Apoptosis in human disease: a new skin for the old ceremony?

Naturally occurring cell death or apoptosis is essential for the maintenance of tissue homeostasis and serves to remove extraneous or dangerous cells in a swift and unobtrusive manner. Recent studies have indicated a role for apoptosis in a plethora of human diseases. Hence, dysregulation of apoptosis has been implicated in autoimmune disease, acquired immune deficiency syndrome, and other viral (and bacterial) infections, as well as in neurodegenerative disorders and cancer. Furthermore, dysregulated apoptosis signaling may impinge on other age-related disorders such as osteoporosis and atherosclerosis and perhaps on the process of aging itself. The present review provides an overview of human diseases, which are associated with defective or inadvertent apoptosis, with examples of pathological conditions in which putative apoptosis defects have been elucidated at the molecular level. Novel apoptosis-modulating therapeutic strategies are also discussed.     

Telocytes in human skin – are they involved in skin regeneration?

Telocytes (TCs), a particular interstitial cell type, have been recently described in a wide variety of mammalian organs ( www.telocytes.com ). The TCs are identified morphologically by a small cell body and extremely long (tens to hundreds of μm), thin prolongations (less than 100 nm in diameter, below the resolving power of light microscopy) called telopodes. Here, we demonstrated with electron microscopy and immunofluorescence that TCs were present in human dermis. In particular, TCs were found in the reticular dermis, around blood vessels, in the perifollicular sheath, outside the glassy membrane and surrounding sebaceous glands, arrector pili muscles and both the secretory and excretory portions of eccrine sweat glands. Immunofluorescence screening and laser scanning confocal microscopy showed two subpopulations of dermal TCs; one expressed c‐kit/CD117 and the other was positive for CD34. Both subpopulations were also positive for vimentin. The TCs were connected to each other by homocellular junctions, and they formed an interstitial 3D network. We also found TCs adjoined to stem cells in the bulge region of hair follicles. Moreover, TCs established atypical heterocellular junctions with stem cells (clusters of undifferentiated cells). Given the frequency of allergic skin pathologies, we would like to emphasize the finding that close, planar junctions were frequently observed between TCs and mast cells. In conclusion, based on TC distribution and intercellular connections, our results suggested that TCs might be involved in skin homeostasis, skin remodelling, skin regeneration and skin repair.     

Metacognition for Spelling in Higher Education Students with Dyslexia: Is There Evidence for the Dual Burden Hypothesis?

We examined whether academic and professional bachelor students with dyslexia are able to compensate for their spelling deficits with metacognitive experience. Previous research suggested that students with dyslexia may suffer from a dual burden. Not only do they perform worse on spelling but in addition they are not as fully aware of their difficulties as their peers without dyslexia. According to some authors, this is the result of a worse feeling of confidence, which can be considered as a form of metacognition (metacognitive experience). We tried to isolate this metacognitive experience by asking 100 students with dyslexia and 100 matched control students to rate their feeling of confidence in a word spelling task and a proofreading task. Next, we used Signal Detection Analysis to disentangle the effects of proficiency and criterion setting. We found that students with dyslexia showed lower proficiencies but not suboptimal response biases. They were as good at deciding when they could be confident or not as their peers without dyslexia. They just had more cases in which their spelling was wrong. We conclude that the feeling of confidence in our students with dyslexia is as good as in their peers without dyslexia. These findings go against the Dual Burden theory (Krüger & Dunning, 1999), which assumes that people with a skills problem suffer twice as a result of insufficiently developed metacognitive competence. As a result, there is no gain to be expected from extra training of this metacognitive experience in higher education students with dyslexia.     

Evidence for infanticide in bottlenose dolphins: an explanation for violent interactions with harbour porpoises?

Most harbour porpoises found dead on the north-east coast of Scotland show signs of attack by sympatric bottlenose dolphins, but the reason(s) for these violent interactions remain(s) unclear. Post-mortem examinations of stranded bottlenose dolphins indicate that five out of eight young calves from this same area were also killed by bottlenose dolphins. These data, together with direct observations of an aggressive interaction between an adult bottlenose dolphin and a dead bottlenose dolphin calf, provide strong evidence for infanticide in this population. The similarity in the size range of harbour porpoises and dolphin calves that showed signs of attack by bottlenose dolphins suggests that previously reported interspecific interactions could be related to this infanticidal behaviour. These findings appear to provide the first evidence of infanticide in cetaceans (whales, dolphins and porpoises). We suggest that infanticide must be considered as a factor shaping sociality in this and other species of cetaceans, and may have serious consequences for the viability of small populations.     

Chronotype distribution in professional rugby players: Evidence for the environment hypothesis?

Individual sport athletes have been shown to comprise unusually high proportions of morning-types (MTs) coupled with a higher prevalence of the morningness-associated PERIOD3 variable number tandem repeat (VNTR) allele, PER3⁵. The degree to which type of sport selected is influenced by either chronotype or genotype, or the extent to which sporting environment contributes to chronotype is unclear. The aim of this study was to assess chronotype and PER3 VNTR polymorphism frequencies in team sport players and non-athletic controls. South African male Super Rugby players (RUG, n = 120) and a control population of males with habitually low levels of physical activity (defined as exercise no more than twice a week; CON, n = 117) took part in this study. Participants completed the Horne–Östberg morningness–eveningness questionnaire to determine chronotype and donated buccal cell or blood samples from which PER3 VNTR genotype was established. There were more MTs in the RUG (47%) than CON group (23%, p < 0.001), more evening-types in the CON group (18%) compared to the RUG group (3%, p < 0.001), but no differences in PER3 VNTR genotype (p = 0.619) or allele (p = 0.758) frequencies. In both groups, more people carried the PER3⁴ allele (RUG: 63%, CON: 62%). Chronotype was associated with genotype in the CON (p = 0.004) but not the RUG group (p = 0.895). Unlike the individual sport endurance athletes previously studied in whom the PER3⁵ allele predominated, the PER3 VNTR genotype distribution in these team sport players was similar to that of the general population. We hypothesise that the absence of any chronotype–genotype relationship in these rugby players is because their diurnal preference is shifted towards morningness through habitual athletic behaviour.     

Evidence for hilltopping in bumblebees?

1. Male bumblebees are known to exhibit a range of mate‐location behaviours, including perching on prominent objects and darting at passing queens, patrolling of scent‐marked flight routes, and waiting outside nest entrances for virgin queens to emerge. Here we provide evidence for a fourth strategy, known as hilltopping. This behaviour is widely known from a range of invertebrates, but has not previously been described in bumblebees. 2. We studied the distribution of bumblebees along transects ascending four hills in Scotland and demonstrate that, relative to workers, males of four bumblebee species or species groups (Bombus lapidarius, B. monticola, B. pascuorum, and B. lucorum/magnus/cryptarum/terrestris) tend to congregate at or near the tops of hills. This is, to our knowledge, the first evidence for hilltopping in bumblebees and the first record of any putative mate‐locating behaviour for male B. pascuorum, a very common species in Europe. 3. We note that, in common with most previous studies of mate‐locating behaviour in bumblebees, attraction of virgin queens and mating were not observed.     

Shift in Black Rhinoceros Diet in the Presence of Elephant: Evidence for Competition?

In African large herbivore assemblages, megaherbivores dominate the biomass and utilise the greatest share of available resources. Consequently, they are considered a separate trophic guild that structures the food niches of coexisting large herbivores. However, there exists little empirical evidence on how food resources are shared within this guild, and none for direct competition for food between megaherbivores. Using the histological analysis of faeces, we explore this phenomenon for African elephant Loxodonta africana and black rhinoceros Diceros bicornis in the Addo Elephant National Park, South Africa, where the accumulated impacts of elephant have reduced browse availability. Despite being unable to generalise beyond our study sites, our observations support the predictions of competition theory (as opposed to optimality theory) by showing (1) a clear seasonal separation in resource use between these megaherbivores that increased as resource availability declined, and (2) rhinoceros changed their selectivity in the absence of elephant (using an adjacent site) by expanding and shifting their diet along the grass-browse continuum, and in relation to availability. Although black rhinoceros are generally considered strict browsers, the most significant shift in diet occurred as rhinoceros increased their preferences for grasses in the presence of elephant. We speculate that the lack of specialised grazing adaptations may increase foraging costs in rhinoceros, through reduced harvest- and handling-efficiencies of grasses. In the short-term, this may be off-set by an enhanced tolerance for low quality food and by seasonally mobilising fat reserves; however, the long-term fitness consequences require further study. Our data suggest that managing elephant at high densities may compromise the foraging opportunities of coexisting browsers. This may be particularly important in small, fenced areas and overlapping preferred habitats where impacts intensify.     

Charles Bonnet Syndrome: Evidence for a Generative Model in the Cortex?

Several theories propose that the cortex implements an internal model to explain, predict, and learn about sensory data, but the nature of this model is unclear. One condition that could be highly informative here is Charles Bonnet syndrome (CBS), where loss of vision leads to complex, vivid visual hallucinations of objects, people, and whole scenes. CBS could be taken as indication that there is a generative model in the brain, specifically one that can synthesise rich, consistent visual representations even in the absence of actual visual input. The processes that lead to CBS are poorly understood. Here, we argue that a model recently introduced in machine learning, the deep Boltzmann machine (DBM), could capture the relevant aspects of (hypothetical) generative processing in the cortex. The DBM carries both the semantics of a probabilistic generative model and of a neural network. The latter allows us to model a concrete neural mechanism that could underlie CBS, namely, homeostatic regulation of neuronal activity. We show that homeostatic plasticity could serve to make the learnt internal model robust against e.g. degradation of sensory input, but overcompensate in the case of CBS, leading to hallucinations. We demonstrate how a wide range of features of CBS can be explained in the model and suggest a potential role for the neuromodulator acetylcholine. This work constitutes the first concrete computational model of CBS and the first application of the DBM as a model in computational neuroscience. Our results lend further credence to the hypothesis of a generative model in the brain.     

Models for human porphyrias: Have animals in the wild been overlooked?

Humans accumulate porphyrins in the body mostly during the course of porphyrias, diseases caused by defects in the enzymes of the heme biosynthesis pathway and that produce acute attacks, skin lesions and liver cancer. In contrast, some wild mammals and birds are adapted to accumulate porphyrins without injurious consequences. Here we propose viewing such physiological adaptations as potential solutions to human porphyrias, and suggest certain wild animals as models. Given the enzymatic activity and/or the patterns of porphyrin excretion and accumulation, the fox squirrel, the great bustard and the Eurasian eagle owl may constitute overlooked models for different porphyrias. The Harderian gland of rodents, where large amounts of porphyrins are synthesized, presents an underexplored potential for understanding the carcinogenic/toxic effect of porphyrin accumulation. Investigating how these animals avoid porphyrin pathogenicity may complement the use of laboratory models for porphyrias and provide new insights into the treatment of these disorders.     

Empathy in chimpanzees: Evidence for theory of mind?

Empathy can be widely defined as the capacity to understand the emotional, visual, or cognitive perspective of another individual and is perhaps reliant on the ability to attribute mental states. Behavioural events that may indicate empathy in chimpanzees,Pan troglodytes, are collated (1) using a questionnaire and (2) from the literature. These case studies are classified in a taxonomy of empathic acts in which empathy is categorized as visual empathy, emotional empathy, concordance and extended empathy. In addition, the circumstances surrounding the empathic acts are discussed: whether the recipient of the empathic act was a relative, an unfamiliar individual, or a heterospecific. The cost to the animal showing empathy, whether it displayed any levels of intentionality and if it communicated to a third party are also analyzed. Rescuing of an individual from a dangerous social or physical situation is the only category where the animal shows empathy under all the specified conditions. From this preliminary analysis it seems the chimpanzees may be capable of showing empathy across a wide range of circumstances.     

Evidence for a direct role of α-MSH in morphological background adaptation of the skin in Sarotherodon mossambicus

Summary The skin colour of the cichlid teleost Sarotherodon mossambicus adapted rapidly to changes in background colour. The physiological adaptation was associated with morphological changes in the dermis. Differences in the dermis were found between fish adapted to a black or white background for 14 days. Number and size of the melanophores as well as the amount of pigment in the cytoplasm of the melanophores were significantly increased in fish adapted to a black background. Changes in the dermis parallelled changes in the state of activity of the two endocrine cell types in the pars intermedia of the pituitary. Both the PAS positive cells and the MSH producing cells were more active when the fish were exposed to a black rather than a white background. Fish continuously infused with -MSH, using an osmotic minipump, had more melanophore cytoplasm and pigment per dermis surface unit area than untreated fish. The activity of the MSH cells in MSH-infused fish exposed to a black background was reduced to a level comparable to the MSH cell activity of untreated fish on a white background. -MSH treated fish that were exposed to a white background had many disintegrating MSH cells. These findings point to inactivation of these cells by exogenous -MSH. The activity of the PAS positive cells was not influenced by treatment with -MSH.     

Fluctuation in excitability of nerve fibres — a model study

Summary In this paper a mathematical model for the fluctuation in excitability of nerve fibres is presented. The model is based on the concept of a threshold subject to noise-like variations. Emphasis is laid on the rate of fluctuation of these disturbances.     

Evidence for matrotrophy in the viviparous sea cucumber Leptosynapta clarki: A role for the genital haemal sinus?

Summary

Viviparity, where the embryos develop in the female reproductive system, is a rare form of reproduction in marine invertebrates, being described in only 14 species of echinoderm. In the intraovarian brooding sea cucumber, Leptosynapta clarki Heding 1928 (cf., Sewell et al. 1995), we used direct evidence (changes in energetic content) to show that significant additional nutrients are provided to the embryos during viviparous development (matrotrophy). In the transition from a structure used to produce gametes to a long-term brooding structure there are visual, histological and transmission electron microscopy (TEM) changes in the structure of the ovarian wall. Changes occur primarily in the cells of the visceral peritoneum and involve an increase in size of the connective tissue/genital haemal sinus (CT/GHS). In the latter part of the brooding period the visceral peritoneum returns to a flattened form, and new oocytes develop along the tubule wall. Similar changes in the intraovarian brooding sea cucumber Oneirophanta mutabilis affinis lead us to suggest that there is a role for the genital haemal sinus in providing nutrition during the brooding period in viviparous echinoderms. Future research is suggested to focus on changes in the ovarian wall structure during the different phases of reproduction (gamete production/brooding) in these species.     

UV-induced changes in the skin: can they be repaired?

Abstract

The damaging effects of UVB light have been described previously and include a number of changes to multiple cell types. At previous meetings of this society, we have shown that Langerhans' cells are the most susceptible to UVB induced damage which can be shown as ultrastructural changes in dendrites, nucleus and cytoplasm by transmission electron microscopy. We have also shown that their patterns of migration from skin to regional lymph node and their ability to present antigens to autologous T cells have been profoundly altered by UVB irradiation.

The aim of this work was to establish if it was possible to reverse any of the damage done to Langerhans' cells by UVB exposure by topical application of a DNA repair enzyme such as T4N5 endonuclease. These experiments were undertaken in a sheep model that allowed collection of cells as they migrate from the skin. This allowed for a direct examination of the migration characteristics and ultrastructural features of all Langerhans' cells before, during, and for 2 weeks after exposure to a single dose of UVB.

Results obtained from this project indicate that treatment by topical application of DNA repair enzyme immediately after UVB irradiation may restore a number of normal immune parameters associated with the structure and function of migrating Langerhans' cells. It appears that there is a dose related correction of the increased tempo of cell migration and some improvements in the number of ultrastructurally damaged Langerhans' cells have also been associated with application of higher doses of DNA repair enzyme. These preliminary findings indicate that some potential therapeutic benefits are associated with the use of such agents in reversing the immunological damage caused by exposure to erythemal doses of UVB light.     

UV-induced changes in the skin: can they be repaired?

The damaging effects of UVB light have been described previously and include a number of changes to multiple cell types. At previous meetings of this society, we have shown that Langerhans' cells are the most susceptible to UVB induced damage which can be shown as ultrastructural changes in dendrites, nucleus and cytoplasm by transmission electron microscopy. We have also shown that their patterns of migration from skin to regional lymph node and their ability to present antigens to autologous T cells have been profoundly altered by UVB irradiation. The aim of this work was to establish if it was possible to reverse any of the damage done to Langerhans' cells by UVB exposure by topical application of a DNA repair enzyme such as T4N5 endonuclease. These experiments were undertaken in a sheep model that allowed collection of cells as they migrate from the skin. This allowed for a direct examination of the migration characteristics and ultrastructural features of all Langerhans' cells before, during, and for 2 weeks after exposure to a single dose of UVB. Results obtained from this project indicate that treatment by topical application of DNA repair enzyme immediately after UVB irradiation may restore a number of normal immune parameters associated with the structure and function of migrating Langerhans' cells. It appears that there is a dose related correction of the increased tempo of cell migration and some improvements in the number of ultrastructurally damaged Langerhans' cells have also been associated with application of higher doses of DNA repair enzyme. These preliminary findings indicate that some potential therapeutic benefits are associated with the use of such agents in reversing the immunological damage caused by exposure to erythemal doses of UVB light.     

Mucosal layers and related nerve fibres in non-chagasic and chagasic human colon—a quantitative immunohistochemical study

Chagasic megacolon is accompanied by extensive myenteric and, simultaneously, moderate submucosal neuron loss. Here, we examined changes of the innervation pattern of the lamina propria (LP) and muscularis mucosae (MM). Two alternating sets of cryosections were taken from seven non-chagasic colonic and seven chagasic megacolonic specimens (the latter included both the dilated megacolonic and the non-dilated transitional oral and anal zones) and were immunohistochemically triple-stained for smooth-muscle actin (SMA), synaptophysin (SYN) and glial acid protein S100 and, alternatively, for SMA, vasoactive intestinal peptide (VIP) and somatostatin (SOM). Subsequent image analysis and statistical evaluation of nervous tissue profile areas revealed that, in LP, the most extreme differences (i.e. increase in thickness or decrease in nerve, glia and muscle tissue profile area, respectively) compared with control values occurred in the dilated megacolonic zone itself. In contrast, the most extreme differences in the MM were in the anal-to-megacolonic zone (except the profile area of muscle tissue, which was lowest in the megacolonic zone). This parallels our previous results in the external muscle coat. A partial and selective survival of VIP-immunoreactive in contrast to SOM-immunoreactive nerve fibres was observed in both mucosal layers investigated. Thus, VIPergic nerve elements might be crucial for the maintenance of the mucosal barrier. The differential changes of neural tissue parameters in LP and MM might reflect a multifactorial rather than a pure neurogenic development of megacolon in chronic Chagas’ disease.     

Oxidative Stress in Phenylketonuria: What is the Evidence?

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.