By: Robert Arntfield, MD
Following successful treatment menstruation urinary tract infection buy generic capecitabine on line, itraconazole can be used for prophylaxis against relapse until immunity recovers breast cancer quilt pattern 500 mg capecitabine fast delivery. Skin and nail infections Mild localised fungal infections of the skin (including tinea corporis womens health honesdale pa quality 500 mg capecitabine, tinea cruris menstruation food order capecitabine 500mg online, and tinea pedis) respond to topical therapy. Systemic therapy is appropriate if topical therapy fails, if many areas are affected, or if the site of infection is difficult to treat such as in infections of the nails (onychomycosis) and of the scalp (tinea capitis). Oral imidazole or triazole antifungals (particularly itraconazole) and terbinafine p. Tinea capitis is treated systemically; additional topical application of an antifungal may reduce transmission. Griseofulvin is used for tinea capitis in adults and children; it is effective against infections caused by Trichophyton tonsurans and Microsporum spp. Fluconazole or itraconazole are alternatives in the treatment of tinea capitis caused by T. Pityriasis versicolor may be treated with itraconazole by mouth if topical therapy is ineffective; fluconazole by mouth is an alternative. Antifungal treatment may not be necessary in asymptomatic patients with tinea infection of the nails. Terbinafine and itraconazole have largely replaced griseofulvin for the systemic treatment of onychomycosis, particularly of the toenail; they should be used under specialist advice in children. Although terbinafine is not licensed for use in children, it is considered to be the drug of choice for onychomycosis. Immunocompromised children Immunocompromised children are at particular risk of fungal infections and may receive antifungal drugs prophylactically; oral triazole antifungals are the drugs of choice for prophylaxis. Fluconazole is more reliably absorbed than itraconazole, but fluconazole is not effective against Aspergillus spp. They are used for the local treatment of vaginal candidiasis and for dermatophyte infections. Systemic absorption may follow use of miconazole oral gel and may result in significant drug interactions. Lipid formulations of amphotericin (Abelcet and AmBisome ) are significantly less toxic and are recommended when the conventional formulation of amphotericin is contra-indicated because of toxicity, especially nephrotoxicity or when response to conventional amphotericin is inadequate; lipid formulations are more expensive. Echinocandin antifungals have a role in the prevention and systemic treatment of fungal infections. Resistance to flucytosine can develop during therapy and sensitivity testing is essential before and during treatment. Flucytosine has a role in the treatment of systemic candidiasis and cryptococcal meningitis. It is the drug of choice for trichophyton infections in 350 Fungal infection children. Duration of therapy is dependent on the site of the infection and may extend to a number of months. Monitor liver function-discontinue if significant and persistent abnormalities in liver function tests develop. Prophylactic antipyretics or hydrocortisone should only be used in patients who have previously experienced acute adverse reactions (in whom continued treatment with amphotericin is essential). Itraconazole should be avoided in patients with ventricular dysfunction or a history of heart failure unless the infection is serious. Monitor liver function if treatment continues for longer than one month, if receiving other hepatotoxic drugs, if history of hepatotoxicity with other drugs, or in hepatic impairment. With oral use For oral liquid, do not take with food; swish around mouth and swallow, do not rinse afterwards. With oral use Patients or carers should be given advice on how to administer itraconazole oral liquid. Consider treatment discontinuation if severe abnormalities in liver function tests. If phototoxicity occurs, consider treatment discontinuation; if treatment is continued, monitor for pre-malignant skin lesions and squamous cell carcinoma, and discontinue treatment if they occur. No information available for severe hepatic cirrhosis- 5 Infection 356 Fungal infection manufacturer advises use only if potential benefit outweighs risk. Child 12-17 years Intravenous vehicle may accumulate if estimated glomerular filtration rate less than 50 mL/minute/1. Monitor liver function before starting treatment, then at least weekly for 1 month, and then monthly during treatment. Patients and their carers should be told how to recognise symptoms of liver disorder, and advised to seek immediate medical attention if symptoms such as persistent nausea, vomiting, malaise or jaundice develop. Patients and their carers should be advised that patients should avoid intense or prolonged exposure to direct sunlight, and to avoid the use of sunbeds. In sunlight, patients should cover sun-exposed areas of skin and use a sunscreen with a high sun protection factor. Patients should seek medical attention if they experience sunburn or a severe skin reaction following exposure to light or sun. In renal impairment liver- and kidney-function tests and blood counts required weekly. Liver- and kidney-function tests and blood counts required (weekly in blood disorders). Pneumocystis pneumonia should generally be treated by those experienced in its management. Severe disease Co-trimoxazole in high dosage, given by mouth or by intravenous infusion, is the drug of choice for the treatment of severe pneumocystis pneumonia. Pentamidine isetionate is a potentially toxic drug that can cause severe hypotension during or immediately after infusion. Corticosteroid treatment can be lifesaving in those with severe pneumocystis pneumonia. The corticosteroid should be withdrawn before antipneumocystis treatment is complete. Prophylaxis against pneumocystis pneumonia should also be considered for severely immunocompromised children. It should not be discontinued if the child has oral candidiasis, continues to lose weight, or is receiving cytotoxic therapy or long-term immunosuppressant therapy. Cotrimoxazole may be used in infants born to mothers with a high risk of transmission of infection. Inhaled pentamidine isetionate is better tolerated than parenteral pentamidine isetionate. Intermittent inhalation of pentamidine isetionate is used for prophylaxis against pneumocystis pneumonia in children unable to tolerate cotrimoxazole. Direct intravenous injection should be avoided whenever possible and never given rapidly; intramuscular injections should be deep and preferably given into the buttock. Powder for injection (dissolved in water for injection) may be used for nebulisation.
However breast cancer zumbathon discount capecitabine 500 mg with mastercard, the weight of the upper arm sometimes pulls the hand away from the face menopause zinc capecitabine 500mg with amex, giving the appearance of voluntary avoidance women's health clinic quesnel buy genuine capecitabine online. The abdominal reflexes are usually present and plantar responses are invariably absent or flexor pregnancy 0-12 weeks buy genuine capecitabine on line. Upon admission she was reportedly unresponsive to verbal command, but when noxious stimuli were administered she withdrew, repetitively thrust her extremities in both flexion and extension, and on one occasion spat at the examiner. She was given 10 mg of diazepam intravenously and 500 mg of phenytoin intravenously in two doses 3 hours apart. Eight hours later, because she was still unresponsive, a neurologic consultation was requested. She lay quietly in bed, unresponsive to verbal commands and not withdrawing from noxious stimuli. Her respirations were normal; her eyelids resisted opening actively and, when they were opened, closed rapidly. Her extremities were flaccid with Psychogenic Unresponsiveness normal deep tendon reflexes, normal superficial abdominal reflexes, and flexor plantar responses. When 20 mL of ice water was irrigated against the left tympanum, nystagmus with a quick component to the right was produced. She recovered full alertness later in the day and was discharged a day later with her neurologic examination having been entirely normal. Comment: this patient illustrates a common problem in differentiating ``organic' from psychogenic unresponsiveness. She had been sedated and had a mild metabolic encephalopathy, but the preponderance of her signs was a result of psychogenic unresponsiveness. She was awake and alert at the time of admission and had a normal neurologic examination. The general physical examination was unremarkable, revealing no changes from the day before. On neurologic examination she failed to respond to either verbal or noxious stimuli. She held her eyes in a tightly closed position and actively resisted passive eye opening, and the lids, after being passively opened, sprung closed when released. The neurologist who examined the patient suggested to the cardiologist that the unresponsiveness was psychogenic and that psychiatric consultation be secured. When the decision was finally made to consult a psychiatrist, the patient, without opening her eyes, responded with the words, ``No psychiatrist. In the latter, the initial examination suggested psychogenic unresponsiveness, but vestibular testing elicited tonic deviation of the eyes without nystagmus. The tonic eye deviation clearly indicated physiologic rather than psychologic unresponsiveness. A rare patient with psychogenic unresponsiveness is able to inhibit nystagmus induced by caloric testing (probably by intense visual fixation), but in that instance there is no tonic deviation of the eyes and the combination of other signs can establish the diagnosis. When a patient with severe organic illness, whether systemic or neurologic, becomes unresponsive, the physician sometimes fails to entertain the possibility that the unresponsiveness is psychogenic and represents a conversion reaction to a difficult psychologic situation. When first examined by a neurologist, he was unresponsive to verbal stimuli but grimaced when stimulated noxiously. Nuchal rigidity and bilateral extensor plantar responses were present, but there were no other positive neurologic signs. Carotid arteriography failed to reveal the cause of his symptoms, which were believed to be caused by leptomeningeal metastases. Two weeks after the initial neurologic examination, he was noted to be lying in bed staring at the ceiling with no responses to verbal stimuli and with 6-mm pupils, which responded actively to light. Because of the confusion about the exact cause of his diminished state of consciousness, an ``Amytal interview' was carried out (see page 307). After 300 mg of intravenous Amytal was given slowly over several minutes, the patient awoke, was fully oriented, and was able to perform the serial sevens test without error. During the course of the discussion, when the problems of his cancer were broached, he broke into tears. A diagnosis of psychogenic unresponsiveness superimposed on metastatic disease of the nervous system was made. The patient was started on psychotropic drugs and he remained alert and responsive throughout the remainder of his hospital stay. Catatonia is a symptom complex characterized by either stupor or excitement accompanied by behavioral disturbances that include, among others, mutism, posturing, rigidity, grimacing, waxy flexibility (a mild but steady resistance to passive motion, which gives the examiner the sensation that he is bending a wax rod), and catalepsy (the tonic maintenance for a long period of time of a limb in a potentially uncomfortable posture where it has been placed by an examiner). In a retroprospective clinical study of patients admitted to a psychiatric unit with catatonic symptoms, only four of 55 were schizophrenic; 39 had affective disorders, three had reactive psychoses, and nine suffered from organic brain diseases, which included toxic psychosis, encephalitis, alcoholic degeneration, and druginduced psychosis. This state is compatible with normal pupillary and oculovestibular function even when the obtundation has a structural origin. In addition, catatonic stupor is accompanied by a variety of autonomic and endocrine abnormalities that give the patient a particularly strong appearance of organic neurologic disease. The patient in a catatonic stupor who presents a problem in the differential diagnosis of stupor or coma usually appears unresponsive to his or her environment. Severe and prolonged catatonic stupor, as described below, is uncommon, since such patients are usually treated early with psychotropic medications before the full picture develops. The patient in catatonic stupor usually lies with the eyes open, apparently unseeing. The skin is pale and frequently marred by acne and has an oily or greasy appearance. Such patients usually do not the two patients above illustrate the difficulties in making a diagnosis of psychogenic unresponsiveness in patients with organic disease. Merskey and Buhrich have stressed the frequency of conversion hysteria in patients suffering from structural disease. They may not blink to visual threat, although optokinetic responses are usually present. The pupils are dilated and there is frequently alternating anisocoria; they are, however, reactive to light. Some patients hold their eyes tightly closed and will not permit passive eye opening. At times there is increased salivation, the patient allowing the saliva either to drool from the mouth or to accumulate in the back of the pharynx without being swallowed. Such subjects may be incontinent of urine or feces or, on the contrary, may retain urine requiring catheterization. Their extremities may be relaxed, but more commonly are held in rigid positions and are resistant to passive motion. The deep tendon reflexes are usually present and there are no pathologic reflexes. She was unresponsive to voice, her eyes were open, and she would direct her eyes to sound and would blink to threat, but would not follow commands and did not respond to noxious stimuli. Physicians whom she recognized entered the room, but she was unable to respond to them. She reported that the noxious stimuli were very painful, but she could not move, nor could she respond to questions. She continued to think that she was dead until somewhat later in the morning, when a nurse whom she knew well sat by the bedside and talked to her gently. Because the nurse was being so nice she thought she had to respond and she began to talk. There had been no history of previous psychologic disorder nor was there any hint during the rest of her hospitalization of a psychologic abnormality.
Reviews by Boyd and Bero (2006) and Boyd (2008) likewise found no systematic descriptions or assessments of these policies breast cancer 7mm mass discount capecitabine master card. The availability women's health birth control pill buy capecitabine amex, representativeness women's health center of jackson wy order capecitabine master card, and quality of the available information are limited in several important ways breast cancer youngest age order genuine capecitabine on line. As noted above, even if the developers of guidelines have conflict of interest policies, they may not refer to them in individual guideline documents. This in turn means that the summaries in the National Guideline Clearinghouse are likely to have no information either. A number of groups have recently revised aspects of their policies, and the committee is aware of other groups that are considering changes. From the policies examined, the committee identified several variations in organization conflict of interest policies and procedures. The frequent lack of transparency of conflict of interest policies limits the ability of guideline readers to consider financial relationships and conflicts of interest as part of their assessment of the credibility of a set of guidelines. To give a sense of what readers of guidelines may encounter, Box 7-3 includes additional examples of the range of summary statements in the National Guideline Clearinghouse. DepartmentofHealthandHumanServiceshastakenstepsto assure that there is technical compliance with ethics statutes and regulations regardingfinancialconflictsofinterest. Potentialnomineesarescreenedforconflictsofinterest,andifanyarefound,theyareasked to divest or forgo certain vaccine-related activities. Conflict of interest forms were American College of Chest Physicians, whose policies are summarized in Box 7-4. Effectiveness of Policies the committee identified no evaluations of the impact of conflict of interest policies on the content of guidelines or other outcomes. The review by Boyd and Bero (2006) also found no rigorous assessments of conflict of interest policies for guideline development and no evaluations of different strategies for implementing or enforcing them. Incompliancewiththispolicy, a superscript number placed by the name of an author denotes an author who hasindicatedanaffiliationwithorganizationswhichhaveinterestsrelatedtothe contentoftheseguidelines. Other Strategies to Limit Bias in the Development of Clinical Practice Guidelines Those committed to the development and implementation of sound, credible, and useful guidelines have devised a number of methods and tools that can be used to support the creation of such guidelines. Several are listed in Box 7-5, roughly according to the step in the process of guideline development described in Table 7-1. Arguably, the most important steps are the conduct of a systematic review of the evidence and the linking of recommendations to the evidence in an explicit fashion. The strategies-and continuing areas of debate and methodological refinement-are described in depth elsewhere (see. In general, they reinforce conflict of interest policies by limiting the opportunity for secondary financial interests to exert undue influence on the primary interest of developing sound guidelines. Unfortunately, as Steinberg and Luce (2005) have observed, rigorous methods for clinical practice guideline development and reviews of the clinical evidence are not applied consistently, and the conclusions of evidence reviews are not always interpreted appropriately. Furthermore, given that the evidence base is weak in many areas, they advise, "physicians, policymakers, and others acting on the basis of judgments, recommendations, or measures. As noted earlier, in addition to developing methods to limit bias, individuals and groups have been developing tools for standardizing the presentation of guidelines and assessing the quality of guidelines across several domains (see. Methodologists have also developed tools ethodologists that can be used to assess the quality of systematic reviews (Shea et al. Although theprimaryrationaleistouselimitedresourcestoevaluateareasthatofferthe greatestpotentialtoimprovethequalityoreffectivenessofhealthcare,another potential benefit is a reduction in the opportunity for financial relationships and othersourcesofbiastoinfluencetheselectionoftopics. Methodologists have developed and tested formal processes for developing consensus and otherwise structuringtheexpertjudgmentprocess(see,e. An independent, expert review of the guidelines and relateddocumentsisanimportanttoolthatcanbeusedtoimprovetheidentification, evaluation, and use of the evidence. The process used to select expert reviewers should explicitly identify and assess reviewer ties with potentially affectedcompanies. These and other instruments are not intended to be used to assess the full substance of the guidelines. In and of themselves, they will not identify, for example, whether key evidence has been overlooked or incorrectly assessed, whether relevant benefits or harms have been ignored or improperly weighed, or whether critical barriers to implementation have been missed. Notwithstanding some shortcomings of guideline assessment tools, their development and application underscore that it is important for documents containing clinical practice guidelines to provide potential users of the guidelines with informative descriptions of the development process, the evidence base, the participants, and the applicable conflict of interest policies. When users of guidelines confront guidelines that lack such descriptions, they would be prudent to treat the guidelines with caution and search for other guidelines that provide appropriate documentation. Even when the developers of clinical practice guidelines use sound methods, they are often limited by shortcomings in the evidence base. A review of the guidelines in the National Guideline Clearinghouse reveals recommendation after recommendation that is supported by weak, mixed, or no evidence. Overall, the combination of a better evidence base for clinical practice guidelines and better tools for assessing that evidence not only strengthens the usefulness of practice guidelines but also reduces the potential for conflicts of interest to bias guidelines. On the basis of its judgment and experience (including experience with conflicting guidelines and guidelines not based on formal reviews of the evidence), the committee believes that the risk of undue industry influence on clinical practice guidelines is significant, and that risk justifies that strong steps be taken to strengthen conflict of interest policies governing the development of guidelines. Groups should publicly disclose with each guideline their conflict of interest policies and procedures and the sources and amounts of indirect or direct funding received for development of the guideline. Groups should disclose their conflict of interest policies and their process for seeking members without conflicts of interest and its results. The disclosure of the relevant financial interests of members of guideline development panels should be sufficiently specific and comprehensive that it helps others judge the severity of the conflicts of interest, including allowing the identification of fiduciary interests. Some committee members also wanted groups that develop guidelines to report publicly all their sources, amounts, and purposes of funding because industry contributions to general revenues. Other committee members were also concerned about the overall reliance of some professional and patient groups on industry funding, but they believed that this reporting of all sources and purposes of funding is not necessary, provided that groups developing guidelines adopt and implement rigorous evidence-based procedures, report indirect and direct funding sources for each guideline, and institute the conflict of interest policies and procedures recommended in this report. Another safeguard would be the continued development of processes for rating guidelines development processes, as described above. Congress requires companies to report payments not only to individuals but also to a range of medical organizations, that information, in combination with the annual reports that many professional society and patient groups issue, should allow the calculation of industry funding as a share of total revenues. Transparency also involves the inclusion of the specified information with each guideline that a group sponsors. Preferably, the information would accompany the written text, but it could-particularly if it is very lengthy-be provided by an Internet link that is maintained through the life of the guideline. In addition to expanded disclosure about funding, the committee recommends an end to direct industry funding of clinical practice guidelines. It recognizes that this step might have the undesirable effect of reducing the involvement of professional societies in guideline development but believes that it is necessary to avoid the conflicts that come from industry financing. It is also likely that an increase in public support for systematic reviews of the evidence would buffer such effects because these reviews are an expensive part of the process of developing evidence-based guidelines. Professional societies and other groups with a shared interest in certain clinical problems could also collaborate on the development of guidelines and spread the costs. In addition, a pooling mechanism might be created-as has been suggested by some for continuing medical education-to support indirect industry funding of the development of clinical guidelines in certain broad categories. Another important step is to exclude or substantially limit the participation of individuals with conflicts of interest on panels that develop clinical practice guidelines. If groups conclude that participants with conflicts of interest are essential to provide the necessary expertise, they should demonstrate to the public that they have made a good faith but unsuccessful effort to find individuals with the required expertise and without conflicts of interest. They should also preclude individuals with conflicts of interest from chairing guideline development panels, restrict the number of individuals with conflicts of interest on panels to a distinct minority. In addition to actions by the institutions directly involved in the development of guidelines, organizations with an interest in unbiased clinical practice guidelines can create incentives for groups that develop guidelines to adopt the recommendations presented in this report. The committee understands that the National Guideline Clearinghouse will be phasing in a requirement for the disclosure of conflicts of interest, but the committee recommends that it extend the requirement to include the disclosure of funding and policy information, consistent with Recommendation 7. It would also be desirable for the clearinghouse or some other entity to begin substantive assessments of the quality of clinical practice guidelines. Some groups that have operated with undisclosed industry support or that have been unwilling to disclose the financial relationships of guideline development panel members may remove themselves from the guideline development process.
In addition menopause 6 months without a period buy 500mg capecitabine fast delivery, recoil protons have track lengths of a few micrometers women's health june 2012 order capecitabine 500mg overnight delivery, so critical damage can womens health 40 is the new 20 buy capecitabine with a visa, with fairly high probability menstrual pads capecitabine 500mg on-line, be caused in neighboring chromosomal structures. The track size is enlarged relative to the nucleus to illustrate the theoretical track structure. For clarity of presentation, the size of the tracks is increased relative to the cell and is not drawn to scale. As the energetic electron interacts with atoms of the material, secondary electrons are produced and kinetic energy is lost. Such collisions can result in deflection of the primary electron from its original path (Figure 1-8, panel A). Important components of the track structure are the clusters of secondary ionizations that occur in a very small volume (see Figure 1-8, panel B). The likely site of health effects of low-dose radiation is the genetic Copyright National Academy of Sciences. Recoil protons with energy of a few hundred kiloelectronvolts appear, in line with the above biophysical considerations, to be the particles that produce maximal cellular damage per unit energy imparted. This is confirmed by various experimental studies that consistently demonstrate the maximal effectiveness of neutrons at a neutron energy of about 0. The dose-effect relationship, E(D), for photons can in many radiobiological investigations be described as a linear quadratic function of absorbed dose: E(D) = aD + bD2. The same has been observed for more complex effects such as opacification of the lens and, more important in the context of risk assessment, induction of tumors in animals. This large maximal value might be seen as an indication of an exceptionally high effectiveness of neutrons at low doses. Experiments with rodents show considerable variation, especially in female mice and rats, and this variation reflects the decisive influence of hormonal status. In experiments with female Sprague-Dawley rats, Shellabarger and others (1980) found that 4 mGy of fast neutrons produced as many mammary neoplasms as 0. In view of this complexity, it appears best to refer to experiments with male mice or rats that determine the overall incidence of solid tumors. Signal transduction from cell membrane phospholipids damaged by free radicals and oxidizing reactions is an important natural process. This is one set of biochemical pathways by which the effects of ionizing radiation may overlap with the effects of endogenous processes, such as macrophage oxidative bursts. These processes may underlie those seen in irradiated cells that have been characterized as "bystander effects" and "adaptation" (see Chapter 2). They note that to extrapolate available epidemiologic and experimental data from high-dose and high-dose-rate studies to the relevant low levels of single isolated tracks, it is essential to develop a more molecular and mechanistic approach based on the amounts, types, and repairability of the early molecular damage that results from the initial physical and chemical processes. The authors conclude that the large deletions seen in radiation-induced mutations may have other mechanisms, such as nonhomologous recombination (Nikjoo and others 1997). Of the interactions that do cause strand breaks, the authors calculate that a small percentage (about 0. As in the low-energy study just described, this model does not include any contribution to the yield of strand breaks from damaged bases. In all experimental studies with rodents, it was difficult or impossible to determine excess tumor rates at -ray doses substantially less than 1 Gy. Ejection of an electron from a water molecule by an incoming photon produces an ionized water molecule, H2O+. Trapping of the electron by polarizing water molecules produces a so-called hydrated electron, e-aq. Hanel and colleagues (2003) have shown that electrons at energies below the threshold for electronic excitation (<3 eV) can decompose gas-phase uracil to generate a mobile hydrogen radical. The cell nucleus consequently is almost anoxic (Joenje 1989), and oxidative damage is quenched about fiftyfold by histones and by suppression of Fenton oxidants. Strong evidence pointing to differences between X-ray damage and oxidative damage has come from studies in the yeast Saccharomyces cerevisiae. A genome-wide collection of nearly 5000 deletion mutants in all nonessential genes is now available for this species. Using this collection, all genes that were required for resistance to the lethal effects of Xrays and hydrogen peroxide were determined (Birrell and others 2001, 2002). Of those that were resistant to either agent, few genes were in common and their rankings were different. Of the top 100 genes conferring resistance to Xrays, only 35 were in the top 100 that were sensitive to hydrogen peroxide (see Annex A-1). These rankings indicate that the types of damage caused by X-rays and hydrogen peroxide were significantly different and required different mechanisms for repair. In another study using these deletion mutants, the oxidative damage caused by five different oxidants was found to differ significantly, indicating an unexpected complexity for oxidative damage (Thorpe and others 2004). Collectively, background radiation is responsible for delivering an average effective dose per person worldwide of about 2. This background value includes radon exposure, the health effects of which are not evaluated in this report. Peroxyl radicals might also account for the production of double base lesions by single radicals that have been observed in irradiated oligonucleotides (Box and others 1995). At the D37 dose of cell killing, it has been calculated that each cell will have sustained 2. However, detailed experimental comparisons between the biological effects associated with the repair of spontaneous damage versus damage due to ionizing radiation have yet to be made. If they are tical with those produced by other oxidizing agents, such as H2O2 in the presence of iron or copper ions or those resulting from the normal metabolic production of free radicals that are by-products of the transport of electrons to oxygen in mitochondria (Dizdaroglu and others 1987, 1991; Gajewski and others 1990; Nackerdien and others 1991; Dizdaroglu 1992; Beckman and Ames 1997). Locally Multiply Damaged Sites Accumulated evidence shows that the products of ionizing radiation may differ from chemically generated oxidation products in their microdistribution rather than in the chemistry of individual lesions (Ward 1981, 1988, 1994). Damaged bases are repaired by mechanisms that involve excision and replacement of individual damaged bases (base-excision repair) or of larger oligonucleotide fragments (nucleotide-excision repair). This strategy (Parikh and others 1998; Waters and others 1999) protects the cytotoxic abasic residue and may delay the rearrangement of the base-free deoxyribose into a reactive free-aldehyde conformation that could cause cross-linking and other unwanted side effects. The temporary inefficiency of this process during early mammalian development could explain the origin of several human syndromes that are associated with expansion of triplet repeats in relevant genes. How cells coordinate these processes and determine which should be used under various circumstances is unknown. Radiation-induced genes represent predominantly cellular signaling molecules, particularly those induced by transactivation by p53. The same factors are also an integral part of the normal process of immunologic rearrangement (Labhart 1999). A homologous sequence may be the other allele on a chromosome of a recently replicated sister-chromatid sequence on a daughter chromatid or a similar sequence in a repetitive region along the same chromosome. In the latter case the sequences may not be identical over long regions, and the mechanism is known as "homeologous" recombination. Recombination between alleles on separate chromosomes occurs at much lower frequency than between identical sequences on sister chromatids or arranged in tandem on the same chromosome. Cells generally exhibit either hRad51 foci or hMre11/hRad50/Nbs foci, but not both, and the choice of which of the mutually exclusive pathways an irradiated cell follows may be determined by Brca1 (Parvin 2001). Dashed arrows and question marks represent possible signaling steps; solid arrows represent reported phosphorylation events. Thus, there are no transcription control or mammalian counterparts of soxR, ada, and lex. This situation presumably reflects the much greater constancy of cellular environment in complex multicellular organisms. Many reports have appeared about adaptive responses involving increased resistance or hypersensitivity in mammalian cells in response to single or multiple doses of ionizing radiation (adaptive effects). There are also reports that the effects of radiation on single cells can influence the response of adjacent nonirradiated cells (bystander effect). These reports are discussed specifically in Chapter 2, but this chapter describes the general stress response and signal transduction pathways that are known to occur after exposure to radiation.
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