Dietary beauvericin and enniatin B exposure cause different adverse health effects in farmed Atlantic salmon.

The extensive use of plant ingredients in novel aquafeeds have introduced mycotoxins to the farming of seafood. The emerging enniatin B (ENNB) and beauvericin (BEA) mycotoxins have been found in the novel aquafeeds and farmed fish. Little is known about the potential toxicity of ENNs and BEA in farmed fish and their feed-to-organ transfer. Atlantic salmon (Salmo salar) pre-smolt (75.3 ± 8.10 g) were fed four graded levels of spiked chemical pure ENNB or BEA feeds for three months, in triplicate tanks. Organismal adverse health end-point assessment included intestinal function (protein digestibility), disturbed hematology (red blood cell formation), bone formation (spinal deformity), overall energy use (feed utilization), and lipid oxidative status (vitamin E). Both dietary BEA and ENNB had a low (<∼0.01%) transfer to organs (kidney > liver > brain > muscle), with a higher transfer for ENNB compared to BEA. BEA caused a growth reduction combined with a decreased protein digestion and feed conversion rate- ENNB caused a stunted growth, unrelated to feed utilization capacity. In addition, ENNB caused anemia while BEA gave an oxidative stress response. Lower bench-mark dose regression assessment showed that high background levels of ENNB in commercial salmon feed could pose a risk for animal health, but not in the case of BEA.

"The fact that I can be in front of others, I am used to being a bit behind": how assistive activity technology affects participation in everyday life.

PURPOSE: This article explores the experiences of mobility-impaired individuals participating in leisure-time physical activities through the use of assistive activity technology (AAT). Its purpose is to highlight how these experiences affect participation in everyday life. This article provides new knowledge about the participation of this population in leisure-time physical activities. METHODOLOGY: Qualitative, semi-structured interviews were analysed according to the stepwise-deductive-inductive approach. During the analysis, self-determination theory (SDT) emerged as a theoretical tool for understanding how social context affects motivation as an interacting concept in the participation of leisure-time physical activity (LTPA). FINDINGS: Individuals with mobility impairments who use AAT for leisure-time physical activities experience opportunities to participate in ordinary and valued activities that allow them to improve their social positions. Further, use of AAT provided the informants with opportunities to alter their daily routines, enjoy time on their own and enhance their personal awareness. Having opportunities to use AAT independently is experienced as a recognition of their individuality. Thus, this article highlights a new aspect of participation as performing a socially valued activity in solitude. CONCLUSIONS: How technology provides opportunities for social interaction influences the informants' experiences and motivation to use technology. LTPA through the use of AAT promotes mastery and personal dignity, thereby revealing a new aspect of participation as being involved in an independent activity. IMPLICATIONS FOR REHABILITATION The allocation system for assistive activity technology requires knowledge about personal motivation for assistive activity technology use and the connection between leisure-time physical activity and social participation. Additional education about and understanding of motivational factors for assistive technology use is needed.

Monitoring release of neurotrophic activity in the brains of awake rats.

Intracerebral microdialysis of awake rats was used to monitor the possible release of neurotrophic factors from brain cells in response to injury and excitation. Perfusates were tested with ganglia bioassays and enzyme immunoassay. Trophic activity was released after implantation of the microdialysis probe into the hippocampus but not into the striatum, as assessed by increased nerve fiber outgrowth from Remak's ganglion. Kainic acid treatment significantly increased the release of trophic activity from hippocampal sites. These findings suggest that the brain responds to mechanical injury as well as to certain excitatory stimuli by regional extracellular release of neurotrophic activity that is not identical to the actions of known neurotrophic factors.

Day activity centres - work for people with intellectual disabilities: a norwegian perspective.

BACKGROUND: Although there is a broad political consensus in Norway that the government should uphold the principles of "full employment" and "work for all", the majority of people with intellectual disabilities in Norway spend their days in segregated work arrangements or at day activity centres. OBJECTIVE: The aim of the current study was to explore what constitutes work and work roles for people with intellectual disabilities and severely limited verbal communication abilities who attend a day activity centre. METHOD: A qualitative ethnographic research design was adopted, and the data were gathered through observing the participants and through conducting conversational interviews with the staff members and the participants with intellectual disabilities. Data were analysed with a hermeneutic approach. RESULTS: The findings showed that even though participants with intellectual disabilities engaged in specific work roles at the day activity centre, these work roles did not constitute work as it is ordinarily conceptualised and valued in society. CONCLUSION: Despite the very real enjoyment that the participants derive from participating in organised occupation, the work that they do has little status or value, and the activity centre itself is not a satisfactory workplace for people with intellectual disabilities.

A non-invasive system for delivering neural growth factors across the blood-brain barrier: a review.

Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment, as well as protect these neurons against a variety of perturbations. Since neurotrophins do not pass the blood-brain barrier (BBB) in significant amounts, a non-invasive delivery system for this group of therapeutic molecules needs to be developed. We have utilized a carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. The biological activity of this carrier system was tested using in vitro bioassays and intraocular transplants; we were able to demonstrate that cholinergic markers in both developing and aged intraocular septal grafts were enhanced by intravenous delivery of the OX-26-NGF conjugate. In subsequent experiments, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate for 6 weeks, resulting in a significant improvement in spatial learning in previously impaired rats, but disrupting the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size as well as an upregulation of both low and high affinity NGF receptors in the medial septal region of rats initially impaired in spatial learning. Finally, OX-26-NGF was able to protect striatal cholinergic neurons against excitotoxicity and basal forebrain cholinergic neurons from degeneration associated with chemically-induced loss of target neurons. These results indicate the potential utility of the transferrin receptor antibody delivery system for treatment of neurodegenerative disorders with neurotrophic substances.

Which is the most suitable number of photon beam portals in coplanar radiation therapy?

PURPOSE: Computer-controlled milling machines for compensator manufacture, dynamic multileaf collimators, and narrow scanned electron or bremsstrahlung photon beams have opened up new possibilities to shape nonuniform fluence profiles and have thus, paved the road for truly three dimensional (3D) dose delivery. The present paper investigates the number of beam portals required to optimize coplanar radiation therapy using uniform and nonuniform dose delivery. METHODS AND MATERIALS: A recently developed algorithm has been used for optimization of the dose delivery in such a way that the probability of achieving tumor control without causing severe reactions in healthy normal tissues becomes as high as possible. This method has been used to optimize the delivered dose distribution for an increasing number of beam portals to determine how many coplanar beam portals are desirable to safely achieve a good treatment outcome. Target volumes in the head and neck, thorax, and abdomen have been investigated. RESULTS: Nonuniform dose delivery allows a considerable improvement in the treatment outcome compared to uniform dose delivery. This is evident both from the probability of achieving complication-free tumor control and the value of relevant properties of the dose distribution, such as the mean value and the standard deviation of the mean dose to target volume and organs at risk. The results also show a close relationship between the dose distribution parameters and the probability of achieving complication-free tumor control. The level of complication-free tumor control first increases rapidly when the number of beam portals is increased, but already reaches a level of saturation after three to five beam portals. When the saturation level has been reached, the standard deviation of the mean dose to the target volume is around 3%. CONCLUSIONS: To achieve optimal expectation value of the treatment outcome, within an accuracy of a few percent as measured by the probability of achieving complication-free tumor control, it is generally sufficient to use three nonuniform beam portals. A very large number of coplanar beams may only raise the probability of achieving complication-free tumor control by 1 to 2%. However, good treatment outcome with three beam portals requires that the directions of incidence of the coplanar nonuniform beams are optimally selected. If, on the other hand, the treatment is performed using uniform beams, it is not possible, even with an infinite number of fields, to obtain as high a level of complication-free tumor control as with a few nonuniform beams. From an optimization point of view, it is sufficient to reach a relative standard deviation of the mean dose to the target volume of around 3%. Improved dose homogeneity beyond this level will, in general, not significantly improve the complication-free tumor control.

Embryonic expression of the mRNA for the rat homologue of the fusin/CXCR-4 HIV-1 co-receptor.

We have previously cloned a human receptor recently shown to be a cofactor for entry of T-tropic HIV-1 strains into CD4+ cells, now named fusin. Stromal derived factor-1 (SDF-1) is an endogenous ligand for fusin, also called CXCR-4. Here we show the distribution of fusin/CXCR-4 mRNA during ontogeny in the rat. The onset of mRNA expression is around embryonic day 9 and the mRNA expression is high in the thymus as well as proliferative areas of the brain during development. Our results suggest: (1) that fusin/CXCR-4 might have a dual role in both brain development and the immune system; (2) that SDF-1 has a role in brain development or that additional physiological ligands exist for this receptor; (3) co-expression of CD4 and fusin/CXCR-4 may make fetuses susceptible to HIV infection during development.

Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year.

This study examined the effects of long-term differential rearing on levels of brain nerve growth factor, its receptors, and their relationships to cognitive function. Adult rats (two months old) were placed into either enriched or standard housing conditions where they remained for 12 months. Animals from the enriched condition group had significantly higher levels of nerve growth factor in hippocampus, visual and entorhinal cortices compared with animals housed in isolated condition. Immunohistochemical analysis of brain tissue from the medial septal area revealed higher staining intensity and fibre density with both the low-affinity and the high-affinity nerve growth factor receptors. Enriched rats performed better than isolated rats in acquisition of spatial learning and had lower locomotion scores in the open field. These results provide further evidence that experimental stimulation results in increased production of trophic factors and structural reorganization in specific brain regions known to be involved in cognitive function.

The clinical value of different treatment objectives and degrees of freedom in radiation therapy optimization.

With inverse radiation therapy planning methods, both biological and physical objective functions can be used to perform the optimization. A biological objective function, namely the probability of achieving tumor control without causing severe complications in normal tissues, P+, has been used to evaluate six different optimization methods. All six methods have been tested on two different clinically relevant treatment geometries. The results show that optimization with a physical objective function which gives the best possible agreement with the desired dose distribution in the least squares sense, may result in severe loss of complication-free tumor control due to insufficient consideration of the organs at risk. It is generally better to use a physical objective function which minimizes the over-dosage when the desired dose distribution can not be exactly reproduced. In all cases the use of physical objective functions results in a lower probability of controlling the tumor without causing severe normal tissue reactions than if the biological objective function, P+, is used. However, the results also show the importance of accurately accounting for beam divergence, dose build-up, beam attenuation, and lateral scatter during the optimization procedure, particularly when the biological objective function is used. The loss in P+ by assuming that all energy deposition kernels are identical and that all the constituent beams have fixed relative weights can be 15% or more. When lateral scatter is not accounted for during the optimization, serious injury to organs at risk may result. This problem is specially severe for organs that are partly or totally encapsulated by the target volume. For superficial target volumes accurate consideration of the dose build-up of the incident pencil beams is fundamental.

Prediction of excess risk of long-term cardiac mortality after radiotherapy of stage I breast cancer.

BACKGROUND AND PURPOSE: Excess cardiac mortality has been reported in long-term follow up of breast cancer patients. Due to these findings it has been emphasized that radiotherapy techniques should be designed to minimize cardiac dose. The present study aims to provide risk figures of long-term excess cardiac mortality following radiotherapy for stage I breast cancer patients, using the relative seriality model. The impact of different modifications of the conventional irradiation technique on the calculated risk value is also analyzed. MATERIAL AND METHODS: One hundred consecutive left-sided stage I breast cancer patients were selected. All patients were treated with post-operative radiotherapy, using tangential 6 MV photon beams. The dose planning of each patient was done by means of a three-dimensional dose planning system. The prescribed mean tumor dose was 50 Gy, 2 Gy/fraction, 5 days a week. For each dose plan the differential heart and myocardium dose-volume histogram (DVH) were calculated. The excess risk of late cardiac mortality was predicted for each patient with the relative seriality model, using a parameter set previously determined. Different methods to decrease the risk of excess cardiac mortality (conventional collimation vs. multileaf collimation (MLC), partial blocking of the target in order to spare the heart and finally a general fluence modulation method) were analyzed. RESULTS AND CONCLUSIONS: The mean value of the calculated excess risk was 1.8%, having the heart as organ at risk, and 2.1% having the myocardium as organ at risk. However, a subgroup of patients where the risk increased up to about 9% (heart) and 12% (myocardium) was found. The risk could be substantially decreased either using an extended blocking of the target or applying the general fluence modulation method.

Expression of activin receptors type I and II only partially overlaps in the nervous system.

In situ hybridization was used to localize mRNA encoding two cooperative serine/threonine kinase receptors. Activin receptor IIA mRNA in the adult rat brain is highly expressed in the dentate gyrus, in the pyramidal neurones of CA3 and CA1, in the entorhinal cortex, in the cortical amygdaloid nucleus and in the amygdalohippocampal area. In the E16 rat embryo, labelling was found in the dorsal root ganglion neurones and in the spinal cord. Activin type I receptor (ALK-2/R-1) labelling was also localized to the hippocampal formation but with an even distribution over the granular cells of the dentate gyrus, the CA3 and CA1 pyramidal neurones, while no labelling was found in the entorhinal or amygdaloid areas. In the E16 rat no neuronal labelling was found. The incomplete overlap of these two expression patterns suggests that these receptors may locally have other partners for forming signalling receptor complexes.

Expression of serine/threonine kinase receptors in traumatic brain injury.

The aim of this study was to investigate the expression of serine/threonine kinase receptors in the brain following traumatic brain injury. We report here that, the recently cloned and characterized bone morphogenetic protein (BMP) receptor type II (BMPR-II) and the activin receptor type IA (ActR-1) Act: mRNAs were simultaneously up-regulated in neurones in the dentate gyrus 6 h after a mild cerebral contusion injury. This findings was specific for these receptors since other investigated genes (i.e. ActR-II, ActR-IB, trkB and c-fos) showed other temporal patterns. These data suggest that type I and type II receptors act together in signal transduction in vivo and that BMPs may be involved in neuronal plasticity after traumatic brain injury.

Effects of neonatal stimulation on later cognitive function and hippocampal nerve growth factor.

This study examined the behavioural and physiological effects of chronic mild stress on neonatally handled and non-handled rats. Neonatally handled and non-handled rats were exposed to chronic mild stress from weaning time to 6 months of age. They were behaviourally tested at 6 months of age, and sacrificed for analysis of nerve growth factor (NGF) in the hippocampus and hypothalamus. In contrast to the reported deleterious effect of acute strong stress, mild stress appeared to stimulate production of NGF in the hippocampus and improve spatial learning in both handled and nonhandled rats. Because neonatal handling produces neuroanatomical changes in the rat hippocampus and enhances cognitive function throughout the rats life span, these results implicate hippocampal NGF in the neuroprotective effects of handling.

Effects of environmental enrichment on cognitive function and hippocampal NGF in the non-handled rats.

In this study we examine whether exposure to differential housing after weaning would counteract the effects of postnatal handling (H) or nonhandling (NH) treatment by affecting learning and memory processes in young rats. In addition, we seek to determine if experience in enriched environment would alter hippocampal nerve growth factor (NGF) levels which is one of the factors known to be involved in the regulation of the survival and differentiation of developing basal forebrain neurones. Rats were either exposed to handling treatment, or left undisturbed starting day 1 after birth through day 21. After weaning on day 22, we exposed half of the H rats and half of the NH rats to environmental enrichment for 60 days. The other respective half of the rats was housed in isolated environmental condition (IC). Behavioural measures were taken in open field test, and spatial water maze test. Exposure to enriched environment following postnatal handling and nonhandling increased hippocampal NGF levels, and improved cognitive function in the both groups, with NH rats being more responsive to the effects of enrichment. Our results suggest that environmental enrichment has the potential to prevent or reduce the cognitive and neurochemical deficits in the adult animals associated with nonhandling.

Hippocampal nerve growth factor levels are related to spatial learning ability in aged rats.

Brain nerve growth factor (NGF) was determined in two groups of aged rats: 'good' and 'poor' performers. The animals were selected out of a population of 40 aged rats (26-28 months old) trained in a spatial learning task. Animals performing well in the test had significantly higher NGF in the hippocampus when compared to 'poor' performers. No differences in the levels of NGF were found in the cortex, septum and cerebellum. The results implicate hippocampal NGF in cognitive functioning of aged rats, and suggests that the forebrain cholinergic neuronal atrophy which has been observed in cognitively impaired aged rats may be due to reduced availability of target-derived NGF.

Environmental influences on the central nervous system and their implications for the aging rat.

Two methods of providing environmental stimulation that were introduced in the 1950s have guided much research on neurobehavioural plasticity. These are neonatal handling and environmental enrichment. Neonatal handling has been shown to permanently affect behaviour and endocrine responses. Recently this manipulation has been shown to have important influences on the aging individual, protecting the hippocampus from age-related dysfunction and neuronal loss. These effects are mediated, in part, by keeping glucocorticoid levels low. This has been characterised by, among other things, elevated expression of glucocorticoid receptors in the hippocampus. Earlier studies have failed to present convincing evidence for differences in hormonal variables between animals housed in enriched and impoverished environments, and have not consistently reported changes in the hippocampus. Recent data from our laboratories have shown that adult animals housed in enriched environments had, like neonatally-handled rats, higher expression of the gene encoding glucocorticoid receptors in the hippocampus. Taken together with the induction of NGF and NGFIA gene expression in the hippocampus of enriched animals, these results implicate genes encoding transcription factors and glucocorticoid receptors in the cascade of events leading to environmentally induced cerebral changes. In addition, these results suggest that environmental enrichment in adulthood, like neonatal handling, may have the potential to protect the aging hippocampus from glucocorticoid neurotoxicity.

Unilateral stimulation or removal of rat vibrissae: analysis of nerve growth factor and tyrosine hydroxylase mRNA in the brain.

Previous work has shown that unilateral manipulation of vibrissae in the rat can lead to behavioral asymmetries and to neuronal changes in the basal ganglia: in brief, vibrissae stimulation led to increases in neostriatal dopamine release, whereas unilateral removal of vibrissae led to asymmetries in striatal afferents and to bilateral changes in mesencephalic dopamine mechanisms which were related to the occurrence of behavioral asymmetries and the later recovery therefrom. In the present study, the analysis of neuronal mechanisms possibly affected by vibrissae manipulation was extended to the nerve growth factor and the expression of tyrosine hydroxylase mRNA. Unilateral stimulation or removal of the vibrissae did not lead to significant changes in tissue levels of nerve growth factor in the neostriatum, parietal cortex (including the barrel cortex) or the hippocampus. In contrast, tyrosine hydroxylase mRNA in the substantia nigra and ventral tegmental area was affected by vibrissae removal but not by stimulation, as a bilateral increase in labeling was observed on the level of individual neurons. This effect was only observed in animals tested 4 h after vibrissae removal but not after 10 days. The results are discussed with respect to the interaction of vibrissae function with the basal ganglia, the neurotransmitter dopamine and mechanism of functional recovery.

Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures.

Nerve growth factor (NGF) protein levels were determined in various forebrain regions using a two-site immunoassay following kindling-induced seizures. In the dentate gyrus the NGF content was significantly elevated 7 days after the last seizure (to 152% of control). In the piriform and parietal cortices, maximal increases were seen at 12 h (to 261% of control) and at 24 h (to 169% of control), respectively, and the NGF content was then normalized at 7 days. The increased production of NGF might be a protective response or could be involved in plastic changes underlying kindling epileptogenesis.

Cloning of a new chicken trkC extracellular isoform and its mRNA expression in E9 sensory and autonomic ganglia.

Neuronal development and maintenance are regulated by trophic interactions with the target tissues and the innervating nerve. The neurotrophin family of polypeptide growth factors, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), are produced in limited amounts in target areas. They bind to tyrosine receptor kinases of the trk family, including trkA, trkB and trkC, which mediate intracellular signalling in the responding neurons. There are reports of different isoforms of trkA, trkB and trkC having different signalling capacities. This study reports a novel deletion of the first cysteine-rich domain in the extracellular part of chicken trkC. We describe the mRNA expression of this isoform compared to non-deleted forms in E9 peripheral ganglia studied by reversetranscriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. We also compare the mRNA expression pattern of two existing signal peptide sequences and the distribution of trkC mRNA detected by the use of a kinase specific probe. The results show that the novel isoform is expressed in peripheral sensory and autonomic ganglia. Moreover both signal peptide forms are detected in these ganglia by RT-PCR. In addition, in situ hybridization results showed a weak mRNA expression of the novel isoform in the E9 dorsal root ganglion (DRG) but not in Remak's ganglion. The two existing signal peptides are equally expressed in the DRG and Remak's ganglion, at labelling densities comparable to those for the full-length catalytic form of trkC.

The effect of mercury vapour on cholinergic neurons in the fetal brain: studies on the expression of nerve growth factor and its low- and high-affinity receptors.

The effects of mercury vapour on the production of nerve growth factor during development have been examined. Pregnant rats were exposed to two different concentrations of mercury vapour during either embryonic days E6-E11 (early) or E13-E18 (late) in pregnancy, increasing the postnatal concentration of mercury in the brain from 1 ng/g tissue to 4 ng/g tissue (low-dose group) or 11 ng/g (high-dose group). The effect of this exposure in offspring was determined by looking at the NGF concentration at postnatal days 21 and 60 and comparing these levels to age-matched controls from sham-treated mothers. Changes in the expression of mRNA encoding NGF, the low- and high-affinity receptors for NGF (p75 and p140 trk, respectively) and choline acetyltransferase (ChAT) were also determined. When rats were exposed to high levels of mercury vapour during early embryonic development there was a significant (62%) increase in hippocampal NGF levels at P21 accompanied by a 50% decrease of NGF in the basal forebrain. The expression of NGF mRNA was found to be unaltered in the dentate gyrus. The expression of p75 mRNA was significantly decreased to 39% of control levels in the diagonal band of Broca (DB) and to approximately 50% in the medial septal nucleus (MS) whereas no alterations in the level of trk mRNA expression were detectable in the basal forebrain. ChAT mRNA was slightly decreased in the DB and MS, significantly in the striatum. These findings suggest that low levels of prenatal mercury vapour exposure can alter the levels of the NGF and its receptors, indicating neuronal damage and disturbed trophic regulations during development.