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Assessment of human cancer risk from animal carcinogen studies is severely limited by inadequate experimental data at environmentally relevant exposures, and procedures requiring modeled extrapolations many orders of magnitude below observable data. We used rainbow trout, an animal model well suited to ultra low-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10,000 animals (ED001). A total of 40,800 trout were fed 0–225 ppm dibenzo[a,l]pyrene (DBP) for four weeks, sampled for biomarker analyses, and returned to control diet for nine months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED10 linear extrapolation method. The study provided observed incidence data down to two above-background liver tumors per 10,000 animals at lowest dose (that is, an un-modeled ED0002 measurement). Among nine statistical models explored, three were determined to fit the liver data well - linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED10 default assumption, and all fell increasingly below the default extrapolation with decreasing DBP dose. Low-dose tumor response was also not predictable from hepatic DBP-DNA adduct biomarkers, which accumulated as a power function of dose (adducts = 100 * DBP1.31). Two-order extrapolations below the modeled tumor data predicted DBP doses producing one excess cancer per million individuals (ED10−6) that were 500–1500-fold higher than that predicted by the five-order LED10 extrapolation. These results are considered specific to the animal model, carcinogen, and protocol used. They provide the first experimental estimation in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.
Assessment of human cancer risk from environmental carcinogen exposures remains a challenging and inexact prospect. According to the March 29, 2005 Guidelines for Carcinogen Risk Assessment (www.epa.gov/cancerguidelines), cancer risk is estimated using a human case-specific dose-response model, if such a model is available (1). In this instance, the effective exposure leading to a specified level of risk may be interpolated directly from the dose-response curve. Alternatively, sufficient information on mode of action and critical parameters may allow development of a biologically-based model to be used in dose-risk characterization on an agent-specific basis. In the absence of either such model, dose-response risk evaluations are derived through extrapolation of experimental animal data from a high dose-response region, which has been measured experimentally, to a low dose-response region of interest, which has not been measured. The uncertainties introduced by these extrapolations remains a point of major concern. According to the 1996 Risk Assessment Workshop overview, "The major problem in cancer risk assessment [will] continue to be the inadequacy of available [low-dose] data on which to conduct more risk assessments."
The magnitude of the problem is outlined in Figure 1. Owing to costs and other limitations, dose-response data from a typical rodent carcinogen bioassay study are generally derived from a few hundred experimental animals, and thus are statistically limited to observations covering only about one order of magnitude, between 10% and 100% incidence. The EPA conservative approach models these high-incidence data to estimate the effective dose of that carcinogen to achieve 10% incidence (ED10), and to generate a lower confidence limit on this dose estimate (LED10) as a conservative point of departure for risk extrapolation. If the carcinogen is non-genotoxic or otherwise expected to produce a non-linear response, a Margin of Exposure procedure is applied to assign an acceptable human exposure. For genotoxic carcinogens, the conservative default assumption is that carcinogen-related cancer risk will extrapolate linearly toward zero exposure, that is, will vary in direct proportion to dose, below the LED10 estimate. Risk assessments based on this procedure can involve extrapolations several orders of magnitude below the actual experimental data. For example, estimation of the lifetime dose leading to one exposure-related (i.e. above-background) cancer case per million individuals (ED10−6) would require extrapolation to five orders of magnitude below the experimentally derived LED10 estimate (Figure 1).
Although there have been two previous large-scale rodent studies that might address this need (2–4), neither study provided treatment-related tumor data below 1% incidence. In any such low-incidence study, the lower limits for examining carcinogen-related, or background-corrected tumor risk will be bounded by several factors, among the most important being background target organ cancer rate. Hence the use of as many as 4080 animals in the BIBRA study (3) to examine N-nitrosodiethylamine (DEN) dose-response for hepatocarcinogenicity in Colworth rats provided insufficient statistical power to examine carcinogen-related tumor response below 5% because that is the approximate background cancer rate for that organ in that rat strain. The potential for large-scale studies is also severely limited by financial constraints (animal purchase and husbandry costs, carcinogen cost and availability, pathology costs) and a need for dedicated infrastructures capable of housing many thousands of individuals simultaneously.
We are investigating the feasibility of providing experimental carcinogen dose-tumor response data extending substantially below the 5% or 1% levels, using a well-established aquatic animal carcinogenesis model that circumvents many of these limitations. The species used in this study, the rainbow trout (Oncorhyncus mykiss), has historic background liver and stomach cancer rates near 0.1% in our facility, can be reared in the tens of thousands at extraordinarily low per diem and personnel costs, requires an infrastructure far less complex and of modest size compared to rodent requirements, and has well established pathologies and protocols for carcinogenesis experimentation (5–7). Based on these attributes, we have designed and completed the first of two four-part studies to determine if the rainbow trout would be capable of providing robust cancer dose-response data extending down to or below its historical background rate of 0.1% in liver.
Much attention also has been given to the possibility that readily quantifiable biomarkers of cancer risk, such as initial target organ carcinogen-DNA adduction (8–10), might provide accessible measures of eventual tumor outcome at exposure levels below those that can yield routinely measurable tumor response, with protocols requiring less time, cost, and infrastructure than an equivalent tumorigenesis bioassay. An obvious limitation to this approach, however, is the need for at least some experimental data to validate or assess biomarker-tumor dose-response correlations, down to measured ultra-low tumor response levels. We have incorporated one such biomarker assessment, qualitative and quantitative target organ DBP-DNA adduct measurements, into our study design to explore low-incidence biomarker correlations. We also assessed the adduction and tumorigenesis properties of several putative DBP intermediary metabolites, cell proliferation during exposure, and oncogenic Ki-ras mutational profiles in tumors at the end of the bioassay period to better understand dose-related mechanisms of tumorigenesis in this model.
DBP was selected as the test compound for this ED001 study due to its potency and widespread distribution in the environment. DBP is considered to be the most powerful naturally occurring carcinogen of the polycyclic aromatic hydrocarbon (PAH) class when tested in animal models of cancer (11, 12). It is effective in multiple species (rat, mouse, trout, medaka), elicits tumors in multiple target organs (mammary gland, skin, liver, lymphoid system, lung in rodents; liver, stomach, swim-bladder in fish), and produces tumors via several routes of exposure (dietary, dermal, i.p. injection, transplacental) (11–16). DBP is found in the environment in particulates formed by combustion of smoky coal (17), in soil and sediment samples (18), and in cigarette smoke condensate (19). The human cancer risk posed by this potent genotoxic compound remains to be established.
Dibenzo[a,l]pyrene (DBP ≥ 98% by HPLC) was obtained from the National Cancer Institute (NCI) Chemical Carcinogen Reference Standard Repository (Chemsyn Laboratories, Lenexa, KS, USA). This potent carcinogen was handled and stored in full compliance with Oregon State University (OSU) and NIH Guidelines for the use of Class C carcinogens. The semi-purified Oregon Test Diet (OTD) was prepared as described previously (20), except that menhaden oil (National Marine Fisheries Service, Charleston, SC, USA) was substituted for salmon oil. DBP was incorporated into the OTD at the stated concentration on a dry ingredients basis. Every batch of diet was assayed for DBP content, and results published elsewhere (21). The DBP dihydrodiols and dihydrodiol epoxides used in the embryo microinjection study were a generous gift of Albecht Seidel (Biochemisches Institute fur Umweltcarcinogene, Grosshansdorf, Germany).
Shasta strain rainbow trout (Oncorhynchus mykiss) were hatched and reared at the OSU Sinnhuber Aquatic Research Laboratory (SARL) under previously detailed procedures (6, 20). All animal protocols were in accordance with NIH Guidelines and approved by the OSU Institutional Animal Care and Use Committee (IACUC). For each of four independent dose-response experiments, trout fry (initial weight 1.5 grams) were randomly assigned to 102 replicate tanks of 100 individuals each, and fed standardized OTD (20) until commencement of carcinogen treatment. Trout fry were then fed ODT only, or one of seven levels of DBP incorporated into OTD, for 4 weeks (Table 1). Each quartile included one sentinel tank of 100 fish in each of the eight exposure groups, to provide for biomarker sampling without disturbing fish density-growth interactions among tanks used for tumor determination. On days 15 and 29, 50 fish per dose per time point were sampled from these tanks for analysis of cell proliferation and DNA adducts. Following DBP treatment all remaining fish were fed OTD for the duration of the study.
Trout at each treatment dose were terminated beginning nine months later, under a gross necropsy protocol requiring 28 days to complete for each of the four replicate studies. Possible growth and time effects on tumor outcome were controlled by reduction of feeding to a minimal-growth maintenance schedule, and use of a random numbers routine assuring an average date of necropsy on day 15 among the replicate tanks at each carcinogen dose. By this strategy, there were no significant differences in tumor incidences among groups necropsied before and after day 15 (data not shown).
At necropsy, trout were deeply anesthetized in tricaine methane sulfonate, weighed, and the gill arches cut to allow bleeding. The liver, stomach, and swim bladder were removed from each fish and examined by a pathologist (JDH) with a dissecting microscope to detect gross tumors. We note that stomach and swim bladder tumors in the trout are readily detectable on the surface of the organs, and over 95% of liver tumors also appear on the surface. Suspect tumor locations were marked on livers and notes taken in order to successfully retrieve all grossly observed tumors. The organs were fixed in Bouin's solution for up to a week. Livers were then cut into 1 mm slices in which any interior tumors show up distinctly as pale yellow spots against the darker mottled background of normal liver tissue. All tumors and questionable lesions from the control and low dose groups were embedded for histological confirmation, but sections were not made from every liver in these groups if neither gross nor hand-slicing observation revealed any lesions. At higher doses, a single slide, having one or more tumors, was made from each tumor-bearing liver. With this protocol liver tumor incidence was histologically verified, whereas tumor multiplicity (not reported) above 1.0 might include some unconfirmed lesions. Sections were routinely stained with hematoxylin and eosin and established criteria for classification of trout liver tumors (6, 22) applied. All pathological confirmation was by a single pathologist (JMS). Among the total of 1603 liver neoplasms identified in the study, the majority (71%) were hepatocellular carcinoma, 17% were mixed hepatocellular/cholangiocellular carcinoma, and 9.5% were hepatocellular adenoma. A few cholangiocellular carcinomas (1.5%), cholangiocellular adenomas (0.6%), and mixed adenomas (0.2%) were observed. Although a detailed morphometric study was not carried out, the observed spectrum of neoplasms was similar to this in all treatment groups and there was no apparent effect of DBP dose on the spectrum of observed tumor phenotypes. All stomach and swimbladder neoplasms examined were papillary adenomas. Whereas stomach adenopapillomas occurred frequently, only a few adenopapillomas were observed in the swim bladder among the thousands of animals examined. The response was too weak in this target to be of value in this investigation and is not further discussed.
DBP-DNA adducts in liver and stomach were examined using 3 pools of 5 samples each, taken from each sentinel tank of fish at days 15 and 29 of DBP treatment. Because trout liver appears largely deficient in global excision repair, bulky DNA adducts accumulate linearly with days of exposure and this time point thus approximates total cumulative DBP-DNA adduction in the target organ (23). DNA was purified and adducts initially characterized by 33P-HPLC post labeling as well as 32P-TLC post labeling, as described previously (14, 24, 25). Total hepatic DBP-DNA adducts were quantified for each treatment group using the more sensitive 32P-TCL post-labeling method. Stomach DNA adducts were not quantified for this study.
Liver and stomach tumor incidence data were modeled as functions of the full range of DBP doses with the single exclusion of the highest dose (225 ppm) liver data due to the observed plateau of the liver tumor incidence as has been previously reported at this dose in the trout model (25). Standard error (SE) bars for pooled total (uncorrected) incidence (Figure 3B) are empirical based on observed variation between quartiles. The variation between replicate quartiles was found to be consistent with binomial variation at each dose modeled with the single exception of the liver data for DBP dose 28.4 ppm where there was considerable over-dispersion between replicate quartiles (11.6 times expected). SE bars for observed background-corrected incidence (Figure 4) are approximate and model-based (asymptotic likelihood-based assuming binomial variation at each dose for total (uncorrected) incidence with a variance-inflation factor of 11.6 included for the 28.4 ppm dose in liver tumor data only).
Nine models with independent background (extra risk) were initially fit to the total tumor incidence data. The Ryzin-Rai model (26) plus eight dichotomous models in the EPA Benchmark Dose Software (27) (gamma, Gompertz, Weibull, multistage, the two probit-type and the two logistic-type models) were all fit by maximum likelihood (assuming a conditionally binomial distribution) using the Nlmixed procedure in SAS version 9.2 (when allowing overdispersion at dose 28.4 ppm) and the EPA BMDS (27) software. Lack of fit was determined by likelihood ratio tests versus a saturated model with a parameter for every dose. Most models fit very poorly and only the three models that fit well are shown in the results. For liver tumor incidence data a quadratic term added to the logit linear in log dose model greatly improved the fit (p=0.003 likelihood ratio test for the quadratic term). Well-fitting linear (or quadratic) logit and probit models are linear (or quadratic) in log of DBP dose. The background incidence is small for both organs and, therefore, the results and conclusions are essentially the same whether one assumes independent background (extra risk) or additive background (added risk). Because the liver incidence pooled across quartiles at dose 28.4 ppm was highly consistent with the trend observed at neighboring doses, the conclusions regarding model lack of fit for liver data were the same whether or not the 28.4 ppm data were included in the modeling and, when it was included, whether or not a random quarter effect was added for the 28.4 ppm dose data.
LED10 values, using high-dose subsets of the observed liver and stomach data were obtained from the Probit procedure in SAS (inversecl option) using logit linear in log dose models and binomial variation (which meant that the over-dispersion of the liver incidence data at the DBP dose of 28.4 ppm would not be included and, therefore, would not penalize the LED10 approach by making it even more conservative). Hepatic DBP-DNA adduct accumulation data were log transformed and then modeled as a linear function of the log of DBP dose using the Reg and Glm procedures in SAS. The low-incidence log-log slope of the Ryzin-Rai model was compared to the adduct log-log slope with a Z-test assuming approximate normality and approximate independence of the two estimates.
To investigate the metabolic origins of trout DBP-DNA adduction, trout embryos 27 days post-fertilization were microinjected with 1 µL of DMSO or 1 µL of DMSO containing either DBP (1, 10, 100, 1000 µg) or one of the following metabolites of DBP (250, 1000 ng): (+)-11,12-dihydrodiol, (−)-11,12-dihydrodiol, (+)-syn-11,12,dihydrodiol-13,14- epoxide, (−)-anti-11,12 dihydrodiol-13,14- epoxide and (±)-8,9-dihydrodiol. Two hundred embryos were injected per treatment group, with the injection directed into the yolk. The injected embryos were placed in incubation trays, hatched and reared to the sac-fry stage according to standard protocols. Three weeks days after hatching (22 days post-injection) and resorption of the yolk sac, two batches of 10 livers were taken from the survivors, immediately frozen in liquid nitrogen and stored at −80°C for adduct analysis. Remaining fish were fed OTD for 11 months, then sampled for tumors as described previously.
Cell proliferation was assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. PCNA was measured in livers and stomachs of 5 fish per dose per quartile sampled on days 15 and 29. Tissues were fixed for 24 hours in 10% neutral buffered formalin, then processed through a graded series of ethanols and xylene for embedding in paraffin. After processing and paraffin embedding, 4–5 µm sections were cut and mounted on charged slides, deparaffinized, and rehydrated in distilled water. The primary antibody was mouse anti-PCNA, PC10 (Dako, Carpinteria, CA), an antibody that has been validated for use in rainbow trout (23). The Dako Envision polymer system conjugated with peroxidase was used for the secondary antibody, and 3-amino-9-ethylcarbazole (AEC) was used as chromagen. Slides were counterstained with hematoxylin and mounted with Crystalmount (Biomeda Corporation, Foster City, CA). For each liver, 500 hepatocytes from each of two sections were counted (1000 per fish). For stomach, 500 surface epithelial cells and 500 glandular epithelial cells were counted per section (1000 of each cell-type per fish).
After digestion of tumor tissue with proteinase K, mutations in Ki-ras were analyzed by 3'-primer mismatch polymerase chain reaction (PCR) as described previously (28). Negative control DNA from livers of untreated animals gave PCR products only with the normal primers under these conditions. Positive mutations were verified by direct sequencing.
The study design (see Table 1) used a protocol incorporating DBP into the standard OTD (5), to elicit tumors in trout liver and stomach. Two preliminary studies of 2000 animals each were conducted over a two-year period in order to select informative doses for the large-scaled experiment, and to permit model statistical calculations for optimal distribution of individuals along the dose range. A 30-year historic data base with the Shasta trout strain in our facility indicated a background liver cancer rate of approximately 0.1%, or 10 tumor-bearing animals per 10,000 individuals. Our aim in the final design was to elicit double this background incidence in liver at the lowest exposure dose (10 additional tumor-bearing animals per 10,000 trout) if the response remained approximately logit linear in log dose, as modeled for the higher dose pilot data, or a lesser number if it did not. The design called for 10,000 control animals (0 ppm DBP) distributed as 25 replicate tanks of 100 animals each for each quartile in the study, in order to provide a measure of true background and its variance. An additional 10,000 trout were similarly committed to estimate tumor response and variance at the lowest DBP exposure dose of 0.45 ppm. A further 18,000 animals were apportioned in decreasing number with increasing dose and anticipated tumor response (Table 1). Dietary DBP doses covered a 500-fold exposure range, and were projected to provide liver tumor incidence data ranging from near background up to approximately 70% at the highest dose.
Of the initial 40,800 trout committed to the study design, 3200 were removed for early biomarker determinations and 32,316 were eventually sacrificed and the data utilized for tumor dose-response assessment (Table 1). Mean tank survival among these animal tanks was 92.4%, and deaths were unrelated to DBP dose. The remaining animals were lost from the study due to isolated malfunctions that disqualified 23 tanks from being considered. The protocol utilized a four-week carcinogen exposure period, after which animals were reared on control diet without DBP exposure for an additional nine months prior to sacrifice for histopathological examination. Logistics required that the study be carried out as four independent replicate experiments, each using one fourth of the animal total.
The observed total liver tumor incidences (background plus carcinogen-driven) for each of the four replicates are depicted in un-modeled, linear coordinates in Figure 2 (2A, entire incidence range; 2B, low incident range expanded). It is evident, especially in Figure 2A, that linear scales compress data in the most pertinent low dose region, and permit only a few general conclusions. The liver data set displayed a generally sigmoidal dose-response curve from above 60% to near zero, with independent replicates at each dose point falling within an absolute incidence range of 0.14 or less for the liver data (Table 1; Figure 2B). The measured pooled (mean) incidences were greater than control at all DBP doses, but not significantly so at either of the two lowest DBP doses, 0.45 and 1.27 ppm (Table 1). For six of the seven doses modeled (see below), the data are consistent with binomial variation between replicates (overall test for over-dispersion p = 0.45). The exception is the 28.4 ppm dose, where there is strong evidence of over-dispersion (deviance/df = 11.6, p<0.0001). Examining the pooled data (Fig 2B, solid line) at low range, as dose decreased the pooled line appeared curvilinear rather than straight as it approached background. Even without modeling, the observed extent of convex or "sublinear" behavior suggests that a low-incidence direct proportionality model would not fit the trout liver data, irrespective of background correction
Figure 2C shows the total tumor incidences in stomach for each of the four quartiles, also on linear coordinates. The four quartiles provided reproducible results, with the variation consistent with binomial variation at every dose (overall test for over-dispersion p = 0.18). DBP produced a less potent dose-response in stomach than in liver and did not approach the plateau observed at highest DBP dose in liver. The measured pooled incidences were greater than control at all DBP doses, but not significantly so at the three lowest doses of DBP (0.45, 1.27, 3.57 ppm). The background incidence in stomach was approximately 1.5 times that in liver (Table 1)
Although Figure 2 provides a useful overview of the focus and range of incidences observed in the two organs, it is clear from the data compression inherent in the linear-linear plot that a different scaling is necessary to more appropriately visualize low-dose, exposure-related tumor response at ultra-low incidence. Many scales are available. Waddell (29), for instance, recently reinterpreted the mouse 2-acetylaminofluorene (2-AAF) ED01 data using a scale linear in response (tumor incidence) but logarithmic in dosage (log 2-AAF molecules/kg/day). This scaling was, however, challenged on the basis of asymmetric data compression artifact (30). By comparison, a simple log-log plot of the trout data set (Figure 3) avoids data compression at low doses and provides a sensitive scaling for examining the EPA conservative default assumption that exposure-related response will vary in direct proportion to carcinogen exposure dose, without any ad hoc assumptions such as those inherent in semi-log scaling. On a log-log plot of background-corrected incidence vs. dose, low-incidence data consistent with direct proportionality will appear as a straight line with slope not significantly different from 1.0, while a slope clearly greater than 1.0 will instead indicate sublinear behavior.
Figure 3A depicts the liver and stomach tumor incidence data sets without correction for observed background, which were 0.12% (95% binomial CI 0.056–0.21%) for liver and 0.18% (95% binomial CI 0.10–0.30%) for stomach. Figure 3B illustrates exposure-related (background-corrected) incidence vs. dose on the log-log. Though the variation in estimates of tumor incidences at the lower doses appear large on a log-log scale (e.g. Figure 2B, Figure 3A, 3B, Figure 4A), it must be noted that these in fact represent experimentally estimated frequencies of such very rare events as 1–2 tumors per 2000 individuals (Table 1). This is why four repeats, each consisting of as many as 25 replicates of 100 animals each were required to reasonably estimate response and its variance at low or zero dose. We note that low precision in estimating true background rate contributes strongly to the wide SE intervals for corrected incidences at the two lowest carcinogen doses and to the fact that the lower SE boundary includes zero for the corrected response in liver at the lowest dose (Figure 4A). Precision for background estimates has decreasing contribution to the SE intervals with increasing dose and observed incidence. These results illustrate that background tumor incidence in the model of choice is perhaps the limiting statistical factor in the design and interpretation of ultra-low dose-response studies.
The carcinogen-related (background corrected) tumor responses in liver and stomach are depicted in Figure 3B. The precise relationships between these responses and the LED10 default response were established by fitting models incorporating both background and dose response to the incidence data in Table 1 (see Statistical Methods). Figure 4A depicts the dose-response part of three well-fitting models, as well as an LED10 extrapolation derived solely from the higher dose/response region of the liver data set. We do not attach a priori any special biological significance to any of the three mathematical functions, but simply use them to explore the degree to which the experimentally measured tumor incidence data are compatible with the EPA default linear extrapolation. As seen in Figure 4, the three dose-response models (Ryzin-Rai, logit quadratic and probit linear) all fit the data extremely well (p > 0.8 for each lack of fit test respectively with 3, 3 and 4 df). In the well-fitting Ryzin-Rai model, there is a slope parameter that describes low-dose behavior. If that parameter is not clearly different from 1.0, then the estimated low-dose behavior is consistent with the EPA low-dose direct proportionality model. In fact, however, the Ryzin-Rai slope parameter is estimated as 2.278, with an asymptotic standard error of 0.356, demonstrating substantial sublinearity and strong evidence against direct proportionality at low dose (p<0.0001, likelihood ratio test that parameter = 1.0). The fitted logistic quadratic and linear probit models lack single slope parameters describing low-dose behavior, but instead show slopes that are even steeper than that for Ryzin-Rai, increasingly so with decreasing DBP dose (Figure 4A) Therefore, we can conclude that none of the three models that do fit the liver data well is compatible with the EPA default model, which would require that tumor response remain in direct proportion to carcinogen dose at low incidence.
A 5-log-order extrapolation of the default curve, using the LED10 estimate from the higher carcinogen doses only, estimates the dose expected to provide one excess cancer in a million individuals (ED10−6) to be 0.126 ppb DBP (Table 2). By comparison, the models fitted to the complete low-dose data set require only a two-order extrapolation to provide ED10−6 estimates. These virtually safe dose estimates for liver range from 66 ppb (Ryzin-Rai) to 186 ppb (linear probit) DBP, doses that are 500–1500-fold greater (less hazardous) than predicted by the linear default procedure (Table 2).
We also explored fitting and extrapolation of the stomach tumor data set. An interesting possibility is that the attenuated response with decreasing dose in stomach reflects a hormetic, or J-shaped, dose-response in this organ (31). However, the suggestion of a J-shaped response curve rests solely on the single data point at lowest DBP dose, which is in fact statistically indistinguishable (P < 0.5) from the responses at zero and 1.27 ppm. The four models that were successfully explored were the LED10 linear extrapolation, Ryzin-Rai, linear probit, and linear logit (Figure 4B). In stomach there was greater variation at the four lowest DBP doses in both the data replicates and the fits of three models, compared with liver. These differences in target organ response assessments occur in large part because our choice of animal distributions for the study was optimized for liver, which had only two thirds the background incidence and a less steep DBP response compared with stomach. This is analogous to the less informative outcome that might result were an ED001 study undertaken without adequate preliminary dose-response data for the major (or only) target organ. As a consequence, model fits for the stomach data are determined chiefly by the high-dose data because the low-dose data are imprecise. Despite these limitations, we were able to conclude that the stomach data, like liver, are not compatible with the EPA default assumption. The logit linear in log dose model (3 parameters) fits the data well (p = 0.336, 5 df lack of fit test), as does a 3-parameter probit in log dose model (p = 0.535, 5df lack of fit test) and a 4-parameter Ryzin-Rai model (p = 0.541, 4 df lack of fit test). The slope estimates at low-dose for both the logistic linear model (1.97, SE 0.071) and Ryzin-Rai models (2.743, SE 0.454) are well above 1.0 indicating substantial sublinearity and strong evidence against direct proportionality (p<0.0001 likelihood ratio test that parameter=1.0). The slopes of the fitted curves were also extrapolated to estimate conservatism of the linear default model for this organ. These virtually safe dose estimates (linear logit, 0.12 ppm; Ryzin-Rai, 0.46 ppm; linear probit, 1.81 ppm) cover a greater range than for liver owing to the greater dispersion in the low-dose stomach data, and are 360 – 5500 times greater than the conservative LED10 10−6 estimate of 0.00033 ppm DBP for cancer risk in stomach.
Initial studies were conducted to resolve and quantify individual DBP-DNA adducts in the trout model, and to explore their metabolic origins (Figure 5–Figure 7.) HPLC resolution of 33P-HPLC postlabeled adducts revealed three major adducts in stomach (Figure 5B), that partially overlapped with those generated by DBP metabolism in human MCF-7 cells (not shown). The major liver adducts were more numerous and much more polar than those in stomach (Figure 5A).
To explore metabolic origins, DBP and several potential metabolic intermediates (Figure 6) were microinjected into trout embryos at total doses up to 1000 ng/embryo, for determination of DNA adduct profiles and gross tumorigenicity. By this protocol, DBP elicited primarily liver-type adducts in total embryo DNA (Figure 7, upper panel), and a potent dose-response for hepatic tumor induction nine months later (Figure 7, lower panel). The synthetic (−)-11,12-dihydrodiol DBP derivative showed adduction and tumorgenicity similar to parent DBP. The (−)-anti-11,12-dihydrodiol-13,14-epoxide elicited primarily stomach-type DNA adducts, and a strong liver tumor response nine months later in liver. Interestingly, no stomach tumors were elicited by this DBP intermediate, which suggests that elements other than DBP adduct phenotype determine tumor organospecificity in this model. The (+)-syn-11,12-dihydrodiol-13,14-expoide showed similar but less extensive stomach-type adduction and liver tumor initiation. The DBP-(+/−)-7,8-dihydrodiol derivative induced no detectable adduction or tumorigenicity. We note that this experiment was not designed with sufficient replicates to establish an absolute carcinogenic potential of each DBP derivative by embryo microinjection. Further interpretation is also limited by the unusually high background liver cancer rate in this particular study.
Following these characterizations, total genomic DBP-DNA adducts were examined as potential biomarkers that might explain, or be used to predict, the shape of the tumor dose-response curve seen in trout liver. Figure 8A compares the un-modeled liver adduct and tumor incidence data sets at low DBP dose. This comparison suggests that use of adduct data as a surrogate for tumor data would be misleading here because the adduct data curve is less steep. This visual impression is born out by modeling results. As seen in Figure 8B, the adduct data set can be modeled successfully on a log-log plot as a straight line (p=0.47 lack of fit test) with a slope of 1.31 (SE 0.07). Although this indicates a significant (p<0.0001) sublinearity in adduct dose-response, it is a small degree of sublinearity compared to that observed in the modeling of the exposure-caused liver tumors. The Ryzin-Rai model gave a low-incidence slope of 2.28 (SE 0.036) on a log-log plot, a slope that is significantly greater than the 1.31 observed in the adduct model (p=0.007 two-sided approximate Z-test). Further, the other two well-fitting models indicate even steeper slopes (and therefore greater sublinearity) than that in the Ryzin-Rai model (Figure 4A). Therefore, use of liver DBP-DNA adducts as biomarkers to predict low-dose tumor response would have been misleading in this study. Specifically, adduct measurements, by being considerably less sublinear, would have suggested that the conservativeness of the LED10 extrapolation was much less than suggested by the actual tumor modeling (Fig. 4A).
It was important to know if non-concordance between adduct and tumor dose-response might be ascribed to dose-dependent changes in DBP metabolism that might alter the types, and hence the possible tumorigenic potencies, of DBP-DNA adducts formed. This was explored by examining the 33P-HPLC profile of hepatic DBP-DNA adducts for dose-dependent changes. As expected, the absolute level of each HPLC adduct peak in liver was seen to increase with DBP dose (Figure 5C), however the ratio among adduct peaks did not appear to change with DBP dose. Hence non-concordance between adduct and tumor dose-responses are not due to dose-dependent alterations in the types of adducts formed by DBP.
We also investigated the effect of DBP dose on the proportion of proliferating cells in livers and stomachs of fish sampled at day 29, the end of carcinogen treatment. There was no evidence for an effect of DBP on PCNA staining among hepatocytes, stomach surface cells, and stomach glandular cells, except for a slight diminishment in liver at highest DBP dose (Figure 9). Therefore, while reduced proliferation might contribute to the plateau in hepatic tumor response at high DBP exposures, there is no evidence that this contributes to the diminishing response at low DBP levels. We did not explore markers of proliferation other than PCNA, or the potential role of dose-dependent apoptosis in this study.
The LED10 default model has, up until now, required extrapolation of measured animal data downwards through five orders of magnitude (100,000-fold below the modeled data set) to estimate the dose producing one excess cancer case in a million animals. The current dataset, however, extends down to an observed 0.02% liver tumor incidence and thus limits the need for extrapolation to less than three orders of magnitude beyond the lowest data point. Extrapolation through this greatly reduced range (200-fold below the modeled data set) by three different well-fitting models provides estimates of the virtual safe dose for liver that are 500 to 1500 times higher than that provided by the conservative LED10 extrapolation (Table 2). Similar results were obtained by modeling of the stomach tumor data. These findings in two different target organs provide the first case-specific experimental measures of the degree of conservatism that might exist for the default linear extrapolation method. A similar ED001 experiment is presently under way with aflatoxin B1, the most potent known human dietary carcinogen, to expand our knowledge of carcinogen specificity in ultra-low dose-response.
The present study examined two commonly considered biomarkers of effective carcinogen treatment, genomic DBP-DNA adducts accumulated during exposure, as well as Ki-ras oncogenic mutational profiles in tumors nine months after DBP treatment. Despite great progress in establishing relationships between carcinogen exposures, target organ carcinogen-DNA adducts, and tumor outcome, previous efforts have been unable to couple tumor with adduct data at ultra-low exposures and incidences. As a consequence, data have not been previously available to directly test the utility of DNA adducts as predictive biomarkers of tumor response at ultra-low incidence. We have shown here that the shapes of the initial carcinogen-DNA adduct dose- response and the eventual hepatic tumor response to carcinogen treatment can be distinctly different. Total genomic DBP-DNA adducts increased not linearly but as a power function of DBP dose, and thus modeled as a straight line with slope 1.31 (SE 0.061; 95% CI 1.19, 1.44) on a log-log scale. This DBP dose-adduct response behavior was significantly different from the DBP dose-tumor incidence response in liver. Two of the three models fitting the liver tumor data well, quadratic logit and linear probit, display increasingly steep slopes, and thus increasing departure from the DBP-DNA adduct line, with decreasing carcinogen dose. For these two models, there is no circumstance under which DBP-DNA adduction could be used to accurately predict tumor response at low exposure, or a virtually safe DBP dose. The third model, Ryzin-Rai, does approach linearity over the low dose-incidence range on the log-log scale (Figure 4A); however, the slope in this region is 2.28, not 1.31 (p<0.007). For this model as well, there is compelling evidence that measurements of genomic DBP-DNA adducts do not provide an accurate biomarker for ultra-low dose cancer risk evaluation.
The effect of these differences on risk evaluation are considerable. Figure 8A compares the shapes of the un-modeled adduct and incidence dose-response curves, normalized at the 10.1 ppm DBP dose point. If we use the fitted adduct function log(adducts) = 2.000 + 1.31 log(DBP) to predict the shape of a theoretical tumor dose-response curve below this 10.1 ppm DBP data point, as might be done in the absence of lower-dose tumor data, we obtain by extrapolation an ED10−6 estimate of 2.5 ppb DBP. This estimate is 20-fold greater than that provided by the LED10 assumption, and thus leads to the conclusion that the LED10 assumption is conservative by a factor of 20 in this case. By comparison, ED10−6 estimates obtained by extrapolation of the models fitted to the entire liver tumor data set were 500–1500 fold larger (less conservative) than the LED10-derived ED10−6 estimate (Table 2). Therefore, use of the adduct data in place of the more sublinear tumor data would lead to a 25- to 75-fold error in estimation of a virtually safe DBP dose, and a comparable difference in the assessment of LED10 conservatism, for this case-specific model.
Discordance between DNA adduction and tumor responses have been recognized for some time now with other carcinogens and animal models. For example, Poirier and Beland (32) found a non-correlation in BALB/C mice treated with 2-acetylaminofluorene between steady-state levels of DNA alkylation in bladder, which appeared to be linear, and bladder tumor incidence at 24 months, which was notably sub-linear. Driver et al. (33) reported a similar discordance between dimethynitrosamine-induced DNA adducts, which were depicted as a straight line plot on linear coordinates, and mesenchymal tumors, which showed a distinct sigmoidal dose-response on similar coordinates. In both studies, however, adduct-incidence correlations were restricted to the higher dose-response region (observed incidences above 0.3% or 1.25%, respectively) and not usable for ultra-low dose-response correlations. The latter study also suffered from absence of statistical treatments to support the claims.
A recent suggestion to incorporate more science into the risk assessment process involves developing high quality mutation dose response data in reporter genes that define the low dose mutagenic potential (8), followed by application of a reasonable safety factor to cover individual differences in metabolism and repair. Although carcinogen-driven DNA adducts provide important information on molecular dose at target tissues, cancer is considered to be a disease of mutations. DNA adducts are not mutations, and can induce mutations only with appropriate cell survival, adduct processing and fixation by replication. Perhaps under certain restricted conditions, cumulative carcinogen-DNA adducts might serve as predictive biomarkers of carcinogen-related (background-corrected) tumor response at ultra-low exposure, for instance where total adducts accumulate linearly with dose, the spectrum and the genomic distribution of adducts are independent of dose, adduct-driven oncogenic mutations remain in direct proportion to dose, and cellular homeostasis is independent of dose. This set of conditions appears not to be met in the present study.
Dose-dependent induction of CYP bioactivation, and/or saturation of limited DBP-DNA adduct repair capacity, are plausible mechanisms to explain the exponential dose-response behavior for genomic DBP-DNA adduction in trout, but can not account for lack of concordance between adduction and tumor induction. Alternative explanations might include non-linear dose-responses for adduction, repair, and/or mutagenesis at genes critical to tumor initiation, rather than genomic DNA. For instance, DBP adduct mutagenic potency may fall off with decreasing dose and adduct concentration, such that the low number of adducts present at ultra-low DBP doses might not drive oncogenic mutations above those from endogenous damage. We have at least partially explored this hypothesis by examining the frequency and spectrum of oncogenic Ki-ras mutations in liver and stomach tumors. Limitations of the approach include restrictions in the types and locations of oncogenic Ki-ras mutations recoverable from tumors, and in our study, a paucity of spontaneous and low-dose tumor fragments for examination (pathology took precedence, and Buoin's fixative precluded mutation examination in fixed tumor specimens). Despite these limitations, there is clear evidence from stomach tumors that DBP-driven mutations in the Ki-ras oncogene were present even at low dose. As seen in Table 3, the frequency distribution of oncogenic mutations in stomach tumors at the two lowest DBP doses (six of six codon 61 adenine based mutations) appeared to differ from those in tumors from the untreated control fish (three codon 12/13 guanine-based mutations, one codon 61 guanine-based mutation), and the differences became substantial at higher doses where the contribution of spontaneous tumors would be negligible (38 of 39 codon 61 adenine-based mutations). The probability that the spectrum of mutations in stomach tumors in controls and in tumors from the two lowest DBP doses should differ by chance alone, i.e. are not DBP based, is small (p = 0.033, Fisher's Exact Test). This result supports the idea that DBP-DNA adducts are contributing functioning, selectable mutations in genes critical for tumor development in this model, at least in one target organ, even at lowest DBP doses. It is intriguing that apparent DBP-driven mutations are detected even in the low-dose range where total tumor incidences in treated and control groups did not differ significantly. This may suggest that carcinogen treatment itself elicits an environment in which cells acquiring carcinogen-driven oncogenic mutations are selected over those carrying spontaneous mutations in the same oncogene. For liver, only three mutant alleles were detected among the five control tumors available for examination, and there was insufficient information to determine if a dose-related shift in mutant allele frequency may have occurred.
The current protocol assessed tumor response in a lower vertebrate tumor model. Non-mammalian status would present an obvious limitation if the present results, which provide an ED10−6 risk evaluation for DBP in trout, were extrapolated directly to humans, or even to rodents. We have suggested no such extrapolation. The goal instead was to provide an expanded experimental data set down to ultra-low exposures and incidences, to use these data for assessment of dose-linearity for tumor response, and to assess the utility of DNA adducts as biomarkers of tumor response at low dose. The results show clearly that the default extrapolation method for low exposure risk evaluation does not apply for this model, carcinogen, and protocol, and that adducts were not useful biomarkers for predicting eventual tumor outcome. While DBP carcinogenic potency may well differ in trout and humans, we have no basis to conclude that the fundamental shape of the DBP dose-tumor response curve would differ in these species.
It is also pertinent to consider the extent to which the deficiency in global repair of bulky DNA adducts seen in the trout model (23) relates to the observed shape of the tumor dose-response curve. One plausible expectation is that models with significantly decreased DNA repair capacity might have a greater tendency toward low-dose linearity than those with greater repair capacity, because they are less capable of adduct removal and mutation avoidance at ultra-low exposures. The fact that the current findings are not consistent with this expectation makes a low-dose-linearity response even less tenable than if the model had substantial DNA repair – that is, an animal with greater repair capacity would be expected to show an even steeper departure from linearity in the low-exposure region, not less. In this regard the trout provides a conservative measure of the conservatism in the LED10 default assumption.
A final consideration is that the present study relates most directly to risk characterization for juvenile cancer, which is second only to accidents as the leading cause of death among children in the US. The focus on juvenile risk is a direct consequence of our less-than-lifetime exposure protocol, which was necessitated by restrictions of the model (long life span, continued growth) as well as insufficiency of pure DB(a,l)P anywhere in the world to permit lifetime exposure in trout or any other vertebrate model. While juvenile cancer risk assessment is undeniably important, it is also pertinent to consider how data gathered from partial life exposure protocols may relate to the more traditional lifetime risk assessments. Based on our historical data, we would expect tumor incidence at any DBP dose to increase with time of treatment and time for tumor growth in the trout model. As a consequence, ED10−6 estimates from this model would be expected to increase with longer treatment or grow-out times. The more important question, however, is whether the fundamental shape of the dose-response (e.g. linear vs. non-linear) would be influenced by either parameter in trout, or any other vertebrate model. If so, then the use of data from life-time exposure/grow-out protocol to assess juvenile cancer risk may provide misleading results, and the reverse would also be true. It is possible, for instance, that the lack of proportionality in tumor response seen at ultra-low DBP dose in this study might reflect a time-dose interaction, in which tumors elicited at low dose grow more slowly than those at high dose. Under this circumstance, non-linearity in dose-response would be an inherent function of our juvenile termination protocol, and as such would be observed for all carcinogens eliciting hepatocellular carcinomas in this model. The most direct data we have on this question derives from our current ED001 study with aflatoxin B1, using a treatment and grow-out protocol identical to that used for DBP. Two of the four independent trials are now completed, and the initial results (34) indicate that AFB1 at low dose elicits a dose-response function that is considerably less steep on a log-log scale than observed in DBP, but still greater than 1.0. If these initial results are confirmed at the end of the study, the degree of sublinearity in tumor response at ultra-low dose in the trout model is determined by the carcinogen, and not the protocol.
The data presented here demonstrate that hepatic tumor response was not in direct proportion to DBP dose, but fell increasingly below direct proportionality (slope 1.0 on log/log scale) with decreasing DBP dose. The shapes of two of the fitted curves for liver (quadratic logit, linear probit) and one of the fitted curves for stomach (linear probit) display increasingly steep slopes with decreasing dose, and thus may be taken to suggest that a finite dose may be reached in which there would be no observable increase above background tumor rate (slope of infinity), that is, a threshold. Although these data are consistent with a threshold interpretation, even the use of over 30,000 animals did not provide proof that a threshold was reached, or would exist, in either target organ for this carcinogen in this model. Several recent studies have explored the existence of a threshold for carcinogenicity by genotoxic carcinogens (29, 30, 35–37). Fukushima et al. (35) examined the induction of DNA adducts, 8-OHdG damage, and aberrant crypt foci biomarkers in the colon of rats treated with 2-amino-1-methyl-6-imidazo[4,5-b]pyridine (PhIP). The study covered an exceptionally wide range of PhIP exposure, 0.001 to 400 ppm fed for 16 weeks, at which time ACF/colon were determined. Rats per treatment ranged from 61 to 244, and observed ACF/colon ranged from 0.3 +/− 0.7 in controls to 5.0 +/− 2.8 at highest dose. By graphical analysis on a semilog scale (log dose vs total ACF) the authors claim evidence for a threshold dose of PhIP of 50 ppm because doses below that did not produce ACF/Foci different from background by simple pair-wise Dunnet-test. However, with variances in biomarker response of this magnitude even 250 animals/group provides insufficient statistical power to assess carcinogen-related response down to a background level of 0.3 ACF/colon, and especially to demonstrate significant departure from linearity in the low dose-response range. (The present study, by comparison, required approximately 27,000 animals treated with zero, 0.45 ppm, or 1.27 ppm DBP for adequate statistical power to demonstrate departure from linearity). In particular, the inability of a Dunnet-test to differentiate between 0.3 +/−0.7 ACF/colon (n=240) at zero dose, and 0.4 +/−0.8 ACF/colon (n=212) at 10 ppm does not provide statistical proof that a threshold has been reached or even that the response is significantly non-linear -- with sufficiently few animals and sufficiently large variances and background, any dose-response study will arrive at an exposure dose that does not elicit a response differing significantly from control. In addition, the semi-logarithmic graphical analysis used by these authors and others (29) is biased toward appearance of a threshold owing to simple mathematical reasons (expanded dose scale and compressed incidence scale). The insensitivity of this scaling for differentiating zero and near-zero incidences at low dose means that even a true proportional dose-response data set, that fits a straight-line-through-the-origin model, will show an apparent threshold on a semi-log scale.
Fukushima et al. (36) reported no-observed-effect levels for induction of the glutathione-S-transferase placental form altered foci biomarker in rat liver by low doses of N-nitrosodiethylamine or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. In this case as well, absence of background correction, variability in response, and limitation in animal numbers mitigate against a robust test of low-dose linearity for either carcinogen. In addition, this model as well as that reported by Williams et al. (37) used a protocol in which carcinogen treatment was followed by extended promotion by phenobarbital. At present, risk assessment models for carcinogenesis consider response to a single agent alone and the influence of a non-genotoxic promoter on the linearity of carcinogen response was not investigated in these studies. Such two-factor exposure protocols will require more intensive dose-dose-response study if we are to understand the interactions of carcinogen and promoter dose on biomarker or tumor response at low exposures and incidences pertinent to human cancer risk assessment.
We thank Dan Arbogast, Greg Gonnerman, Shiela Cleveland, Eric Johnson, Chance McDonald, Pat Loveland, Kate Mathews, Margaret Pratt, and Melissa Haendel for their assistance. This work was supported by National Institutes of Health Grants ES07060, ES03850, ES00210, ES04766, ES11267, and ES013534.
Supporting Information Available: The full tumor dataset (on a per-tank basis) is available in the supporting information section.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Claims based on traditional homeopathic practice, not accepted medical evidence. Not FDA evaluated.
The uses for our products are based on traditional homeopathic practice. They have not been reviewed by the Food and Drug Administration.
Indications :: Be gone Painful Urination helps with ache in the small of the back, frequent urge to urinate but passing only a small amount of urine.
Directions: Adults 2 pellets every 3 hours for 2 days. Then 2 pellets morning and night for 2 weeks. Children: 1 pellet. Repeat as necessary.
Ingredients :: Active ingredients HPUS: Berberis Vulg 6c (burning pains), Terebinthina 6c (frequent urging), Lycopodium 6c (hot urine): Inactive ingredient: sucrose pill
300 Pills

subset: commoncrawl


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What follows is a purely subjective list of books on historical subjects which I have read and enjoyed over the past few years. Not all of them are particularly highbrow, but I found all of them entertaining and enlightening.
Stephen Alford, The Watchers: A Secret History of the Reign of Elizabeth I (2012)
Jane Ashelford, The Art of Dress: Clothes and Society, 1500-1914 (1998)
Jeremy Black, The British Abroad: The Grand Tour in the Eighteenth Century (1985)
Tim Blanning, The Triumph of Music: Composers, Musicians and Their Audiences, 1700 to the Present (2009)
Francois Boucher and Yvonne Deslandres, 20,000 Years of Fashion: The History of Costume and Personal Adornment (1998)
Deborah Cohen, Household Gods: The British and Their Possessions (2006)
L. Davidoff and C. Hall, Family Fortunes: Men and Women of the English Middle Class, 1780-1850 (1987)
Brian Dolan, Ladies of the Grand Tour (2001)
Niall Ferguson, Empire: How Britain Made the Modern World (2012)
Orlando Figes, Natasha's Dance: a Cultural History of Russia (2003)
Robin Fleming, Britain After Rome: The Fall and Rise, 400-1070 (2011)
Antonia Fraser, The Weaker Vessel: Woman's Lot in Seventeenth-Century England (1984)
Julie Fromer, A Necessary Luxury: Tea in Victorian England (2008)
Simon Garfield, Our Hidden Lives: The Remarkable Diaries of Post-War Britain (2011)
Vic Gatrell, The First Bohemians: Life and Art in London's Golden Age (2013)
Paul Langford, Englishness Identified: Manners and Character, 1650-1850 (Oxford, 1999)
Elizabeth Langland, Nobody's Angels: Middle-Class Women and Domestic Ideology in Victorian Culture (1995)
Thad Logan, The Victorian Parlour: A Cultural Study (2001)
Andrew Marr, A History of Modern Britain (2009)
Simon Sebag Montefiore, Jerusalem: The Biography (2012)
Marjorie Morgan, National Identities and Travel in Victorian Britain (2001)
Ian Mortimer, The Time-Traveller's Guide to Medieval England (2009)
Ian Mortimer, The Time-Traveller's Guide to Elizabethan England (2012)
Margaret Ponsonby, Stories from home: English domestic interiors, 1750-1850 (2007)
Roy Porter, London: A Social History (1994)
Eugene Rogan, The Arabs: A History (2011)
Simon Schama, The Story of the Jews: Finding the Words, 1000 BCE – 1492 (2013)
Avi Schlaim, The Iron Wall: Israel and the Arab World (2015)
Frederick Taylor, Exorcising Hitler: The Occupation and Denazification of Germany (2011)
Keith Thomas, Man and the Natural World: Changing Attitudes in England 1500-1800 (1991)
Keith Thomas, The Ends of Life: Roads to Fulfilment in Early Modern England (2010)
Amanda Vickery, The Gentleman's Daughter: Women's Lives in Georgian England (2003)
Amanda Vickery, Behind Closed Doors: At Home in Georgian England (2009)
Lucy Worsley, If Walls Could Talk: An Intimate History of the Home (2012)
For those interested in historical fiction, I recommend Hilary Mantel's two excellent books on Thomas Cromwell (Wolf Hall and Bring up the Bodies), along with Lampedusa's The Leopard, an evocative tale of the declining Sicilian aristocracy during the period of Italian unification. For a lighter read, the first three books of the Outlander series are great fun, as are most of Bernard Cornwell's novels (his Warlord trilogy, set in fifth-century Britain, is especially good).


text: Scripsit Branden Robinson <firstname.lastname@example.com> > On Tue, Mar 11, 2003 at 12:16:42AM +0100, Henning Makholm wrote: > > Given that the component covered by the QPL is just the compiler, it > > seems that there is no reason why QPL 6 is even relevant for that > > particular piece of sofware. > Have you communicated with the oCaml folks before? Not personally. However, I've worked together with people who've tried to raise them about getting permission to GPL the runtime system of Moscow ML (which is derived from an earlier version of oCaml and thus has interited a non-free license). As far as I know, they have not responded to license-related inquires at all. > Do you think they would be amenable to dual-licensing the compiler > under the QPL and GPL? I'm not sure. Rumor in the functional-programming community has it that they actually do want the patch clause, lest their cool compiler technology would be too easily reused in implementations of unworthy languages like Java (!). I don't know how much truth there is here, though. However, I hope we agree that QPL as it stands *is* DFSG-free. -- Henning Makholm "Fuck Lone."


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Mentor/Facilitator - Big Brothers Big Sisters
Cause Areas
WhenIt's flexible! We'll work with your schedule.
WhereSchools in Calhoun County and Anniston City SchoolAnniston, AL 36201
Big Brothers/Big Sisters needing volunteers to be facilitators for the, Big Brothers and
Big Sisters and the students that they are working with. This would involve going into
the schools and just watching over the mentor and students to make sure they are
arriving on time and doing what they are required to do. You can pick the school of
your choice.
- People Skills
- Mentoring
- Child Welfare
- Community Outreach
- Child Care
- Relationship Building
Good Match For
Teens People 55+
Requirements & Commitment
- Driver's License Needed
- Orientation or Training
- one to two hours one day a week
- This would be perfect for a retired educator or anyone who likes to help children


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So… it's only the 3rd week of the year, and I am successfully "behind" on blogging!?! Whatever… last year, I only blogged 3 times total (that blog has been removed due to lame-ness). So… a lot of people think that because I am married to a phenomenal photographer… that I must be incredibly talented as well? Not so much… I can make a mean mac-n-cheese (from the box), but we leave the artsy fartsy stuff to the one and only– Travis Ryan Hoehne . However, occasionally I venture out of my comfort zone and … get ready for it… … are you ready?…. I GET CRAFTY!! There, I said it! So this week, I decided to handmake cards for friends. I took some pics, so you can see what I've been up to while my children took a 4 hour nap today.
These next few are just of the cutest kids in the world… (in my extremely biased opinion). Yes, we give them spoonfuls of peanut butter as a snack sometimes ; ) We require them sit still, because… as you can imagine… they would much rather paint the furniture with it! Zion was trying to not smile… I'll take it! He made up for it when he insisted on a little photo shoot the next day ; )
And a little pic of the happy couple… we got a "day-cation" to Sonoma and had a great time at Cornerstone Gardens!


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Fr 31/03/2017
Sa 01/04/2017
Su 02/04/2017
Mo 03/04/2017
Tu 04/04/2017
We 05/04/2017
Th 06/04/2017
AAA - AAA - Text
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text: Hotel Ambiente A warm welcome awaits you at the mid size, 3x000D star Hotel Ambiente in Munchen. The hotel offers restaurant facilities. Rooms at the Hotel Ambiente. All rooms have a hairdryer. Rooms have wireless internet access available. All rooms feature a stocked minibar. Other Info. The hotel offers an airport shuttle service. Pet owners and their well behaved pets are welcome at the hotel. Hotel guests can make use of the concierge service that is provided.


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Champion AC
- 4729 Shavano Oak
- San Antonio, TX 78249 | View Map
- (210) 699-0022
- https://www.championac.com
Business Description:
- Champion AC is a full service air conditioning and heating company located in San Antonio, TX. We offer AC repair, AC replacement and annual maintenance plans.
- heating & air conditioning
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Patti's Review
I was told someone would come and inspect the work after it was done. No one ever did
Hi Patti,
Thanks for taking the time to provide us this feedback. Please let me know when a good time is to come out and inspect the work. I will personally do the inspection and we apologize for the confusion. Have a great week.
Ben HubbertChampion AC commented on 11/03/2015


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What's for dinner? Fortunately this age-old question has a quick, flavor-filled answer: Smithfield Marinated Fresh Pork. Our 100% fresh pork cuts are slow-marinated and perfectly seasoned. We've done the work for you so you can have a hassle-free, delicious dinner any night of the week. Simply grill, roast or sauté and you've got a delicious dinner ready in minutes.
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I am really proud of the fact that I'm finally accustomed to eating Indian food. I love to taste food from different countries, because that's the best way to learn more about their culture right? Or maybe that's just me. Being that I can't eat spicy food I was very pleased with the quality, taste, and the variety of dishes available at Haldi. Not only was I able to taste dishes from the newly renovated menu by Michelin-starred chef Hemant Mathur, but I also had a chance to enjoy the renovated and beautiful restaurant itself.
Haldi is co-owned by chef Hemant Mathur who is also the co-owner of five other New York City restaurants: Malai Marke, Chola, Dhaba, Kokum, and Chote Nawab. For Haldi's newly revonated menu, Chef Hemant Mathur was inspired by Calcutta and incorporates a variety of unique and flavorful Bengali-Indian dishes to the menu.
Both the interior and the atmosphere at Haldi is very relaxing. The dim lighting inside the restaurant makes for a romantic date night or a great place to catch up with some friends where you have no distractions. The staff itself is very attentive to your needs and very pleasant to speak with. If you can't eat food that is too spicy Chef Hemant Mathur will tone it down for you.
Every dish that was brought out was more amazing than the last dish. Chef Hemant Mathur chose a few dishes the from the renovated menu for my guest and I to taste; the dishes were an eclectic mix of flavorful, succulent, and very well prepared Bengali-Indian cuisine. From this menu, my guest and I enjoyed eating Bengali Bites like the Jhal Muri which is puffed rice, peanuts, green chutney, and tomatoes; the Luchi Aloo Dum which is an amazing puffy bread that is stuffed with baby potatoes, onions, and tomatoes; and the Chingri Malai which consists of Shrimp, coconut, and tamarind.
Following the Bengali Bites we had some Dak Bunglow Chicken Curry; Lal Maas, a red chili paste with ginger-garlic and tomatoes; and Vegetable Biryani, which is a rice dish that is packed with vegetables. This dish was served with boondi raita, which is a popular Indian dish that is like a dip and contains plain yogurt and boondi (fried chickpea flour). Not only were we not done, but Chef Mathur saved the best for last with the Mustard Chicken Kebabs served with a tomato Chutney; a Flounder Fish Kebab with an apricot chutney; and Baby Lamp Chops with a mango chutney. All three chutneys were cooked and served to perfection. The taste, texture, and the thickness were unlike any other. For dessert we had Chenna Payesh, which are steamed cheese dumplings, saffron cardamom milk and roasted almonds; and the Rum Balls which were made with fig and chocolate cakes, semi-sweet calibut chocolate roasted cashews.
The most memorable dish is the Chingri Malai. The combination of shrimp, coconut, and tamarind is just heavenly! The first impression is always important to me especially when it comes to food, and it's hard when I'm not used to eating a specific cuisine like Indian Food. But Haldi is really one of the best ones out there! If you have not made reservations yet, then you need to pick up a phone and check out the restaurant. Haldi has a great atmosphere, amazing food, and is affordable? What else do you really need?
If you are intrigued and want to try out the newly renovated menu make sure to visit Haldi at 102 Lexington Avenue; reservations can be made by calling 212-213-9615.
Twisted Talk: Are you a fan of Indian Cuisine? Will you be going to Haldi in the near future? Discuss below!


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Starting with the development of the city as a bronze age settlement on the castle rock and on through the dangerous political climate of the 16th century Edinburgh Through The Ages also shows how the city came of age during the Scottish 'enlightenment' becoming a hotbed of artistic and philosophical achievement as figures such as Allan Ramsey jr. and intellectuals like David Hume won it the title of 'the Athens of the North'.
Edinburgh has also bequeathed more than its fair share of scientific inventions on the world from the pneumatic tyre to the television and the Forth Bridge which holds the title of the greatest engineering achievement of its time.
Edinburgh Through The Ages examines the huge architectural legacy of a city which moved American President Thomas Jefferson to describe its New Town as one of the wonders of the age.
The sporting life of the city is also examined, from the great rivalry between Hibs & Hearts to the hallowed turf of the Murrayfield rugby fortress as well as the legacy of having held two Commonwealth Games.
Richard Demarco's own unique insights and astonishing knowledge of his home town will reveal the heart and soul of this most complex and beautiful of capital cities.
This audiobook is based on the DVD of the same name.
©2005 Green Umbrella; (P)2008 Summersdale Publishers Ltd
"Not an audio book"
This is the sound track off of a TV special. I'm sure it was a lovely special on TV, but not worth it as an audio file.
"Great historical information....very bad narration"
I enjoyed the historical information in this book however the narration and recording is poor and has no fluidity. Disappointing . Sounds like an old radio program from the 30's.
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Many developing nations continue to explore the efficient use and application of ICT devices to improve social services.
In the small West African state of the Gambia, the government has begun a project to use mobile phones to track the attendance of teachers in schools.
The country's Minister for Basic and Secondary Education, Fatou Lamin Faye who was addressing the official commissioning of Rlg Assembly Plant Complex near Banjul over the weekend gave little details about the innovation.
She however said teachers especially at the basic and high schools as well as those in rural areas will be tracked by the project.
She said the project is part of interventions to enhance quality education delivery in schools and ensure discipline among teachers.
The Minister said the project was conceived after numerous concerns over poor attendance of teachers in classrooms which often reflect the poor academic performance of pupils and students.
She said the location of Rlg's Plant strengthens the government's hand to successfully implement the project using mobile phones to be assembled locally by Rlg Gambia.
"We can reflect today on the quest for vibrant entrepreneurship growth and progress for our vision 2020 and we can think ahead to a future of continued achievement and success in the Gambia. We salute today Rlg Gambia's resolve to serve the entire spectrum of the country's population by offering a variety products and solutions in the supply of phones and its accessories," the Minister told the function.
She said her government was considering the use of locally assembled laptops by teachers to improve teaching and learning.
The Gambia has a population of 1.7 million people and is seeking to use education, technology and tourism to advance the course of economic emancipation.


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The Elder Scrolls IV: Oblivion
Game Info:
|PC, Xbox360
|Bethesda Softworks
|Zenimax Media
|Minimum Req.:
|2000MHz Pentium 4 or AMD equiv.
4.6GB HDD space
64MB DX8 video card
Windows 2000/XP
|Reviewer's Machine:
|AMD Athlon64 2300MHz
74GB 10,000RPM Raptor
256MB GeForce 6800GT
Windows XP
Editor review
The CRPG reaches dizzying new heights
I don't know how many of you recall the early days of Ultima Underworld and to be completely honest, I can't remember it all too well either. The game was released before I even set foot in this country, but the game's effect on the course of history and of roleplaying still echo to this day. Ultima Underworld was destined to change the face of gaming; it had one of the first and most complex 3D engines ever used in a RPG. Even more amazing is that it predates Wolfenstein 3D. The impact that Elder Scrolls IV: Oblivion has had on the world of RPGs can only be compared to something as legendary as Ultima Underworld. Morrowind set the stage and Oblivion delivered the tour-de-force performance. Never have I seen an RPG so well received by both the hardcore gamers as well as mainstream players who may have never even heard of the Elder Scrolls games. No doubt the game's key selling point is its mindblowing visuals, but it still embodies all of the things that make the Elder Scrolls the prime CRPG of any generation.
The story revolves around the Imperial Province, a locale that hasn't been central to any Elder Scrolls story since the early days of Arena. You play as a seemingly non-descript prisoner currently being held at the Imperial lockup when you suddenly find the big cheese, Emperor Uriel Septim and his contingent of Blades members knocking on your cell door. Turns out there's a secret passage in your cell and fortunately for you, the Emperor is kind enough to allow you to accompany his group out of the prison. Your luck, however, doesn't hold out as the Emperor is attacked by unknown assailants and slain right in front of your face. For some odd reason, he entrusts you with the Amulet of Kings and charges you with the task of bringing it to a man named Jauffre. You later find out that with the Emperor dead and the Amulet of Kings collecting dust, there's no stopping the Daedra from opening Oblivion Gates and unleashing the terrible fiends within.
Players of Morrowind will find the gameplay to be familiar, with the major differences being in the size of the game world and the boosted number of quests. Bethesda boasts that the above-ground world of Oblivion has about 16 square miles of territory; sprinkled with various explorable locations like dungeons, ruins, caves, and uncharted towns. You can either choose to explore on foot or on horseback and impatient gamers will no doubt welcome the quick-travel feature, which will instantly drop you on any previously discovered location. With 16 square miles of explorable land, you'd think you'd be hopelessly lost trying to find your next destination; fortunately, that isn't the case. The world map marks all of the locations you've found and will also guide you to your next quest destination. Gone are the days of frustration over vaguely written quest logs because this system makes it almost impossible to get lost.
But of course, who wouldn't want to get lost in this world? There's so much to do that it'd be a waste of time to go for the main quest right away. You can join the Fighters' Guild and butt heads with a rival guild or you can case houses during the day and rob them at night. The spirit of open-endedness is rife in this game and it has something to offer any kind of player, whether they're murderers, crusaders, vampires, or thieves!
Perhaps the most notable difference from Morrowind is Oblivion's completely reworked interface. There's little doubt that its simplied interface is a result of its Xbox360 counterpart. It's intuitive and functional, but is obviously wasn't designed with the PC in mind. The menu covers the entire screen and the icons and text are incredibly large; even at 1600x1200 it only displays a maximum of six items! If you're a packrat like I am, that means a ton of scrolling just to get to the item you're looking for. These issues also extend to the map, which has no zoom features whatsover and no location list, leading to some wild dragging to plot your next destination. The utter lack of a minimap is equally disappointing, but the compass tries to fill this niche by notifying the player if they are nearing a location.
Bethesda also decided to employ level scaling in this game; a feature that is none too popular in either PC or console gaming. The last game I recall using this feature was Final Fantasy VIII and still had major balance issues. In a nutshell, level scaling strengthens or weakens enemies according to the player's level. It can do this with boosted stats or better equipment, so don't be too surprised if you see a goblin wearing rare Elven armor. For the most part the system works well for warriors and the like, but for stealthier and magical classes, it can get downright brutal.
Just like with Morrowind, Oblivion's trump card is its visuals. Bar none, the PC version is the best looking RPG on any platform. The polygon counts are beyond reckoning, the textures are nearing photorealism, its use of HDR brings lighting to a whole new level, and the amount of detail put into this rendition of Tamriel almost makes the real world look a little mundane in comparison. The randomly generated faces are nice touch as well; almost every person you encounter will have a totally unique look to them. They also have facial expressions that change depending on their disposition, but it doesn't quite come close to what we saw in Half-Life 2. Even with my dated hardware, I was able to get playable framerates at 1600x1200 along with 2xAA and Bloom Lighting with all of the options maxed with the exception of shadows. Playing with HDR was possible, but the FPS hit was much higher than even 4xAA so I decided against it. For the most part, the frame rate stayed a shade under 30FPS in outdoor scenes, but was over 40FPS indoors; though there were areas where the engine would choke for no apparent reason. Make no mistake, this game will need a beefy system to get the highest visual splendor possible. It performs better than Morrowind in many cases, but this game will push your rig to its limits. If you don't have previous or current generation hardware, you might want to consider the Xbox360 version; while it won't offer you the best possible visuals, it does give you a more than favorable compromise between performance and looks. However, if you've got the latest and greatest in PC hardware, then by all means go for the PC version; there are mods that can remove the limitations in draw distance and low quality LOD maps that are leftovers from the Xbox360 version.
The audio is standard fare; sound effects are really nothing to brag about and nothing to complain about either. You get a few musical tracks depending on the situation, whether it be battle or dungeon. The biggest addition would be the fully voiced dialogue; nothing is left for the player to read for themselves. It adds another dimension of realism, but since there are so many characters in Tamriel; you're bound to hear voices and phrases repeat several times. One extreme example would be the beggars; when you first speak to them they sound dessicated and run down, but the second you ask them about a rumor all of a sudden it sounds like they've been given a new lease on life!
While this is the most mainstream Elder Scrolls game ever; it still doesn't quite have the universal appeal of something like Halo or Gran Turismo. The level progression system takes a bit of getting used to and the amount of involvement required to get the most out of this game may turn away some gamers. However, if you're looking for the most engrossing RPG in the market, then you've found it. I spent an easy 74 hours playing this game and such a number is almost unheard of in the world of CRPGs, but leave it to the Elder Scrolls series to give you more than what you paid for. Whether you're just a beginner, breaking into the world of RPGs or a seasoned veteran looking to for a world to spend a whole month in, then Oblivion should be your next destination.
Reviewed by Toma-kun
December 29, 2008
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It's that time again where I share with you my most played songs of the month!
Before we talk music, let me just tell how glad I am for the Month of November to be almost over. Blogging everyday is actually harder than it seems and I really want to go back to my old schedule ahah
Also my bedroom has been under construction and today I went to IKEA to buy a few things to decorate it when it's ready for it. I'll might share on the blog the final result :)
Without further do let's see what I've been listening non stop for the past weeks:
- Flicker - Lorde (Kanye West Rework)
- New Flame - Chris Brown ft Usher
- Latch - Natalie Taylor
- Style - Taylor Swift
- Blank Space - Taylor Swift
- Please Don't Stop the Rain - James Morisson
- Promises - Jhene Aiko
- Dead Air - CHVRCHES
- Tudo O Que Vocé Quiser - Luan Santana
- Stronger Than Ever - Raleigh Richie
For more songs, you can follow my playlists on Spotify - spotify:user:[analeote]


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So far it is a close call don't you think?
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Hillary is pretty transparent, even without meaning to be.
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I could agree with that.
Hillary is who she is. I believe she wants the public to know what she stands for and therefore does not beat around the bush. I hope she does run for President, but not sure if she is yet. I wanted her to win over our current President, whom in my opinion has made this country worse off.
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...and what planet are you from?
What does she stand for, but perhaps the question should be; how much would she charge to stand for something?
Seem all we know about her service for the US is that she collected millions from other countries...surely her phone messages could have shown she did more than that? Or maybe it is the more she doesn't want us to know about?
I would think so as both excel in deceit, both have majored in lying and both seem to suffer from a case of megalomania. I have also noticed that both seem to possess an imperial "I" syndrom.
The differences however, are glaring; Obama does not depend on his wife, whereas Clinton, without Bill would probably still be chasing ambulances. With that then, I would say that Clinton is the least transparent and coated with more lead the Obama. Any discerning eye, however, can see through both of them.
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HAHAHA! Oh goodness, one can only hope she'll at least come up with a better way to begin a string of lies than, "Let me be clear...".
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In a news conference, Deanna Favre announced she will be the starting Quarterback for the Green Bay Packers football team next season.
Deanna asserts that she is qualified to be the starting QB because she had spent 16 years married to Brett while he played QB for the Packers - even though she has actually never played football at any level from grade school up, never ran the offense of any team, nor ever played the game.
During this period of time, she became familiar with the definition of a corner blitz, the nickel package, man-to-man coverage, so she is now completely comfortable with all the other terminology involving the Packers offense.
A survey of Packers fans shows 50% of those polled supported the move.Does this sound idiotic and unbelievable ... or familiar to you?
Hillary Clinton makes the same claims as to why she is qualified to be the President of the United States and 50% of Democrats polled agree.
She has never run a city, county, or state during her "career" as being Bill Clinton's wife. When told Hillary Clinton has experience because she has 8 years in the White House, my immediate thought was,
"So does the pastry chef, and the person who picks up dog poop from the White House Lawn."
When it comes to running the State Department, among her 3 biggest (& only) achievements was getting a US Ambassador and 3 other Americans killed, by pretending terrorism had been defeated with lies.....Her words still echo..."what difference does it make?" The other two achievements? Let's see, concealing and destroying government property (her email scandal) and now revelations in a new book that while serving as Secretary of State Hillary Clinton shaped State Department policy to reward big money foreign donors to her family foundation.
Do I think Hillary Clinton will be as transparent as Obama?
Obama? the guy who lies every time he opens his mouth. This year the White House set a record for censoring government files and denying access to requested information, according to an analysis by the Associated Press published Wednesday. The backlog of unanswered FOIA requests grew to more than 200,000 last year – an increase of 55 percent from the previous year. The administration reduced the number of employees tasked with responding to information requests by about 9 percent this year, the AP also noted.
Obama has not even been able to present the appearance of transparency in his administration, nor would Hiliary.
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Hillary And Most Powerful Women
August 24, 2011 by Post Team
Hillary And Most Powerful Women, German Chancellor Angela Merkel tops the Forbes list of most powerful women in the world, which is dominated by politicians, entrepreneurs and leading media and entertainment. U.S. Secretary of State Hillary Clinton, who almost beat Obama when he sought the Democratic nomination in 2008, was second, followed by Brazilian President Rousseff.
"Our list reflects the diverse paths and dynamics of power for women today, if it leads to a nation or setting the agenda on critical issues of our time," said Moira Forbes, Editor & ForbesWoman president, said in a statement.
Eight Heads of State and made 29 CEOs of Forbes 100 Most Powerful Women released Wednesday. Have an average age of 54 and collectively control and 30 billion dollars. Twenty-two are single.
"Through her many spheres of influence, these women have come to power through the connectivity, the ability to build a community around the organizations they oversee, the nations leading causes they defend and their personal brands," Forbes said.
Merkel was quoted as head of global real economy in Europe. Clinton was praised for skillfully Middle East is WikiLeaks revelations and revolutions in its second year on the job, while Rousseff made history as the first woman to lead the greatest economic power in Latin America.
Rounding out the top five were the CEO of PepsiCo U.S. Indra Nooyi, who oversees food and 60 billion and the rule of drinks, and Facebook COO Sheryl Sandberg, who was credited with preparing the bid of the booming social network that could bring to the extent and $ 100 million.
Forbes said the women on the list came to power not only through money and power, but also thanks to the media, through the reach and influence.
Lady Gaga and the newly named The New York Times executive editor, Jill Abramson, came in 11 and 12.
Gaga was also the youngest member of the list to 25, while Queen Elizabeth of Britain, which ranked No. 49, was the largest in 85 years.
U.S. The first lady Michelle Obama, who last year ranked first, fell to No. 8 in the current ranking.
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Disclaimer: The views expressed on this site are that of the authors and not necessarily that of U.S.S.POST.


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rand paul
Rand Paul Still Undecided on White House Run, Says He Would Be 'Friendly Competitor' for Ted Cruz
FORT WORTH, Texas (AP) — U.S. Sen. Rand Paul of Kentucky says he and Texas counterpart Ted Cruz will be "friendly competitors" should both run for president in 2016.
Rand Paul: Obama Has Violated the Constitution, Civil Liberties
OXON HILL, Md. (AP) — Kentucky Sen. Rand Paul says President Barack Obama is running roughshod over Americans' civil liberties.
Stonecipher: Ayotte Should Be GOP's 2016 Presidential Candidate
It was not long after President Barack Obama was reelected president that names for the 2016 race began to fly out as potential front runner. However, Shreveport political consultant Elliott Stonecipher says none of those names will do the job.
#StandWithRand Top Tweet During Rand Paul Filibuster Tonight
A small group, led by Republican Senator Rand Paul of Kentucky, is stalling the Senate tonight by waging an old-school, speak-until-you-can-speak-no-more filibuster (also deemed the #filiblizzard) over the government's use of lethal drone strikes.


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What Questions to Ask When Hiring a Chief Knowledge Officer
Abstract: One of our members is about to hire a chief knowledge officer (CKO) and asked APQC to supply some interview questions to put to the candidates. Of course, we have no shortage of suggestions, but we decided to solicit input from our KM Edge group on LinkedIn, as well. Below are just three of APQC's suggestions as well as excerpts from the responses provided by members of our LinkedIn community. If you have additional suggestions, we would love to hear them–please post your thoughts in the comments section at the end of this entry.
Carla O'Dell: What to Ask When Hiring a CKO. American Productivity and Quality Center (Articles and White Papers), June 15, 2009
Copyright © American Productivity and Quality Center. All Rights Reserved.


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Peter Kell - Australian Securities and Investments Commission
Last quote by Peter Kell
BMW Finance had a sales-driven culture that failed to comply with the requirements of the credit laws and resulted in poor outcomes for many consumers.feedback
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Peter Kell has been quoted in 2 different articles. Most recently, Peter Kell has been quoted saying, "We think the introduction of those reforms helped bring these issues to the surface." in an article called Australia banks to repay at least $136 mln to clients for mischarged fees -regulator. This is only one of 2 quotes from Peter Kell. To see more examples Peter Kell's views and opinions, check out the section below. You can filter Peter Kell's quotes by date and by topic to see, for example, what Peter Kell said about surface recently and in the past.
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The Journal of Postsecondary Education and Disability
WeThe Journal of Postsecondary Education and Disability
Welcome to the website for AHEAD's Journal of Postsecondary Education and Disability (JPED). As the official journal of the Association on Higher Education and Disability, the JPED serves as a resource to our members and other professionals dedicated to the advancement of full participation in higher education for persons with disabilities. The Journal is the leading forum for scholarship in the field of postsecondary disability support services. A refereed journal, the JPED has been published for over 15 years, bringing to the field scholarly publications on a variety of related topics that emphasize research, issues, and trends related to the theory and practice of postsecondary disability services.
Online Issues of the Journal of Postsecondary Education and Disability
This page gives AHEAD members access to online, full-text versions of the JPED beginning with Volume 9, 1991. AHEAD archives the JPED here after 24 months of print publication. Accessible versions of all of the JPED issues are always available upon request.
For information about submitting a manuscript to the JPED, please visit the Publications page.


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Hi There! Is this Your First Time?
Did you know if you Register you have access to free search tools including the ability to save listings and property searches? Did you know that you can bypass the search altogether and have listings sent directly to your email address? Check out our how-to page for more info.
The data relating to real estate for sale on this website comes in part from the (IDX)Internet Data Exchange Program of the Albemarle Area Association of Realtors, Multiple Listing Service. Real estate listings held by brokerage firms other than the Realtor owner of this website are marked with the Internet Data Exchange logo (IDX) or the Internet Data Exchange brief/thumbnail logo and detailed information about them includes the name of the listing firm.
Information on this website is provided exclusively for consumers personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing.


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HTC LifeSentry - Medical Alert System
Our Medical Alert System Is Your Key To Independent Living!
Only $150 for the system and $27.99 per month for monitoring
Living independently is the desire of most individuals. However there are times when living alone can mean that there is nobody to assist during an emergency. HTC LifeSentry offers the ability to summon assistance at any time with a simple push of a button.
Our advanced two-way technology:
- Is programmed to call our central station in case of an emergency
- Gives you 24/7 monitoring
- Lets you communicate directly through the pendant
HTC LifeSentry's base station plugs into any standard telephone jack and will allow you to communicate your message instantly and efficiently from up to 600 feet away from your base station. The system should cover your average home and into the front, back and side yards.
HTC LifeSentry
|HTC LifeSentry Equipment - $150
|24-hour Monitoring - $27.99
- Simply push the HELP button to connect to our central station
- Provides communication to central station directly through the pendant
- Full house and yard coverage of up to 600 feet
- Gives you 24/7 monitoring
- You own your equipment
- Water resistant pendant
Emergency Wall Communicator
Pricing includes installation.
|Additional pendant, purchased with a new system - $69.99
|Additional pendant, added to an existing system - $100
For more information contact 843-369-2222. Click here for the HTC LifeSentry User Guide.
Entry Title: HTC LifeSentry - Medical Alert System
Entry ID: 1674


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We're halfway through 2014 and for all of us, it's likely that the pressures from work and school have kicked in by now. While some of us adapt well to stress, some of us break from the pressure and suffer from mood swings. Stress is something that just sets in and before we know it, we're feeling unhappy and gloomy over our lack of freedom and time to ourselves for rest, relaxation and for our partners.
Hence, here's our call for a JOYFUL JULY!
As some of you have heard elsewhere, HAPPINESS IS A CHOICE. While we know that isn't always the case, there are times when we must make a conscious decision which is happiness.
So, what is joy to you? For us at LoveByte, joy is simply being able to grow old and spend a lifetime with the love of your life, blissfully entering the last stages of your existence while still making beautiful memories together. That requires effort against the odds, for not just a day or two, not weeks, nor months, but years. We can't say for sure what will happen decades from now. However, what we can do is to pace steadily towards our goal. If ageing with your partner's your dream too, then make it happen by appreciating him/her everyday. If you aren't doing so yet, start now. Allow yourself to love and be loved and embrace the joy of it all. Let this July be a joyful one for not just you but your boo too. Create unforgettable memories, have breakfast in bed, have a movie marathon at home…. basically just enjoying the simple pleasures in life and most importantly, each other's company.
Stressed as you may be, take time out for love. Love brings joy and empowers you in ways no amount of coffee every can. (: Emerge stronger, happier byt he end of July – not just as an individual, but as a couple.
We hope that everyone can live, love, laugh, have joy, be kind, and stay happy this July! :D
With Joy and Love,
LoveByte Cupid :3