Associate Professor, Indiana University School of Medicine
There is good evidence that such tolerance is highly dependent on the genetic context of the mutation (i acne 5 months postpartum cheap 40mg ciscutan fast delivery. These issues are discussed in depth elsewhere (Thacker 1992); here it is sufficient to note that genetic context can result in up to a twentyfold change in induced mutation frequencies in autosomal genes (Bradley and others 1988; Amundson and Liber 1991) skin care help discount ciscutan. Stated simply skin care tips in hindi order ciscutan 5 mg otc, gene loss mutations are characteristic of radiation skin care while pregnant discount 40mg ciscutan with visa, but their recovery in viable cells can be a major limiting factor. As shown later, these features are important for consideration of carcinogenic mechanisms and are also discussed in respect of germline mutagenesis. Evidence for a close relationship between gene mutations and chromosome aberrations is that several induced gene mutations are associated with macroscopic region-specific chromosomal deletions or rearrangements (Cox and Masson 1978; Thacker and Cox 1983; Morris and Thacker 1993). For technical reasons, dose-response relationships for gene mutations are far less precise than those for chromosome aberrations. In general, however, a linear or linear-quadratic relationship provides a satisfactory descrip- tion of the dose-response down to ~200 mGy (Thacker 1992) and, from limited data, at lower doses. The exceptions to this are the data from a particularly sensitive in vivo system that scores reversion mutations (as hair color changes) at the pink-eyed unstable (Bonassi and others 1995) locus in the mouse. The following sections consider specific aspects of cellular response relating to cell cycle effects, adaptive responses to radiation, the transfer of damage signals between cells (bystander effects), induced and persistent genomic instability, low-dose hyper-radiation sensitivity, and other aspects of dose-response. This persistent instability is expressed as chromosomal rearrangements, chromosomal bridge formation, chromatid breaks and gaps, and micronuclei (Grosovsky and others 1996; Murnane 1996; Poupon and others 1996; Limoli and others 1997a; Suzuki and others 1998) in the progeny of cells that survive irradiation. Reduction in cell cloning efficiency several generations after irradiation is called delayed lethality; it is supposedly a manifestation of genomic instability associated with an increase in lethal mutations (Seymour and Mothersill 1997). The spectrum of these de novo mutations resembles that of spontaneous mutations (i. There is controversy, however, as to whether all of these different end points represent the same fundamental chromosomal alterations that result in genomic instability (Chang and Little 1992; Morgan and others 1996; Limoli and others 1997a; Little 1998; Mothersill and others 2000a). There is controversy concerning the fundamental radiation target and lesions that result in genomic instability. There are also data indicating that reactive oxygen species (Limoli and others 2001; Little 2003), potentially persistent over several generations, may play an important role in ongoing genomic instability. In addition, alterations in signal transduction pathways may be involved (Morgan and others 1996), and alterations in nucleotide pools have been shown to lead to genomic instability (Poupon and others 1996). Another possibility is that damage to centrosomes might be an important target because centrosome defects are thought to result in genomic instability through missegregation of chromosomes (Pihan and others 1998; Duensing and others 2001) that would result in aneuploidy (Duensing and Munger 2001). Chromosome instability can be associated with prolonged B/F/B cycles; these cycles arise as a consequence of breakage of fused sister chromatids when their centromeres are pulled in opposite directions during anaphase, with subsequent re-fusion in the next cell cycle. However, because the nonreciprocal translocations provide telomeres that stabilize the marker chromosome, those chromosomes that donate the nonreciprocal translocations can become unstable due to the loss of their telomeres. Then, a subsequent nonreciprocal translocation can serve to transfer instability to another chromosome (Murnane and Sabatier 2004; Sabatier and others 2005). Thus, the loss of a single telomere can result in transfer of instability from one chromosome to another, leading to extensive genomic instability. The importance of telomere loss as a mechanism for chromosome instability through B/F/B cycles in cancer has been emphasized by the demonstration that telomerase-deficient mice that are also deficient in p53 have a high cancer incidence (Artandi and others 2000; Chang and others 2001; Rudolph and others 2001). The analysis of the tumor cells from these mice demonstrated the presence of chromosome rearrangements typical of B/F/B cycles, including gene amplification and nonreciprocal translocations commonly seen in human cancer. A question that has to be addressed is the relevance of radiation-induced genomic instability for radiation-induced cancer, and a corollary of this question is the relationship among expression of p53, radiation-induced apoptosis, and radiation-induced genomic instability. Evidence has been presented that radiation-induced apoptosis can occur via p53-dependent and p53-independent mechanisms (Strasser and others 1994) initiated by damage in the nucleus (Guo and others 1997) or cytoplasm-membrane (Haimovitz-Friedman 1998). This damage results in cells undergoing apoptosis either during interphase without attempting division (Endlich and others 2000), several hours after they have divided a few times (Forrester and others 1999), or during an aberrant mitosis (Endlich and others 2000). In accord with the guardian-of-the-genome hypothesis, mouse tumors undergoing apoptosis in a p53-independent manner contained abnormally amplified centrosomes, aneuploidy, and gene amplification (Fukasawa and others 1997). Also, a decrease in radiation-induced apoptosis associated with nonfunctional p53 or expression of Bcl2 correlated with an increase in mutagenesis (Xia and others 1995; Cherbonnel-Lasserre and others 1996; Yu and others 1997). However, there is evidence that radiation-induced genomic instability is independent of p53 expression (Kadhim and others 1996).
In most studies where external radiation dose estimates were available acne yellow crust cheap ciscutan 40mg fast delivery, death rates were also compared in relation to levels of radiation exposure within the study population skin care industry order 5 mg ciscutan visa. For all cancer mortality (excluding leukemia) acne zyme buy ciscutan 20mg on line, the estimates of radiation-induced excess risk varied from negative to several times greater than those derived from linear extrapolation from high-dose studies (Table 8-3) acne 5 year old purchase ciscutan 5 mg visa. Moreover, because of the large degree of uncertainty, many of these estimates were consistent with an even wider range of possibilities, from negative risks to excess risks at least an order of magnitude greater than those on which the current radiation protection recommendations have been based. Results of such analyses are shown in Tables 8-3 and 8-4 for all cancers excluding leukemia and for leukemia, respectively. In most studies, analyses of mortality in relation to cumulative external radiation dose were conducted for many specific types of cancer. These studies have generally not shown significant increases in risk among exposed workers for most cancer types examined, although a few positive associations have been found (Table 8-3). The confidence intervals in these studies were wide, and the estimates of risk were consistent with those on which current radiation protection recommendations are based. The association in the Hanford study was not significant when follow-up was extended to 1986 (Gilbert and others 1993b). Given the number of associations examined, some of the significant results observed may have been due to chance. Several points must be kept in mind when making comparisons of these worker-based risk estimates and confidence intervals with those based on high-dose-rate studies. The most important are possible biases and uncertainties in dose estimates, errors in outcome data, and inadequate adjustment for confounders. Design Issues Among the very large and potentially most informative cohort studies reviewed in this chapter, two present a number of problems that limit their informativeness. There could have been some confounding of the dose-response because of associations between the probability of successful linkage and factors. This is the only study in which associations have been observed between radiation dose and all-cause mortality, all cancer mortality (without any clear relation to specific cancers), mortality due to cardiovascular diseases (males and females), and fatal accidents (males only). Almost three-quarters of the cohort consists of radiation workers employed in different settings (dentistry, medicine, industrial radiography), where radiation control may be very different (possibly less uniform and systematic due to the much smaller numbers of persons monitored in individual workplaces) than in the nuclear industry. Consequently the study has little power to estimate possible health risks associated with occupational radiation exposure. Adequacy of the Dose Estimates High-Energy Photon Doses the accuracy and precision of individual dose estimates in the nuclear industry is a function of time, place, radiation energy and quality, the geometry of the radiation exposure, and the location of the dosimeter on the body of the worker. Results of reanalyses of data using different approaches to estimate doses from missing dosimeters or below-threshold readings have yielded similar results to the analyses based on original data (Inskip and others 1987; Little and others 1993). In the three-country combined analyses, a retrospective dosimetry study was carried out to identify the various sources of biases and random errors in dosimetry for workers in each of the facilities included and to estimate the magnitude of these errors. However, available dose estimates may have overestimated dose to the bone marrow by up to 20%. For deep organs, the factor is likely to be smaller, of the order of several percent. Random errors in dose estimates are likely to bias the risk estimates downwards, compared to estimates from high-dose studies, which have been based on organ doses. At lower exposure levels however, practices for recording subthreshold doses have resulted in a slight underestimation of doses from predominant higher-energy photon exposure (Fix and others 1997). In the three-country combined analyses, there was little indirect evidence for an association between cumulative dose and mortality from smoking-related cancers, respiratory diseases, or liver cirrhosis; thus, it is unlikely that smoking or alcohol consumption are strongly correlated with radiation dose (Cardis and others 1995). Doses from Neutrons, Low- and Very-High-Energy Photons, and Internal Contamination In the three-country study, efforts were also made to identify workers with substantial doses from radiations other than high-energy photons (mainly from neutrons, low-energy radiation, and contamination with radionuclides, particularly plutonium), for whom recorded dose estimates may be in error. Although it was not possible to identify all such workers, risk estimates based on restricted dosimetry analyses, which excluded all such workers who could be identified, did not differ greatly from those based on the standard approach (-0.
Palsy of the sixth nerve is encountered in 57% of cases acne chart buy discount ciscutan 20 mg line, lower cranial nerves in 36% acne scar removal discount ciscutan 30 mg free shipping, sensory fifth in 27% acne routine cheap ciscutan 30 mg overnight delivery, third in 22% acne excoriee order ciscutan 10mg on line, and optic neuropathy in 12%. The median time from symptom onset to diagnosis has been reported as 10 months (Forsyth et al. Radiographic assessment reveals a midline soft tissue mass associated with osteolytic bone destruction and occasional calcifications. Staged surgeries using different approaches may be needed for removal of the tumor (Gay et al. Even in the best of circumstances, however, this can be accomplished in only 67% of patients due to involvement of critical neurovascular structures (Maira et al. Because of the invasive nature of the tumor, local recurrences are the rule and most of these appear within 3 years of treatment with the mean interval to the first recurrence being 12. Despite various salvage treatments, stabilization of disease at the time of recurrence is uncommon (Hug et al. Proton beam irradiation resulted in a 59% to 63% 5 year local control rate and a 72% to 79% 5 year survival (Castro et al. Older age, female gender, high proliferative index, and large intracranial tumor volume are negative prognostic factors, and in these cases more aggressive management is warranted (Forsyth et al. Several, mainly unsuccessful, chemotherapeutic attempts have been made to treat patients with chordoma. Use of vincristine alone or in combination with methotrexate resulted in a degree of symptomatic improvement (Harwick and Miller, 1979; Fuller and Bloom, 1988). These tumors have a distinct predilection for females, who make up more than 80% of patients in the series of tympanic, jugular, and vagal paragangliomas. Paragangliomas are slow-growing tumors that extend along anatomic planes of least resistance (along blood vessels and mastoid air-cell tracts and through cranial nerve foraminae). Malignancy occurs in 10% of cases, and catecholamine secretion is detected in another 5%. Hearing loss occurs in 90% of patients with glomus tympanicum tumors and in 70% of patients with glomus jugulare tumors, but only rarely in patients with glomus vagale tumors. Pulsatile tinnitus, an audible bruit, or spontaneous aural bleeding can be seen in 60% to 70% of patients with tympanicum or jugulare tumors and in 30% of those with vagale paragangliomas. Involvement of the facial nerve occurs in approximately 20% of patients with tympanicum or jugulare tumors. The vertical mastoid segment is the usual site of compression, although compression in the soft tissue of the stylomastoid foramen may also occur. Dysfunction of the lower cranial nerves occurs in 13% of patients with glomus jugulare tumors and in 70% of patients with glomus vagale tumors. A change in voice may precede other symptoms by 2 to 3 years in patients with glomus vagale tumors. If present, hypoglossal paresis denotes tumor extension into the hypoglossal canal or high in the neck. Pathology Macroscopically, paragangliomas have a beefy red brown to gray appearance, with hemorrhage or fibrosis. They may have a thin capsule and are composed of round or polygonal epithelioid cells. Nuclei are centrally located with finely clumped chromatin and a moderate amount of eosinophilic, granular cytoplasm. Immunohistochemical stains confirm the neuroendocrine nature of the chief cells, which are diffusely and strongly positive for neuron-specific enolase, synaptophysin, and chromogranin. In contrast, the sustentacular cells may show positivity for S-100 protein, glial fibrillary acidic protein, and nerve growth factor receptor. Nuclear pleomorphism, necrosis, mitoses, and even vascular or neural invasion, may be seen in benign tumors and are not sufficient criteria for the diagnosis of malignancy, which is encountered in 2% to 13% of cases.
B acne genetics ciscutan 40 mg discount, Fluid is seen above (solid arrow) and below (open arrow) superior belly of right lateral pterygoid skin care mask order ciscutan 10mg fast delivery. The recognition of muscle alterations may lead to a correct diagnosis and improved understanding of the clinical symptomatology and disease pathophysiology under investigation acne laser removal purchase cheapest ciscutan and ciscutan. Fritts skin care for pregnancy generic ciscutan 10 mg online, Becky Borgerson, and the technical staff at the Center for Diagnostic Imaging are sincerely appreciated. Temporomandibular joint: diagnosis of internal derangements using magnetic resonance imaging. Mandibular coronoid process locking: a prospective study of frequency and association with internal derangement of the temporomandibular joint. Mandibular condylosis and apertognathia as presenting symptoms in progressive systemic sclerosis (scleroderma). It is designed as a review for the practicing ophthalmologist and as a preparatory course for the candidate for board examinations in ophthalmology. A self-assessment quiz will be given, followed by a didactic lecture and then the quiz will be repeated. Subjects of less importance will be included in the outline but mentioned only briefly in the lecture. It is not possible to cover all ocular tumors in this outline or in the discussion. For more comprehensive reading, please see the textbooks cited at the end of this outline. Ophthalmic tumor review- Shields - 2 2 Review of Ophthalmic Tumors Self-assessment Quiz 1. This eyelid lesion in an 80-year-old patient has shown slowly progressive enlargement for two years. Which of the following has been described as a complication of corticosteroid injection of the condition shown in the photograph? This conjunctival lesion has shown slow enlargement in a 55-year-old person for 8 years. A young child with pigmented cutaneous macules and painless progressive visual loss for 12 months develops ipsilateral axial proptosis as shown. Clinical 1 Rough-surfaced elevated, well-defined lesion 2 Can be sessile or pedunculated lesion b. Outward acanthosis, proliferation of basal cells Ophthalmic tumor review- Shields - 5 5 2. Small lesion-primary excision; Larger lesion: biopsy prior to definitive surgery 2. Nevoid basal call carcinoma syndrome (Gorlin-Goltz Syndrome) Autosomal dominant, 0. Dyskeratosis and mitotic activity d Treatment: Similar to basal cell carcinoma; may require orbital exenteration C. About 5 % of all malignant eyelid tumors; can metastasize Can metastasize to regional lymph nodes and distant organs Origins: Meibomian glands, Zeis glands, or caruncle May be multicentric in origin b. Wide excision if malignant transformation suspected Ophthalmic tumor review- Shields - 9 9 2. Diffuse plexiform variant typical of neurofibromatosis Early S-shaped curve to upper eyelid Proptosis due to orbital component b. Merkel Cell Tumor (neuroendocrine carcinoma of skin) Ophthalmic tumor review- Shields - 11 11 a. Bilateral placoid yellow eyelid lesions Ophthalmic tumor review- Shields - 13 13 2. Squamous papilloma is the most common - can evolve into squamous cell carcinoma d. Acanthosis, dyskeratosis, prominent rete pegs Ophthalmic tumor review- Shields - 16 16 2. Double freeze-thaw cryotherapy to conjunctival margins 8 Closure of conjunctiva with absorbable sutures d. Local excision of highly suspicious nodules Quadrantic map biopsies Limbal peritomy 360 Cryotherapy from underside of conjunctival Closure of conjunctiva with absorbable sutures. Double freeze-thaw cryotherapy to conjunctival margins 8 Closure of conjunctiva with absorbable sutures 9. Prominent mass of lymphatic channels Often continuous with orbital lesion Frequent hemorrhage-chocolate cysts Management-Difficult; surgical debulking d.
