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Environmental Estrogens. Thelarche is de ned as the development of breast tissue in preadolescent females (typically <8 years of age). Since 1979 physicians have monitored an epidemic level of thelarche on the island of Puerto Rico. The cause of thelarche in Puerto Rico is not known; however, evidence strongly implicates exposure to endocrine-disrupting agents. Analyses of blood samples from thelarche and nonthelarche children for environmental chemicals with known estrogenic activity revealed that 68% of the thelarche children contained signi cantly high levels of several types of phthalate esters. Only a single nonthelarche child contained a signi cant amount of phthalate ester and only one type of phthalate ester was found in this individual. Phthalate esters are used as plasticizers and are ubiquitous environmental contaminants. They have been shown to cause a variety of endocrine-related effects in animal models and some phthalate esters have been shown to be estrogenic in vitro. The association between phthalate ester exposure and the high incidence of thelarche in Puerto Rico does not establish causality but has generated concern that environmental agents are responsible for this condition. Kepone (chlordecone) is an organochlorine insecticide (Figure 17.5) that was manufactured in Hopewell, Virginia, from the mid-1960s to 1975. In 1975 the Center for Disease Control determined that employees of the manufacturing facility and other residents of Hopewell, totaling over 200 individuals, had been signi cantly contaminated with this insecticide. Exposed individuals reported a variety of symptoms. Foremost, among the symptoms of Kepone sickness were neurological disorders presenting as tremors, weight loss, and nervousness. However, subsequent evaluations revealed that males exposed to Kepone also experienced testicular dysfunction that was characteristic of estrogen exposure. Later laboratory studies demonstrated that Kepone was an estrogen receptor agonist, which could explain its adverse effects on the male reproductive system.

HEURISTIC 10.3.4. Following the general heuristics for subexponential distributions the large buffer over ow is due to one (isolated) large arrival An . At the moment when this happens (say, time n) the queue length process is, because of the stability condition EA < EC, typically very small in comparison to B. Similarly, Cn is much smaller than B. Hence, the amount that is lost at the time of over ow is approximately QB An 1 Cn 1 B % An 1 B . n Accuracy of Theorem 10.3.2 was demonstrated [31, 33] with many numerical and simulation experiments. Here, an example is presented. Example 10.3.5. Take Cn 2 and an arrival distribution P A 0 1, 2 P A i 0:461969=i4 ; i > 0, EA 0:5553. Then, we numerically compute the loss rates lB for the maximum buffer sizes B 100i; i 1; . . . ; 7. The results are loss presented with circles in Fig. 10.1. Note that for B 700 we needed to solve a

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FIGURE 16.2 The biophysics underlying immunocamou age is dependent on the intrachain molecular exibility of the mPEG polymer. Rigid linear molecules have a small radius of gyration (Rg) and fail to effectively camou age the cell surface. In contrast, the linear, but highly exible, mPEG polymer yields a large zone of steric occlusion. The size of the area of protection is dependent on the length (L) of the polymer and its resultant Rg. As noted, the immunocamou aged area produced by the exible mPEG effectively covers a large surface area relative to the very small number of grafted polymers.

LOG10 (loss rate)

Hypothyroidism describes the clinical state arising from a de ciency in thyroid hormone. Toxicity resulting in hypothyroidism is manifested at several organ systems as

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Table 17.4 Clinical Manifestations of Hypothyroidism Organ System Skin Cardiovascular Respiratory Digestive Muscle Nervous Manifestation Puffy appearance, dry, course, yellow-tinted skin brittle nails, wound healing slowed, hair loss Enlarged heart, changes in electrocardiographs Maximal breathing capacity reduced, obstructive sleep apnea, uid accumulation in the pleural cavity Reduced appetite with modest weight gain Stiffness, aching Slowing of intellectual functions, lethargy, headaches

well as the heavy hydration of the polymer chain itself, a small number of grafted mPEG sterically occupies and occludes a large three-dimensional volume, thereby giving rise to the immunocamou age of membrane proteins and carbohydrates (Figure 162) The potential utility of immunocamou age was apparent from the early work by Abuchowski and Davis on the pegylation of puri ed proteins, which resulted in improved solubility, in vivo longevity, vascular retention, and decreased/absent in vivo immunogenicity even after repeated administration of PEG-conjugated xenogeneic proteins32,33 As a consequence of these attributes, a number of pegylated proteins are clinically used for enzyme-replacement therapy34 38 Similarly, polymerized PEG-hydrogels have been investigated as immunoprotective barriers for transplanted cells39 43 However, only recently has mPEG grafting to intact, viable cells and tissues been explored To date, the majority of these studies have focused on the prevention of allorecognition.

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