Motor response to a dopamine D3 receptor preferring agonist compared to apomorphine in levodopa-primed 1-methyl-4-phenyl1,3,3,6-tetrahydropyridine monkeys

ABSTRACT The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(ϩ)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 Ϯ 4.5 g/kg) and PD 128,907 (averaging 41.7 Ϯ 4.4 g/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopaprimed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia

Organic pollutants in sea-surface microlayer and aerosol in thecoastal environment of Leghorn—(Tyrrhenian Sea)

The levels of dissolved and particle-associated n-alkanes, alkylbenzenes, phthalates, PAHs, anionic surfactants and surfactant fluorescent organic matter ŽSFOM. were measured in sea-surface microlayer ŽSML. and sub-surface water ŽSSL. samples collected in the Leghorn marine environment in September and October 1999. Nine stations, located in the Leghorn harbour and at increasing distances from the Port, were sampled three times on the same day. At all the stations, SML concentrations of the selected organic compounds were significantly higher than SSL values and the enrichment factors ŽEFsSML concentrationrSSL concentration. were greater in the particulate phase than in the dissolved phase. SML concentrations varied greatly among the sampling sites, the highest levels Žn-alkanes 3674 mgrl, phthalates 177 mgrl, total PAHs 226 mgrl. being found in the particulate phase in the Leghorn harbour. To improve the knowledge on pollutant exchanges between sea-surface waters and atmosphere, the validity of spray drop adsorption model ŽSDAM. was verified for SFOM, surface-active agents, such as phthalates, and compounds which can interact with SFOM, such as n-alkanes and PAHs. q2001 Elsevier Science B.V. All rights reserved

Foot Pressure Wearable Sensors for Freezing of Gait Detection in Parkinson’s Disease

Freezing of Gait (FoG) is a common symptom in Parkinson's Disease (PD) occurring with significant variability and severity and is associated with increased risk of falls. FoG detection in everyday life is not trivial, particularly in patients manifesting the symptom only in specific conditions. Various wearable devices have been proposed to detect PD symptoms, primarily based on inertial sensors. We here report the results of the validation of a novel system based on a pair of pressure insoles equipped with a 3D accelerometer to detect FoG episodes. Twenty PD patients attended a motor assessment protocol organized into eight multiple video recorded sessions, both in clinical and ecological settings and both in the ON and OFF state. We compared the FoG episodes detected using the processed data gathered from the insoles with those tagged by a clinician on video recordings. The algorithm correctly detected 90% of the episodes. The false positive rate was 6% and the false negative rate 4%. The algorithm reliably detects freezing of gait in clinical settings while performing ecological tasks. This result is promising for freezing of gait detection in everyday life via wearable instrumented insoles that can be integrated into a more complex system for comprehensive motor symptom monitoring in PD

Designing a mHealth clinical decision support system for Parkinson's disease: a theoretically grounded user needs approach.

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment

NMDA receptor genotypes associated with the vulnerability to develop dyskinesia

Dyskinesias are involuntary muscle movements that occur spontaneously in Huntington's disease (HD) and after long-term treatments for Parkinson's disease (levodopa-induced dyskinesia; LID) or for schizophrenia (tardive dyskinesia, TD). Previous studies suggested that dyskinesias in these three conditions originate from different neuronal pathways that converge on overstimulation of the motor cortex. We hypothesized that the same variants of the N-methyl--aspartate receptor gene that were previously associated with the age of dyskinesia onset in HD were also associated with the vulnerability for TD and not LID. Genotyping patients with LID and TD revealed, however, that these two variants were dose-dependently associated with susceptibility to LID, but not TD. This suggested that LID, TD and HD might arise from the same neuronal pathways, but TD results from a different mechanism

Early thinking palliative care for people with Parkinson's disease: A thematic synthesis based on a systematic mixed-methods review

Background: Parkinson's disease is a progressive neurodegenerative disorder. Awareness and the evidence supporting the merits of palliative care (PC) approaches to people with Parkinson's disease (PwP) are increasing. Objective: This review aimed to address four key questions related to PC for PwPs and their caregivers: i) What are the indicators for timely access to PC? ii) When should PC be introduced? iii) What are the current care models for providing PC? iv) What are the barriers and facilitators at the organizational level? Methods: A systematic literature search was conducted in PubMed, CINAHL, Cochrane, EMBASE, and MEDLINE (2006–2024). Six reviewers independently screened abstracts and full texts, and thematic synthesis was applied to develop analytical themes. Reporting followed PRISMA guidelines. Results: Out of 894 studies, 70 were included. PwPs were infrequently referred to PC services, and while several referral criteria were identified, no consensus emerged. Barriers to accessing PC included insufficient information, inadequate education, difficulties determining referral timing, limited home-based care options, inconsistent provider support, and disparities linked to socioeconomic and cultural factors. Facilitators included improved care coordination and education for PwPs, caregivers, and healthcare providers. Effective PC models were identified, including home-based, hospital-based, and community-based approaches, which improved quality of life and reduced healthcare costs. Conclusions: Establishing consensus on referral timing and criteria is essential for integrating PC into Parkinson's disease care. Overcoming barriers requires enhanced education, better care coordination, and targeted interventions to address disparities, ensuring comprehensive, patient-centred care for PwPs and their caregivers

Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients

Spondylo-meta-epiphyseal dysplasia (SMED) with short limbs and abnormal calcifications (SMED-SL) is a rare, autosomal recessive human growth disorder, characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly and premature calcifications. Recently, three missense mutations and one splice-site mutation in the DDR2 gene were identified as causative genetic defects for SMED-SL, but the underlying cellular and biochemical mechanisms were not explored. Here we report a novel DDR2 missense mutation, c.337G>A (p.E113K), that causes SMED-SL in two siblings in the United Arab Emirates. Another DDR2 missense mutation, c.2254C>T (p.R752C), matching one of the previously reported SMED-SL mutations, was found in a second affected family. DDR2 is a plasma membrane receptor tyrosine kinase that functions as a collagen receptor. We expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. We found that all SMED-SL missense mutants were defective in collagen-induced receptor activation and that the three previously reported mutants (p.T713I, p.I726R and p.R752C) were retained in the endoplasmic reticulum. The novel mutant (p.E113K), in contrast, trafficked normally, like wild-type DDR2, but failed to bind collagen. This finding is in agreement with our recent structural data identifying Glu113 as an important amino acid in the DDR2 ligand-binding site. Our data thus demonstrate that SMED-SL can result from at least two different loss-of-function mechanisms: namely defects in DDR2 targeting to the plasma membrane or the loss of its ligand-binding activity