The effects of neutrons in Hiroshima. Implications for the risk estimates

Risk estimates for radiation-induced late effects are relevant to various considerations in radiation protection. Most of these considerations relate to small doses for which no excess risk can be seen even in extensive epidemiological studies. Risk coefficients for radiation protection must, therefore, be based on uncertain extrapolation of observations obtained at moderate or high doses. The extrapolation can not be replaced, as yet, by new, more direct information on processes such as radiation-induced genetic instability or adaptive response. While the new findings indicate complexities that may be highly relevant to the effectiveness- or lack of effectiveness- of radiation at low doses, they remain insufficiently understood to permit a decision as to whether dose-effect relations are linear, curvilinear, or have a threshold in dose. In view of these uncertainties radiation-protection regulations are, today, based on the conservative assumption of a linear dose dependence without threshold. This approach assures a sufficient degree of protection, but it may become unreasonably over-conservative, when the cautious hypothesis is treated as proven fact, and when-in addition-the assumed initial slope of the dose relation is not critically evaluated. A reliable evaluation needs to be based on the follow-up of the atom-bomb bomb survivors, and several major aspects of current interest are discussed here. a) Mortality from solid tumours in Hiroshima shows a statistically significant excess at a colon dose of 50 mGy; however, it is likely that this is the result of a bias in assigning causes of death. b) The solid cancer mortality data of the atom-bomb survivors are consistent with linearity in dose, but they can be shown to be equally consistent with a considerable degree of curvature. c) Even with the present dosimetry system, DS86, a substantial part of the effect at small doses in Hiroshima could be due to neutrons. If this is the case, the risk estimates for gamma-rays need to be accordingly decreased. d) Numerous neutron-activation measurements in Hiroshima indicate that the DS86 underestimates the neutron doses. The evidence is, up to now, based only on activation products of low energy neutrons, but efforts are currently underway to determine activation products of high energy neutrons. If these measurements should substantiate the present trend, the cancer data in Hiroshima would cease to be reliable proof of an effect of gamma-rays at low doses. Instead the dose dependence for gamma-rays could be purely quadratic, and any initial slope in the linear-quadratic dependence might well be attributable to neutrons only.     

Chemoimmunotherapy: reengineering tumor immunity

Cancer chemotherapy drugs have long been considered immune suppressive. However, more recent data indicate that some cytotoxic drugs effectively treat cancer in part by facilitating an immune response to the tumor when given at the standard dose and schedule. These drugs induce a form of tumor cell death that is immunologically active, thereby inducing an adaptive immune response specific for the tumor. In addition, cancer chemotherapy drugs can promote tumor immunity through ancillary and largely unappreciated immunologic effects on both the malignant and normal host cells present within the tumor microenvironment. These more subtle immunomodulatory effects are dependent on the drug itself, its dose, and its schedule in relation to an immune-based intervention. The recent approvals of two new immune-based therapies for prostate cancer and melanoma herald a new era in cancer treatment and have led to heightened interest in immunotherapy as a valid approach to cancer treatment. A detailed understanding of the cellular and molecular basis of interactions between chemotherapy drugs and the immune system is essential for devising the optimal strategy for integrating new immune-based therapies into the standard of care for various cancers, resulting in the greatest long-term clinical benefit for cancer patients.     

An alternative to allosteric interactions as causes of sigmoid dose versus response curves application to glucose-induced secretion of insulin

It is shown that a signoid dose vs. response curve will occur in any biological system in which the stimulant compound must diffuse significant distances to reach responding cells, even when the cells themselves respond according to Michaelis-Menten kinetics. Isolated pancreatic islets releasing insulin in response to glucose stimulation have been used as a specific example. Since diffusion and/or other physical processes can produce global effects which could account for the sigmoidal nature of a dose vs. response curve, the existence of complex molecular mechanisms of hormone-receptor interaction can not be inferred solely from the character of a dose vs. response relation.     

The initial part of the survival curve: does it predict the outcome of fractionated radiotherapy?

The publication of a number of single-cell survival curves in vitro has stimulated radiobiologists and radiotherapists to analyze the survival characteristics of these curves for their ability to be predictive of the radioresponses of the tumors from which they were derived. Parameters of interest have been the steepness of the initial slope, the single-dose survival at 2 Gy, the mean inactivation dose, and the extrapolation number along with the D0 dose. An assessment of these correlations shows considerable overlap between the values of particular survival parameters even when tumors thought to be the most responsive are compared to those thought to be the least responsive. The importance of the full repair of sublethal damage in the analysis is noted, and a number of factors which may limit effective correlations between cell survival parameters and tumor response are discussed.     

An alternative to allosteric interactions as causes of sigmoid dose versus response curves. Application to glucose-induced secretion of insulin.

It is shown that a sigmoid dose vs. response curve will occur in any biological system in which the stimulant compound must diffuse significant distances to reach responding cells, even when the cells themselves respond according to Michaelis-Menten kinetics. Isolated pancreatic islets releasing insulin in response to glucose stimulation have been used as a specific example. Since diffusion and/or other physical processes can produce global effects which could account for the sigmoidal nature of a dose vs. response curve, the existence of complex molecular mechanisms of hormone-receptor interaction can not be inferred solely from the character of a dose vs. response relation.     

Tests for Trend in Binary Response

Tests for trend are important in analyzing data where the binary response in ordered categories is of interest. An example is in toxicology where the response in various dose groups is observed. For testing an association between the dose and the response the approach from Cochran and Armitage is widely used. However the result of this test is highly dependent on the scores assigned to the dose groups. Various dose assignments can lead to different outcomes. As an alternative the isotonic regression, a nonparametric method, is proposed. The outcome of this approach is independent of the quantification of the dose. Both methods (Cochran‐Armitage test and isotonic regression) are compared within a simulation study to an isotonic version of the Pearson's Chi‐squared test and the Wilcoxon rank sum test.     

Anti-nociceptive effect of synthesized di-hydroxy flavones: possible mechanism

Renewed interest on the research on the flavonoids is gaining more importance. Earlier literature on flavonoids indicated a significant anti-nociceptive action for flavones and mono-substituted flavones. However, they exhibited a ceiling effect. The present study was undertaken by new synthesizing six disubstituted flavones (DHFs) since poly substituted ones are expected to produce more potent effect. Their anti-nociceptive effect and the role of opioid involvement were studied using acetic acid induced abdominal constriction assay. All the six DHFs administered in elicited a dose related inhibition of abdominal constrictions indicating the presence of the anti-nociceptive response. However, these substances also showed a similar ceiling effect. Like other flavonoid substances, they also utilized opioid pathways. It is suggested that these newly synthesized DHFs can be included along with other flavonoids while attempting clinical trial for analgesic use.     

Exploring Extra-Binomial Variation in Teratology Data Using Continuous Mixtures

Discrete data from animal teratology experiments are known to exhibit extra-binomial variation. For example, we discuss a dominant lethal assay experiment in which male mice are exposed to various levels of radiation and are then mated to females. The response of interest is the number of resorptions out of the number of implantations. Most statistical work on analyzing such data has focused on modeling response rates as a function of dose of a suspected teratogen (radiation in this case) while accounting for the extra-binomial variability when calculating standard errors of the regression coefficients. Sometimes, however, when an unobserved genetic or exposure variable is suspected, the shape of the mixing distribution is of interest. We propose a mixture of beta-binomials (MBB) family of distributions that includes the non-parametric mixture of binomials model of Laird (1978) as a special case. The MBB family can accommodate a mixing distribution with one or more modes, and we develop a bootstrap test for multimodality. We apply the method to data from a dominant lethal teratology experiment.     

Hormesis: changing view of the dose-response,a personal account of the history and current status

This paper provides a personal account of the history of the hormesis concept, and of the role of the dose response in toxicology and pharmacology. A careful evaluation of the toxicology and pharmacology literatures suggests that the biphasic dose response that characterizes hormesis may be much more widespread than is commonly recognized, and may come to rival our currently favored ideas about toxicological dose responses confined to the linear and threshold representations used in risk assessment. Although hormesis-like biphasic dose responses were already well-established in chemical and radiation toxicology by the early decades of the 20th century, they were all but expunged from mainstream toxicology in the 1930s. The reasons may be found in a complex set of unrelated problems of which difficulties in replication of low-dose stimulatory responses resulting from poor study designs, greater societal interest in high-dose effects, linking of the concept of hormesis to the practice of homeopathy, and perhaps most crucially a complete lack of strong leadership to advocate its acceptance in the right circles. I believe that if hormesis achieves widespread recognition as a valid and valuable interpretation of dose-response results, we would expect an increase in the breadth of evaluations of the dose-response relationship which could be of great value in hazard and risk assessment as well as in future approaches to drug development and/or chemotherapeutics.     

Prevention by a platelet-derived factor (platelet factor 4) of induction of low dose tolerance to pneumococcal polysaccharides

It was previously shown that human or mouse serum, and platelet factor 4 (PF4) prepared from human platelet releasate, counteracts nonspecific immunosuppression induced in mice by injection of concanavalin A or syngeneic gamma-irradiated lymphoma cells. The present studies show that PF4 prepared from normal mouse or human serum by absorption to heparin-agarose and elution between 0.5 and 1.5 M NaCl is also active in this respect. The ability of PF4 to counteract antigen-specific suppression of the antibody response to pneumococcal polysaccharide (pps) was now studied. PF4 derived from human or mouse serum as well as recombinant PF4 interferes with induction of antigen-specific low dose tolerance when they are injected at the same time as a low dose (0.2 microgram) of type 14 pps 3 days before an optimal immunizing dose (25 micrograms). Furthermore, injection of platelet releasate at the time of an optimal primary immunizing dose of pps type 14 enhances the secondary response to killed bacteria injected 2 weeks later, but not the primary response itself. Both effects are interpreted as due to interference with antigen-specific suppressor cell induction during primary immunization. Injection of PF4 is much less effective in reversing low dose tolerance to an optimal immunizing dose (0.1 microgram) of type 3 pps induced by injection of 0.005 microgram of this antigen. Differences in the mechanism of tolerance induction for the two pps types that might be responsible for this are discussed.     

Multiplicity-adjusted inferences in risk assessment: benchmark analysis with quantal response data

A primary objective in quantitative risk or safety assessment is characterization of the severity and likelihood of an adverse effect caused by a chemical toxin or pharmaceutical agent. In many cases data are not available at low doses or low exposures to the agent, and inferences at those doses must be based on the high-dose data. A modern method for making low-dose inferences is known as benchmark analysis, where attention centers on the dose at which a fixed benchmark level of risk is achieved. Both upper confidence limits on the risk and lower confidence limits on the "benchmark dose" are of interest. In practice, a number of possible benchmark risks may be under study; if so, corrections must be applied to adjust the limits for multiplicity. In this short note, we discuss approaches for doing so with quantal response data.     

桩蛋白与肾脏

桩蛋白(paxillin,Pax)作为细胞骨架蛋白的关键调节蛋白之一,具有对细胞外刺激发应的潜能,在多种信号转导途径中起到结构和信号转导的承接作用.近年来有关Pax在细胞黏附与迁移中的作用备受关注,同时与肾脏发育及肾脏疾病发生的关系也日渐受到重视,现将目前相关研究作简单综述.     

Regulation of IgG responses by helper and suppressor T cells activated by pneumococcal capsular polysaccharides

Type 2 antigens are usually unable to prime the helper T cells (TH) required for secondary IgG antibody responses. However, previous results from this laboratory indicated that low doses of the type 2 antigen polyvinylpyrrolidone (PVP) could activate T cells which provided help to PVP-primed B cells for the production of PVP-specific IgG antibody. Therefore, it was of interest to determine if other type 2 antigens may also be able to activate TH. Low doses of S19 or S3 (subimmunogenic for a primary IgM response) activated TH capable of providing help to S19- or S3-CRBC-primed B cells for a secondary IgG response. Higher doses of these antigens (optimally immunogenic for a primary IgM response) activated suppressor T cells (TS). Removal of these TS prior to transfer of T cells to recipient mice resulted in expression of TH function. Therefore, the preferential activation of TH versus TS was dependent on the dose of antigen used for priming. TH activated by low doses of S19 expressed Thy 1 and L3T4 and were antigen specific. In contrast to the ability of low doses of PVP to prime B cells for secondary IgG responses, low doses of S3 and S19 did not prime capsular polysaccharide-specific IgG memory B cells. High doses of S3 were able to prime B cells if TS precursors were first removed by treatment of mice with cyclophosphamide (Cy), whereas high doses of S19 did not prime B cells for secondary IgG responses in either Cy-treated or control mice. These results are discussed in relation to the general observations that type 2 antigens may not activate antigen-specific TH.     

Continual reassessment method: a practical design for phase 1 clinical trials in cancer

This paper looks at a new approach to the design and analysis of Phase 1 clinical trials in cancer. The basic idea and motivation behind the approach stem from an attempt to reconcile the needs of dose-finding experimentation with the ethical demands of established medical practice. It is argued that for these trials the particular shape of the dose toxicity curve is of little interest. Attention focuses rather on identifying a dose with a given targeted toxicity level and on concentrating experimentation at that which all current available evidence indicates to be the best estimate of this level. Such an approach not only makes an explicit attempt to meet ethical requirements but also enables the use of models whose only requirements are that locally (i.e., around the dose corresponding to the targeted toxicity level) they reasonably well approximate the true probability of toxic response. Although a large number of models could be contemplated, we look at a particularly simple one. Extensive simulations show the model to have real promise.     

Comparison of low and high dose cosyntropin stimulation tests in the diagnosis of adrenal insufficiency in septic shock patients

Stress situations such as septic shock are accompanied by activation of the HPA axis. Some patients do not activate this axis in stress situations. This blunted response is currently designated as critical illness-related corticosteroid insufficiency (CIRCI). Currently the 250 μg cosyntropin stimulation test is the preferred diagnostic test for CIRCI. Few papers explored the role of the 1 μg cosyntropin test in septic shock patients. In this study, we compared both tests in septic shock patients taking a special interest in the population with intermediary baseline cortisol. Prospective noninterventional study included 74 septic shock patients. After measurement of baseline cortisol all patients received 1 μg of cosyntropin i. v. and 4 h later 249 μg of cosyntropin. We compared the cortisol increase after each test and its relation to mortality and vasopressor therapy. There was a moderate correlation in response to low and high dose cosyntropin, r(s)=0.55. This correlation in patients with baseline cortisol between 10-34 μg/dl is, r(s)=0.67. The increase induced by both tests was equally accurate to identify mortality and time of vasopressor withdrawal. Low and high dose cosyntropin tests presented a moderate correlation in patients with baseline cortisol between 10-34 μg/dl. Both tests are equally accurate to identify mortality and time of vasopressor therapy. These results suggest that both tests could be used to diagnose CIRCI.     

Maximum likelihood estimation for cytogenetic dose-response curves

In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.     

A dose-response model incorporating nonlinear kinetics

This paper introduces a dose-response model for toxic quantal response data based on hit theory applied to the dose unit as transformed by a nonlinear kinetic equation. When spontaneous background response is included in the model, the resulting dose-response model has four parameters. The maximum likelihood estimators and their large-sample properties are given. Likelihood ratio tests of interest are developed, including one for whether the model is one-hit in the transformed dose and one to check whether nonlinear kinetics is operative. The use of the model for low-dose extrapolation is presented. Finally, the procedures developed are illustrated on data from three animal carcinogenicity bioassays that show, respectively, concave, linear, and convex dose-response curves in the observed data.     

Transient behavior of arterial systems in response to flow pulses

The arterial system is characterized geometrically as a system of branched elastic fluid lines whose frequency response is then known in the sense of the Fourier transform. For convenience of visualization the transient response of the individual tube to an input pressure-flow pair is represented in the time domain by kernel functions indicating the hybrid effect of viscosity and momentum on the line impedance and damping characteristics. The system as a whole is then divided into a zone of smaller tubes (below 3 mm) and a zone of larger tubes extending up to the aorta. It is shown that as a system each labyrinth of tubes below the 3 mm size may be replaced by a single impedance transformation which is dominantly resistive-capacitive. In the larger tubes, the transformation of the pulse wave at different stations is considered a point of interest. Therefore hand calculated examples are worked to derive the response of a system involving some of the larger vessels to a pressure or flow pulse of the typical shape seen near the heart. The result suggests that the dicrotic wave seen in the pressure pulse of mammals is due to the hybrid viscosity-momentum nature of the longer fluid lines in relation to the gradation of unmatched terminal impedances with which they are terminated. Damping of the higher frequency components is also accounted for.     

Thiazide-induced hypercholesterolemia: sex differences

Thiazide diuretics are used commonly to treat hypertension. Unfortunately, they also are known to elevate serum cholesterol levels. Because serum lipid fraction levels differ between the sexes, possible sex-related differences in thiazide-induced changes in serum total cholesterol (TC), triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) levels were examined. Four groups of male and female hamsters were treated for a minimum of 3 months with hydrochlorothiazide (HCTZ) at zero, 1, 2 or 4 mg/kg/day. At zero dose, there was no difference in TG levels between the sexes; however, females had significantly higher TG concentrations than did males at 1, 2 and 4 mg HCTZ (all p less than 0.05). Females demonstrate a significant dose response with HCL-C levels increasing with increasing doses of HCTZ, (r = 0.983; p less than 0.02); in contrast males had a similar increase in HDL-C at all dose levels (all p less than 0.05) thus there was no demonstrable dose response (r = 0.539). Total cholesterol concentrations were significantly higher in the females than in males (p less than 0.05) at all 3 dose levels as well as at zero dose. Further, the females demonstrated a direct dose response in TC levels (r = 0.986; p less than 0.02) while the males showed no such dose response (r = 0.824; p less than 0.01). Based on these findings we conclude that: 1) HCTZ increases TG, TC and HDL-C levels in both male and female hamsters; 2) TC levels are higher in females than in males regardless of HCTZ dose; 3) only females show a dose-dependent increase in HCL-C and TC in response to HCTZ. These sex-related changes in lipid fractions occurring with HCTZ treatment, if they occur in humans, may contribute to sex-related differences in rates and severity of atherosclerosis in HCTZ-treated populations.