The effect of dopamine agonists on adaptive and aberrant salience in Parkinson's disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinson's disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus-reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus-reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus-reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward

indCAPS: A tool for designing screening primers for CRISPR/Cas9 mutagenesis events

Genetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence-identified mutations that alter a restriction enzyme recognition site can be readily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) in Arabidopsis thaliana. The tool suggested primers that successfully distinguished between wild-type and edited alleles of a target locus and facilitated the isolation of two novel ahk3 null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles at http://indcaps.kieber.cloudapps.unc.edu/

Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Patients with rheumatoid arthritis (RA) are known to be at increased risk of infection, particularly if they are taking drugs with immunomodulatory effects. There is a need for more information on the risk of influenza in patients with RA.</p> <p>Methods</p> <p>A retrospective cohort study was carried out using data gathered from a large US commercial health insurance database (Thomson Reuters Medstat MarketScan) from 1 January 2000 to 31 December 2007. Patients were ≥18 years of age, with at least two RA claims diagnoses. The database was scanned for incidence of seasonal influenza and its complications on or up to 30 days after an influenza diagnosis in RA patients and matched controls. Other factors accounted for included medical conditions, use of disease-modifying anti-rheumatic drugs (DMARDs), use of biological agents, influenza vaccination and high- or low-dose corticosteroids. Incidence rate ratios (IRRs) were calculated for influenza and its complications in patients with RA.</p> <p>Results</p> <p>46,030 patients with RA and a matching number of controls had a median age of 57 years. The incidence of influenza was higher in RA patients than in controls (409.33 vs 306.12 cases per 100,000 patient-years), and there was a 2.75-fold increase in incidence of complications in RA. Presence or absence of DMARDs or biologics had no significant effect. The adjusted IRR of influenza was statistically significant in patients aged 60–69 years, and especially among men. A significantly increased rate of influenza complications was observed in women and in both genders combined (but not in men only) when all age groups were combined. In general, the risk of influenza complications was similar in RA patients not receiving DMARDs or biologics to that in all RA patients. Pneumonia rates were significantly higher in women with RA. Rates of stroke/myocardial infarction (MI) were higher in men, although statistical significance was borderline.</p> <p>Conclusions</p> <p>RA is associated with increased incidence of seasonal influenza and its complications. Gender- and age-specific subgroup data indicate that women generally have a greater rate of complications than men, but that men primarily have an increased rate of stroke and MI complications. Concomitant DMARD or biological use appears not to significantly affect the rate of influenza or its complications.</p

Reminiscence therapy and intergenerational interventions for enhancing the self-identity and social inclusion of older people and People Living with Dementia [PLDs]

This chapter provides a brief background on dementia and reminiscence therapy before discussing the effectiveness of reminiscence therapy in general for older people and, in particular, for older people living with dementia.One of the most common psychosocial treatments in general for older people and, in particular, for older people living with dementia [PLDs] is reminiscence therapy. Recalling and sharing memories from the past can assist in retaining a sense of self and historical identity, which in turn can reduce depressive symptoms and enhance social interactions and overall well-being.Intergenerational reminiscence interventions are then discussed, including Montessori-based activities bringing together PLDs and school and preschool children before discussing intergenerational learning to foster greater increased social inclusion and understanding between generations.Reminiscence work, using an intergenerational approach, suggests mutual benefits for both older and younger persons with elderly participants reporting less loneliness and better quality of life, while children’s attitudes towards the older people are changed in a positive way. Taking part was consistently related with higher levels of positive engagement and lower levels of negative forms of engagement than those seen in standard activities. Intergenerational programs or interventions have the potential to have a positive impact on both children and older adults by increasing positive perceptions of each other and thereby challenging negative intergenerational stereotypes and attitudes. These interventions have been promoted by the World Health Organization as a sociocultural activity that can be beneficial to health by supporting active ageing among older people and enhance their health and well-being and quality of life.The chapter ends with a reflection of the implication for practice of reminiscence and intergenerational programs for older people and older people living with dementia insofar as their potential for promoting greater intergenerational social inclusion is concerned.There is great potential for even greater involvement of education and schools including preschools in intergenerational interventions, providing that the design and implementation of reminiscence or intergenerational programs should ensure an appropriately structured environment, consider carefully pragmatic and logistical issues which need to be taken into account for optimal implementation, consider the cultural context of both younger and older participants, and consider promoting the transfer of outcomes into the community

Intact Reward Learning but Elevated Delay Discounting in Parkinson's Disease Patients With Impulsive-Compulsive Spectrum Behaviors

It has been postulated that impulsive-compulsive spectrum behaviors (ICBs) in Parkinson's disease (PD) reflect overvaluation of rewards, resulting from excessive dopaminergic transmission in the ventral striatum. However, as the ventral striatum is also strongly implicated in delay discounting, an alternative explanation would be that, similar to stimulant-dependent individuals, PD patients with ICBs impulsively discount future rewards. To test these hypotheses, we investigated whether 36 medicated PD patients with and without ICBs differed from controls on measures of stimulus-reinforcement learning and delay discounting. There was a clear double dissociation between reward learning and impulsivity in PD patients with and without ICBs. Although PD patients without ICBs were impaired at learning stimulus–reward associations for high-probability stimuli, PD patients with ICBs were able to learn such associations equally as well as controls. By contrast, PD patients with ICBs showed highly elevated delay discounting, whereas PD patients without ICBs did not differ from controls on this measure. These results contradict the hypothesis that ICBs in PD result from overvaluation of rewards. Instead, our data are more consistent with a model in which excessive dopaminergic transmission induces a strong preference for immediate over future rewards, driving maladaptive behavior in PD patients with ICBs