Ocular toxoplasmosis: more than just what meets the eye

Toxoplasma gondii is an intracellular parasite whose life cycle may include the man as an intermediate host. Close to a billion people are infected with this parasite worldwide. Ocular lesions may occur in up to 25% of those individuals infected. The infection may occur intra-uterus, through the placenta when the mother is infected during pregnancy. The parasite may also infect adults after the ingestion of contaminated food products, most notably meats or water. We have shown that although congenital and post-natal (acquired) infection results in similar ocular lesions, the immunological mechanisms behind the development of disease are different. On the other hand, contrary to published data obtained in mice, we were unable to find evidence that the T. gondii express superantigen activity for human lymphocytes. Our findings are important because they suggest that superantigen activity is not important as a pathological mechanism in human disease. Our data also suggest that, whereas the ocular lesion caused by infection after birth is the result of an excessive or dysfunctional immune response, the lesions caused by congenital infection may be due to a lack of an appropriate response to the parasite.     

Alternative test methods in inhalation toxicology: Challenges and opportunities

Requirements under the new European Union rules regarding Registration, Evaluation & Authorization of Chemicals (REACH) necessitate widespread toxicological safety testing of existing and new chemicals. Given the enormity of new and already in-service chemicals that fall under this new rule, obtaining inhalation toxicity testing data has unique challenges when compared to most biotesting regimes due to the complexity, time and expense involved in conducting standardized inhalation assessments of whole animals. A number of in vitro approaches have been used to obtain respiratory system-related information, but there is no universal or accepted test system to replace inhalation exposure studies. There are many considerations that must be satisfied before adopting any single in vitro bioassay or battery of such assays to substitute for whole animal inhalation data. These considerations relate mostly to the relevance of the bioassay(s) regarding selection of bioassay cell type(s), dose, and fundamental study procedures. There are data in the literature although these have not been well-assessed for such applications, and there exist perhaps more relevant unpublished data in the private sector that could provide guidance on this issue. The formation of a coalition of scientists to assess current knowledge and perhaps to consider a basic comparative study where consensus approaches (with frank discussions of their strengths and weaknesses) would be invaluable to the testing community and to the ultimate protection of human health. In May 2007, a Congress of government, industry, and academic scientists met at the Federal Institute for Risk Assessment (BfR), Berlin, on the subject of Alternative Test Methods in Inhalation Toxicology. The stimulus for the meeting arose from the European Union's (EU) recent implementation of the new REACH safety testing requirements for commercial chemicals and products. Attendees at the meeting presented a panoply of data and perspectives on the state of the science on alternative testing methods and how these might aid safety assessments of inhaled materials. The focus of many presentations was on the fundamental attributes of inhalation toxicology and how these are translated or otherwise addressed in alternative in vitro test methods. There was recognition of the needs and the potential for progress through collaboration, but there remains a clear need for continued discussion and proactive support to a broad-based comparative study. The present discussion provides one perspective of this complex issue and how the science community might collaborate to develop acceptable alternative approaches based in science that have utility in inhalation toxicological assessments.     

Ocular coloboma: Genetic variants reveal a dynamic model of eye development

Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2–19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.     

Ocular dominancy in conjugate eye movements at reading distance

We recorded conjugate eye movements to elucidate whether ocular dominancy was present at reading distance in 21 normal volunteers with the right-handedness by using a video-oculographic (VOG) measurement. This included the velocity of smooth pursuits, and the latency and velocity of saccades. We defined the dominant eye for each subject by means of the near-far alignment test and 20 subjects showed the right dominant eyes. Although the ocular dominancy was not found in the velocity of smooth pursuit and vertical saccades, the velocity of horizontal saccades in the dominant eyes was faster than that in the non-dominant eyes. These results suggest that the dominant eye is functionally activated prior to non-dominant eye in horizontal saccades at reading distance, which thus indicates the functional dominancy of the dominant eye in conjugate eye movements.     

Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation

The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and gammadelta T cells create an antigen-presentation environment that leads to CD4(+) and CD8(+) alpha/beta T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.     

Endocrine toxicology: A Review of the application of endocrinology in experimental toxicology

In the past endocrine toxicology has not been a common subject in routine toxicity studies. However, since the endocrine system is an important integrating system of the body, controlling the major physiological functions, it is important to investigate the mechanism of action of exogenous compounds in endocrine target organs or hormonal target cells. The following procedure is suggested to detect effects on the endocrine system in routine toxicity experiments: (1) determination of the weight of endocrine organs and histology as screening parameters; (2) determination of circulating hormones in combination with morphological or immunocytochemical methods: (3) specific function tests and in vitro methods to determine dysfunction of specific endocrine organs or cells. That the use of such an approach has provided insight into the mechanism of action of chemical compounds will be demonstrated by results of endocrine toxicity studies with the antibiotic compound sulphadimidine, interfering with thyroid hormone synthesis as a secondary mechanism leading to thyroid tumour formation, the androgenic compound trenbolone acetate, used for growth promotion, for which the disturbance of the gonadal function formed the basis for the establishment of the no-observed-hormonal-effect level, the antibacterial compound furazolidone, suspected of having an oestrogenic activity which was hypothesized as the underlying mechanism for the observed mammary tumour formation, and the antimicrobial agent carbadox, used as feed additive for pigs, for which the interference with adrenal function, resulted in a severe disturbance of the water and salt balance in target animals. Originally presented at ECCP 93.     

Endocrine toxicology: A Review of the application of endocrinology in experimental toxicology

In the past endocrine toxicology has not been a common subject in routine toxicity studies. However, since the endocrine system is an important integrating system of the body, controlling the major physiological functions, it is important to investigate the mechanism of action of exogenous compounds in endocrine target organs or hormonal target cells. The following procedure is suggested to detect effects on the endocrine system in routine toxicity experiments: (1) determination of the weight of endocrine organs and histology as screening parameters; (2) determination of circulating hormones in combination with morphological or immunocytochemical methods: (3) specific function tests and in vitro methods to determine dysfunction of specific endocrine organs or cells. That the use of such an approach has provided insight into the mechanism of action of chemical compounds will be demonstrated by results of endocrine toxicity studies with the antibiotic compound sulphadimidine, interfering with thyroid hormone synthesis as a secondary mechanism leading to thyroid tumour formation, the androgenic compound trenbolone acetate, used for growth promotion, for which the disturbance of the gonadal function formed the basis for the establishment of the no-observed-hormonal-effect level, the antibacterial compound furazolidone, suspected of having an oestrogenic activity which was hypothesized as the underlying mechanism for the observed mammary tumour formation, and the antimicrobial agent carbadox, used as feed additive for pigs, for which the interference with adrenal function, resulted in a severe disturbance of the water and salt balance in target animals.Originally presented at ECCP 93.     

Reproductive toxicology: the science today

Reproductive toxicology is concerned with chemical or physical agents interfering with fertility in both gender. Adverse effects may be induced directly, especially in adult males by damaging the semen producing epithelium (e.g., DBCP), or indirectly, predominantly by interfering with sex hormonal homeostasis. Many critical events must occur during well-defined periods of prenatal and early postnatal development of the reproductive system. Most of such differentiation processes, several of which in the male critically depend on inducing influences of androgens, cannot take place at later stages, and lack of "imprinting" will result in irreversible defects or dysfunctions. These processes might be disturbed by interfering agents (e.g., by anti-androgens: feminization), provided that the exposure is high enough. Several of the processes known to be essential for male development can also be altered in females by exposure to a large excess of androgens (masculinization). Essential processes required for normal male development include: 1) androgen-dependent differentiation of the male phenotype during late embryonic development, 2) differentiation of the male secondary sex organs during the fetal period, 3) formation of a fixed number of Sertoli cells during the perinatal period, 4) imprinting of male sexual behavior in defined brain areas during the perinatal period, 5) imprinting of the pulsatile GnRH regulation of hypophysial hormone formation in both gender via the hypothalamico-hypophysial axis, and 6) differentiation of the male organism during puberty. Many effects on fertility can be induced on the adult organism. Besides a direct action on the receptors, inhibition of the feed back mechanism that guarantees sex hormonal homeostasis is another mode of action. Many synthetic steroid compounds exhibit effects on more than one receptor, thus causing a complex situation. This must also be taken into account when analyzing possible effects of "ecohormones." Adverse hormonal actions are well established from experience in clinical and experimental medicine, using either natural or synthetic sex hormones, or enzyme inhibitors. Possible effects of "environmental" agents either mimicking or inhibiting sex hormonal actions are less well studied in clinical trials. Because of considerable species differences in hormonal effects, especially in pharmacokinetics, data of animal studies are of limited predictive value for extrapolations in preventive hazard minimization (but may be useful for revealing possible mechanisms of action). Data of in-vitro studies are even less suitable for extrapolations. It may be doubted that exposure of the general population to "ecohormones" or "xenohormones" is sufficient to induce clear-cut clinical effects. Adverse effects induced by, e.g., greatly unbalanced diets or after accidental overdoses cannot be excluded.     

Ocular static and dynamic light scattering: a noninvasive diagnostic tool for eye research and clinical practice

The noninvasive techniques of static and dynamic light scattering are emerging as valuable diagnostic tools for the early detection of ocular and systemic diseases. These include corneal abnormalities, pigmentary dispersion syndrome, glaucoma, cataract, diabetic vitreopathy, and possibly macular degeneration. Systemic conditions such as diabetes and possibly Alzheimer's disease can potentially be detected early via ocular tissues. The current state of development of these techniques for application to ophthalmic research and ultimately clinical practice is reviewed.     

离体兔眼实验的建立及其初步评价

目的 建立离体兔眼实验方法,评价此实验的预测力和可靠性.方法 参照欧洲替代方法验证中心推荐的离体兔眼实验方法并结合具体条件,建立适合本实验室的离体兔眼实验方法.同步采用离体兔眼实验和兔眼刺激实验对26种受试物的眼刺激性进行检测,对2种实验分级结果的一致性和可靠性进行统计分析.结果 离体兔眼实验对26种受试物的眼刺激性分...     

Optimality of position commands to horizontal eye muscles: A test of the minimum-norm rule

Six muscles control the position of the eye, which has three degrees of freedom. Daunicht proposed an optimization rule for solving this redundancy problem, whereby small changes in eye position are maintained by the minimum possible change in motor commands to the eye (the minimum-norm rule). The present study sought to test this proposal for the simplified one-dimensional case of small changes in conjugate eye position in the horizontal plane. Assuming such changes involve only the horizontal recti, Daunicht's hypothesis predicts reciprocal innervation with the size of the change in command matched to the strength of the recipient muscle at every starting position of the eye. If the motor command to a muscle is interpreted as the summed firing rate of its oculomotor neuron (OMN) pool, the minimum-norm prediction can be tested by comparing OMN firing rates with forces in the horizontal recti. The comparison showed 1) for the OMN firing rates given by Van Gisbergen and Van Opstal and the muscle forces given by Robinson, there was good agreement between the minimum-norm prediction and experimental observation over about a +/-30 degrees range of eye positions. This fit was robust with respect to variations in muscle stiffness and in methods of calculating muscle innervation. 2) Other data sets gave different estimates for the range of eye-positions within which the minimum-norm prediction held. The main sources of variation appeared to be disagreement about the proportion of OMNs with very low firing-rate thresholds (i.e., less than approximately 35 degrees in the OFF direction) and uncertainty about eye-muscle behavior for extreme (>30 degrees ) positions of the eye. 3) For all data sets, the range of eye positions over which the minimum-norm rule applied was determined by the pattern of motor-unit recruitment inferred for those data. It corresponded to the range of eye positions over which the size principle of recruitment was obeyed by both agonist and antagonist muscles. It is argued that the current best estimate of the oculomotor range over which minimum-norm control could be used for conjugate horizontal eye position is approximately +/-30 degrees. The uncertainty associated with this estimate would be reduced by obtaining unbiased samples of OMN firing rates. Minimum-norm control may result from reduction of the image movement produced by noise in OMN firing rates.     

The three-dimensional scintillation dosimetry method: test for a 106Ru eye plaque applicator

The need for fast, accurate and high resolution dosimetric quality assurance in radiation therapy has been outpacing the development of new and improved 2D and 3D dosimetry techniques. This paper summarizes the efforts to create a novel and potentially very fast, 3D dosimetry method based on the observation of scintillation light from an irradiated liquid scintillator volume serving simultaneously as a phantom material and as a dose detector medium. The method, named three-dimensional scintillation dosimetry (3DSD), uses visible light images of the liquid scintillator volume at multiple angles and applies a tomographic algorithm to a series of these images to reconstruct the scintillation light emission density in each voxel of the volume. It is based on the hypothesis that with careful design and data processing, one can achieve acceptable proportionality between the local light emission density and the locally absorbed dose. The method is applied to a Ru-106 eye plaque immersed in a 16.4 cm3 liquid scintillator volume and the reconstructed 3D dose map is compared along selected profiles and planes with radiochromic film and diode measurements. The comparison indicates that the 3DSD method agrees, within 25% for most points or within approximately 2 mm distance to agreement, with the relative radiochromic film and diode dose distributions in a small (approximately 4.5 mm high and approximately 12 mm diameter) volume in the unobstructed, high gradient dose region outside the edge of the plaque. For a comparison, the reproducibility of the radiochromic film results for our measurements ranges from 10 to 15% within this volume. At present, the 3DSD method is not accurate close to the edge of the plaque, and further than approximately 10 mm (<10% central axis depth dose) from the plaque surface. Improvement strategies, considered important to provide a more accurate quick check of the dose profiles in 3D for brachytherapy applicators, are discussed.