not divide regularly and generally long lived. Liver cells is an example of this cell type, these cell types exhibit a degree radioresistance. Fixed postmitotic cells do not divide. Cells beloning to this classification are regarded to be highly differentiated and highly specialized in both morphology and function. These cells are replaced by differentiating cells in the cell maturation lines and are regarded as the most radioresistant cell types. Nerve and muscle cells are prime examples (Hall, 2005). Michalowski proposed a type of classification which divides tissues into hierarchical (H-type) and flexible (F-type) populations. Within this classification cells are grouped in 3 distinct categories: Stem cells, that continuously divide and reproduce to give rise to both new stem cells and cells that eventually give rise to mature functional cells. Maturing cells arising from stem cells and through progressive division eventually differentiate into an end-stage mature functional cell. Mature adult functional cells that do not divide Examples of H-type populations include the bone marrow, intestinal epithelium and epidermis; these cells are capable of unlimited proliferation. In F-type populations the adult cells can under certain circumstance be induced to undergo division and reproduce another adult cell. Examples include; liver parenchymal cells and thyroid cells. The two types represent the extremes in cell populations. It should be noted that most tissue populations exist between the extremes, these exhibit characteristics of both types where mature cells are able to divide a limited number of times. The sensitivity to radiation can be attributed to the length of the life cycle and the reproductive potential of the critical cell line within that tissue (Hall, 2005). Cell cycle dependent radiosensitivity As cells progress through the cell cycle various physical and biochemical changes occur (Fig. 4). These changes influence the response of cells to ionizing radiation. Variations in radiosensitivity for several cell types at different stages of the cell cycle has been documented (Hall, 2005). Following the law of Bergonie and Tribondeau that cells with high mitotic activity are most radiosensitive, it was found that cells in the mitotic phase (M-phase) of the cell cycle are most sensitive. Late stage gap 2 (G2) phase cells are also very sensitive with gap 1 (G1) phase being more radioresistant and synthesis (S phase) cells the most resistant (Domon, 1980). Fig. 4: Cell cycle of proliferating cells representing the different phases leading up to cell division. The G0 resting phase for cells that do not actively proliferate has been included since T-lymphocytes naturally occur in this phase (Hall, 2005). Nonproliferating cells, generally cells that are fully differentiated, may enter the rest phase G0 from G1 and remain inactive for long periods of time. Peripheral T-lymphocytes seldom replicate naturally and remain in G0 indefinately. Lymphocyte Radiosensitivity The hematopoietic system is very sensitive to radiation. Differential blood analyses are routinely employed as a measure of radiation exposure. This measurement is based on the sensitivity of stem cells and the changes observed in the constituents of peripheral blood due to variations in transit time from stem cell to functioning cell (Hall, 2005). It has been shown that lymphocytes, although they are resting cells (G0 phase) which do not actively proliferate nor do have a long dividing future hence do not meet the criteria of a radiosensitive cell type as described above are of the most radio sensitive cells. The reasons for their acute sensitivity cannot be explained (Hall, 2005). Furthermore two distinct subpopulations T-lymphocytes with respect to radiosensitivity were found in peripheral blood. The small T-lymphocyte which is extremely radiosensitive and disappears almost completely from the peripheral blood at doses of 500 mGy (Kataoka, 1974, Knox, 1982 and Hall, 2005). Cytogenetic expression of ionizing radiation induced damage The primary target in radiotherapy is the double helix deoxyribonucleic acid (DNA) molecule (Rothkam et al. 2009). This macro molecule contains the genetic code critical to the development and functioning of most living organisms. The DNA molecule consists of two strands held together by hydrogen bonds between the bases. Each strand is made up of four types of nucleotides. A nucleotide consists of a five-carbon sugar (deoxyribose), a phosphate group and a nitrogen containing base. The nitrogen containing bases are adenine, guanine, thymine or cytosine. Base pairing between two nucleotide strands is universally constant with adenine pairing with thymine and guanine with cytosine (Fig. 5). This attribute permits effective single strand break repair since the opposite strand is used as a template during the repair process. The base sequence within a nucleotide strand differs; the arrangement of bases defines the genetic code. The double helix DNA molecule is wound up on histones and bou nd together by proteins to form nucleosomes. This structure is folded and coiled repeatedly to become a chromosome. Fig. 5: The double helix structure of a DNA molecule consists of two neucleotide strands held together by hydrogen bonds between the bases. Figure modified from http://evolution.berkeley.edu/evolibrary/article/history_22 by P Beukes. Ionizing radiation can either interact directly or indirectly with the DNA strand. When an ionization event occurs in close proximity to the DNA molecule direct ionization can denature the strand. Ionization events that occur within the medium surrounding the DNA produce free radicals such as hydrogen peroxide through radiolysis of water. Damage induced by ionizing radiation to the DNA include base damage (BD), single strand breaks (SSB), abasic sites (AS), DNA-protein cross-links (DPC), and double strand breaks (DSB) (Fig. 6). Fig. 6: Examples of several radiation induced DNA lesions. Figure modified from Best B (9) by P Beukes. Low-LET radiation primarily causes numerous single strand breaks, through direct and indirect interaction (Hall, 2005). Single strand breaks are of lesser biological importance since these are readily repaired by using the opposite strand as a template. High-LET radiation damage is dominated by direct interactions with the DNA molecule. Densely ionizing radiation has a greater probability to induce irreparable or lethal double strand breaks since energy deposition occurs in discrete tracks (Hall, 2005). The number of tracks will be fewer but more densely packed compared to low-LET radiation of equivalent doses. Several techniques to quantify chromosomal damage and chromatid breaks have been established. These range from isolating DNA and passing it through a porous substrate or gel (Hall, 2005) by applying an external potential difference too advanced techniques of visually observing and numerating chromosomal aberrations of interphase cells. Cytogenetic chromosome aberration assays of peripheral blood T-lymphocytes to assess radiation damage include but are not limited to: premature chromosome condensation (PCC) assay, metaphase spread dicentric and ring chromosome aberration assay (DCA), metaphase spread fluorescence in situ hybridisation (FISH) translocation assay and cytokinesis blocked micronuclei (CBMN) assay (Fig. 7). Fig. 7: Different cytogenetic assays on peripheral T-lymphocytes for use in biological dosimetry. Figure modified from Cytogenetic Dosimetry IAEA, 2011. PCC occurs when an interphase cell is fused with a mitotic cell. The fusion causes the interphase cell to produce condensed chromosomes prematurely. Chromosomal aberrations can thus be analysed immediately following irradiation without the need for mitogen stimulation or cell culturing. Numeration of dicentrics in metaphase spreads has been used with great success to assess radiation damage in cells since the 1960s (Vral et al, 2010). The incidence of these aberrations follows a linear quadratic function with respect to the dose. Unstable aberrations like dicentrics or centric rings are lethal to the cell hence not passed on to daughter cells (Hall, 2005). In contrast translocations are stable aberrations; these are not lethal to the cell and passed on to daughter cells. Examination of translocations thus provides a long term history of exposure. Although the abovementioned techniques are very accurate and well described, the complexity and time consuming nature of the assays has stimulated the development of automated methods of measuring chromosomal damage. Micronuclei (MN) formation in peripheral blood T-lymphocytes lends itself to automation, since the outcome of radiation insult is visually not too complex with limited variables. DNA damage incurred from ionizing radiation or chemical clastogens induce the formation of acentric chromosome fragments and to a small extent malsegregation of whole chromosomes. Acentric chromosome fragments and whole chromosomes that are unable to engage with the mitotic spindle lag behind at anaphase (Cytogenetic Dosimetry IAEA, 2011). Micronuclei originate from these acentric chromosome fragments or whole chromosomes which are excluded from the main nuclei during the metaphase/anaphase transition of mitosis. The lagging chromosome fragment or whole chromosome forms a small separate nucleus visible in the cytoplasm of the cell. Image recognition software can thus be employed to quantify radiation damage by applying classifiers that describe cell size, staining intensity, cell separation, aspect ratio and cell characteristics when numerating MN frequency in BN cells. The classifiers are fully customizable depending on cell size, staining technique or cell type that will be used. Rationale for this study The principal objective of this study is to define RBE variations for high-LET radiation with respect to radiosensitivity. Specifically this is done for very high energy neutrons and Auger electrons. In general the response of different cell types vary much more to treatment with low-LET radiation compared to high-LET radiation (Broerse et al. 1978). Radiosensitivity differences have been demonstrated for different cancer cell lines (Slabbert et al. 1996) as well as various clonogenic mammalian cells (Hall, 2005) exposed to both high and low-LET radiation. In general there is an expectation and in certain cases some experimental evidence to support less variations in radiosensitivities of cells to high-LET radiation. Furthermore the ranking in the relative radiosensitivity of cell types changed for neutron treatments compared to exposure to X-rays (Broerse et al. 1978). To quantify the radiation risk of individuals exposed to cosmic rays or mixed radiation fields of neutrons and ÃŽÂ ³-rays, several experiments were conducted to ascertain biological damage induced by neutron beams of various energies (Nolte et al., 2007). Clonogenic survival data (Hall, 2005), dicentric chromosome aberrations (Heimers 1994) and micronuclei formation (Slabbert et. al 2010) have been followed. Chromosome aberration frequencies have been quantified and this represent radiation risk to neutron energies ranging from 36 keV up to 14.6 MeV (Schmid et al. 2003). To complement these studies additional measurements have been made for blood cells exposed to 60 MeV and 192 MeV quasi monoenergetic neutron beams (Nolte et al. 2007). Comparisons of RBE values obtained in these studies are shown in figure 1. Significant changes in the maximum relative biological effectiveness (RBEM) of these neutron sources are demonstrated as a function of neutron energy, with a maximum value of 90 at 0.4 MeV. RBEM drop to  ±15 for neutron energies higher than 10 MeV and it appears that the RBEM remain constant up to 200 MeV. The RBEM value of 47 -113 reported by Heimers et al. (1999) is not consistent with these observations. Fig. 1: RBEM values for neutrons of different energies after Nolte et al. (2007) The data shown in Fig. 1 was obtained by using the blood of a single donor. This to ensure consistency in the biological response for different neutron energies used in different radiation facilities in different parts of the world. Keeping the donor constant has the advantage that only a single data set for the reference radiation was needed. These measurements were done over several years. In all these studies, dicentric chromosome aberrations were followed. As informative as these investigations may be, it is doubtful if RBE values obtained from blood samples from a single donor are indeed representative for the wider population to state radiation weighting factors. It is unclear if RBE values for high energy neutrons will vary when measured with cells with different inherent radiosensitivities. Warenius et al. (1994) demonstrated that the RBE of a 62.5 MeV neutron beam increases with increase in radioresistance to 6 MV X-rays. Similarly Slabbert et al (1996) using a 29 MeV p(66)/Be neutron with an average energy of 29 MeV, noted a statistically significant increase in the RBE values for cell types with increased radioresistance to 60Co ÃŽÂ ³-rays. Although these investigators used 11 different cell types, few of these were indeed radioresistant to 60Co ÃŽÂ ³-rays. Close inspection of the data shows that the relationship between neutron RBE and radioresistance to photons disappear when the cell type with the highest resistance to ÃŽÂ ³-rays (Gurney melanoma) is removed from the data set Slabbert et al. 1996). In a follow up study the authors failed to demonstrate the relationship for a p(66)/Be neutron beam but such a relationship was demonstrated for a d14/Be neutron beam (Slabbert et al. 2000). It therefore appears that the relationship for RBE and radioresistance is dependent on the selection of cells used in the study as well as the neutron energy. Using lymphocytes Vral et al. (1994) demonstrated a clear reduction RBEM values for 5,5 MeV neutrons with an increase in the ÃŽÂ ±-values of dose effect curves obtained for 60Co ÃŽÂ ³-rays. This for lymphocytes obtained from six healthy donors. Using only four donors Slabbert et al. (2010) also demonstrated a relationship between RBEM neutrons and radiosensitivity to 60Co y rays. In the latter case the RBEM values are lower as can be expected since these investigators used a higher energy neutron source. Although a significant relationship between these parameters has been demonstrated by the investigators, the cohort of 4 donors in the study is very small. In fact 2 out of the 4 donors have different RBEM values but appear to have the same radiosensitivity. A study using larger number of donors with blood cells exposed to high energy neutrons is clearly needed. This in particular too verify the findings above indicating a different wR for donors of different sensitivity. The studies of RBE variations with neutron energy by Schmid et al., (2003), Nolte et al. (2005) and were conducted dicentric formations observed in metaphase spreads. It is known that more than six months were used to analyse the data for different doses for blood cells obtained from a single donor exposed to a single neutron energy. It follows that some method of automation to assist the radiobiological evaluation of cellular radiation damage is needed to quantify wR values as a function of radiosensitivity. Recently a semi-automated image analysis system, Metafer 4, this holds promise to test numerous donors for micronuclei formations Study to include more participants hence Metaferà ¢Ã¢â€š ¬Ã‚ ¦.

Conflict with “Macbeth” and “World War Poetry” Essay

During this essay I am going to write about the many diverse ways in which conflict is presented in William Shakespeare’s Macbeth and Wilfred Owen’s Poetry of World War 1. I will be comparing the ways in which Macbeth and 3 poems written by Owen; Mental Cases, The Next War and Dulce Et Decorum Est, link with each other. Macbeth is a play written in 1606 by Shakespeare who wrote plays to entertain his audience. On the other hand, Owen was a soldier in World War 1 when he wrote famous poems; he wrote them to tell us about the tragedies of war and he expressed his thoughts and feelings about war and conflict. Owen’s poems are influenced by his own experiences of war. In Macbeth the conflict shown by Macbeth and the other characters, gives us an idea of how Macbeth’s rivalry between certain characters in the play depicted the whole play itself. For example, Macbeth’s conflict with King Duncan shows how Macbeth was such an easy target for the witches bec ause they predicted he would be the next Thane of Cawdor which came true, then they predicted he would be the next King, but when Duncan announced Malcolm to be the next heir to the throne, Macbeth become insecure and had the thoughts of killing Duncan. â€Å"I have no spur to prick the sides of my intent, but only vaulting ambition which o’erleaps itself† – Macbeth’s excessive ambition is like a horse that tries to jump too high but it falls on the other side of the fence, also Shakespeare uses a metaphor to describe Macbeth’s ambition as ‘vaulting’ like a horse. Shakespeare brings the idea of Macbeth killing Duncan to life. Similarly, Wilfred Owen presents the conflict in his poems in ways which he relentlessly unveils the full scale of the war’s horrors. For example, in Owen’s poem ‘Mental Cases’, the conflict the soldiers have with the violent conditions they had to live in, Owen presents the mental torment suffered by the patients in this poem. He uses the simile â€Å"like a wound† to show that their wounds are still fresh and present in their minds. The words such as ‘blade’ and ‘bleeds afresh’ suggest that they have be en brutally ripped open by the conflict happening in their minds. Owen’s poem ‘Mental Cases’ shows us the mental anguish the soldiers had to go through during the World War. He uses the simile â€Å"baring teeth that leak like skulls, teeth wicked† to describe the soldiers as skeletons because they’re half dead from fighting continuously in the war; this shows how the poems title ‘Mental Cases’ links with the whole concept of the soldiers being half dead because their minds have been taken over by  the trauma of the war. â€Å"Batter of guns and shatter of flying muscles† – the use of violent imagery to emphasise the way in which the soldiers are continuously surrounded by gun-shots (‘batter of guns’) and dead bodies (‘flying muscles’). â€Å"Dawn breaks open like a wound that bleeds afresh† – Owen uses a simile, also a personified phrase to highlight the way the soldiers wake up to constant violence around them. Wilfred Owen uses words such as ‘skulls’ to show that the soldiers were like skeletons; half dead. Also he uses ‘ravished’ to give more power to the poem, to demonstrate that the horrors have taken over the soldiers’ minds. This poem links with Macbeth due to the way in which Macbeth is mentally tormented because of the crimes he’s committed which are now acting upon him, just the way the patients are mentally tormented because of the tragic war. Shakespeare uses the personified phrase â€Å"art th ou not fatal vision sensible to feeling as to sight?† to accentuate that Macbeth can only see the dagger in his mind but it’s not really there. â€Å"Here’s the smell of blood still, all the perfumes of Arabia will not sweeten† – Shakespeare manipulates the use of the senses to show that Lady Macbeth is saying that there is no perfume of this world which shall ‘sweeten’ our sinful hands; which emphasises that Lady Macbeth still thinks about the murder of King Duncan. Shakespeare also uses the simile â€Å"that not look like inhabitants o’the earth† to show that the witches aren’t humans; they don’t belong to the earth. â€Å"If it were done when ‘tis done, then ‘twere well it were done quickly† Shakespeare presents the idea of past and present; to kill Duncan quickly would be better. â€Å"Thy bones are marrowless, thy blood is cold† – Macbeth says to the ghost of Banquo; he has no marrow in his bones, his blood is cold. Shakespeare uses words such as ‘fatal’ to show the mental torment Macbeth is going through whilst h e sees the dagger in his mind. Also he uses ‘inhabitants’ to describe the way the witches look; they don’t look like they live on earth. In Owen’s poem ‘The Next War’ he presents the inner conflict of the war because the poem is based on the idea of not being afraid of death but getting used to the fact that death comes everyday to them. In the beginning of the poem Owen has written a quote from Siegfried Sassoon â€Å"war’s a joke for me and you, while we know such dreams are true† – this is an unusual sonnet because sonnets are usually on love and romance, but this one is on war. Owen uses personification like â€Å"out there we’ve walked quite friendly up to Death; sat  down and eaten with him, cool and bland† to emphasise that mostly all the soldiers are used to seeing people die and when death comes its normal for them. Also Owen describes death as ‘cool’ and ‘bland’ – these are oxymorons because they have an unusual perspective of war. â€Å"He’s spat at us with bullets and he’s coughed† – Owen u ses personification to show how death has tortured the soldiers. Owen uses many language techniques to bring the idea of welcoming death to the soldiers’ lives. Wilfred Owen uses words like ‘courage’ to emphasise the soldiers’ characters. Also he uses ‘green thick odour’ to represent the ‘odour’ as the poisonous gas that caused many soldiers’ deaths. This poem links with Macbeth because in this poem Owen talks about the courage these soldiers had and how they got used to seeing their men die all the time, however, in Macbeth, Macbeth is looked at as ‘brave Macbeth’ who has ‘disdaining fortune’ because he won the battle for Scotland and was looked at as a hero. â€Å"For brave Macbeth – well he deserves that name – disdaining fortune, with his brandish’d steel† – Shakespeare describes Macbeth as a courageous warrior. However, during the play we find out that Macbeth has planned to kill Duncan, but then feels a slight regret in going fourth with the murder â€Å"we will proceed no further in this business. He hath honour’d me of late, and I have bought golden opinions from all sorts of people†. In this scene, Lady Macbeth attacks Macbeths manliness and makes him feel like he less of a man â€Å"And live a coward in thine own esteem†. â€Å"But screw your courage to the sticking place† – Shakespeare uses a metaphor here to show the power in which Lady Macbeth has; she wants Macbeth to tighten his courage to the limit, so he can go fourth and kill Duncan. Lady Macbeth tries to convince him by calling him a ‘coward’ and unmanly. Macbeth is convinced enough to murder Duncan which eventually lead to his own down fall. ‘Dulce Et Decroum Est’ meaning ‘Die for Your Country’ is another famous poem of Wilfred Owen’s where it links to battlefield conflict and inner conflict. The poem is based on the whole concept of war, and how the soldiers fight for their country throughout the world war. â€Å"Bent double like old beggars, coughing like hags† – Owen uses two similes to describe the soldiers as ‘beggars’ and ‘hags’, due to the way they live in. â€Å"Men marched asleep† – this use of characterisation brings to life the way in which the soldiers were continuously marching during their days, and nights. Owen also uses an oxymoron to bring sarcasm into the poem  Ã¢â‚¬Å"of gas shells dropping softly behind† – gas shells are usually very loud and dangerous but Owen makes out the gas shells were ‘soft’. â€Å"As under a green sea I saw him drowning.† – a metaphor to describe the poisonous gas, and Owen’s persona of his friend drowning in the gas. â€Å"Guttering, choking, and drowning† – the use of onomatopoeia gives effect of the way in which Owen presents the conflict of the war. Owen also uses personified techniques to show the inner conflict of how the soldiers’ minds were taken over by the tragic war â€Å"If you could hear, at every jolt, the blood† – the effect that Owen uses to ‘hear the blood’. Owen gives the impression that these soldiers are broken and describes them to be helpless. Wilfred Owen uses words such as ‘deaf’ from the gun shots and bombs and ‘blind’ from the tear gas and smoke; he uses pitiful language to reveal the reality of war. This poem links with Macbeth, because Owen talks about the way in which the soldiers die for their country and linking back to Macbeth, he fought a battle for his country. However, the soldiers in the poem are described as ‘beggars’ and ‘hags’, on the other hand, Macbeth is described as ‘brave’. Macbeth has a higher reputation because he had killed the enemy of King Duncan’s. Shakespeare describes the nature of war as if it is a game or a sport â€Å"doubtful it stood, as two spent swimmers that do cling together† – using the word ‘swimmer’ relates to sport and ‘doubtful’ makes them want to try harder and think of swimming where they are pushing the water away racing to the finish line makes the reader create a picture of Macbeth and Banquo slashing away with their swords creating a sea of dead soldiers and blood behind them fighting their way to glory. It is only at the end of the play that Macbeth finally discovers his fate; after being told that Macduff had been, â€Å"untimely ripped from his mothers’ womb†. Macbeth describes the witches as â€Å"Juggling Fiends† Macbeth is accusing the witches of deliberately juggling their words so that he could not understand them. This is a clever quote as Macbeth has just realised his life is in ruins, but the audience knew this earlier. The witches have changed Macbeth from a brave warrior to an evil, murderous, traitor, underlining the conflict of good and evil. â€Å"By the pricking of my thumbs, something wicked this way comes† – this quote is significant as it illustrates the change in Macbeth throughout the play, now even the witches consider Macbeth to be evil. However, when looking at the path of destruction that Macbeth has left behind him it isn’t very  surprising. Just one man driven by his ambition to be king has led to a chain reactio n of murders. There are many important conflicts in Macbeth, like the conflict between Lady Macbeth and Macbeth, the conflict between the good which is represented by Macduff and the evil which is represented by Macbeth, and Macbeth versus himself, his inner struggle, and all of those conflicts lead to Macbeth’s down fall. Shakespeare gave a truthful, but interesting effect to show war and conflict in that time and age of Shakespeare. There are also many significant conflicts in the World War 1 which Wilfred Owen wrote about in all of his famous poems, like the conflict between the soldiers and death; the way in which the soldiers have to welcome death because it’s likely they will die. This conflict leads to the soldiers becoming mentally tormented. Owen always revealed the truth about war and conflict.

A Fair Perspective on Ucla Essay Samples

A Fair Perspective on Ucla Essay Samples In the end, the detail of real speech makes the scene pop. It is possible to just choose a couple of the most gripping moments from these types of experiences and go over the total trajectory of your interests, and your essay is going to be a winner. The long-term vision by contrast can be a little bit more eye-popping. It's possible to also refer to past essays and other discussion to the bottom of this page. Otherwise, you must beef up your details. The author starts with a rather thorough story of an event or description of an individual or place. Bridget's essay is extremely strong, but there continue to be a couple little things that could be made better. Stephen's essay is rather effective. The second portion of this essay would like you to examine the present instead. Generally, the very first, setup, section of the essay needs to be shorter, as it won't be focused on what you were doing. This write-up is here to assist. For more help, have a look at our article on finding excellent tips for your essay topic. The New Angle On Ucla Essay Samples Just Released The second section should choose the remainder of the space. By the conclusion of high school, a number of the experiences that you're most proud of don't have a tendency to be the type of things that wind up on your resume. There is not anything wrong with this sort of pickespecially if you truly are a person who tends to excel in those classes which are right up your interest alley. After that, ask that man to spell out the scene back to you. Top Choices of Ucla Essay Samples Even though some events have long-term or even lifetime ramifications, it's usually more advisable to concentrate on recent events si nce they shed more light on who you are at the moment. Bear in mind, your CV should only be a couple of pages, so make sure to continue to keep descriptions to a minimum. Allow it to sit for a couple days untouched. Also, to be able to become. UCLA is among the most well-known universities in California. The course incorporates extensive opportunities for critical writing in a selection of forms and for a wide range of audiences, in addition to building research skills for an assortment of applications, including a culminating portfolio undertaking. It includes extensive opportunities for critical writing in a variety of forms and for a variety of audiences, as well as building research skills for a variety of applications, including (but not limited to) a culminating portfolio project. This program is unusual since it is linked to a base literature training course. Board members are going to have place to create announcements and bring up community problems. Before you can create your community a better place, you've got to discover the things that could be ameliorated. Community is a rather important point to colleges. You're able to define community as you see fit, just ensure you speak about your function in that community. Because personal statements are short, you just won't have enough time to spell out everything you've loved about a specific subject in enough detail to make it count. One of your recommendations ought to be from your existing boss and the second one someone in a place of seniority. Possessing a well built, functional website delivers a convenience factor that's priceless. A community website offers information and details to residents and board members with a couple of easy clicks 24 hours each day 7 days each week. Ucla Essay Samples - Dead or Alive? It's very useful to take writing apart as a way to see just the way that it accomplishes its objectives. This is only one approach to approach choosing prompts. Here are a few suggestions for strategies to use this resource effectively. Avoid using multiple distinctive fonts. The 5-Minute Rule for Ucla Essay Samples Therefore, if you're not already committed to a particular plan of study, don't worry. It offers a forum for refining these argumentative arts and abilities. In this instance, it's college admissions officers who need to discover students that are eager to learn and be exposed to new ideas and ideas. If you're on an immediate path to a certain area of study or career pursuit, admissions officers definitely need to understand that.

How to get an Order of Protection

What do you do when you feel unsafe with someone in your family or household? Contacting law enforcement and getting an order of protection may be for you.   The Facts An order of protection (also called a restraining order) is an official legal document, signed by a judge, that is filed against a current or former family member or household member or other similar relationship. The order forces that individual to keep at a distance and is intended to prevent his or her abusive behavior toward you. Enforceable in court, it can be drafted to meet your specific needs as they apply to your situation. How It Works An order of protection can require the abuser to stay away from you and limit other forms of access; it can prevent the abuser from contacting you by phone, cell phone text messages, email, mail, fax, or third parties. It can force the abuser to move out of your home, give you exclusive use of your car, and award you temporary custody of your children along with child support, spousal support, and the continuation of insurance coverage. If the order of protection is violated by the abuser—if he or she visits you at home, in the workplace, or anywhere else or makes phone calls, sends emails, or attempts to contact you—the abuser can be arrested and placed in jail. How to Obtain One To get an order of protection, you have several options. You can contact the states or district attorney or inform the police that you wish to apply for an order of protection. You can also go to the county in which you or your abuser resides, and ask the court clerk for Order of Protection forms, which must be filled out. After the paperwork is filed, a hearing date will be set (typically within 14 days) and you will be required to appear in court on that day. The hearing may take place either in family court or criminal court. The judge will ask you to prove that you have experienced abuse or been threatened with violence. Witnesses, police reports, hospital and physician reports, and evidence of physical abuse or assault are often necessary to convince the judge to issue an order of protection. Physical evidence of abuse such as injuries caused by abuse or photos that show past injuries, property damage, or objects used in the assault will help make your case. How It Protects You The order of protection provides you an opportunity to define your safety needs. If children are involved, you can request custody and restrictions on visitation or no contact orders. Whenever the abuser violates the terms of the order of protection, you should call the police. Once you obtain one, it is imperative that you make multiple copies of the document. It is important that you carry a copy of your order protection at all times, particularly if you have children and there are custody and visitation limitations. Sources â€Å"Domestic Violence.†Ã‚  American Bar Association, www.americanbar.org/groups/public_education/resources/law_issues_for_consumers/protection_howget/.â€Å"Obtaining an Order of Protection.†Ã‚  FamilyEducation, 25 July 2006, www.familyeducation.com/life/divorce-law/obtaining-order-protection.