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Fractionation of the dose or low-dose-rate exposures resulted in a linear dose-response consistent with expectations of radiobiological theory in which the dose-response is linear quadratic for acute exposures and linear for low-dose-rate exposures, with the linear slope of the linear quadratic predicting the low-dose-rate and fractionation responses. These results are compatible with the apparent role of alterations in chromosome 2 in initial events for murine myeloid leukemogenesis and consistent with mechanistic predictions of dose and time-dose relationships described previously. Low-dose-rate exposures, although significantly less effective with respect to induction of thymic lymphoma than single acute exposures, still resulted in a complex dose-response with a clear suggestion of a large threshold (Ullrich and Storer 1979c). These results should not be unexpected since the development of thymic lymphoma in mice following irradiation is an extremely complex process. The target cells for induction of thymic lymphoma are thought to be in the bone marrow rather than the thymus, and the pathogenesis of the disease appears to be largely mediated through indirect mechanisms with cell killing playing a major role (Kaplan 1964, 1967; Haran-ghera 1976). For example, the expression of thymic lymphoma can be substantially reduced or eliminated by protection of bone marrow stem cells from radiation-induced cell killing. The complex nature of the pathogenesis of this disease and the lack of a comparable counterpart in humans argues against thymic lymphoma as an appropriate model for understanding dose-response and time-dose relationships in humans. In spite of the large numbers of animals used, analyses of the data with respect to dose-response models could not distinguish between linear and linear-quadratic models (Ullrich and Storer 1979b). However, when the data for low-dose-rate exposures were considered as well, they were most compatible with a linearquadratic model (Ullrich and Storer 1979c). Importantly, with respect to low-dose effects, these data support a linear response at low doses that is independent of exposure time. Such a response is consistent with predictions of the mechanistic model outlined earlier in this chapter. Although the number of animals used was smaller, a study examining radiation-induced lung and mammary adenocarcinomas in female Balb/c mice reached similar conclusions with respect to dose-response functions and low-dose risks (Ullrich and Storer 1979c; Ullrich 1983). This model was tested further in a series of experiments comparing the effectiveness of single acute exposures, acute fractionated exposures, and low-dose-rate exposures on the induction of lung and mammary tumors in the Balb/c mouse (Ullrich and others 1987). Importantly, in this study the hypothesis of time independence of effects at low doses was critically tested and found to hold. Specifically, similar effects were observed whether the same total dose was delivered as acute low-dose fractions or as low-dose-rate exposures. While the data for solid tumors described above are compatible with mechanistic models detailed earlier in this chapter, there are data sets that do not support a linear-quadratic dose-response model. Extensive data for mammary cancer induction in the Sprague-Dawley rat appear more consistent with a linear model over a wide range of doses and with linear, time-independent effects at low doses, low-dose fractions, and low dose rates (Shellabarger and others 1980). Although questions have been raised about the applicability of this model system to radiation-induced breast cancer in humans, much of the data from this rat model, from the mouse model in Balb/c mice, and from epidemiologic studies in exposed human populations appear to be consistent with respect to low-dose risk functions (Preston and others 2002b). In contrast to the data for leukemia and for pituitary, Harderian gland, lung, and mammary cancer described above, data from studies examining radiation-induced ovarian cancer in mice and bone and skin cancer in various animal species are more compatible with threshold dose-response models. In each instance it appears that an important role for cell killing in the process of neoplastic development and progression may explain these observations. Fry and his coworkers (1986) have shown that X-ray-initiated cells can be promoted to develop skin tumors by exposure to ultraviolet light. Based on such observations it is logical to speculate that the multiple high-dose fractions of radiation that are generally required to induce skin tumors in mouse skin are acting not only to initiate cells but also to induce tissue damage via cell killing, which in turn acts as a promoting stimulus to facilitate the progression of these initiated cells into skin tumors. Likewise in the rat, the high doses required to produce tumors are likely to produce both transformation of cells and sufficient cell killing to promote the transformed cells. It is also important to note studies by Jaffe and Bowden demonstrating that multiple low doses of radiation to the skin that did not produce tissue damage were not effective in promoting skin tumors initiated by chemical agents (Jaffe and Bowden 1986). These data support the view that the predominant role for low-dose radiation is tumorigenic initiation. Unfortunately most of the available data have focused on observations of effects rather than dissecting potential underlying mechanisms. Attempts have been made to model bone tumorigenesis however, and these models have again focused on an important role for a mechanism involved in the expression of initiated cells in controlling tumor development (Marshall and Groer 1977). Although speculative, it is likely that mechanisms similar to those proposed for skin tumorigenesis involving the cell-killing effects of radiation are likely involved in producing a threshold response for bone tumors. Fractionation Kinetics Studies using fractionation regimens have been useful in addressing issues of time-dose relationships in radiation carcinogenesis. In a few instances, investigators have also used In fact, this is one of the few instances for which a linear relationship could be rejected statistically. Studies in other mouse strains, while having less statistical power, also suggest a high sensitivity to induction of ovarian tumors at relatively low doses but with an apparent threshold (Lorenz and others 1947; Ullrich and Storer 1979c). This relatively unusual dose-response combining a threshold with high sensitivity to induction is unique to the mouse. Ovarian cancer in the mouse appears to involve an indirect mechanism for induction involving oocyte cell killing and subsequent alterations in the pituitary ovarian hormonal interactions (Kaplan 1950; Foulds 1975; Bonser and Jull 1977). The hormonal alterations are the proximate cause of tumor formation, with the role of radiation being relatively indirect as a result of its cell-killing effects. A threshold appears to exist because a certain level of oocyte killing is required to cause the hormonal alterations that result in ovarian tumor formation. This difference in sensitivity is apparently because mouse and human oocytes are at different stages of differentiation in the ovary (Brewen and others 1976). The unique sensitivity of the mouse ovary to radiation makes it unlikely that results using this model system would have general applicability to risks in humans. Radiation-induced skin cancer has been studied in both mice and rats, although the majority of such studies have focused on the rat model because the rat is significantly more sensitive to skin tumor induction than the mouse (Burns and others 1973, 1975, 1989a, 1989b). In both rats and mice, relatively high total doses are required to induce skin cancer, and there is a clear threshold below which no tumors are seen. Multiple repeated radiation exposures are generally required for tumors to develop in mouse skin, while a single high dose (>10 Gy) is capable of inducing tumors in rat skin. It was for skin tumorigenesis that many of the concepts of multistage carcinogenesis were developed, including concepts related to initiation, promotion, and progression, and it is within this framework that the data for radiation-induced skin tumors are best considered (Jaffe and Bowden 1986; Burns and others 1989b). It appears from a variety of studies that single doses of ionizing radiation are capable of initiating cells with neoplastic potential, but that these cells require subsequent promotion in order to develop into tumors (Hoshino and Tanooka 1975; Yokoro and others 1977; Jaffe and Bowden 1986). Without this promotion these latent initiated cells will not express their neoplastic potential. Studies have been conducted examining repair kinetics associated with skin tumorigenesis following localized irradiation of rat skin by Burns and coworkers (1975). In the mouse, repair kinetics were determined by examining tumor development in the mouse ovary and mouse lung following whole-body irradiation (Yuhas 1974; Ullrich 1984; Ullrich and others 1987). The experimental design for these studies has been to compare tumorigenic effects following a single acute exposure with the effects after a similar total dose split into two equal fractions separated in time by hours or days. When there is interaction between the two doses the tumorigenic effectiveness would be predicted to approximate that for the single acute exposure, while if there is recovery from carcinogenic injury, the effectiveness of the split doses would be lower. A simple approach to determining whether cellular-based or tissue-based factors play a limiting role in radiation tumorigenesis is to compare a 24 h fractionation scheme with that in which the time between fractions is much longer and more compatible with tissue kinetics. Not surprisingly, considering the role of cell killing in its pathogenesis, studies examining radiation-induced ovarian tumorigenesis have indicated a recovery time between fractions of 24 h or less (Yuhas 1974). Likewise data for skin tumorigenesis in the rat, for which cell-killing effects appear to play a role in neoplastic development, a recovery time of approximately 4 h has been reported (Burns and others 1973, 1975). More interesting are data for the induction of lung adenocarcinomas in Balb/c mice (Ullrich and others 1987). Cell killing has not been seen to play a major role in the pathogenesis of this tumor, and the doses used in the fractionation studies are not in the range where cell killing would be likely to produce significant tissue damage (Meyer and others 1980; Meyer and Ullrich 1981). A comparison of the tumorigenic effects of two 1 Gy fractions separated by either 24 h or 30 d with that for a single dose of 2 Gy indicated full recovery by 24 h with no further reduction in tumorigenic effectiveness when the time between fractions was increased to 30 d. Additional studies compared the lung tumorigenic effects produced at a total dose of 2 Gy delivered as a single acute exposure to those of multiple 100 mGy fractions separated by 24 h as well as to continuous low-intensity exposures delivered at a dose rate of 4 mGy/h. The observation of a similar reduction in lung adenocarcinomas following both the low-dose-rate and the fractionated exposure regimens also provides support for recovery kinetics in the range of 24 h or less. Hoshino and Tanooka (1975) examined the persistence of latent carcinogenic damage in irradiated mouse skin. Importantly, they found that radiation-initiated cells could persist as latent carcinogenic damage for up to 400 d.

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Bony expansion and erosion are common, including widening of the pterygopalatine fossa and anterior bowing of the posterolateral maxillary sinus wall. Extension often occurs into the sphenoid, maxillary, and ethmoid sinuses as well as the orbit, middle cranial fossa, and cavernous sinus. Sinus or otomastoid obstruction with mucosal edema and retained secretions is common. Preoperative catheter angiography and therapeutic embolization often facilitate surgical excision. Angiomatous polyp and hemangiopericytoma are very rare in childhood but may be mistaken for angiofibroma. The orbit and paranasal sinuses are common sites of origin of rhabdomyosarcoma (see Fig. Similar to the other small "blue" round cell tumors, these are hypercellular tumors that often manifest as infiltrating soft tissue masses with bone destruction and regional or systemic metastases. Langerhans cell histiocytosis is a reticuloendothelial disorder histologically characterized by tissue infiltration with reticulum cells, histiocytes, plasmocytes, and leukocytes (see Chapter 8). The involvement may be isolated (formerly eosinophilic granuloma), or there may be dissemination with cutaneous, visceral, and bony involvement. Lymphoma is another common malignant tumor of the head and neck region in childhood. Hodgkin disease often manifests as cervical lymphadenopathy and spreads contiguously along nodal chains. The origin may be in the nasopharynx, sinuses, adenotonsillar region (Waldeyer ring), or salivary glands. Fibromatous tumors are mesenchymal neoplasms that may be isolated and benign (solitary fibroma) or aggressive and malignant (fibromatosis, fibrosarcoma). The fibromatous tumor is a locally infiltrating pseudoneoplastic process characterized by fibroelastic proliferation. In other forms there may be widespread visceral and bony involvement without metastases (e. The juvenile form usually involves musculoskeletal structures but not the viscera. Osseous and Chondroid Tumors Osseous and chondroid tumors may arise from the facial bones or from the skull base and may secondarily involve the nasal cavity, sinuses, and nasopharynx. Osteoma, a benign osseous neoplasm, is rare in childhood, but most often arises in the frontal or ethmoid sinus. The imaging appearance depends on the histiologic subtype (cortical, cancellous, or fibrous), varying from a sclerotic lesion to a soft tissue density. Osteochondroma is a benign osteocartilaginous exostosis that may arise from the mandible, maxilla, sphenoid bone, zygoma, or nasal septum. Imaging shows a miniature metaphysis, growth plate, and cartilaginous cap that are continuous with the bone of origin. Malignant degeneration is indicated by a disorganized appearance and involvement of the parent bone. Fibrous dysplasia is an idiopathic and benign fibro-osseous disorder that may be monostotic, polyostotic, or part of the McCune-Albright syndrome. The maxilla and mandible are most frequently involved, unilaterally or bilaterally (Fig. There may be encroachment upon the neurovascular foramina, orbit, nasal structures, or sinuses (see Fig. Lesion growth may continue after skeletal maturation, but conversion to sarcoma is rare. Ossifying fibroma is a circumscribed fibrous neoplasm that progressively ossifies. Cementifying fibroma is another fibro-osseous tumor that is aggressive and tends to recur. Giant cell tumor, giant cell reparative granuloma, aneurysmal bone cyst, and osteoblastoma (Fig. These often have overlapping pathologic findings, and combined lesions are well known. The latter finding, however, has also been reported with lymphatic malformation, venolymphatic malformation, and telangiectatic osteosarcoma. As previously discussed, cherubism is an autosomal dominant disorder with progressive giant cell tumor involvement of the mandible and maxilla in childhood (misnomer "congenital fibrous dysplasia"-see Fig. Chondrosarcoma is a malignant bone neoplasm of cartilage origin that may arise de novo, from an osteochondroma, or following radiotherapy. Chordoma is rare tumor that arises from intraosseous notochordal remnants in the skull base near synchondroses. The chondroid form of chordoma may be indistinguishable from chondrosarcoma on imaging. Osteosarcoma, fibrosarcoma, and Ewing sarcoma are other rare mesenchymal neoplasms that arise in this region as primary or secondary neoplasms (e. Osteosarcoma may appear as a soft tissue mass with bony destruction and spiculated periosteal bone reaction, or as a partially calcified or ossified osteoid matrix mass. Fibrosarcoma and Ewing sarcoma produce soft tissue masses and permeative bony destruction, but no osteoid or chondroid matrix elements. Neuroblastoma, the most common of these tumors, may arise in or involve the skull base, nose, sinuses, or orbit, usually as part of metastatic disease (see Figs. Esthesioneuroblastoma (olfactory neuroblastoma) is a very rare tumor that arises from the olfactory groove and produces extensive destruction of the sinuses, orbit, and adjacent skull base and extends intracranially. They are characterized by small round cell infiltrations similar to those of neuroblastoma. Progonomas are rare retinal anlage tumors, often contain melanin, tend to arise from the cranial base, and invade the adjacent nasosinus structures or orbit. Schwannomas, neurofibromas, and plexiform neurofibromas rarely arise in the nasal cavity, paranasal sinuses, or nasopharynx. Paragangliomas are vascular, but slow-growing, tumors that may arise within the jugular bulb (glomus jugulare), middle ear cavity (glomus tympanicum), or the auricular branch of the vagus nerve (glomus vagale). Conductive hearing loss, pulsatile tinnitus, and a red retrotympanic mass are characteristic. Extensive local involvement is frequent, along with intracranial invasion and metastases. Vascular complications include internal jugular vein invasion, compression, and thrombosis. Langerhans cell histiocytosis occasionally involves the temporal bone and may be bilateral (Fig. Metastasis the most common metastatic tumors of the temporal bone are neuroblastoma and leukemia. Tumors of Cutaneous and Mucosal Epithelial Origin Nasal papillomas are benign mucosal tumors that often extend into the maxillary, ethmoid, sphenoid, or frontal sinuses. Squamous cell carcinoma and adenocarcinoma of the nasal cavity and sinuses are extremely rare in childhood. Imaging often demonstrates a sinus mass of homogeneous density and intensity with bone destruction. Necrosis and hemorrhage may occur, along with regional extension, nodal spread, and distant metastases. Ear and Temporal Bone Congenital cholesteatoma grows from ectopic epithelial rests (Fig. The most common site is the anterior middle ear cavity, although it may also arise in the external canal, petrous apex, or mastoid, or deep to an atresia plate (see Fig. Usually there is conductive hearing loss and a white mass behind an intact tympanic membrane. Temporal bone involvement is uncommon and usually monostotic in fibrous dysplasia. Painless fibro-osseous expansion may be associated with external canal narrowing, hearing loss, or secondary cholesteatoma. The differential diagnosis may include other fibro-osseous lesions, benign or malignant. It arises from the sutures of the tympanic ring, is usually localized, and is often bilateral. Osteoma is an uncommon benign bony tumor that is usually unilateral and more often arises in the outer bony canal.


  • Sometimes a spray to numb the throat is also used. A mouth guard will be placed in your mouth to protect your teeth. Dentures must be removed.
  • True Gonadal Intersex
  • Do you take any prescription or non-prescription medications? Which ones?
  • Do you have a fever?
  • Irrigation (washing of the skin), perhaps every few hours for several days
  • CT scan of the chest
  • Evaluate red blood cell production or destruction
  • Precancerous growths (keratoses)

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It is caused by central retinal vein occlusion, diabetic retinopathy and ocular ischemic syndrome. The ischemic retina releases a vasoformative substance which induces neovascularization of the anterior segment. Gonioscopically, a fibrovascular membrane covering the trabecular meshwork is demonstrated. Recurrent hyphema often complicates the picture the treatment of neovascular glaucoma is not effective. Early neovascularization can be treated by panretinal photocoagulation and direct treatment of angle vessels with argon laser. Routine filtration surgery often fails to reduce the pressure, but Ahmed, Molteno or Krupin-Denver valve implantation, that drains aqueous into the subconjunctival space, is effective. Glaucoma Associated with Intraocular Tumors Intraocular tumors like uveal melanomas and retinoblastoma may cause secondary glaucoma. The rapidly growing tumor may push the lensiris diaphragm forward thus causing angleclosure glaucoma. An obstruction of trabecular meshwork may occur by tumor cells, macrophages containing tumor cells or inflammatory cells and debris. Intraocular tumors may induce neovascularization of the iris and the angle of the anterior chamber, thus cause neovascular glaucoma. Sometimes, the tumor is so situated as to press upon the vortex veins and impede the venous outflow from the eye resulting in secondary glaucoma. Primary or metastatic tumors of the ciliary body may directly invade the angle of the anterior chamber. The Myocilin gene of primary open-angle glaucoma and that controlling corticosteroid responsiveness are closely related. Deposition of mucopolysaccharides in the trabeculum, tightening of the lysosomal membrane and an increased aqueous humor formation are the probable mechanisms of steroid-induced glaucoma. Medrysone, loteprednol and fluromethalone have a low potency for inducing ocular hypertension. It is, therefore, nondesirable to use potent water soluble corticosteroids (dexamethasone or betamethasone) for minor eye ailments for prolonged periods. The withdrawal of topical corticosteroids lowers the pressure, however, some patients need treatment with topical -blockers and systemic acetazolamide. The theory of reverse pupillary block suggests that iris acts as a valve resulting in higher pressure in the anterior chamber than the posterior chamber causing posterior bowing of the iris. Pigment granules shedding from the iris occurs due to rubbing of the posterior surface of iris with the zonule. Argon laser trabeculoplasty and laser iridotomy may minimize the reverse pupillary block, if present. Epidemic Dropsy Glaucoma or Toxic Glaucoma Toxic glaucoma may be found in patients of epidemic dropsy and is characterized by headache, colored halos, normal or deep anterior chamber, an open angle of the anterior chamber and marked elevation of intraocular pressure associated with generalized edema of the body. The epidemic dropsy glaucoma is non-congestive in nature and is caused by the toxic action of sanguinarine, an active alkaloid in the seeds of Argemone mexicana. The glaucoma develops following consumption of mustard oil adulterated Glaucoma with the oil of Argemone mexicana. Secondary glaucomas may also develop in a number of other clinical conditions such as iridocorneal endothelial syndrome (Chandler syndrome, essential iris atrophy, Cogan-Reese 249 syndrome), nanophthalmos, retinopathy of prematurity, Fuchs hetrochromic iridocyclitis and glaucomatocyclitic crisis. It is suspended between the iris and the vitreous by the zonule which connects it with the ciliary body. The radii of curvature of anterior and posterior surfaces of the lens are 10 mm and 6 mm respectively. The centers of anterior and posterior surfaces are known as anterior pole and posterior pole, respectively. The consistency of the superficial part (cortex) of the lens is softer than the central (nucleus). The lens continues to grow throughout life and relative thickness of the cortex increases with age. The capsule is thicker in front than behind, the thickness being greater towards the equator, just anterior to the attachment of suspensory ligament, than at the pole. The lens epithelium is a single layer of cubical cells that forms the anterior subcapsular epithelium. Diseases of the Lens the posterior epithelial cells elongate to form the lens fibers in early embryonic life, hence the epithelium is not present posteriorly. The cells show high mitotic activity and form new cells which migrate towards the equator. The fibers formed earlier lie in the deeper plane (nucleus of the lens), the newer ones occupy a more superficial plane. Surrounding the embryonic nucleus lies the fetal nucleus Diseases of the Lens corresponding to the lens at birth. The most peripheral part of the lens consists of cortex (young lens fibers) and the lens capsule (See Fig. Suture lines, formed by the end-to-end joining of these fibers, appear Y-shaped when viewed on a slit-lamp. The adult lens measures 5 mm anteroposteriorly and 9 mm equatorially and weighs about 255 mg. In old age, it is of amber color, firmer in consistency and more flat on both the surfaces. Zonular fibers or suspensory ligament of lens originate from basal laminae of the nonpigmented epithelium of ciliary body. The zonular fibers get inserted onto the anterior and the posterior lens capsule in a continuous fashion. The fibers hold the lens in position and enable the ciliary muscle to act during accommodation. The lens maintains its transparency by maintenance of water and electrolyte balance. The lens has higher levels of potassium ions and amino acids and lower levels of sodium and chlorine ions and water than the surrounding aqueous and vitreous humors. The electrolyte balance between inside and outside of the lens is maintained by selective permeability of the lens cell membrane and the activity of the sodium pump situated in the cell membrane of the lens epithelium and the lens fiber. The combination of active transport and membrane permeability is known as pump-leak system of the lens. The sodium is pumped across the anterior surface of the lens into the aqueous humor and potassium moves from the aqueous into the lens. This arrangement results in a sodium-potassium gradient across the lens; potassium being higher at the front and sodium being higher at the back of the lens. Normally the intracellular level of calcium in the lens is about 30 mM while the extracellular calcium level is close to 2 mM. The simple diffusion allows the waste products of the lens metabolism to leave the lens. Lens derives its energy from carbohydrates and structural material from amino acids. As lens is an avascular structure, it has an overall low metabolic rate which is evident by the low rates of consumption of oxygen and utilization of glucose. The carbohydrate metabolism in the lens occurs by glycolysis, citric acid cycle, hexose-monophosphate shunt and sorbitol pathway. Amino acids and fatty acids are oxidized in the mitochondria of the lens epithelium via citric acid cycle. However, degenerative changes in the lens are common and they often result in the partial or complete loss of transparency. Clinically, cataract may be classified on the basis of morphology or underlying etiology. Maternal infections Morphological Classification Depending on the location and configuration of opacities, cataract can be classified as: 1. Cataract associated with systemic diseases Developmental Cataract Developmental cataracts are usually present at birth (congenital) or may manifest after birth. However, following factors play important role in the formation of developmental cataract. Heredity: A strong hereditary predisposition is found in about 25% of all developmental cataracts.

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Spectrum of chromosomal aberrations in peripheral lymphocytes of hospital workers occupationally exposed to low doses of ionizing radiation. The elimination of low-dose hypersensitivity in Chinese hamster V79-379A cells by pretreatment with x rays or hydrogen peroxide. Small doses of high-linear energy transfer radiation increase the radioresistance of Chinese hamster V79 cells to subsequent x irradiation. An association between the radiation-induced arrest of G2-phase cells and low-dose hyper-radiosensitivity: a plausible underlying mechanism? Low-dose hyper-sensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. The current mortality rates of radiologists and other physician specialists: specific causes of death. The current mortality rates of radiologists and other physician specialists: deaths from all causes and from cancer. Radiationinduced breast cancer: long-term follow-up of radiation therapy for benign breast disease. Dose- and time-response for breast cancer risk after radiation therapy for benign breast disease. Incidence of primary malignancies other than breast cancer among women treated with radiation therapy for benign breast disease. The mortality and cancer morbidity experience of employees at the Chapelcross plant of British Nuclear Fuels Ltd, 1955-1995. The mortality and cancer morbidity experience of workers at the Springfields uranium production facility, 1946-95. The mortality and cancer morbidity experience of workers at the Capenhurst uranium enrichment facility 1946-95. Paternal radiation exposure and leukemia in offspring: the Ontario case-control study. Genetic disease in offspring of longterm survivors of childhood and adolescent cancer treated with potentially mutagenic therapies. Loss of heterozygosity at the proximal-mid part of mouse chromosome 4 defines two novel tumor suppressor gene loci in T-cell lymphomas. Radiation dose, chemotherapy and risk of soft tissue sarcoma after solid tumours during childhood. Effects of x rays and fission neutrons on an induced proliferative response in lung type 2 epithelial cells. Proliferative responses of type 2 lung epithelial cells after x rays and fission neutrons. Incidence of childhood malignancies in the vicinity of West German nuclear power plants. Transformation of C3H 10T1/2 cells by low doses of ionizing radiation: a collaborative study by six European laboratories strongly supporting a linear dose-response relationship. Mortality from breast cancer after irradiation during fluoroscopic examinations in patients being treated for tuberculosis. Cell-cycle-dependent radiation-induced oncogenic transformation of C3H 10T1/2 cells. Low doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice. Effects of exposure to low-dose-rate (60)Co gamma rays on human tumor cells in vitro. Comparison of cell killing and cell proliferation during continuous irradiation for six different cell lines. A method for estimating occupational radiation dose to individuals, using weekly dosimetry data. Induction of nuclear factor kappa B after low-dose ionizing radiation involves a reactive oxygen intermediate signaling pathway. The influence of track structure on the understanding of relative biological effectiveness for induction of chromosomal exchanges in human lymphocytes. Myeloid leukaemia frequency after protracted exposure to ionizing radiation: experimental confirmation of the flat dose-response found in ankylosing spondylitis after a single treatment course with x-rays. Two-event model for carcinogenesis: biological, mathematical and statistical considerations. Mechanisms of carcinogenesis and biologically based models for estimation and prediction of risk. Case-control study of malignant melanoma among employees of the Lawrence Livermore National Laboratory. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. The use of restriction endonucleases to study the mechanisms of chromosome damage. Possible distinct molecular carcinogenic pathways for bladder cancer in Ukraine, before and after the Chernobyl disaster. Genetic background affects susceptibility to mammary hyperplasias and carcinomas in Apc(min)/+ mice. Survival of human epithelial cells irradiated with cobalt 60 as microcolonies or single cells. Cell-cell contact during gamma irradiation is not required to induce a bystander effect in normal human keratinocytes: evidence for release during irradiation of a signal controlling survival into the medium. Mechanisms and implications of genomic instability and other delayed effects of ionizing radiation exposure. Involvement of energy metabolism in the production of "bystander effects" by radiation. Relationship between radiation-induced low-dose hypersensitivity and the bystander effect. Occupational radiation exposure and mortality: second analysis of the National Registry for Radiation Workers. The manner of dependence of the permissible dose of radiation on the amount of genetic damage. Role of induced genetic instability in the mutagenic effects of chemicals and radiation. Chromosome rearrangements resulting from telomere dysfunction and their role in cancer. Induction of sister chromatid exchanges by extremely low doses of alpha-particles. Unexpected sensitivity to the induction of mutations by very low doses of alpha-particle radiation: evidence for a bystander effect. Epistatic interactions between skin tumor modifier loci in interspecific (spretus/musculus) backcross mice. Chromosomal instability in acute myelocytic leukemia and myelodysplastic syndrome patients among atomic bomb survivors. Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors. Alpha particles initiate biological production of superoxide anions and hydrogen peroxide in human cells. Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man. Tritium and Other Radionuclide Labelled Organic Compounds Incorporated in Genetic Material. Genetic studies at the Atomic Bomb Casualty Commission-Radiation Effects Research Foundation: 1946-1997. The children of parents exposed to atomic bombs: estimates of the genetic doubling dose of radiation for humans. Prevalence of hepatitis B surface antigen, hepatitis Be antigen and antibody, and antigen subtypes in atomic bomb survivors. Report of the National Institutes of Health Ad Hoc Working Group to Develop Radioepidemiological Tables. Prevalence of mutations of ras and p53 in benign and malignant thyroid tumors from children exposed to radiation after the Chernobyl nuclear accident. Untargeted mutation of the maternally derived mouse hypervariable minisatellite allele in F1 mice born to irradiated spermatozoa.

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Clinical Features the orbital cysticercosis presents with proptosis and often mimics orbital pseudotumor. Other clinical features include restricted ocular motility, ptosis and recurrent inflammation. Human beings are infected due to the consumption raw pork containing Trichinella larvae. Systemic corticosteroids are given with antihelminthics to control the inflammatory reaction. Clinical Features Headache, vomiting and diarrhea are early symptoms, later a typhoid-like syndrome may develop. The larvae may induce inflammation of the eyelid, the conjunctiva and the extraocular muscle. However, topical and systemic corticosteroids, and oral albendazole 25 mg/kg/day or mebendazole 200-400 mg 3 times a day for 10 days may provide relief. Etiology Echinococcosis is caused by the larval form of Echinococcus granulosus which lives in the intestine of dogs and cats. The cyst formed by the tapeworm is called hydatid cyst or echinococcal cyst, often found in liver and lungs. Cysticercosis Clinical Features the larvae of echinococcus may invade the orbit and cause proptosis and signs of space-occupying lesion in the orbit. The tapeworm lives in the small intestine and its head or scolex is attached to the intestinal wall. The larvae of the worm can reach the lymphatic and the blood circulation through autoinfection by ano-rectal route. It causes cysts formation in the extraocular muscles, under the Treatment the cyst must be removed by excision. Oral albendazole 15 mg/kg/day for 4-12 weeks or 424 Textbook of Ophthalmology Etiology the thrombosis of the cavernous sinus may occur due to the spread of infection from orbital cellulitis, otitis, facial furuncles and erysipelas. Diseases of Paranasal Sinuses involving Orbit Orbit is often involved in the diseases of the paranasal sinuses. Mucocele of the frontal sinus causes proptosis and downward displacement of the eyeball associated with edema of the upper lid. Ethmoidal sinusitis or polyp displaces the eyeball laterally and cases diplopia and chemosis. Distension or malignancy of the maxillary sinus causes buldging and displacement of the globe upwards. The fracture of the floor of the orbit following a blunt trauma causes classical features. Both inflammatory and neoplastic lesions of the paranasal sinuses can lead to erosion of the bony wall of orbit. Clinical Features the signs and symptoms of cavernous sinus thrombosis are almost the same as that of orbital cellulitis. Differentiation of cavernous sinus thrombosis from orbital cellulitis is difficult in the initial stages. However, the presence of edema in the mastoid region owing to the thrombosis of emissary veins, and transfer of the symptoms to the other eye (50% of cases) in the form of paralysis of lateral rectus muscle are of great diagnostic importance. Thrombosis of cavernous sinus is often accompanied by cerebral symptoms, vomiting and rigors. Clinical Features Pain associated with ocular movements is highly indicative of idiopathic orbital inflammation. Unilateral headache and severe orbital pain associated with ophthalmoplegia are characteristics of Tolosa-Hunt syndrome. Treatment the disease is preventable by prophylactic chemotherapy and avoidance of manipulation or squeezing of pyogenic boils over the face and nose. Massive doses of broad-spectrum antibiotics, preferentially by intravenous route, for 3-4 weeks together with anticoagulants may control the infection and bring about the resolution. Systemic corticosteroids may be instituted under antibiotic cover to reduce inflammation and edema. The idiopathic sclerosing inflammation of the orbit may present a diagnostic dilemma since it has minimal inflammatory signs. Both Graves ophthalmopathy and myositis cause thickening of the extraocular muscles. The former causes thickening of the muscle belly while in the latter the entire muscle is thickened along with its tendon. Histopathologically, idiopathic orbital inflammation presents cellular infiltrates mostly consisting of lymphocytes, plasma cells and eosinophils associated with varying amount of fibrosis. An idiopathic granuloma at the apex of the orbit is found in Tolosa-Hunt syndrome. Idiopathic Orbital Inflammation or Pseudotumor of the Orbit the idiopathic orbital inflammation, previously referred to as pseudotumor of the orbit, is a nonneoplastic orbital lesion characterized by a pleomorphic cellular response associated with fibrovascular reaction. Etiology Clinically the idiopathic orbital inflammation may present as dacryoadenitis, myositis, sclerotenonitis and Tolosa-Hunt syndrome. Inflammation of the extraocular muscles of the orbit is termed as orbital myositis. Besides pseudotumor, myositis is also seen in thyroid ophthalmopathy, sarcoidosis, cysticercosis and lymphoma. Chronic sclerosingform of myositis with increased fibrosis and less inflammation occurs in sclerotenonitis. Tolosa-Hunt syndrome is caused by a nonspecific inflammation within the superior orbital fissure or cavernous sinus. Treatment All cases of idiopathic orbital inflammation should be treated with high doses of systemic corticosteroids (adult dose 60-80 mg of prednisolone). Orbital irradiation (13000 cGys) and immunosuppressants (cyclophosphamide 200 mg/day) may be useful in controlling the idiopathic sclerosing inflammation of the orbit. Fibroblasts are extremely sensitive to stimulation by cytokines and immunoglobulins released during the course of an immune reaction. Stimulation of fibroblasts results in production of hyaluronic acid, a glycosaminoglycan, which increases the osmotic load and passive swelling of extraocular muscles and orbital fat. Clinical Features Graves ophthalmopathy is predominantly associated with Graves hyperthyroidism (90%). However, it may occur only in 1% cases of primary hypothyroidism and 6% cases with a normal functioning thyroid (euthyroid). The systemic features of the disease include tachycardia, tremors and a raised basal metabolic rate. The most common ocular symptom of thyroid ophthalmopathy is ocular pain or discomfort which may be associated with dry eyes. Diplopia, lacrimation, photophobia and blurred vision are other symptoms of the disease. Unilateral or bilateral eyelid retraction is the most common feature of Graves ophthalmopathy seen in more than 90% of patients. Chemosis, conjunctival erythema over the insertion of medial and lateral rectus muscles, fullness of eye and superior limbic keratoconjunctivitis may be found. Pathogenesis Exophthalmos in Graves ophthalmopathy results from a discrepancy between the volume of orbit and increased volume of swollen retrobulbar Fig. Classical signs of the disease including eyelid retraction, proptosis, restrictive extraocular myopathy and optic nerve dysfunction. Most cases of Graves ophthalmopathy need supportive care such as ocular lubricants and tear substitutes. Correction of thyroid function abnormality with thyroxine and oral radioactive iodine (I-131) therapy. The pretreatment and posttreatment low-dose corticosteroids help restoration of the euthyroid state and improvement in ocular condition. Orbital decompression to relieve the visual loss from compressive optic neuropathy b. It is contraindicated in diabetic patients because it can exacerbate diabetic retinopathy. The eyeball is kept in position in the orbit by its fascial attachments and extraocular muscles. Normally, the apex of the cornea does not protrude beyond the plane of upper and lower margins of the orbit.

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Finally, other recent studies clarified a spectrum of therapeutic sensitivity of these tumors. As above discussed, Gleason pattern 4, cribriform morphology is a prostate cancer subtype associated with unfavorable clinicopathological factors [33]. These observations support the use of immunotherapy with immune checkpoint blockade inhibitors for the treatment of these prostate tumors [140]. In a recent phase 2 randomized clinical trial, Olaparib in combination with Abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with Abiraterone alone [151]. However, more serious adverse events were observed in patients who received Olaparib and Abiraterone than Abiraterone alone [151]. These findings were confirmed in a more recent study showing that defective mismatch repair was associated with mismatch repair gene mutations and increased immune, cell, immune checkpoint, and T cell-associated transcripts [154]. Prostate adenocarcinomas with focal pleomorphic giant cell features are rare prostate cancer subtype with dismal clinical prognosis. These eventsof 136 Medicines 2019, 6, 82 27 then trigger cellular processes such as proliferation and cell invasion. These events then trigger cellular processes such as proliferation and cell invasion. Medicines 2019, 6, 82 29 of 136 the main drug therapy of prostate cancer consists in reducing the levels of androgens, sutaining the survival and the proliferation of prostate cancer cells. Androgen deprivation is the standard treatment strategy for metastatic prostate cancer, but patients undergoing this therapy invariably relapse despite the treatment induces castrate androgen level. More particularly, as prostate cancer progresses, pronounced changes in androgen metabolism are observed, involving increased expression of steroidogenic enzymes, as well as mutations in some key components of the steroidogenic machinery [165]. This mutant was subsequently shown to be F877L; F877L spontaneous mutations have been detected in patients treated with Enzaluitamide [168]. For many years the standard therapy for men with a condition of metastatic prostatic cancer remained androgen deprivation therapy, mainly based either on orchiectomy or on the administration of gonadotropin-releasing hormone antagonists. These observations support the use of Abiraterone plus Prednisone as a standard of care in patients with high-risk metastatic prostate cancer. Worst toxicity grade was similar, even if different in the specific events, in the two treatment arms [184]. The drug combination of Abiraterone and Prednisone was shown to slightly, but significantly improve Medicines 2019, 6, 82 32 of 136 the overall survival compared to Prednisone + Placebo (median overall urvival 34. Patients who progress with Abiraterone treatment may still have some benefit from subsequent Docetaxel therapy [189]. Other studies have been carried out using Enzalutamide-a new antiandrogen receptor antagonist. Importantly, Enzalutamide improved clinical outcomes irrespective of age of patients [193]. However, administration of the drug to older patients (aged 75 years or greater) should be made with caution, in view of the increased falls and cardiac events [193]. These results support the view that in this category of patients Enzalutamide induces a significant 71% lowering of the risk of metastasis or death than placebo. The analysis of patient-reported outcomes in this study showed that patients who received Enzalutamide had low pain levels and prostate cancer symptom burden and high health-related quality of life compared to those in the placebo group [196]. These findings support the view that Enzalutamide induces a clear clinical benefit by delaying pain progression, symptom worsening, and decrease in functional status compared with placebo [196]. Apalutamide is a new second-generation antiandrogen that has a structure and a mechanism of action similar to Enzalutamide; however, despite similar in vitro profiles, Apulatamide had in vivo increased potency compared to Enzalutamide. Importantly, Apalutamide not only improved metastasis-free survival, but also prolonged the time to symptomatic progression [202]. Duralutamide treatment significantly prolonged the metastasis-free survival from 18. Two recent studies have addressed the important problem of evaluating the impact of androgen deprivation therapy in localized prostate cancer. Neoadjuvant hormone therapy followed by radical prostatectomy results in favorable pathologic responses in some patients, but longer follow-up is required to assess the impact of the neoadjuvant therapy on recurrence rates. Studies of neoadjuvant-intensive androgen deprivation represent a tool to investigate the mechanisms of drug resistance. In patients where two or three tumor foci were dissected and analyzed, it was observed a common clonal origin, but multiple Medicines 2019, 6, 82 34 of 136 oncogenic alterations unique to each focus were also identified [211]. These findings support the view that neoadjuvant intense androgen deprivation select subclones with oncogenic alterations present in primary prostate cancers [212]. A retrospective analysis on a large set of patients undergoing radical prostectomy and postsurgery androgen deprivation therapy showed that (a) patients with luminal tumors exhibit increased androgen signaling and (b) patients with luminal B tumors have poorer outcomes, but potentially improved response to postoperative androgen deprivation therapy [212]. It is important to note that for the patients with localized prostate cancer there is no indication for androgen deprivation therapy and the current therapeutic approachjes are represented by either total prostatectomy or a so-called "watchful-waiting" approach. It is commonly believed that total prostatectomy reduces mortality among men with localized prostate cancer, but evidence derived from randomized clinical trials with long-term follow-up is very limited. In this context, it is particularly important to mention a recent randomized study by the Scandinavian Prostate Cancer Group with a 29-year follow-up, showing that patients with localized prostate cancer and a long-life expectancy benefited from radical prostectomy, with a mean of 2. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer [213]. Inhibition of this mechanism reduced tumor growth and restored standard therapy efficacy [214]. Medicines 2019, 6, 82 38 of 136 Interestingly, a recent study showed that inhibition of de novo lipogenesis (fatty acid synthase) may represent a new strategy to reduce androgen receptor signaling in castration-resistant prostate cancer [242]. This analysis showed (a) a progressive increase of the frequency of alterations of these three genes and this phenomenon was still more evident taking into account the frequency of co-alterations of at least two of these genes; (ii) no significant changes at the level of the mutational tumor burden; and (iii) a very pronounced increase in the percentage of copy number altered genome (Figure 5) [245]. Various molecular mechanisms are responsible for Myc overexpression in prostate cancer cells. Myc protein stabilization seems to be a major mechanism contributing to Myc overexpression in this tumor. Some recent studies have elucidated peculiar mechanisms of prostate cancers overexpressing c-Myc. Prostate cancer cells, as well as the large majority of tumor cells, exhibit increased telomerase activity. Surprisingly, a high percentage of these tumors exhibited metastases to distant lymph nodes [294]. These findings have potential implications for future immunotherapy studies [301]. Furthermore, an increase in oncogenic driver mutations in African tumors was observed [317]. Recently, Tonon and coworkers reported the mutational profile of 25 localized prostate cancers from African Carribean men, and compared it to the findings observed in 15 French Caucasian prostate cancer patients. Among men undergoing radical prostatectomy at equal-access centers, alhough black men had an increased risk of biochemical recurrence, they had simila risks of aggressive disease, recurrence, metastasis, and prostate cancer-related death compared with white men, and the risk of biochemical recurrence was similar after taking into account risk parameters [324]. The findings of these two studies support the view that racial differences in prostate cancer mostly rely on early stages of disease development. A great limitation of this classification derives from the lack of integration with genomic data, which could be useful to better stratify the patient risk and to define a more personalized risk assessment. Decipher is 22-gene genome classifier and its capacity to predict clinical outcome was supported by several clinical studies. Thus, the genomic classifier predicted metastasis on multivariate analysis in a high-risk population after radical prostectomy: the cumulative incidence of metastasis at 5 years after radical prostectomy was 2. The Genomic Classifier Scoring system, together with clinical nomograms, allows the identification of patients most at risk for rapid metastatic progression [333]. The meta-analysis of five studies, involving a total of 975 patients, including 855 patients with individual patient-level data, showed tha Decipher Genomic improves the prognostication post-prostectomy, as well as within all clinicopathologic, demographic, and treatment subgroups [335]. Prostate cancer is heterogeneous and multifocal, with the presence of multiple, genomically independent tumors identified in ~80% of patients undergoinhg radical prostectomy for localized prostate cancer. This heterogeneity represents a potential problem and an impediment for the development of single bioipsy-based prognostic biomarkers and for the development of of precision Medicines 2019, 6, 82 48 of 136 medicin approaches based on single biopsy analysis.

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About 10% of all genes (470) showed some degree of sensitivity to ionizing radiation. Comparison between these data sets is complicated by different methods of reporting and different technical approaches to determining sensitivity. Comparisons were therefore made in general terms rather than gene by gene, and only those genes were considered that were reported by both groups. The committee first compared the genes required for resistance against hydrogen peroxide as reported by two independent research groups, to establish the consistency of the data (Figure 1A-1). A set containing about 200 genes was common to both groups as necessary for resistance to hydrogen peroxide. Since different methods were used to detect sensitivity and rank the strains, some differences are not surprising. The common set of 150 genes required for resistance to both ionizing radiation and hydrogen peroxide included those involved in postreplication repair and recombination, but the genes that ranked among the most sensitive toward ionizing radiation were ranked lower on the list for hydrogen peroxide (Birrell and others 2002). The committee then compared the genes required for resistance to different oxidizing agents with those required for resistance to X-rays (Figure 1A-2). The overlap was small in comparison to the number of genes required for resistance to ionizing radiation; conversely, more than half of the genes required for resistance to each oxidant were also required for resistance to ionizing radiation. The relevance of these comparisons to this report lies in the attempts that have been made to explain low-dose ionizing radiation as no more than a special case of oxidative damage (Pollycove and Feinendegen 2003). If this were true, low doses of ionizing radiation would be insignificant compared to the levels of naturally occurring reactive oxygen species and could therefore be ignored as having no detrimental health effects. Numbers in regions of overlap represent the number of genes responsible for resistance against two agents as reported by one or another group. Mutants sensitive to hydrogen peroxide included an overrepresentation of mitochondrial respiratory functions, but those sensitive to diamide encompassed genes involved in vacuolar protein sorting. This makes it especially difficult to predict what kinds of damage would result from endogenous reactive oxidative species. Endogenous damage could present its own unique spectrum of genes required for resistance, different from each of the exogenous sources as well as from ionizing radiation. These included genes required for transcription, protein trafficking, and vacuolar function. Homologous recombination may therefore mask some of the effects caused by loss of genes on pathways that may be minor in yeast but more important in mammalian cells (Swanson and others 1999; Gellon and others 2001; Morey and others 2003). For example, mice that are defective in apurinic endonuclease are embryonic lethals, and blastocysts derived from these nulls are radiosensitive (Xanthoudakis and others 1996; Ludwig and others 1998). Although the results described in yeast do indicate differences between ionizing radiations and oxidizing agents, the extent of differences or of overlap may not be the same in mammalian cells. In the 1970s, somatic cell genetic techniques were developed to allow the quantification and characterization of specific gene mutations arising in irradiated cultures of somatic cells. In more recent years, findings of persistent postirradiation genomic instability, bystander effects, and other types of cellular response have posed additional questions regarding the mechanisms underlying the cytogenetic and mutagenic effects of radiation and their potential to contribute to radiation tumorigenesis. This chapter considers the general aspects of dose-response relationships for radiobiological effects and subsequently reviews the largely cellular data on a range of radiobiological end points. Many of the conclusions reached from this review, when aggregated with those of Chapters 1 and 3, contribute to the judgments made in this report about human cancer risk at low doses and low dose rates. In this way the dose to an irradiated population is considered in the context of, among other factors, the natural background radiation received. Low- 1Because the older dose term "rad" is used in some figures, the committee notes here that 1 Gy = 100 rads. For the purposes of this report, it does not include background radiation of about 1. Theoretically, the term represents the single-hit intratrack component, and represents the two-hit intertrack component. An alternative interpretation is that the D2 term may arise from multiple tracks that would increase the overall burden of damage in a cell and thereby partially saturate a repair 43 Copyright National Academy of Sciences. As the dose is reduced, the term becomes less important, and the doseresponse relationship approaches linearity with a slope of. For doses delivered in multiple fractions or at low dose rates, in which case the effects during the exposure period are independent and without additive or synergistic interactions, the dose-response relationship should also be linear with a slope of. Theoretically, the value of should be the same for high and low dose rates and for single or multiple doses, and there should be a limiting value, 1, so that reducing the dose rate further would not reduce the term (see Figure 2-1 for an illustration of these concepts). If only acute high-dose data are available, the slope (1) for the linear extrapolation of the data for acute doses that approach zero (tangent to curve A) is used. Note, the contribution from the term (D2) equals the contribution from the term (D) (i. For this dose equal to /, the incidence for curve D is equal to the difference between the incidence for curve A and the incidence for curve D; thus, curve A intersects the linear curve B at the dose equal to /. The curved solid line for high absorbed doses and high dose rates (curve A) is the "true" curve. The linear, no-threshold dashed line (curve B) was fitted to the four indicated "experimental" points and the origin. The dashed curve C, marked "low dose rate," slope Ex, represents experimental high-dose data obtained at low dose rates. Several factors may affect the theoretical dose-response relationships described above, namely: variations in radiosensitivity during the cell cycle; induction of an adaptive response to an initial exposure, which can reduce the effect of later exposures; a bystander effect that causes an irradiated cell to have an effect on a nearby unirradiated cell; the induction of persistent genomic instability; and hyper-radiation sensitivity in the low-dose region. These factors, together with data on the induction of gene/chromosomal mutations in somatic cells are discussed in subsequent sections of this chapter. These early conclusions, based primarily on work with plant cells, are supported by subsequent studies with mammalian cells. The quantitative cytogenetic systems developed over the years, particularly in G0 human lymphocytes, have been utilized in studies on the effects of dose, dose rate, and radiation quality. The fundamental arguments supporting this widely accepted conclusion have been discussed in depth (Bender and others 1974; Scott 1980; Cornforth and Bedford 1993; Natarajan and Obe 1996). In the following paragraphs, a brief outline is provided of the current state of knowledge of the mechanisms that are believed to play a role in the induction of chromosomal aberrations (see Bedford and Dewey 2002 for a detailed discussion). Aberrations formed following irradiation of cells in the G0/G1 phase of the cell cycle are dicentric exchanges, centric rings, and monocentric exchanges (translocations). However, the concept of proximity-promoted interaction of lesions gives more weight to lesions arising along the path of single tracks. The precise mechanism of formation of these complexes remains uncertain, but multiple pairwise exchanges involving the same chromosomes play some part (Edwards and Savage 1999). In these studies (Darroudi and others 1998; Greinert and others 2000) a substantial portion of exchanges have been shown to form rapidly, although some require several hours. Overall, biophysical approaches to the modeling of doseresponse for chromosomal aberrations, although not without some uncertainties on mechanisms, imply that the singletrack component of radiation action will dominate responses at low doses and low dose rates (i. Below that dose, the statistical power of the data was not sufficient to exclude the theoretical possibility of a dose threshold for radiation effects. On the basis of direct observation and theory, the conventional cytogenetic view is that all such chromosomal damage sustained within a given cell cycle will be fixed and then expressed at the first postirradiation mitosis. This prediction has been tested as part of a recent study (Pala and others 2001) that showed dicentric yields falling by up to a factor of 4 between the first and second postirradiation cell division. It seems therefore that the vast majority of initial unrepaired and misrepaired lesions are expressed as chromosomal damage at the first division. Cells carrying unbalanced chromosomal exchanges (dicentrics) or substantial chromosomal losses are not expected to contribute to the viable postirradiation population. By contrast, cells carrying small deletions or balanced exchanges such as reciprocal translocations are likely to remain viable, and some may have the potential to contribute to tumor development. Later in the chapter this conventional view is contrasted with data implying that in some circumstances, a certain fraction of irradiated cells can express chromosomal damage over many cell cycles (i. The proposition that this induced instability phenotype can contribute to tumorigenesis is explored in Chapter 3. Not unexpectedly, molecular analyses of radiation-induced somatic mutations at a number of loci provide evidence of induction of point mutations in single genes and of small and large deletions that may encompass a number of physically linked genes (Sankaranarayanan 1991; Thacker 1992). An important factor in the induction and recovery of deletion-type, multilocus mutations is the degree to which multiple gene loss may be tolerated by the cell.

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It also made it possible to develop more reliable estimates for site-specific cancers due to the higher-quality diagnostic information compared with that based on death certificates. The longer follow-up period and larger number of cancer deaths and cases allowed more precise evaluation of risk and also more reliable assessment of the long-term effects of radiation exposure. For other cancer sites, data suitable for quantitative risk assessment were limited; for example, medical exposures often involve large therapeutic doses. Two of the most important sources of uncertainty are (1) the possible reduction in risk for exposure at low doses and low dose rates (i. For cancer sites other than breast and thyroid (where data on Caucasian subjects are available), the committee presents estimates based on the assumption that the excess risk due to radiation is proportional to baseline risks (relative risk transport) and also presents estimates based on the assumption that the excess risk is inde- Copyright National Academy of Sciences. As a central estimate, the committee recommends a weighted estimate of these two results with the ratio of the two used to reflect the uncertainty in transporting risks. The committee provides estimates of lifetime risks of both cancer incidence and mortality for leukemia, all solid cancers, and cancers of several specific sites (stomach, colon, liver, lung, female breast, prostate, uterus, ovary, bladder, and all other solid cancers). As an example, Table 12-13 shows the estimated number of incident cancer cases and deaths that would be expected to result if a population of 100,000 persons with an age distribution similar to that of the entire U. The estimates are accompanied by 95% subjective confidence intervals that reflect the most important sources of uncertainty, namely, statistical variation, uncertainty in the factor used to adjust risk estimates for exposure at low doses and low dose rates, and uncertainty in the method of transport. Consideration of additional sources of uncertainty would increase the width of these intervals. Mortality estimates are reasonably compatible with those in previous risk assessments, particularly if uncertainties are considered. For many cancer sites, uncertainty is very large, with subjective 95% confidence intervals covering greater than an order of magnitude. All details of these models are not given, but the general approaches that have been used are described. Separate models were developed for mortality from leukemia, breast cancer, respiratory cancer, digestive cancer, and all other cancers. The model for breast cancer mortality was based on both A-bomb survivor data and Canadian fluoroscopy patients. Models were also developed for breast and thyroid cancer incidence, although no lifetime risk estimates based on these models were presented. The thyroid cancer incidence model was based on children in the Israel Tinea Capitis Study (Ron and Modan 1984) and the Rochester Thymus Study (Hempelmann and others 1975). For cancers other than leukemia, a linear model was used with a nonspecific recommendation to reduce the estimates obtained through linear extrapolation by a factor between 2 and 10 for doses received at low dose rates. These estimates were based on a multiplicative transportation model in which relative risks were assumed to be the same for the U. The risk measure used was the excess lifetime risk, which excludes radiationinduced deaths in persons who would have died from the same cause at a later time in the absence of radiation exposure. Estimates of the number of excess deaths (with confidence intervals), the total years of life lost, and the average years of life lost per excess death were given. For the single exposure scenario, separate estimates were presented for leukemia, breast cancer, respiratory cancer, digestive cancer, and other cancers, with each presented for both sexes and nine age-atexposure groups. Based on this approach, about 500 cancer deaths would be predicted from exposure of 0. For a working population (excluding children), about 400 cancers would be predicted (4. Although a major objective in developing these weighting factors was to estimate the detrimental effects of radiation exposures that deliver nonuniform doses to various organs of the body, they can also be used to obtain lifetime risks for site-specific cancers. This is done by multiplying these factors by the lifetime risk estimates for all cancers. Land and Sinclair estimated lifetime risks for several types of cancer using agespecific risk coefficients from Japanese A-bomb survivors (taken from Shimizu and others 1990). Final recommendations were based on results obtained by averaging results over countries and over two of the mod- Copyright National Academy of Sciences. Specifically, risks for those exposed early in life decreased more rapidly than the risk for those exposed later, and the decrease was less rapid for women than for men. The attained-age model generally gives lower lifetime risks because of the attenuation of risks as people age. To obtain estimates of the parameters quantifying the modifying effects of sex, age at exposure, and attained age, an approach described by Pierce and colleagues (1996) was used. With this approach, the parameters, and were set equal to those for all solid cancers unless there was evidence of significant departure from these values. This is accomplished by specifying uncertainty distributions for each of several sources and then combining these distributions using Monte Carlo simulations. Estimates based on both relative and absolute transportation models were presented. With the absolute risk model, the absolute magnitude of the radiation risk is assumed not to depend on the baseline risk, whereas with the relative risk model, the magnitude of the radiation risk is assumed to be proportional to the baseline risk. Because baseline risks for site-specific cancers vary considerably from country to country, estimates based on the two models can differ substantially. For leukemia, only absolute transportation was used, since differences in the two approaches were trivial. Estimates are based on linear models with no modification for low doses and low dose rates, although in some cases reduction by a factor of 2 or so was recommended. The first estimate is based on relative risk transportation; the second on absolute risk transportation. This model was chosen because it provided a slightly better fit to the data than a model that allowed risks to vary over the full range of exposure and attained ages [i. The parameters, and were estimated from an analysis of all solid cancers excluding thyroid and nonmelanoma skin cancer, although cancers that occur in only one sex were excluded in estimating N; the estimated values of, and were, respectively, 0. With this approach, the common values noted above were used unless there was evidence that the site-specific values differed significantly from these common values. The assessment of uncertainty in the estimated parameters, some of which were site-specific and some of which were common to several sites, was complex and made use of an approach known as joint analysis (Pierce and Preston 1993); joint analysis allows some parameters to depend on cancer site whereas others are assumed to be common to several sites. In fact, uncertainty was a fundamental part of the process in that the emphasis was not on determining single point estimates, but on estimating the uncertainty distribution. Exceptions were thyroid cancer, where models were based on a pooled analysis of data from six different study populations by Ron and colleagues (1995a). Nonmelanoma skin cancer risks were estimated from a special A-bomb survivor data set used by Ron and colleagues (1998a). Because adjudication of compensation claims for possibly radiation-related cancer is almost always specific to organ site, the list of sites for which models were provided was more extensive than most previous risk assessments. The rationale for this was that the range of uncertainty is of interest regardless of whether or not a statistically significant dose-response association has been observed. All leukemia models were based on a linear-quadratic function of dose, with equal contributions of the linear and quadratic terms. With the exception of sampling variability, the uncertainty distributions for the individual sources were based on informed but nevertheless subjective judgments. The material that follows describes analyses that were conducted to evaluate several possible models for solid cancer risks, including models that allow for dependence on age at exposure alone, on attained age alone, on time since exposure instead of attained age, and on the use of different functional forms to express these dependencies. Confidence intervals (95%) were usually calculated as the estimate plus and minus 1. For estimates of linear coefficients of dose, these were calculated on a logarithmic scale. Occasionally (as noted) confidence intervals were calculated using the likelihood profile. These are based on differences in the maximized log likelihood statistics, often referred to as deviances. For leukemia, the parametric model is that described by Preston and coworkers (2004).

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Furthermore, although this listing is the largest of its kind, it is not exhaustive. Broad philosophies and movements not defined by organized religious bodies are, of course, more difficult to obtain statistics for. Some sociologists define religion as a belief system shared by a group of individuals. The database has thousands of broad classifications, religions, branches, individual churches, etc. Article was created by Dede Paquette and John Ryan as a project during their studies at National-Louis University and used with permission from Dede Paquette. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this presentation will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. Neither can there be any guarantee that the acquisition described in this presentation will be completed, or that it will be completed as currently proposed, or at any particular time. There can be no guarantee that Novartis or any potential products that would be obtained with Endocyte will achieve any particular future financial results, or that Novartis will be able to realize any potential strategic benefits or opportunities as a result of the proposed acquisition. Novartis is providing the information in this presentation as of this date and does not undertake any obligation to update any forwardlooking statements as a result of new information, future events or otherwise. Until closing, Endocyte will continue to operate as a separate and independent company. Clinical trials of tropifexor in combination with Allergan and Pfizer compounds in accordance with collaboration agreements with those companies. Access Principles apply to how we research, develop and commercialize globally (though the focus of this slide is specifically R&D) 2. Programs are not yet finalized 47 Novartis R&D and investor update November 5, 2018 Value and pricing in life-long rare disease treatment 10-year drug cost vs. Inotersen and Patisiran for Hereditary Transthyretin Amyloidosis: Effectiveness and Value. The fitted regression model for the trend line is: y=63723x + 3E+06, with an R-squared value as Report 041618. Percentage of patients in later lines of therapies was calculated based on the treatment rate of the previous line. The acquisition of Endocyte is subject to customary closing conditions, including receipt of regulatory approvals and Endocyte stockholders approval. For presentation in response to an unsolicited request for medical information subject to local approval. Trends in stage distribution for patients with non-small cell lung cancer: A National Cancer Database survey. Non-small cell lung cancer: epidemiology, riskf actors, treatment, and survivorship. Fulvestrant given on Day 1 and Day 15 of the first 28-day cycle, then Day 1 of subsequent 28-day cycles. Patients receiving hydroxyurea or erythropoietin were included if prescribed for the preceding 6 months and dose was stable for at least 3 months. Domingo C et al; the prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation. Lancet Respir Med 2016;4:699-707 (225 mg bid, wk12) 104 Novartis R&D and investor update November 5, 2018 Fevipiprant development: targeting biologic efficacy with oral simplicity Exacerbation reduction % reduction over 52 weeks Administration Fevipiprant1 Targeted efficacy profile 30 50 Benralizumab2 Mepolizumab3 28 42 51 53 Reslizumab4 Dupilumab5 46 50 59 67 1. Recurrence of Subretinal Fluid Recurrence of Intraretinal Fluid Macular Hemorrhage Loss of Vision 4. At Week 48, the majority of patients (56% and 51%) were maintained on q12w injection interval i n Hawk and Harrier respectively with remaining patients on q8w regimen (key secondary endpoints); greater than 75% of these patients continued on q12w dosing up to Week 96. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Siponimod 2 mg is the current therapeutically relevant dose for multiple sclerosis. Siponimod 2 mg is the current therapeutically relevant dose for multiple sclerosis *p<0. Work and activity impairment were assessed by the general health version of the Work Productivity and Activity Impairment questionnaire. Corrona Report: Real-World Data From the Corrona Psoriasis Registry June 15, 2018. Data cut-off 31-08-2018, Novartis Pharmaceuticals Q3 2018 Financial Report dated October 2018 2. Copaxone Safety consistent with the known fingolimod profile Copaxone 20mg N = 324 -40. Screening month -1 to Day 0 Dose-blind treatment 12 months Follow-up Fingolimod 0. Rituxan is a registered trademark of Biogen Inc 169 Novartis R&D and investor update November 5, 2018. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Cataloging-in-Publication Data Dietary reference intakes : the essential guide to nutrient requirements / Jennifer J. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. Its goal is to serve as a practical, hands-on reference to help guide health professionals in the United States and Canada in their day-to-day task of assessing and planning for the nutrient needs of individuals and groups of people. Without introducing new data or conclusions, this document recasts essential ideas from the original reports in an accessible and more compact form. They were developed in recognition of the growing and diverse uses of quantitative reference values and the availability of more sophisticated approaches for dietary planning and assessment purposes. Thus, although governed by scientific rationale, informed judgments were often required in setting reference values. Where data were available, criteria of nutritional adequacy were carefully identified; these criteria are listed in tables in each nutrient chapter. Also, as new information or new methods of analysis are adopted, these reference values undoubtedly will be reassessed. The purpose of this independent review is to provide candid, confidential, and critical comments that will assist the institution in making its published book as sound as possible and to ensure that the book meets institutional standards. We wish to thank the following individuals for their review of this report: Lawrence Appel, Johns Hopkins Medical Institutions; Stephanie A. Although these reviewers provided many constructive comments and suggestions, they were not asked to endorse nor did they see the final draft of the book before its release and publication. Behney, who was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered.

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The Effects of Price Transparency Regulation on Prices in the Healthcare Industry, the Baker Institute, 2013. Reducing Regulation and Controlling Regulatory Costs Executive Order 13771, titled Reducing Regulation and Controlling Regulatory Costs, was issued on January 30, 2017. It has been determined that this proposed rule, if finalized, would be a regulatory action for the purposes of Executive Order 13771. Federalism Analysis Executive Order 13132 establishes certain requirements that an agency must meet when it promulgates a proposed rule (and subsequent final rule) that imposes substantial direct costs on State and local governments, preempts State law, or otherwise has federalism implications. The authority citation for part 405 continues to read as follows: Authority: 42 U. For purposes of this section, direct supervision means that the physician or nonphysician practitioner must be immediately available to furnish assistance and direction throughout the performance of the procedure. It does not mean that the physician or nonphysician practitioner must be present in the room when the procedure is performed. The authority citation for part 412 is revised to read as follows: Authority: 42 U. The authority citation for part 410 continues to read as follows: Authority: 42 U. Administrative practice and procedure, Health facilities, Medicare, Puerto Rico, Reporting and recordkeeping requirements. The authority citation for part 416 continues to read as follows: Authority: 42 U. The authority citation for part 419 continues to read as follows: Authority: 42 U. The provisions in this subpart are issued under the authority of section 1833(t)(2)(F) of the Act, which authorizes the Secretary to develop a method for controlling unnecessary increases in the volume of covered hospital outpatient department services. This subpart specifies the process and requirements for prior authorization for certain hospital outpatient department services as a condition of Medicare payment. Prior authorization means the process through which a request for provisional (a) Prior authorization as condition of payment. The authority citation for part 486 is revised to read as follows: Authority: 42 U. This rate is adjusted for the distributions of age, sex, race, and cause of death among eligible deaths. Hospital means an institution in any State in which State or applicable local law provides for the licensing of hospitals, that is licensed as a hospital pursuant to such law or is approved, by the agency of such State or locality responsible for licensing hospitals, as meeting the standards established for such licensing. For purposes of this definition, a State includes each of the several States, the District of Columbia, Puerto Rico, the Virgin Islands, Guam, American Samoa, and the Northern Mariana Islands. Items and services means all items and services, including individual items and services and service packages, that could be provided by a hospital to a patient in connection with an inpatient admission or an outpatient department visit for which the hospital has established a standard charge. Examples include, but are not limited to, supplies, procedures, room and board, use of the facility and other items (generally described as facility fees), services of employed physicians and non-physician practitioners (generally reflected as professional charges), and any other items or services for which a hospital has established a standard charge. Machine-readable format means a digital representation of data or information in a file that can be imported or read into a computer system for further processing. Payer-specific negotiated charge means the charge that a hospital has negotiated with a third party payer for an item or service. Service package means an aggregation of individual items and services into a single service with a single charge. Shoppable service means a service package that can be scheduled by a health care consumer in advance. Standard charge means the regular rate established by the hospital for an item or and service provided to a specific group of paying patients Third party payer means an entity that is, by statute, contract, or agreement, legally responsible for payment of a claim for a health care item or service. Department of Veterans Affairs and Military Treatment Facilities operated by the U. Unless otherwise stated, hospital charge information must be made public electronically via the internet. A hospital must include all of the following corresponding data elements in its list of standard charges, as applicable: (1) Description of each item or service provided by the hospital. The information described in paragraph (b) of this section must be published in a single digital file that is in a machine-readable format. The hospital must clearly indicate the date that the information was most recently updated. The hospital must update the standard charge information described in paragraph (b) of this section at least once annually. The hospital must clearly indicate the date that the standard charge data was most recently updated, either within the file itself or otherwise clearly associated with the file. A hospital must include, as applicable, all of the following corresponding data elements when displaying its payer-specific negotiated charges for the shoppable services selected under paragraph (a) of this section: (1) A plain-language description of each shoppable service. For shoppable services not provided by the hospital, the charge must be indicated as ``N/A'. Each payer-specific charge must be clearly associated with the name of the third party payer. This date is the latest date of the following: (A) the first day the hospital is required to meet the requirements of this part. Even if the hospital is in violation of multiple discrete requirements of this part, the maximum total sum that a single hospital may be assessed per day is $300. They are prescribed to patients for daily use, and come in the form of tablets or capsules of varying dosages. Prescription stimulants are sometimes abused however-that is, taken in higher quantities or in a different manner than prescribed, or taken by those without a prescription. Because they suppress appetite, increase wakefulness, and increase focus and attention, they are frequently abused for purposes of weight loss or performance enhancement (e. Euphoria from stimulants is generally produced when pills are crushed and then snorted or mixed with water and injected. When taken in doses and via routes other than those prescribed, prescription stimulants can increase brain dopamine in a rapid and highly amplified manner (similar to other drugs of abuse such as methamphetamine), thereby disrupting normal communication between brain cells and producing euphoria and, as a result, increasing the risk of addiction. Stimulants can increase blood pressure, heart rate, and body temperature and decrease sleep and appetite. At high doses, they can lead to serious cardiovascular complications, including stroke. Addiction to stimulants is also a very real consideration for anyone taking them without medical supervision. Addiction most likely occurs because stimulants, when taken in doses and routes other than those prescribed by a doctor, can induce a rapid rise in dopamine in the brain. Furthermore, if stimulants are abused chronically, withdrawal symptoms-including fatigue, depression, and disturbed sleep patterns-can result when a person stops taking them. Additional complications from abusing stimulants can arise when pills are crushed and injected: Insoluble fillers in the tablets can block small blood vessels. All stimulants work by increasing dopamine levels in the brain- dopamine is a neurotransmitter associated with pleasure, movement, and attention. The therapeutic effect of stimulants is achieved by slow and steady increases of dopamine, which are similar to the way dopamine is naturally produced in the brain. The doses prescribed by physicians start low and increase gradually until a therapeutic effect is reached. Values are presented as means (+standard deviations) (the cut-offs of these parameters have been derived from the following references). Low sodium, high natriuretic peptides, high plasma renin activity, high aldosterone and catecholamines, high endothelin-1, high adrenomedullin, high vasopressin. Values are presented as means (+ standard deviations) (the + cut-offs of these parameters have been derived from the following references).