The du2J mouse model of ataxia and absence epilepsy has deficient cannabinoid CB1 receptor-mediated signalling

Key point summary • Cerebellar ataxias are progressive debilitating diseases with no known treatment and are associated with defective motor function and, in particular, abnormalities to Purkinje cells. • Mutant mice with deficits in Ca2+ channel auxiliary α2δ-2 subunits are used as models of cerebellar ataxia. • Our data in the du2J mouse model shows an association between the ataxic phenotype exhibited by homozygous du2J/du2J mice and increased irregularity of Purkinje cell firing. • We show that both heterozygous +/du2J and homozygous du2J/du2J mice completely lack the strong presynaptic modulation of neuronal firing by cannabinoid CB1 receptors which is exhibited by litter-matched control mice. • These results show that the du2J ataxia model is associated with deficits in CB1 receptor signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity due to reduced α2δ-2 subunit expression. Knowledge of such deficits may help design therapeutic agents to combat ataxias. Abstract Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca2+ channel function. The ‘ducky’ du2J mouse model of ataxia and absence epilepsy represents a clean knock-out of the auxiliary Ca2+ channel subunit, α2δ-2, and has been associated with deficient Ca2+ channel function in the cerebellar cortex. Here, we investigate effects of du2J mutation on PC layer (PCL) and granule cell (GC) layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone-Purkinje cell(IN-PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du2J/du2J, but not +/du2J, mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du2J alleles to manifest fully. du2J mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN-PC synapses, but was associated with increased sIPSC amplitudes. du2J mutation ablated cannabinoid CB1 receptor (CB1R)-mediated modulation of spontaneous neuronal spike firing and CB1Rmediated presynaptic inhibition of synaptic transmission at IN-PC synapses in both +/du2J and du2J/du2J mutants; effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du2J ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity and the ataxic phenotype.

Zinc in plants

Zinc (Zn) is an essential component of thousands of proteins in plants, although it is toxic in excess. In this review, the dominant fluxes of Zn in the soil-root-shoot continuum are described, including Zn inputs to soils, the plant availability of soluble Zn(2+) at the root surface, and plant uptake and accumulation of Zn. Knowledge of these fluxes can inform agronomic and genetic strategies to address the widespread problem of Zn-limited crop growth. Substantial within-species genetic variation in Zn composition is being used to alleviate human dietary Zn deficiencies through biofortification. Intriguingly, a meta-analysis of data from an extensive literature survey indicates that a small proportion of the genetic variation in shoot Zn concentration can be attributed to evolutionary processes whose effects manifest above the family level. Remarkable insights into the evolutionary potential of plants to respond to elevated soil Zn have recently been made through detailed anatomical, physiological, chemical, genetic and molecular characterizations of the brassicaceous Zn hyperaccumulators Thlaspi caerulescens and Arabidopsis halleri.

Aspects of in vitro and in vivo research approaches directed towards identifying probiotics and prebiotics for human use

The microbiota of the human gastrointestinal tract plays a key role in nutrition and health. Through the process of fermentation, gut bacteria metabolize various substrates (principally dietary components) to end products such as short-chain fatty acids and gases. This anaerobic metabolism is thought to contribute positively toward host daily energy requirements. However, under certain circumstances, the fermentative process may produce undesirable metabolites. This may cause the onset of gut disorders that can be manifest through both acute and chronic conditions. Moreover, the gut flora may become contaminated by transient pathogens that serve further to upset the normal community structure. There has been a recent increase in the use of dietary components that help to maintain, or even improve, the gut microflora "balance." Probiotics are live microbial feed supplements added to appropriate food vehicles (usually fermented milks), whereas prebiotics are dietary carbohydrates that have a selective metabolism in the colon and serve to increase numbers of bacteria seen as desirable. Because of their purported health-promoting properties, lactic acid-producing bacteria, including bifidobacteria, are the usual target organisms. The market value and biological potential of both approaches are enormous. This article will summarize how efficacious types can be identified.

Effects of single- and multi-strain probiotics on biofilm formation and in vitro adhesion to bladder cells by urinary tract pathogens

Inhibition of biofilm seems to be a major mechanism of urinary tract pathogen exclusion, related to, and possibly dependent upon, the probiotic ability to reduce environmental pH. Exclusion via competition of binding sites is a possible in vivo mechanism for these probiotics. If an additive or synergistic effect exists between strains within a mixture, it does not manifest itself in a greater effect through these two inhibitory mechanisms.

Speech acts, responsibility and commitment in poetry

Philosophy has tended to regard poetry primarily in terms of truth and falsity, assuming that its business is to state or describe states of affairs. Speech act theory transforms philosophical debate by regarding poetry in terms of action, showing that its business is primarily to do things. The proposal can sharpen our understanding of types of poetry; examples of the ‘Chaucer-Type’ and its variants demonstrate this. Objections to the proposal can be divided into those that relate to the agent of actions associated with a poem, those that relate to the actions themselves, and those that relate to the things done. These objections can be answered. A significant consequence of the proposal is that it gives prominence to issues of responsibility and commitment. This prominence brings philosophical debate usefully into line with contemporary poetry, whose concern with such issues is manifest in characteristic forms of anxiety.

Reducing noise associated with the Monte Carlo Independent Column Approximation for weather forecasting models

The Monte Carlo Independent Column Approximation (McICA) is a flexible method for representing subgrid-scale cloud inhomogeneity in radiative transfer schemes. It does, however, introduce conditional random errors but these have been shown to have little effect on climate simulations, where spatial and temporal scales of interest are large enough for effects of noise to be averaged out. This article considers the effect of McICA noise on a numerical weather prediction (NWP) model, where the time and spatial scales of interest are much closer to those at which the errors manifest themselves; this, as we show, means that noise is more significant. We suggest methods for efficiently reducing the magnitude of McICA noise and test these methods in a global NWP version of the UK Met Office Unified Model (MetUM). The resultant errors are put into context by comparison with errors due to the widely used assumption of maximum-random-overlap of plane-parallel homogeneous cloud. For a simple implementation of the McICA scheme, forecasts of near-surface temperature are found to be worse than those obtained using the plane-parallel, maximum-random-overlap representation of clouds. However, by applying the methods suggested in this article, we can reduce noise enough to give forecasts of near-surface temperature that are an improvement on the plane-parallel maximum-random-overlap forecasts. We conclude that the McICA scheme can be used to improve the representation of clouds in NWP models, with the provision that the associated noise is sufficiently small.

Molecular targets of cannabidiol in neurological disorders

Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular phar- macology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeu- tics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent with modulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.

The impact of foreign direct investment and openness on Vietnamese economy

This thesis examines the impact of foreign direct investment (FDI) on Vietnamese economy based on Partial Adjustment Model and time series data from 1976 to 2004. FDI is shown to have not only short run but also long run effect on gross domestic product (GDP) of Vietnam. However, elasticity of GDP with respect to FDI is small and it will take many years to fully manifest itself. The impact of trade openness on GDP has also been examined and it is shown to be stronger than that of FDI. The paper offers a number of explanations and discusses briefly suggestions in order to increase the contribution of FDI to Vietnam’s economic development.

Pre-diabetes i fokus : Patienters förståelse och upplevelse av pre-diabetes i mötet med personer i samma situation

Syfte: Att beskriva personers upplever att få pre-diabetes som en del av livet. Metod: Kvalitativ design. Studien genomfördes med fokusgrupper bestående av personer med pre-diabetes. Tre olika grupper med totalt 12 personer ingick i studien. Resultat: Ur diskussionerna kunde tre olika kategorier urskiljas. Pre-diabetes som en del av livet, egen erfarenhet och kunskap om tillståndet samt behov av information och stöd för ökad kunskap om livsstilsförändringar. Pre-diabetes var för de flesta studiedeltagare ett okänt begrepp. Känslor som osäkerhet och rädsla för tillståndet, samt för eventuell utveckling till manifest diabetes var vanligt. Det ansågs värdefullt att få besked i tidigt skede om förhöjda blodsockervärden, eftersom individen då hade möjlighet att påverka sin livsstil och förebygga annan sjukdom. Alla deltagare önskade mer kunskap och stöd kring pre-diabetes och livsstilsåtgärder. Respondenterna beskrev besvikelse över vårdpersonalens bemötande i samband med beskedet om förhöjda blodsockervärden. Informationen ansågs vara för knapphändig vilket gav uppfattning om att tillståndet inte var något att bry sig om. Konklusion: Respondenterna ville i största möjligaste utsträckning förhindra utvecklingen av T2DM genom egenvårdsinsater i form livsstilsförändringar. För att lyckas med det uppgav studiedeltagarna behov av information om vad tillståndet pre-diabetes innebär. Personer som får pre-diabetes bör få saklig information, råd och stöd om tillståndet i samband med beskedet.

Folkmusikundervisningen på fiol och gitarr och dess historiska rötter

How folk musicians of today learn to play their instruments is an over-all question in this article. One violin lesson and one guitar lesson have been observed at Framnäs folk high school. Three research questions were formulated. What do the two lessons have in common? What are the differences? How could the folk music education of today be related to the Swedish fiddler movement in the 1920s and other folk music traditions? Theoretically, the interpretation of the results was based on the mimesis theory of Ricoeur. Two teachers and three students participated in the study. The results showed that the lessons were structured in a similar way and dominated by master apprenticeship teaching. The violin teacher showed a more respectful attitude towards the tradition compared to the guitar teacher. Great parts of the manifest ideology of the fiddler movement seems to have become concealed into a latent or frozen ideology in the formal folk music education of today. There seems to be no big differences between learning the music by way of visiting an older fiddler hundred years ago compared to the study of music today at a formal institution.

Letters, authority and secrecy : The case of Karagwe in Tanzania

This paper aims to show how letters, as a genre of literacy, are used in Karagwe in Tanzania, in relation to authority and secrecy. It is shown that literacy, in the form of letters, plays an important role in the negotiation of authority. Authorities as well as ordinary people use letters according to official norms to claim or manifest authority, while grassroots forms of literacy, dominated forms, are used to resist authorities. Through secret messages and letters people find opportunities to resist that are less dangerous than open rebellion, although the effects may be limited because of the secrecy. It is also shown how children are socialized into this pattern of secrecies through literacy as they are used as messengers. When delivering secret letters and messages, they may be said to exercise a passive voice through literacy.

Dissonant Voices : Philosophy, Children's Literature, and Perfectionist Education

Dissonant Voices has a twofold aspiration. First, it is a philosophical treatment of everyday pedagogical interactions between children and their elders, between teachers and pupils. More specifically it is an exploration of the possibilities to go on with dissonant voices that interrupt established practices – our attunement – in behaviour, practice and thinking. Voices that are incomprehensible or expressions that are unacceptable, morally or otherwise. The text works on a tension between two inclinations: an inclination to wave off, discourage, or change an expression that is unacceptable or unintelligible; and an inclination to be tolerant and accept the dissonant expression as doing something worthwhile, but different. The second aspiration is a philosophical engagement with children’s literature. Reading children’s literature becomes a form of philosophising, a way to explore the complexity of a range of philosophical issues. This turn to literature marks a dissatisfaction with what philosophy can accomplish through argumentation and what philosophy can do with a particular and limited set of concepts for a subject, such as ethics. It is a way to go beyond philosophising as the founding of theories that justify particular responses. The philosophy of dissonance and children’s literature becomes a way to destabilise justifications of our established practices and ways of interacting. The philosophical investigations of dissonance are meant to make manifest the possibilities and risks of engaging in interactions beyond established agreement or attunements. Thinking of the dissonant voice as an expression beyond established practices calls for improvisation. Such improvisations become a perfectionist education where both the child and the elder, the teacher and the student, search for as yet unattained forms of interaction and take responsibility for every word and action of the interaction. The investigation goes through a number of picture books and novels for children such as Harry Potter, Garmann’s Summer, and books by Shaun Tan, Astrid Lindgren and Dr. Seuss as well narratives by J.R.R. Tolkien, Henrik Ibsen, Jane Austen and Henry David Thoreau. These works of fiction are read in conversation with philosophical works of, and inspired by, Ludwig Wittgenstein and Stanley Cavell, their moral perfectionism and ordinary language philosophy.

Maternal health care professionals perspective on the provision and use of antenatal and delivery care : a qualitative descriptive study in rural Vietnam

Background. High quality maternal health care is an important tool to reduce maternal and neonatal mortality. Services offered should be evidence based and adapted to the local setting. This qualitative descriptive study explored the perspectives and experiences of midwives, assistant physicians and medical doctors on the content and quality of maternal health care in rural Vietnam. Method. The study was performed in a rural district in northern Vietnam. Four focus group discussions with health care professionals at primary health care level were conducted. The data was analysed using qualitative manifest and latent content analysis. Result. Two main themes emerged: "Contextual conditions for maternal health care" and "Balancing between possibilities and constraints". Contextual conditions influenced both pregnant women's use of maternal health care and health care professionals' performance. The study participants stated that women's uses of maternal health care were influenced by economical constraints and cultural norms that impeded their autonomy in relation to childbearing. Structural constraints within the health care system included inadequate financing of the primary health care, resulting in lack of human resources, professional re-training and adequate equipment. Conclusion. Contextual conditions strongly influenced the performance and interaction between pregnant women and health care professionals within antenatal care and delivery care in a rural district of Vietnam. Although Vietnam is performing comparatively well in terms of low maternal and child mortality figures, this study revealed midwives' and other health care professionals' perceived difficulties in their daily work. It seemed maternal health care was under-resourced in terms of staff, equipment and continuing education activities. The cultural setting in Vietnam constituting a strong patriarchal society and prevailing Confucian norms limits women's autonomy and reduce their possibility to make independent decisions about their own reproductive health. This issue should be further addressed by policy-makers. Strategies to reduce inequities in maternal health care for pregnant women are needed. The quality of client-provider interaction and management of pregnancy may be strengthened by education, human resources, re-training and provision of essential equipment.

Europeisk familjelycka : Om användandet av familjemetaforen i EU

The re-unification of a family of nations: usages of the family metaphor in the EU This article analyses usages of the family metaphor in the EU. It starts up with a scrutiny of feminist theories of the nation-as-family metaphor. Introducing the concept of domopolitics, the author infers that the family, on the one hand, connotes to feelings of security and homelyness and, on the other hand, fears of the well-known, of immanent threats to in-group cohesion. The significance of the family metaphor in the EU rhetoric connects to a renewed emphasis on distinct values, principles and norms that balance the otherwise technocratic image of the EU. He further applies the nation-as-family metaphor to contemporary EU rhetoric. In the analysis, he infers that all three dimensions of the metaphor (ethnic, civil and hierarchic) are manifest in the EU political language making its use an enterprise that strives at moving beyond, but not completely away from the nation-state paradigm.

Att bli, att vara och att ha varit - om ingångar i och utgångar ur Jehovas vittnen i Sverige

Summary To become, to be and to have been: about the  Jehovah’s Witnesses The Watchtower Bible and Tract Society, in the following text referred to as the Jehovah’s Witnesses or “the organisation”, is a worldwide Christian organisation with about 6.7 million members. The organisation has many times, without any success so far, proclaimed Armageddon when they expect Jehovah to return to Earth. They interpret the Bible in their own, often very literal way, and require their members to live according to these interpretations. Among the consequences of this, members are forbidden to vote, to do military service or to receive blood transfusions. Apart from attending the three weekly meetings, members are expected to be active in missionary work, known as “publishing”. If a member fails to do a certain number of hours’ publishing, he or she risks being deprived of active membership status Sweden in general is considered to be a society where the population is not very religious. The formerly state-governed Lutheran church has lost its influence and the vast majority of ordinary Swedes do not visit church on other occasions than weddings, funerals or christenings. Expressing one’s own religious values has become somewhat of a private matter where publicity is seldom appreciated, which is contrary to the practice of the Jehovah’s Witnesses. This is one of the reasons why the Jehovah’s Witnesses are commonly perceived by average Swedes as a “suspicious” religious organisation. The aim and methods of the study This dissertation seeks to describe and investigate the entering and leaving of a highly structured and hierarchical religious community, exemplified in this case by the Jehovah’s Witnesses. What are the thoughts and aspirations of someone who is considering becoming a Jehovah’s Witness? What are the priorities and what experiences seem important when a person is going through such a process? And when this person has finally reached his or her goal of becoming a member, is it the same motivation that makes him or her stay in the organisation for longer periods of time, possibly for the rest of their lives, or does it change during the process of entering, or does this motivation change its character during the transition from entering to being a regular member? Why do some of the members change their attitude to the Jehovah’s Witnesses from rejoicing to bitterness? And how does this process of exit manifest itself? In what way is it different from the process of entry? The respondents in this study were chosen from both active members of the Jehovah’s Witnesses in Sweden and those who have left the organisation for personal reasons. Repeated interviews with ten active members of the organisation have been conducted in the course of the study and compared to equal numbers of former members. The interviews have been semi-structured to deal with questions of how a person has come into contact with the organisation; how they retrospectively experienced the process of entry; the reasons for becoming a member. Questions have also been asked about life in the organisation. The group of “exiters” have also been asked about the experience of leaving, why they wanted to leave, and how this process was started and carried out. In addition to this I have analysed a four-year diary describing the time inside and the process of leaving the organisation. This has given me an extra psychological insight into the inner experience of someone who has gone through the whole process. The analysis has been done by categorising the content of the transcribed interviews. An attempt to outline a model of an entry and exit process has been made, based on ideas and interpretations presented in the interviews. The analysis of the diary has involved thorough reading, resulting in a division of it into four different parts, where each part has been given a certain key-word, signifying the author’s emotional state when writing it. A great deal of the information about the Jehovah’s Witnesses has been collected through discussion boards on the Internet, informal talks with members and ex-members, interviews with representatives of the organisations during visits to its different offices (Bethels), such as St. Petersburg, Russia, and Brooklyn, New York, USA. The context Each organisation evolves in its own context with its own norms, roles and stories that would not survive outside it. With this as a starting point, there is a chapter dedicated to the description of the organisation’s history, structure and activities. It has been stated that the organisation’s treatment of its critical members and the strategies for recruiting new members have evolved over the years of its history. At the beginning there was an openness allowing members to be critical. As the structure of the organisation has become more rigid and formalised, the treatment of internal critics has become much less tolerated and exclusion has become a frequent option. As a rule many new members have been attracted to the organisation when (1) the day of Armageddon has been pronounced to be approaching; (2) the members of the organisation have been persecuted or threatened with persecution; and (3) the organisation has discovered a “new market”. The processes for entering and exiting How the entering processes manifest themselves depends on whether the person has been brought up in the organisation or not. A person converting as an adult has to pass six phases before being considered a Jehovah’s Witness by the organisation. These are:  Contact with the Jehovah’s Witnesses, Studying the bible with members of the organisation, Questioning, Accepting, Being active as publisher (spreading the belief), Being baptised.  For a person brought up in the organisation, the process to full membership is much shorter:   Upbringing in the organisation, Taking a stand on the belief, Being baptised. The exit process contains of seven phases:   Different levels of doubts, Testing of doubts, Turning points, Different kinds of decisions, Different steps in executing the decisions, Floating, a period of emotional and cognitive consideration of membership and its experiences, Realtive neutrality.   The process in and the process out are both slow and are accompanied with anguish and doubts. When a person is going through the process in or out of the organisation he or she experiences criticism. This is when people around the adept question the decision to continue in the process. The result of the criticism depends on where in the process the person is. If he or she is at the beginning of the process, the criticism will probably make the person insecure and the process will slow down or stop. If the criticism is pronounced in a later phase, the process will probably speed up. The norms of the organisation affect the behaviour of the members. There are techniques for inclusion that both bind members to the organisation and shield them off from the surrounding society. Examples of techniques for inclusion are the “work situation” and “closed doors”. The work situation signifies that members who do as the organisation recommends – doing simple work – often end up in the same branch of industry as many other Jehovah’s Witnesses. This often means that the person has other witnesses as workmates. If the person is unemployed or moves to another town it is easy to find a new job through connections in the organisation. Doubts and exclusions can lead to problems since they entail a risk of losing one’s job. This can also result in problems getting a new job. Jehovah’s Witnesses are not supposed to talk to excluded members, which of course mean difficulties working together. “Closed doors” means that members who do as the organisation recommends – not pursuing higher education, not engaging in civil society, working with a manual or in other way simple job, putting much time into the organisation – will, after a long life in the organisation, have problems starting a new life outside the Jehovah’s Witnesses. The language used in the organisation shows the community among the members, thus the language is one of the most important symbols. A special way of thinking is created through the language. It binds members to the organisation and sometimes it can work as a way to get back into the normative world of the organisation. Randall Collins’s (1990, 2004) thoughts about “emotional energy” have enabled an understanding of the solidarity and unity in the organisation. This also gives an understanding of the way the members treat doubting and critical members. The members who want to exit have to open up the binding/screening off. A possible way to do that is through language, to become aware of the effect the language might have. Another way is to search for emotional energy in another situation. During the exit process, shame might be of some importance. When members become aware of the shame they feel, because they perceive they are “acting a belief”, the exit process might accelerate.