Predicting the safety of medicines in pregnancy: A workshop report.

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), "Predicting the Safety of Medicines in Pregnancy - a New Era?", was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.

Does First Nations ancestry modify the association between gestational diabetes and subsequent diabetes: a historical prospective cohort study among women in Manitoba, Canada.

BACKGROUND: Over the past 30 years, the prevalence of diabetes has steadily increased among Canadians, and is particularly evident among First Nations (FN) women. The interplay between FN ancestry, gestational diabetes and the development of subsequent diabetes among mothers remains unclear. METHODS: After excluding known pre-existing diabetes, we explored whether FN ancestry may modify the association between gestational diabetes and post-partum diabetes among women in Manitoba (1981-2011) via a historical prospective cohort database study. We analysed administrative data in the Population Health Research Data Repository using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: Gestational diabetes was diagnosed in 11 906 of 404 736 deliveries (2.9%), 6.7% of FN and 2.2% of non-FN pregnant women (P < 0.0001). Post-partum diabetes during ≤ 30 years follow-up was more than three times higher among FN women than among non-FN women (P < 0.0001). Diabetes developed in 76.0% of FN and 56.2% of non-FN women with gestational diabetes within the follow-up period. The hazard ratio of gestational diabetes for post-partum diabetes was 10.6 among non-FN women and 5.4 among FN women. Other factors associated with a higher risk of diabetes included lower family income among FN and non-FN women and rural/remote residences among FN women. Among non-FN women, urban residence was associated with a higher risk of diabetes. CONCLUSION: Gestational diabetes increases post-partum diabetes in FN and non-FN women. FN women had substantially more gestational diabetes or post-partum diabetes than non-FN women, partially due to socio-economic and environmental barriers. Reductions in gestational diabetes and socio-economic inequalities are required to prevent diabetes in women, particularly in FN population.

The contribution of VEGF signalling to fostamatinib-induced blood pressure elevation.

BACKGROUND AND PURPOSE: Fostamatinib is an inhibitor of spleen tyrosine kinase (TK). In patients, fostamatinib treatment was associated with increased BP. Some TK inhibitors cause BP elevation, by inhibiting the VEGF receptor 2 (VEGFR2). Here, we have assessed the mechanistic link between fostamatinib-induced BP elevation and inhibition of VEGF signalling. EXPERIMENTAL APPROACH: We used conscious rats with automated blood sampling and radio telemetry and anaesthetized rats to measure cardiovascular changes. Rat isolated aorta and isolated hearts, and human resistance vessels in vitro were also used. NO production by human microvascular endothelial cells was measured with the NO-dependent probe, DAF-FM and VEGFR2 phosphorylation was determined in mouse lung, ex vivo. KEY RESULTS: In conscious rats, fostamatinib dose-dependently increased BP. The time course of the BP effect correlated closely with the plasma concentrations of R406 (the active metabolite of fostamatinib). In anaesthetized rats, infusion of R406 increased BP and decreased femoral arterial conductance. Endothelial function was unaffected, as infusion of R406 did not inhibit hyperaemia- or ACh-induced vasodilatation in rats. R406 did not affect contraction of isolated blood vessels. R406 inhibited VEGF-stimulated NO production from human endothelial cells in vitro, and treatment with R406 inhibited VEGFR2 phosphorylation in vivo. R406 inhibited VEGF-induced hypotension in anaesthetized rats. CONCLUSIONS AND IMPLICATIONS: Increased vascular resistance, secondary to reduced VEGF-induced NO release from endothelium, may contribute to BP increases observed with fostamatanib. This is consistent with the elevated BP induced by other drugs inhibiting VEGF signalling, although the contribution of other mechanisms cannot be excluded.

The contributions of First Nations ethnicity, income, and delays in surgery on mortality post-fracture: a population-based analysis.

UNLABELLED: We examined the independent contributions of First Nations ethnicity and lower income to post-fracture mortality. A similar relative increase in mortality associated with fracture appears to translate into a larger absolute increase in post-fracture mortality for First Nations compared to non-First Nations peoples. Lower income also predicted increased mortality post-fracture. INTRODUCTION: First Nations peoples have a greater risk of mortality than non-First Nations peoples. We examined the independent contributions of First Nations ethnicity and income to mortality post-fracture, and associations with time to surgery post-hip fracture. METHODS: Non-traumatic fracture cases and fracture-free controls were identified from population-based administrative data repositories for Manitoba, Canada (aged≥50 years). Populations were retrospectively matched for sex, age (within 5 years), First Nations ethnicity, and number of comorbidities. Differences in mortality post-fracture of hip, wrist, or spine, 1996-2004 (population 1, n=63,081), and the hip, 1987-2002(Population 2, n=41,211) were examined using Cox proportional hazards regression to model time to death. For hip fracture, logistic regression analyses were used to model the probability of death within 30 days and 1 year. RESULTS: Population 1: First Nations ethnicity was associated with an increased mortality risk of 30-53% for each fracture type. Lower income was associated with an increased mortality risk of 18-26%. Population 2: lower income predicted mortality overall (odds ratio (OR) 1.15, 95% confidence interval (CI) 1.07-1.23) and for hip fracture cases (OR 1.18, 95%CI 1.05-1.32), as did older age, male sex, diabetes, and >5 comorbidities (all p≤0.01). Higher mortality was associated with pertrochanteric fracture (OR 1.14, 95% CI 1.03-1.27), or surgery delay of 2-3 days (OR 1.34, 95% CI 1.18-1.52) or ≥4 days (OR 2.35, 95% CI 2.07-2.67). CONCLUSION: A larger absolute increase in mortality post-fracture was observed for First Nations compared to non-First Nations peoples. Lower income and surgery delay>2 days predicted mortality post-fracture. These data have implications regarding prioritization of healthcare to ensure targeted, timely care for First Nations peoples and/or individuals with lower income.

The post-fracture care gap among Canadian First Nations peoples: a retrospective cohort study.

UNLABELLED: Despite targeted attempts to reduce post-fracture care gaps, we hypothesized that a larger care gap would be experienced by First Nations compared to non-First Nations people. First Nations peoples were eight times less likely to receive post-fracture care compared to non-First Nations peoples, representing a clinically significant ethnic difference in post-fracture care. INTRODUCTION: First Nations peoples are the largest group of aboriginal (indigenous or native) peoples in Canada. Canadian First Nations peoples have a greater risk of fracture compared to non-First Nations peoples. We hypothesized that ethnicity might be associated with a larger gap in post-fracture care. METHODS: Non-traumatic major osteoporotic fractures for First Nations and non-First Nations peoples aged ≥ 50 years were identified from a population-based data repository for Manitoba, Canada between April 1996 and March 2002. Logistic regression analysis was used to examine the probability of receiving a BMD test, a diagnosis of osteoporosis, or beginning an osteoporosis-related drug in the 6 months post-fracture. RESULTS: A total of 11,234 major osteoporotic fractures were identified; 502 occurred in First Nations peoples. After adjustment for confounding covariates, First Nations peoples were less likely to receive a BMD test [odds ratio (OR) 0.1, 95% confidence interval (CI), 0.0-0.5], osteoporosis-related drug treatment (OR, 0.5; 95% CI, 0.3-0.7), or a diagnosis of osteoporosis (OR, 0.5; 95% CI, 0.3-0.7) following a fracture compared to non-First Nations peoples. Females were more likely to have a BMD test (OR, 5.0; 95% CI, 2.6-9.3), to be diagnosed with osteoporosis (OR, 1.7; 95% CI, 1.5-2.0), and to begin drug treatment (OR, 4.1; 95% CI, 2.7-6.4) compared to males. CONCLUSIONS: An ethnicity difference in post-fracture care was observed. Further work is needed to elucidate underlying mechanisms for this difference and to determine whether failure to initiate treatment originates with the medical practitioner, the patient, or a combination of both. It is imperative that all residents of Manitoba receive efficacious and equal care post-fracture, regardless of ethnicity.

The interaction of ethnicity and chronic disease as risk factors for osteoporotic fractures: a comparison in Canadian Aboriginals and non-Aboriginals.

INTRODUCTION: Efforts to develop global methods for absolute fracture risk prediction are currently limited by uncertainty over the validity of these models in non-White populations. Aboriginal Canadians have higher fractures rates than non-Aboriginals. This analysis examined the interaction of ethnicity with diabetes mellitus, disease comorbidity and substance abuse as possible explanatory variables. METHODS: A retrospective, population-based matched cohort study of fracture rates was performed using Manitoba administrative health data (1984-2003). The study cohort consisted of 27,952 registered Aboriginal adults (aged 20 years or older) and 83,856 non-Aboriginal controls (matched three to one for year of birth and gender). Diabetes mellitus, number of ambulatory disease groups (ADGs), substance abuse and incident fractures were based upon validated definitions. Poisson regression analyses of fracture rates modelled the explanatory variables as main effects and two-way interactions with ethnicity. RESULTS: Osteoporotic fracture rates were approximately twofold higher in the Aboriginal cohort (p<0.0001). Diabetes, greater number of ADGs and substance abuse were all more common in the Aboriginal cohort (all p<0.0001). These factors were associated with increased fracture rates (all p<0.0001) and significantly higher population attributable risk percent in the Aboriginal cohort (all p<0.0001). However, no significant interactions between the risk factors and ethnicity were observed (p>0.1 for all interaction effects). CONCLUSION: Greater prevalence of diabetes, comorbidity and substance abuse contributes to higher rates of fracture. The relative risk of fracture for these factors is similar for both Aboriginal and non-Aboriginals despite large differences in absolute fracture risk and risk factor prevalence.

Biomarkers of drug-induced vascular injury.

In pre-clinical safety studies, drug-induced vascular injury is an issue of concern because there are no obvious diagnostic markers for pre-clinical or clinical monitoring and there is an intellectual gap in our understanding of the pathogenesis of this lesion. While vasodilatation and increased shear stress appear to play a role, the exact mechanism(s) of injury to the primary targets, smooth muscle and endothelial cells are unknown. However, evaluation of novel markers for potential clinical monitoring with a mechanistic underpinning would add value in risk assessment and management. This mini review focuses on the progress to identify diagnostic markers of drug-induced vascular injury. Von Willebrand factor (vWF), released upon perturbation of endothelial cells, is transiently increased in plasma prior to morphological evidence of damage in dogs or rats treated with vascular toxicants. Therefore, vWF might be a predictive biomarker of vascular injury. However, vWF is not an appropriate biomarker of lesion progression or severity since levels return to baseline values when there is morphological evidence of injury. A potential mechanistically linked biomarker of vascular injury is caveolin-1. Expression of this protein, localized primarily to smooth muscle and endothelial cells, decreases with the onset of vascular damage. Since vascular injury involves multiple mediators and cell types, evaluation of a panel rather than a single biomarker may be more useful in monitoring early and severe progressive vascular injury.

Bioremediation of acid mine drainage: an introduction to the Wheal Jane wetlands project.

Acid mine drainage (AMD) is a widespread environmental problem associated with both working and abandoned mining operations. As part of an overall strategy to determine a long-term treatment option for AMD, a pilot passive treatment plant was constructed in 1994 at Wheal Jane Mine in Cornwall, UK. The plant consists of three separate systems; each containing aerobic reed beds, anaerobic cell and rock filters, and represents the largest European experimental facility of its kind. The systems only differ by the type of pre-treatment utilised to increase the pH of the influent minewater (pH<4): lime-dosed (LD), anoxic limestone drain (ALD) and lime free (LF), which receives no form of pre-treatment. The Wheal Jane pilot plant offered a unique facility and a major research project was established to evaluate the pilot plant and study in detail the biological mechanisms and the geochemical and physical processes that control passive treatment systems. The project has led to data, knowledge, models and design criteria for the future design, planning and sustainable management of passive treatment systems. A multidisciplinary team of scientists and managers from the U.K. universities, the Environment Agency and the Mining Industry has been put together to obtain the maximum advantage from the excellent facilities facility at Wheal Jane.

Chemical behaviour of the Wheal Jane bioremediation system.

The effectiveness of remediation of the highly acidic and transition metal polluted mine water discharge from the Wheal Jane Mine by the Wheal Jane Passive Treatment Plant is described. The success of the remediation required that all the system components work as predicted. The study shows considerable success in the removal of key toxic metals and clearly demonstrates the potential for natural attenuation of acid mine drainage, particularly iron oxidation, by microbial populations. The Wheal Jane Passive Treatment Plant provides the only experimental facility of its kind.

The Wheal Jane wetlands model for bioremediation of acid mine drainage.

Acid mine drainage (AMD) is a widespread environmental problem associated with both working and abandoned mining operations. As part of an overall strategy to determine a long-term treatment option for AMD, a pilot passive treatment plant was constructed in 1994 at Wheal Jane Mine in Cornwall, UK. The plant consists of three separate systems, each containing aerobic reed beds, anaerobic cell and rock filters, and represents the largest European experimental facility of its kind. The systems only differ by the type of pretreatment utilised to increase the pH of the influent minewater (pH <4): lime dosed (LD), anoxic limestone drain (ALD) and lime free (LF), which receives no form of pretreatment. Historical data (1994-1997) indicate median Fe reduction between 55% and 92%, sulphate removal in the range of 3-38% and removal of target metals (cadmium, copper and zinc) below detection limits, depending on pretreatment and flow rates through the system. A new model to simulate the processes and dynamics of the wetlands systems is described, as well as the application of the model to experimental data collected at the pilot plant. The model is process based, and utilises reaction kinetic approaches based on experimental microbial techniques rather than an equilibrium approach to metal precipitation. The model is dynamic and utilises numerical integration routines to solve a set of differential equations that describe the behaviour of 20 variables over the 17 pilot plant cells on a daily basis. The model outputs at each cell boundary are evaluated and compared with the measured data, and the model is demonstrated to provide a good representation of the complex behaviour of the wetland system for a wide range of variables.

Role of a neuronal small non-messenger RNA: behavioural alterations in BC1 RNA-deleted mice.

BC1 RNA is a small non-messenger RNA common in dendritic microdomains of neurons in rodents. In order to investigate its possible role in learning and behaviour, we compared controls and knockout mice from three independent founder lines established from separate embryonic stem cells. Mutant mice were healthy with normal brain morphology and appeared to have no neurological deficits. A series of tests for exploration and spatial memory was carried out in three different laboratories. The tests were chosen as to ensure that different aspects of spatial memory and exploration could be separated and that possible effects of confounding variables could be minimised. Exploration was studied in a barrier test, in an open-field test, and in an elevated plus-maze test. Spatial memory was investigated in a Barnes maze and in a Morris water maze (memory for a single location), in a multiple T-maze and in a complex alley maze (route learning), and in a radial maze (working memory). In addition to these laboratory tasks, exploratory behaviour and spatial memory were assessed under semi-naturalistic conditions in a large outdoor pen. The combined results indicate that BC1 RNA-deficient animals show behavioural changes best interpreted in terms of reduced exploration and increased anxiety. In contrast, spatial memory was not affected. In the outdoor pen, the survival rates of BC1-depleted mice were lower than in controls. Thus, we conclude that the neuron-specific non-messenger BC1 RNA contributes to the aptive modulation of behaviour.

Post-hatch activity-dependent modulation of visual asymmetry formation in pigeons.

The embryonically induced visual lateralization in pigeons can be modified by occlusion of one eye after hatching. Here we show that this deprivation effect could be also attained by short-term blocking of retinal activity with tetrodotoxin (TTX), leading to a dominance of the ipsilateral hemisphere in a visual discrimination task. This lateralization pattern resulted from a performance increase conveyed by the non-deprived hemisphere, while performance with the TTX-injected eye did not differ from that of saline-injected controls. Thus, post-hatch modulation of visual lateralization is mediated by TTX-sensitive, activity-dependent neuronal mechanisms. The transient silencing of one visual input alters the activity balance between the left and right eye system, enhancing visuoperceptive skills in the relatively higher active hemisphere.

Toxoplasmosis in Indo-Pacific humpbacked dolphins (Sousa chinensis), from Queensland.

OBJECTIVE: To describe the clinical signs, gross pathology, serology, bacteriology, histopathology, electron microscopy and immunohistochemistry findings associated with toxoplasmosis in four Indo-Pacific humpbacked dolphins (Sousa chinensis) that stranded in Queensland in 2000 and 2001. DESIGN: Clinical assessment, gross necropsy, and laboratory examinations. PROCEDURE: Necropsies were performed on four S. chinensis to determine cause of death. Laboratory tests including serology, bacteriology, histopathology and transmission electron microscopy were done on the four dolphins. Immunohistochemistry was done on the brain, heart, liver, lung, spleen and adrenal gland from various dolphins to detect Toxoplasma gondii antigens. RESULTS: Necropsies showed all of four S. chinensis that stranded in Queensland in 2000 and 2001 had evidence of predatory shark attack and three were extremely emaciated. Histopathological examinations showed all four dolphins had toxoplasmosis with tissue cysts resembling T. gondii in the brain. Tachyzoite stages of T. gondii were detected in the lungs, heart, liver, spleen and adrenal gland, variously of all four dolphins. Electron microscopy studies and immunohistochemistry confirmed the tissues cysts were those of T. gondii. All four dolphins also had intercurrent disease including pneumonia, three had peritonitis and one had pancreatitis. CONCLUSION: Four S. chinensis necropsied in Queensland in 2000 and 2001 were found to be infected with toxoplasmosis. It is uncertain how these dolphins became infected and further studies are needed to determine how S. chinensis acquire toxoplasmosis. All four dolphins stranded after periods of heavy rainfall, and coastal freshwater runoff may be a risk factor for T. gondii infection in S. chinensis. This disease should be of concern to wildlife managers since S. chinensis is a rare species and its numbers appear to be declining.

Regulation of surface water quality in a Cretaceous Chalk catchment, UK: an assessment of the relative importance of instream and wetland processes.

To investigate the relative importance of instream nutrient spiralling and wetland transformation processes on surface water quality, total nitrogen (TN) and total phosphorus (TP) concentrations in a 200-m reach of the River Lambourn in the south-east of England were monitored over a 2-year period. In addition, the soil pore water nutrient dynamics in a riparian ecosystem adjacent to the river were investigated. Analysis of variance indicated that TN, TP and suspended sediment concentrations recorded upstream of the wetland were statistically significantly higher (P < 0.05) than those downstream of the site. Such results suggest that the wetland was performing a nutrient retention function. Indeed, analysis of soil pore waters within the site show that up to 85% of TN and 70% of TP was removed from water flowing through the wetland during baseflow conditions, thus supporting the theory that the wetland played an important role in the regulation of surface water quality at the site. However, the small variations observed (0.034 mg TN l(-1) and 0.031 mg P l(-1)) are consistent with the theory of nutrient spiralling suggesting that both instream and wetland retention processes have a causal effect on surface water quality.

Parallel working memory for spatial location and food-related object cues in foraging pigeons: binocular and lateralized monocular performance.

During foraging, animals can increase their success by both remembering feeding sites and remembering food-related object cues. Because earlier studies have tested either the site or object memory in isolation, the aim of the present study was to evaluate how efficiently birds can utilize both memories simultaneously. Furthermore, the idea was tested that lateralization might be the principle of brain organization that allows for efficient parallel processing. Pigeons learned to search for food in a complex maze with 16 baited sites. To obtain the maximum reward they had to perform two tasks in parallel, a spatial working memory task and an object-specific working memory task. Birds performed well on this dual task but, compared with spatial working memory alone, they were impaired during the first choices of a trial (Experiment 1). When the left and the right brain hemispheres were tested separately by means of monocular occlusion (Experiment 2), object discrimination was better when birds used their right eye/left hemisphere. This was most pronounced during the first choices of a trial. On the spatial component of the task, performance on binocular trials was better than on monocular trials, but monocularly both hemispheres performed at the same level. Results show that on this dual task, discrimination of food-related object cues predominantly involved the left brain hemisphere whereas both hemispheres contributed equally to spatial performance.

Genetic study of SOX9 in a case of campomelic dysplasia.

Campomelic dysplasia (CD) is a sporadic autosomal dominant syndrome that results in skeletal malformation and developmental abnormalities. Death usually occurs neonatally as a result of respiratory insufficiencies, but life expectancy varies depending on the severity of the phenotype. XY sex reversal is common in CD, and a range of genital defects is observed in males and females. CD is due to mutations in SOX9, a member of the SOX (SRY-related HMG box) gene family. SOX9 is a transcription factor involved in chondrogenesis and sex determination. We present a CD patient with a normal 46,XX karyotype and female phenotype. Single-stranded conformation polymorphism analysis of DNA from this CD patient demonstrated a single-stranded conformation polymorphism shift in the C-terminal region of SOX9. DNA sequencing showed a frameshift mutation resulting from the insertion of a single guanine residue in nucleotide region 1,453-1,456. This insertion mutation creates a mutant SOX9 open reading frame that is 201 nucleotides longer than the normal gene. It has been shown that the C-terminal region of SOX9 is responsible for the transactivating ability of the protein. The frameshift identified here affects approximately half of the protein region needed for full transactivating function. We hypothesize that residual SOX9 function may explain why this patient survived infancy.

Asymmetry pays: visual lateralization improves discrimination success in pigeons.

Functional cerebral asymmetries, once thought to be exclusively human, are now accepted to be a widespread principle of brain organization in vertebrates [1]. The prevalence of lateralization makes it likely that it has some major advantage. Until now, however, conclusive evidence has been lacking. To analyze the relation between the extent of cerebral asymmetry and the degree of performance in visual foraging, we studied grain-grit discrimination success in pigeons, a species with a left hemisphere dominance for visual object processing [2,3]. The birds performed the task under left-eye, right-eye or binocular seeing conditions. In most animals, right-eye seeing was superior to left-eye seeing performance, and binocular performance was higher than each monocular level. The absolute difference between left- and right-eye levels was defined as a measure for the degree of visual asymmetry. Animals with higher asymmetries were more successful in discriminating grain from grit under binocular conditions. This shows that an increase in visual asymmetry enhances success in visually guided foraging. Possibly, asymmetries of the pigeon's visual system increase the computational speed of object recognition processes by concentrating them into one hemisphere while preventing the other side of the brain from initiating conflicting search sequences of its own.

Development of object permanence in food-storing magpies (Pica pica).

The development of object permanence was investigated in black-billed magpies (Pica pica), a food-storing passerine bird. The authors tested the hypothesis that food-storing development should be correlated with object-permanence development and that specific stages of object permanence should be achieved before magpies become independent. As predicted, Piagetian Stages 4 and 5 were reached before independence was achieved, and the ability to represent a fully hidden object (Piagetian Stage 4) emerged by the age when magpies begin to retrieve food. Contrary to psittacine birds and humans, but as in dogs and cats, no "A-not-B error" occurred. Although magpies also mastered 5 of 6 invisible displacement tasks, evidence of Piagetian Stage 6 competence was ambiguous.

Lateralized interhemispheric transfer of color cues: evidence for dynamic coding principles of visual lateralization in pigeons.

Visual feature discrimination tasks in pigeons reveal a right eye/left hemisphere dominance at the population level. Anatomical studies and lesion data show this visual lateralization to be related to asymmetries of the tectofugal system, which ascends from the tectum over the n. rotundus to the forebrain. Anatomically, this system is characterized by numerous morphological and connectional asymmetries which result in a bilateral visual representation in the dominant left hemisphere and a mostly contralateral representation in the subdominant right hemisphere. Ontogenetically, visual lateralization starts with an asymmetrical embryonic position within the egg, which leads to asymmetries of light stimulation. Differences in exposure to light stimulation between the eyes result in activity differences between the ascending tectofugal pathways of the left and the right hemisphere, which are transcribed during a critical time span into morphological asymmetries. The asymmetries established after this transient period finally start to determine the lateralized processes of the visual system for the entire life span of the individual. We now can show that these anatomical lateralizations are accompanied by asymmetries of interocular transfer, which enable a faster shift of learned color cues from the dominant right to the left eye than vice versa. In summary, our data provide evidence that cerebral asymmetries are based both on "static" anatomical and on "dynamic" process-dependent principles.