A pilot study on the impact of a pottery workshop on the well-being of people with dementia.

OBJECTIVE: This study seeks to assess the impact of a pottery workshop as a creative arts programme and discover the extent to which people with dementia taking part in an artistic and creative activity engage with it, experience a feeling of well-being, and improve their mood state. In addition, the study will seek to answer the question of whether taking part in a programme of creative activities improves the self-esteem of people with dementia. METHOD: The research used an uncontrolled, repeated measures design. Thirty users of the National Reference Centre for Alzheimer's and Dementia care in Salamanca (Spain) in a moderate to advanced stage of dementia (Global Deterioration Scale 4, 5, or 6) were divided into five intervention groups that received ten 45-minute sessions in which they were helped by facilitators to make different ceramic pieces. The participants were assessed before and after the intervention with a self-esteem scale, and they rated their mood before and after the sessions on a graphic scale. During the art sessions, two observers recorded the presence of multiple indicators of well-being. RESULTS: The intervention was found to have a significant impact on mood and self-esteem that was independent of the participants' Global Deterioration Scale. Regarding the tool used to observe well-being, the participants scored highly in the domains of sustained attention, pleasure, self-esteem, and normalcy, with low scores in negative affect and sadness. CONCLUSIONS: Pottery may be a highly suitable activity for people with dementia, as they may enjoy both the activity and the creative process, with it triggering a positive mood during the sessions, providing psychological well-being and reinforcing their self-esteem.

Effects of Dog-Assisted Therapy on Social Behaviors and Emotional Expressions: A Single-Case Experimental Design in 3 People With Dementia.

This study examined the effects of dog-assisted therapy (DAT) on social behaviors, emotional manifestations, and experience during the activity of 3 people with dementia residing in a specialized dementia unit. The study used an A-B-A-B withdrawal single-case experimental design with two 5-session phases, baseline and DAT, replicating the same activities in each phase. The sessions were recorded and 2 independent coders quantified the frequency of social behaviors along with an assessment of the emotional manifestations and experience during the activity. Comparing with baseline sessions, DAT sessions showed an increase in prosocial behaviors (leans, looks, and verbalizations) and a significant impact on emotional manifestations with heightened pleasure. Dog-assisted therapy sessions also led to a better experience, with higher participation, pleasure, and relationship with others, together with lower rejection and displeasure than in the baseline sessions. Dog-assisted therapy seems to be a nonpharmacological therapy with potential to improve quality of life of people with dementia through promoting social behaviors and positive emotional manifestations.

Activation of Kappa Opioid Receptor Regulates the Hypothermic Response to Calorie Restriction and Limits Body Weight Loss.

Mammals maintain a nearly constant core body temperature (Tb) by balancing heat production and heat dissipation. This comes at a high metabolic cost that is sustainable if adequate calorie intake is maintained. When nutrients are scarce or experimentally reduced such as during calorie restriction (CR), endotherms can reduce energy expenditure by lowering Tb [1-6]. This adaptive response conserves energy, limiting the loss of body weight due to low calorie intake [7-10]. Here we show that this response is regulated by the kappa opioid receptor (KOR). CR is associated with increased hypothalamic levels of the endogenous opioid Leu-enkephalin, which is derived from the KOR agonist precursor dynorphin [11]. Pharmacological inhibition of KOR, but not of the delta or the mu opioid receptor subtypes, fully blocked CR-induced hypothermia and increased weight loss during CR independent of calorie intake. Similar results were seen with DIO mice subjected to CR. In contrast, inhibiting KOR did not change Tb in animals fed ad libitum (AL). Chemogenetic inhibition of KOR neurons in the hypothalamic preoptic area reduced the CR-induced hypothermia, whereas chemogenetic activation of prodynorphin-expressing neurons in the arcuate or the parabrachial nucleus lowered Tb. These data indicate that KOR signaling is a pivotal regulator of energy homeostasis and can affect body weight during dieting by modulating Tb and energy expenditure.

Discovery of Modulators of Adipocyte Physiology Using Fully Functionalized Fragments.

Defects in adipocyte function associated with obesity drive the development of systemic insulin resistance and type 2 diabetes. Agents that correct obesity-linked adipocyte dysfunction serve as useful insulin sensitizers in humans, as is exemplified by the thiazolidinediones (TZDs). We have developed a new platform that integrates advanced chemoproteomics with phenotypic screening to identify small molecules that promote differentiation and lipid storage in adipocytes, and, in tandem, their molecular target(s). These molecules mimic the activity of TZDs in culture and thus may also serve as insulin sensitizers in vivo. Central to this platform is the use of fully functionalized fragment (FFF) probes that consist of a variable, fragment-like recognition element linked to an alkyne-diazirine group that enables the photoactivated capture of probe-bound proteins directly in living cells and subsequent copper-catalyzed azide-alkyne cycloaddition to reporter tags for enrichment and identification of these probe-bound proteins by mass spectrometry. This platform, which can be adapted to diverse screens and cell types beyond adipocytes, has the potential to uncover new biological pathways amenable to pharmacological modulation that may impact human disease.

ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue.

Obesity develops when energy intake chronically exceeds energy expenditure. Because brown adipose tissue (BAT) dissipates energy in the form of heat, increasing energy expenditure by augmenting BAT-mediated thermogenesis may represent an approach to counter obesity and its complications. The ability of BAT to dissipate energy is dependent on expression of mitochondrial uncoupling protein 1 (UCP1). To facilitate the identification of pharmacological modulators of BAT UCP1 levels, which may have potential as antiobesity medications, we developed a transgenic model in which luciferase activity faithfully mimics endogenous UCP1 expression and its response to physiologic stimuli. Phenotypic screening of a library using cells derived from this model yielded a small molecule that increases UCP1 expression in brown fat cells and mice. Upon adrenergic stimulation, compound-treated mice showed increased energy expenditure. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.

Novel bisaryl substituted thiazoles and oxazoles as highly potent and selective peroxisome proliferator-activated receptor delta agonists.

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.