Topics discussed include analyzing behavior and movement patterns of the same; use of data for analyzing the same; and use of single parameterization for observing tag loss in California sea lions. Forty-six adult female sea lions were successfully captured, studied physiologically, tested for disease states, and released unharmed. Five mortalities occurred: two sea lions drowned in pools of water on the haulouts; two died of telazol anesthesia complications; and one died early in inhalation anesthesia. Choice of animal, stalking, and darting methods were important factors in avoiding problems with capturing these animals. Isoflurane can be delivered safely for over 2 hr of spontaneous ventilation and anesthesia in this species. Associations between the Alaska Steller Sea Lion Decline and Commercial Fisheries. At that time, several procedural restrictions were placed on the commercial fisheries of the region in an effort to reduce the potential for human-induced mortality on sea lions. Several years have elapsed since these restrictions were put into place, and questions about their efficacy remain. Applying Novel Approaches to Old Datasets: Utilizing Opportunistic Observations and Bayesian Estimation to Describe Spatial Use Patterns for Steller Sea Lions. The Platforms of Opportunity data have not previously been used to identify marine mammal habitat because they contain sightings without associated effort records. In this study a novel approach was used to overcome this issue through development of an effort index that allowed for calculation of effort-corrected Steller sea lion encounter rates. Yearround encounter rate estimates were derived in addition to breeding and non-breeding season encounter rates. Although the results of this analysis confirmed many of the areas known to be important Steller sea lion habitat, several previously unrecognized high-use areas were identified. Current critical habitat designated areas only encompass about 37% of high use areas estimated using this methodology. A Remote Biopsy System Used to Sample Steller Sea Lion (Eumetopias Jubatus) Blubber. All parts of the biopsy head were sterilized, using an autoclave or disinfected with boiling water, prior to each use. Sampling was conducted April to July 2002-2004 across the Alaskan range of Steller sea lions. Using Age Structure to Detect Impacts on Threatened Populations: A Case Study with Steller Sea Lions. However, rapid shifts in age structure can occur even while 228 population size remains relatively static. We used time-varying matrix models to study age-structure information as a tool for improving detection of survivorship and fecundity change and status. We applied the methods to Steller sea lions (Eumetopias jubatus), a long-lived endangered marine mammal found throughout the North Pacific Rim. Population and newborn counts were supplemented with information on the fraction of the population that was juvenile, obtained by measuring animals in aerial photographs taken during range-wide censuses. By fitting the model to 1976-1998 data, we obtained maximum-likelihood estimates and 95% confidence intervals for juvenile survivorship, adult survivorship, and adult fecundity in the mid-1980s, late 1980s, and 1990s. We used a series of nested models to test whether the data were best fit by a model with one, two, or three temporal changes in demographic rates, and we fit the models to different lengths of data to test the number of years of data needed to detect a demographic change. The declines in the early 1980s were associated with severely low juvenile survivorship, whereas declines in the 1990s were associated with disproportionately low fecundity. We repeated these analyses, fitting only to the count data without the juvenile-fraction information, to determine whether the age-structure information changed the conclusions and/or changed the certainty and speed with which demographic-rate changes could be detected. The juvenile-fraction data substantially improved the degree to which estimates from the model were consistent with field data and significantly improved the speed and certainty with which changes in demographic rates were detected. Validation of a Fecal Glucocorticoid Assay for Steller Sea Lions (Eumetopias Jubatus). Feces were freeze-dried, extracted with a methanol vortex method, and assayed for glucocorticoids. However, the two males had higher baselines, higher peaks, and more delayed peaks than the females.
Syndromes
Whatever mechanism is responsible, these results illustrate the importance of routine ophthalmologic screening of patients receiving chronic corticosteroid therapy. Naphthalene Accidental exposure to naphthalene results in cortical cataracts and retinal degeneration (Grant, 1986; Potts, 1996). Naphthalene itself is not cataractogenic; instead, the metabolite 1,2-dihydro-1,2dihydroxynaphthalene (naphthalene dihydrodiol) is the cataractinducing agent (van Heyningen and Pirie, 1967). Subsequent studies using biochemical and pharmacologic techniques, in vitro assays, and transgenic mice showed that aldose reductase in the rat lens is a major protein associated with naphthalene dihydrodiol dehydrogenase activity and that lens aldose reductase is the enzyme responsible for the formation of naphthalene dihydrodiol (Sato, 1993; Lee and Chung, 1998; Sato et al. In addition, in vivo and in vitro studies have shown that aldose reductase inhibitors prevent naphthalene-induced cataracts (Lou et al. Finally, there is a difference in naphthalene-induced cataract formation between albino and pigmented rats, with the latter showing a faster onset and more uniform cataract (Murano et al. Phenothiazines It has been known since the 1950s that schizophrenics receiving phenothiazine drugs as anti-psychotic medication develop pigmented deposits in their eyes and skin (Grant, 1986; Potts, 1996). The pigmentation begins as tiny deposits on the anterior surface of the lens and progresses, with increasing dose, to involve the cornea as well. The phenothiazines combine with melanin to form a photosensitive product that reacts with sunlight, causing formation of the deposits. The amount of pigmentation is related to the dose of the drug, with the annual yearly dose being the most predictive dose metric (Thaler et al. More recent epidemiologic evidence demonstrates a dose-related increase in the risk of cataracts from use of phenothiazine-like drugs, including both antipsychotic drugs such as chlorpromazine and nonantipsychotic phenothiazines (Isaac et al. Corticosteroids Systemic treatment with corticosteroids causes cataracts (Urban and Cotlier, 1986). Observable opacities begin in the posterior subcapsular region of the lens and progress into the cortical region as the size of the lesion increases. It was estimated that 22% of patients receiving corticosteroid immunosuppressive therapy for renal transplants experienced cataracts as a side effect of therapy (Veenstra et al. The use of inhaled corticosteroids-commonly prescribed asthma therapy-was once thought to be without this risk, but subsequent epidemiologic evidence documented a significant association between inhaled steroidal therapy and development of nuclear and posterior subcapsular cataracts (Cumming et al. There are two proposed mechanisms through which corticosteroids might cause cataracts. The regular hexagonal array structure of normal lens epithelial cells is disrupted and appears reticulated, while gaps appear between the lateral epithelial cell borders in lenses of humans with steroidinduced cataracts (Karim et al. The interested reader is referred to the excellent references in the Introduction as well as to numerous outstanding websites devoted exclusively to the retina. The mammalian retina is highly vulnerable to toxicant-induced structural and/or functional damage due to (1) the presence of a highly fenestrated choriocapillaris that supplies the distal or outer retina as well as a portion of the inner retina; (2) the very high rate of oxidative mitochondrial metabolism, especially that in the photoreceptors (Linsenmeier, 1986; Ahmed et al. The histogenic steps of development of the neurons and glial components are well characterized. Therefore, toxicological effects in the rodent retina have relevance for chemical exposure during the early gestation period in humans as well as during early postnatal development. The retina contains a wide diversity of synaptic transmitters and second messengers whose developmental patterns are well described. Moreover, the rodent retina is easily accessible, it has most of the same anatomical and functional features found in the developing and mature human retina, and the rat rod pathway is similar to that in other mammals (Dowling, 1987; Finlay and Sengelbaub, 1989; Berman, 1991; Chun et al. Finally, rat rods have similar dimensions, photochemistry, and photocurrents as human and monkey rods (Baylor et al. These general and specific features underscore the relevance and applicability of using the rodent retina to investigate the effects of chemicals on this target site as well as a model to investigate the neurotoxic effects of chemicals during development. These alterations and deficits include, but are not limited to visual field deficits, scotopic vision deficits such as night blindness and increases in the threshold for dark adaptation, cone-mediated (photopic) deficits such as decreased color perception, decreased visual acuity, macular and general retina edema, retinal hemorrhages and vasoconstriction, and pigmentary changes. Another review by Wolfensberger (1998) concentrates on toxic effects on the retinal pigment epithelium. The main aim of this section is to discuss in detail several chemicals and drugs (1) that are currently used as pharmacological agents or environmentally relevant neurotoxicants; (2) whose behavioral, physiologic, and/or pathologic effects on retina are known; and (3) whose retinal site(s) and/or mechanism of action are well characterized. In addition, the effects of organic solvents and organophosphates on retinal function and vision are discussed, as these are emerging areas of concern.
These enzymes have been conserved during evolution presumably because they perform an important physiological function. Second, substrates can bind to relatively o discrete sites within the active site. For the most part, these enzymes can be divided into two groups: a group that is known to metabolize fatty acids and/or eicosanoids and a group that has no known function (so-called orphan enzymes), as shown in Table 6-9. In many cases, these enzymes hydroxylate the terminal methyl group (-hydroxylation) distal to the carboxylic group, which is thermodynamically unfavorable compared with hydroxylation of a methylene group. Following -hydroxylation, the terminal hydroxymethyl group can be further oxidized to convert the original fatty acid/eicosanoid to a dicarboxylic acid. Activation of Xenobiotics by Cytochrome P450 Biotransformation by cytochrome P450 does not always lead to detoxication, and several examples have been given previously where the toxicity or tumorigenicity of a chemical depends on its activation by cytochrome P450. A variety of cytochrome P450-dependent reactions are involved in the activation of the chemicals listed in Table 612. The conversion of polycyclic aromatic hydrocarbons to tumorforming metabolites involves the formation of bay-region diolepoxides, as shown in. The initial step in the conversion of aromatic amines to tumor-forming metabolites involves N-hydroxylation, as shown for 2-amino-6-nitrobenzylalcohol. In the case of acetaminophen, activation to hepatotoxic metabolite involves dehydrogenation to N acetylbenzoquinoneimine, as shown in. A similar reaction converts butylated hydroxytoluene to a toxic quinone methide, as shown in. The myelotoxicity of benzene depends on its conversion to phenol and hydroquinone. The toxicity of several organophosphorus insecticides involves oxidative group transfer to the corresponding organophosphate, as shown for the conversion of parathion to paraoxon in. The hepatotoxicity of carbon tetrachloride involves reductive dechlorination to a trichloromethyl free radical, which binds to protein and initiates lipid peroxidation, as shown in. The hepatotoxicity and nephrotoxicity of chloroform involves oxidative dechlorination to phosgene. Oxidative and reductive dehalogenation both play a role in the activation of halothane, although hepatotoxicity in rats is more dependent on reductive dehalogenation, whereas the immune hepatitis in humans is largely a consequence of oxidative dehalogenation, which leads to the formation of neoantigens (Pohl et al. Some of the chemicals listed in Table 6-12 are activated to toxic or tumorigenic metabolites by mechanisms not mentioned previously. For example, N -nitrosodimethylamine, which is representative of a large class of tumorigenic nitrosamines, is activated to an alkylating electrophile by N -demethylation, as shown in. The rearrangement of this epoxide to a carbonyl is accompanied by migration of chlorine, which produces the highly reactive metabolite, trichloroacetyl chloride, as shown in. Pyrroles themselves are nucleophiles, but electrophiles are generated through the loss of substituents on the pyrrolizidine nucleus, as shown in. Cyclophosphamide and ifosfamide are examples of chemicals designed to be activated to toxic electrophiles for the treatment of malignant tumors and other proliferative diseases. These drugs are nitrogen mustards, which have a tendency to undergo intramolecular nucleophilic displacement to form an electrophilic aziridinium species. In the case of cyclophosphamide and ifosfamide, the nitrogen mustard is stabilized by the presence of a phosphoryl oxygen, which delocalizes the lone pair of nitrogen electrons required for intramolecular nucleophilic displacement. For this reason, formation of an electrophilic aziridinium species requires hydroxylation by cytochrome P450, as shown in. Hydroxylation of the carbon atom next to the ring nitrogen leads spontaneously to ring opening and elimination of acrolein. In the resultant phosphoramide mustard, delocalization of the lone pair of nitrogen electrons to the phosphoryl oxygen is now disfavored by the presence of the lone pair of electrons on the oxygen anion; hence, the phosphoramide undergoes an intramolecular nucleophilic elimination to generate an electrophilic aziridinium species. Many of the chemicals listed in Table 6-12 are also detoxified by cytochrome P450 by biotransformation to less toxic metabolites. Rearrangement of trichloroethylene epoxide can be accompanied by migration of chlorine, which produces chloral (trichloroacetaldehyde), or hydrogen, which produces dichloroacetylchloride. Chloral is much less toxic than dichloroacetylchloride; hence, migration of the chlorine during epoxide rearrangement is a detoxication reaction, whereas migration of the hydrogen is an activation reaction. These few examples serve to underscore the complexity of factors that determine the balance between xenobiotic activation and detoxication.
Fragment analysis represents a practical strategy because it enables comprehensive detection of a wide variety of possible length mutations and has high analytic sensitivity. Further, it can provide semiquantitative information regarding the relative amount of mutated alleles. Limitations of this approach include the inability to objectively quantitate mutant allele burdens, the inability to determine the exact change in nucleotide sequence, and the inability to detect nonlength-affecting mutations such as substitution mutations. However, this assay does not characterize the specific sequence alteration in the mutant allele and may be challenging to interpret, especially for cases with mutation levels that approach the detection limit of the assay. Samples with a lower abundance of mutant alleles, and consequently a decreased fraction of heteroduplexes that produced fluorescence decay during the melting analysis, usually produce a melting curve that may not differ significantly from that of wildtype samples. The presence of a mutation alters the melt profile due to mismatched double-stranded heteroduplexes of mutant and wild-type fragments. Multiplexed reactions can be designed with multiple primers of differing lengths for simultaneous amplification of multiple genomic targets. When a mutation is present, an alternative dideoxynucleotide triphosphate is incorporated, resulting in a different colored peak with a different amplicon length than the expected wild-type one. The single nucleotide extension assay is particularly useful for the simultaneous detection of recurrent point mutations. Clinically, it has been employed for analyses of mutational hotspots in multiple genes involved in melanomas, nonsmall-cell lung cancers, breast cancers, and metastatic colorectal cancers. This assay, however, can only detect mutations that are immediately adjacent to the 3 to the end of the primer. PrinciPles of oncology for each analysis is visualized adequately to produce unequivocal sequence readout. Sanger sequencing can also provide semiquantitative information about mutation levels in a sample based on the evaluation of average peak drop values from forward and reverse mutant peaks on sequence chromatograms. Limitations of this approach include low throughput and limited diagnostic sensitivity. In general, heterozygous mutations at allelic levels lower than 20% may be difficult to detect by Sanger sequencing. The amount of light produced is proportional to the number of incorporated nucleotides in the sequence. When a nucleotide is not incorporated into the reaction, no pyrophosphate is released and the unused nucleotide is degraded by apyrase. Mutations appear as new peaks in the pyrogram sequence or variations of the expected peak heights. This method has higher analytical sensitivity than Sanger sequencing and can provide quantitative information about mutation levels in a sample. A microfluidic pyrosequencing platform is available for massive parallel sequencing. However, this method is not well suited for detecting mutations that are scattered across the entire gene because pyrosequencing read lengths are limited to 100 to 250 base pairs. For the quantitative assessment of gene amplification, a locusspecific probe and a centromeric probe are labeled with two different fluorophores. The signals generated by each of these probes are counted and a ratio of the targeted gene to the chromosome copy number is calculated. The amount of signal produced by the locus-specific probe is proportional to the number of copies of the targeted gene in a cell. For the detection of deletion mutations, dual-probe hybridization is usually performed using locus-specific probes. For instance, for the detection of 1p/19q codeletion in oligodendrogliomas, locusspecific probe sets for 1p36 and 19q13, and 1q25 and 19p13 (control) are used. A signal pattern with 1p and 19q signals that are less than control signals is consistent with deletion of these loci. Gene rearrangements/chromosomal translocations in hematologic or solid malignancies can be tested using locus-specific dualfusion or break-apart probes. Dual-color, dual-fusion translocation assays employ two probes that are located in two separate genes involved in a specific rearrangement. Dual-color, dual-fusion translocation assays are very specific for detecting a selected translocation.
Modulation of the neurofibromatosis type 1 gene product, neurofibromin, during Schwann cell differentiation. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Functional roles of the nucleotide-binding folds in the activation of the cystic fibrosis transmembrane conductance regulator. A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34. Nonsense mutations at Arg1947 in two cases of familial neurofibromatosis type 1 in Japanese. Detection of fusion transcripts generated by the inversion 16 chromosome in acute myelogenous leukemia. Loss of neurofibromin in adrenal gland tumors from patients with neurofibromatosis type I. Characterization of naturally occurring cutaneous neurofibromatosis in Holstein cattle: a disorder resembling neurofibromatosis type 1 in humans. Physical localization of microsatellite markers at the ataxia-telangiectasia locus at 11q22-q23. Differential phylogenetic footprinting as a means to identify base changes responsible for recruitment of the anthropoid gamma gene to a fetal expression pattern. Molecular characterization of 16p deletions associated with inversion 16 defines the critical fusion for leukemogenesis. Acute myelocytic leukemia with inv(16) produces a chimeric transcription factor with a myosin heavy chain tail. Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia. Microdissection and microcloning of chromosomal alterations in human breast cancer. Novel missense mutation (G314R) in a cystic fibrosis patient with hepatic failure. Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Methods for precise sizing, automated binning of alleles, and reduction of error rates in large-scale genotyping using fluorescently labeled dinucleotide markers. The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage. Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups. Hereditary hemochromatosis: gene discovery and its implications for population-based screening. A large sample of Finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter. Two color hybridization analysis using high density oligonucleotide arrays and energy transfer dyes. Enhanced high density oligonucleotide array-based sequence analysis using modified nucleoside triphosphates. Construction of an approximately 700-kb transcript map around the familial Mediterranean fever locus on human chromosome 16p13. Determination of ancestral alleles for human singlenucleotide polymorphisms using high-density oligonucleotide arrays. Complete maternal isodisomy of chromosome 8 in an individual with an early-onset ileal carcinoid tumor. Identification and characterization of JunD missense mutants that lack menin binding. Royal C, Baffoe-Bonnie A, Kittles R, Powell I, Bennett J, Hoke G, Pettaway C, Weinrich S, Vijayakumar S, Ahaghotu C, Mason T, Johnson E, Obeikwe M, Simpson C, Mejia R.
Karpasa (Gossypol). Actoplus Met.
Source: http://www.rxlist.com/script/main/art.asp?articlekey=96148
The high count for the surveys was 953 seals on 29 August, with a mean count of 750 animals. Cape Newenham continues to be an important haulout for the threatened northern sea lion. The haulout was surveyed from the air and ground between late April and late October. Approximately 30 sea lions were also observed in December during an unrelated flight. Composition of sea lions at the haulout was variable, with the percent juveniles ranging from 8-23 throughout the season. Eight tagged sea lions were seen during ground observations; numbers were read from three of the tags. Distribution, Abundance, Reproduction and Behaviour of Steller Sea Lions (Eumetopias Jubatus) in Prince William Sound, Alaska. Spatial Structure and Age-Sex Composition of Steller Sea Lions on Tuleny Island (Sakhalin Region). About 80 % of the sea lions concentrate in harem rookeries in reproductive period, and about 20 % are on bachelors sites. Females prevail on harem sites (> 80 %), but males - in hauling grounds (> 78 %). The number of bulls on harem sites is twice lower than the number of indifferent bulls on bachelors grounds. Halfbulls are absent on harem sites, and the number of young males and bachelors is insignificant. Bulls are 5-6 % (45 % harem ones); females 85-88 %; others about 6 % (young sea lions 2-3 %, bachelors 3-4 %). The agesex structure on the capes is more variable: bulls are 7-13 %, halfbulls 11-12 %, others (mainly bachelors) 71-82 %. Generally, the structure of harem rookeries is more ordered then the structure of the whole herd of Steller sea lions because of certain mechanisms of its regulation. The Contemporary Condition and Some Demographic Characteristics of the Steller Sea Lion (Eumetopias Jubatus) Reproductive Group on Tyuleniy Island, Sea of Okhotsk. The resulting abundance of sea lions on Tyuleniy Island in 2010 exceeded 1500, which was almost ten times as many as their number in 1989. A total of about 100 bulls, 60 harem bulls, 1000 females, and 700 pups were recorded there. As many as 133 previously branded Steller sea lions were found and 109 of them (81. Among immigrants, 29% were branded individuals of reproductive groups from the Kuril Islands, 54% were from the Iony Islands, 16% were from the Yamsky Islands, and about 1% were from Kamchatka. The oldest Steller sea lion (21 years of age) was one that was branded on the Srednego Islands in 1989. The rate of marked animal return from 175 pups that were branded on Tyuleniy Island the year before was 13. New Data on the Abundance of the Northern Fur Seal (Callorhinus Ursinus), Steller Sea Lion (Eumetopias Jubatus), and Spotted Seal (Phoca Largha) on Tyuleniy Island, Sea of Okhotsk. Based on the surveys in June and July of 2013, the total estimated number of northern fur seals is 115000. The direct counts showed 5000 bulls, 30300 females, and 34700 pups (31500 live and 3200 dead). The total decrease in the number of females and pups for the recent 4 years is 18. The purpose of this ship-based study was to continue to monitor the status and trends of the western stock of Steller sea lions (Eumetopias jubatus) by counting and measuring pups at rookeries during the breeding season from Dutch Harbor to the end of the Aleutian Islands chain. All these studies will provide a basis for assessing the status and trends of Steller sea lion pup production in Alaska and Russia during 2002 Loughlin, T. This total count includes 10,000 in Russia (15% of the range-wide count), 47,960 in Alaska (70%), 6,109 in British Columbia (9%), 2,261 in Oregon (3%), and 1,764 in California (3%). We estimated the 1989 world population based on a calculation for total pups and obtained a range-wide estimate of 116,000 total animals, or about 3948% of the 240,000-300,000 estimated 30 yr ago. The previous population estimate of 240,000-300,000 is similar to our estimate of 245,000290,000.
Cardiac output diminishes 3040% between the ages of 25 and 65 years, as do renal and hepatic blood flows (Woodhouse and Wynne, 1992; Cody, 1993; McLean and Le Couteur, 2004). McLean and Le Couteur (2004) presented evidence that aging of the sinusoidal endothelium reduced oxygen delivery and drug transfer from blood to hepatocytes. Schmucker (2005) and Herrlinger and Klotz (2001) did not find significant relationships between aging and P450 activities in human liver. Information is available on certain age-related aspects of xenobiotic clearance other than metabolism. Plasma protein binding of drugs generally remains unaltered or diminishes modestly with age (Grandison and Boudinot, 2000). Renal clearance diminishes with advancing age, due to parallel annual decreases of 0. Blood levels of the parent compounds remained relatively constant during adulthood, but metabolite levels or amounts metabolized frequently varied during the pediatric and geriatric years (Sarangapani et al. Gender Some of the physiological and biochemical differences between men and women have the potential to alter tissue dosimetry and health effects of certain solvents. The investigators located few data on gender-dependent dermal or pulmonary absorption of solvents or other chemicals. Distribution of water- and lipid-soluble solvents can vary substantially between men and women (Schwartz, 2003). Women typically have smaller volumes of distribution for polar solvents, but larger volumes of distribution for lipophilic solvents (Gandhi et al. Lean body mass decreases from 76 to 52%, and body fat increases from 33 to 49% in females between the ages of 25 years and 6570 years. Nomiyama and Nomiyama (1974) found that women retain less inhaled acetone and ethyl acetate than similarly exposed men. The major sex differences in P450-mediated hepatic metabolism in rats are not seen in humans or most other mammals (Nakajima, 1997). Some of the differentially expressed genes involve drug and steroid metabolism, but the biological significance of these variances is unknown. No marked gender differences in P450-catalyzed oxidation reactions have been identified in humans (Schmucker et al. Women were found to have a higher blood:air partition coefficient, a higher percent of body fat and higher maximum rate of benzene metabolism than men. Women exhibited higher blood benzene levels and a 23 26% increase in benzene metabolism, potentially placing them at greater risk than men with equivalent exposures. Relatively little is known about potential influences of contraceptives, hormone replacement therapy, or pregnancy on the metabolism and disposition of xenobiotics (Gleiter and GundertRemy, 1996). The menstrual cycle with its hormone changes may influence the metabolism of some xenobiotics (Fletcher et al. Plasma volume increases 50% in pregnant women, resulting in a decrease in albumin concentration and plasma protein binding of many drugs (Fletcher et al. Cardiac output increases 50%, due to increases in stroke volume and heart rate (Silvaggio and Mattison, 1994). Uterine blood flow, renal plasma flow, and glomerular filtration rise substantially, though no information on hepatic blood flow is apparently available. Simulated vinyl chloride levels, for example, were 4 orders of magnitude lower in the neonates. Fetal/neonatal isopropanol levels were forecast to be orders of magnitude lower than maternal levels. Genetics A variety of genetic polymorphisms for biotransformation have been found to occur at different frequencies in different ethnic groups (Daly et al. Polymorphisms for xenobiotic-metabolizing enzymes may affect the quantity and quality of enzymes and the outcomes of exposures to solvents (Ingelman-Sundberg et al. It is important to note that culturally linked environmental factors also contribute to ethnic differences in metabolism and disposition of solvents and other chemicals.
The risk estimates are based largely on the analysis of Japanese atom bomb survivors. The occupational guidelines for radiation protection developed from the 1990 document are 100 mSv in 5 years (average, 20 mSv per year) with a limit of 50 mSv in any single year. Mental retardation for those exposed in utero is a finding in the atom bomb survivor cohort and is now included in the risk estimates. An attempt was made to calculate the total detriment and is given the notation aggregated detriment. The aggregated detriment is the product of four factors: the probability of attributable fatal cancer, the weighted probability of nonfatal cancer, the weighted probability of severe hereditary effects, and the relative length of life lost. The nominal probability of fatal cancer per sievert, F, and the aggregated detriment are shown in Table 25-4. A cancer lethality fraction, K (the fraction of total cancer that is lethal), is used as a weighting factor for nonfatal cancers. The total weighted detriment is then F + K (1 - K)F/K = F(2 - K) the aggregated detriment is then the product of F(2 - K) times the relative length of life lost, l/lav, for a particular can- cer. Recommendation for Lifetime Exposure to (age Ч 10 mSv) or approximately 700 mSv, with an average annual limit of 20 mSv and a maximum annual limit of 50 mSv. The absorbed dose depends on the biological and physical half-times of the element in the body. For this reason, the concepts of committed equivalent dose and committed effective dose were derived to accommodate the potential for the dose to be delivered over long periods after incorporation in the body. The committed dose is taken over a 50-year interval after exposure and is equal to Ht,50 = t0 +50 Ht dt t0 (25-19) where Ht,50 = 50-year dose to tissue T for a single intake at time t0, and Ht = equivalent dose rate in organ or tissue T at time t. For longer-lived nuclides, the committed equivalent dose will be greater than the annual equivalent dose and must be calculated on an individual basis. Negligible Individual Risk Level (Negligible Dose) the current radiobiologic principle commonly accepted is that of linear, nonthreshold cancer induction from ionizing radiation. Thus, regardless of the magnitude of the dose, a numerical cancer risk can be calculated. This value is in addition to that received from natural background radiation (about 2 mSv). Ionizing radiation loses energy and slows down by forming ion pairs (a positively charged atom and an electron). Different ionization densities result from gamma rays, beta particles, and alpha particles. Individual tracks vary widely about this value because of the stochastic nature of energy deposition, i. For example, a 4-MeV alpha-particle track yields on average, about 30,000 ionizations (3 Gy, 300 rad) in an average-sized cell nucleus. There was a long-standing belief that the cell nucleus must be irradiated for any biological effect to occur. In the past 15 years, research on epigenetic effects has shown this is not the case. Epigenetic (or nontargeted) effects include genomic instability (the increase in genomic alterations), bystander effects (damage that occurs in cells not traversed by radiation but close by), cytoplasmic/membrane effects (bystander effects after cytoplasm irradiation), clastogenic effects (detrimental effects from irradiated plasma), abscopal effects (partial volume irradiation induces damage in the whole organ), and transgenerational (instability passed through the germ line) effects. The new information concerning epigenetic effects (Little, 2006), although adding immensely to biological and mechanistic understanding, should not affect risk calculations which are based on observed exposure response in human and animal populations. The underlying mechanistic information should lead to better lifetime risk projection models. Within a cell, the indirect effect occurs over very short distances, of the order of a few nanometers. The study used the heavy ions 12 C(6+) and 36 Ar(18+) and showed that direct ionization is a small contributor to base damage and hydroxyl radicals are major contributors. Attempts have also been made to predict the frequencies of different damage types from the knowledge of radiation track structure, with certain assumptions about the minimum energy deposition (number of ionizations) required.
The performance of the PathVysion Kit was validated using the procedures provided in the package insert only. The cell in this image shows the one orange, two green signal pattern indicative of the 1p36 deletion. The cell in this image shows the one orange, two green signal pattern indicative of the 19q13 deletion. In an abnormal cell with a deletion in the 1p36 region fewer than two orange signals will be observed. This probe allows status assessment of the following two chromosome regions: 19q13 and 19p13. In a normal cell with two intact copies of chromosome 19, two orange and two green signals will be observed. In an an abnormal cell with a deletion in the 19q13 region fewer than two orange orange signals will be observed. In a hybridized abnormal cell containing the deletion, a one orange (1O) signal pattern will be observed. In an abnormal cell with a simple t(22q12), a one fusion, one green, one orange signal pattern will be expected. The hybridized probe fluoresces with moderate to bright intensity both in interphase nuclei and on metaphase chromosomes. In a normal cell with two intact copies of chromosome 2, two green and two orange signals will be observed. The hybridized probe fluoresces with moderate to bright intensity both in interphase nuclei and metaphase chromosomes. Used as single probes, or in multicolor probe sets, these products are designed to identify various chromosome translocations, deletions, chromosomal gains, as well as other rearrangements associated with specific hematopoietic 46 disorders. These probes can be applied to a variety of sample types prepared for metaphase or interphase analysis. One p16 gene locus is deleted and both chromosome 9 homologs are present as indicated by one orange and two green signals, respectively. The anticipated signal pattern in abnormal cells having a chromosomal breakpoint within the gap between the two probe targets on one chromosome 12 is one orange, one green, and one fusion signal. In a cell harboring the t(9;22), one orange, one green, and one orange/green (yellow) fusion signal pattern (1O1G1F) will be observed. Minor breakpoint (m-bcr) signal patterns mayappear as one orange, one green, and two fusion signals. A region of about 300 kb containing low-copy number repeats has been eliminated from the probe which introduces a gap in the coverage of the probe target. In a nucleus containing a simple balanced t(9;22), one orange and one green signal from the normal 9 and 22 chromosomes and two orange/green (yellow) fusion signals, one each from the derivative 9 and 22 chromosomes, will be observed (1O1G2F). The pattern of t(16;16)(p13;q22) results in an adjacent or fused red/ green signal on the q arm of one of the 16 chromosomes and a green signal on the other arm of 16, while the 16 chromosome homolog will only contain the red signal on one arm. On the metaphase cell, contains the red signal on one arm and the green signal on the other arm. Hybridization of this probe to interphase and metaphase nuclei of normal cells is expected to be seen as two aqua signals. Normal hybridization: Normal hybridization showing two orange and two green signals. Cytogenetically, the t(12;21) is a subtle abnormality and thus not easily detectable with standard cytogenetic banding techniques. Abnormal hybridization: Nucleus showing the one green/orange fusion, one green and one orange signal pattern. The use of this product for diagnosis, monitoring or risk assessment has not been established. The pattern in a nucleus containing an inv(16) results in separate red and green signals appearing on opposite arms of the inverted 16 chromosome. In an abnormal cell containing the deletion, the one orange, two green signal pattern will be observed. This probe can provide a better indication of the presence of the 11q23 translocation than a single color probe design.
Another key chemical reaction in metal toxicology is metalmediated oxidative damage. Nickel and chromium are two examples of metals that act, at least in part, by generation of reactive oxygen species or other reactive intermediates (Kasprazak, 2002). Alternatively, metals may displace redox active essential elements from their normal cellular ligands, which, in turn, may result in oxidative cellular damage. For instance, cadmium, which is not redox active, may well cause oxidative stress through the release of endogenous iron, an element with high redox activity (Valko et al. Metals can also induce an array of aberrant gene expression, which, in turn, produces adverse effects. An array of aberrant hepatic gene expressions occurs in adult mice after in utero arsenic exposure, which could be an important molecular event in arsenic hepatocarcinogenesis (Liu et al. Factors Impacting Metal Toxicity the standard factors that impact the toxic potential of all chemicals apply to the metals as well. Exposure-related factors include dose, route of exposure, duration, and frequency of exposure. Because metals can be quite reactive, and the portal of entry is often initially the organ most affected, as with the lung after inhalation. Host-based factors that can impact metal toxicity include age at exposure, gender, and capacity for biotransformation. For instance, it is quite clear that younger subjects are often more sensitive to metal intoxication, as, for example, with the neurotoxicity of lead in children. The major pathway of exposure to many toxic metals in children is food, and children consume more calories per pound of body weight than adults. Moreover, children have higher gastrointestinal absorption of metals, particularly lead. The rapid growth and proliferation in the perinate represent opportunities for toxic effects, including potentially carcinogenesis, of metallic agents, and several metals. Fetal-stage toxicity of metals is well documented, as with methylmercury, and many metals are teratogenic. For many inorganics there is no impediment to transplacental transport, as with lead or arsenic, and human fetal blood lead levels are similar to maternal levels. Elderly persons are also believed to be generally more susceptible to metal toxicity than younger adults. Recognition of factors that influence toxicity of a metal is important in determining risk, particularly in susceptible subpopulations. This would include the precise metal compound and its valence state or speciation. For instance, methylmercury is a potent neurotoxin, whereas the inorganic mercurials primarily attack the kidney. Similarly, the oxidation state of chromium can differentiate the essential (naturally occurring trivalent chromium) from toxic species (hexavalent chromium). Lifestyle factors such as smoking or alcohol ingestion may have direct or indirect impacts on the level of metal intoxication. For instance, cigarette smoke by itself contains many toxic metals, such as cadmium, and it is thought that smoking will double the lifetime burden of cadmium in nonoccupationally exposed individuals. Other components of cigarette smoke may also influence pulmonary effects, as, for instance, with metals that are lung carcinogens. Alcohol ingestion may influence toxicity by altering diet, reducing essential mineral intake, and altering hepatic iron deposition. The composition of the diet can significantly alter gastrointestinal absorption of various dietary metals. The need to accumulate essential metals dictates the evolution of systems for the safe transport, storage, and utilization as well as, within limits, elimination of excess. For example, metallothionein is a metal-binding protein that may function in the homeostatic control of zinc (Cousins et al. Such factors imply that a threshold would exist for toxicity due to essential metal exposure. In this regard, the essential metallic elements would be expected to show a "U"-shaped doseresponse curve in that, at very low exposure levels, toxic adverse effects would occur from deficiency, but at high exposure levels toxicity also occurs. The nonessential toxic metals can mimic essential elements and disrupt homeostasis, as with cadmium which will potentially displace zinc to bind to zinc-dependent transcription factors and enzymes (Waalkes, 2003). Adaptive mechanisms can be critical to the toxic effects of metals, and organisms have a variety of ways in which they can adapt to otherwise toxic metal insults.
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