Diagnostic Strategies for Restorations Management: A 70-Month RCT.

We aimed to evaluate the impact of 2 visual diagnostic strategies for assessing secondary caries and managing permanent posterior restorations on long-term survival. We conducted a diagnostic cluster-randomized clinical trial with 2 parallel groups using different diagnostic strategies: (C+AS) based on caries assessment, marginal adaptation, and marginal staining aspects of the FDI (World Dental Federation) criteria and (C) based on caries assessment using the Caries Associated with Restorations or Sealants (CARS) criteria described by the International Caries Detection and Assessment System (ICDAS). The treatment for the restoration was conducted based on the decision made following the allocated diagnostic strategy. The restorations were then clinically reevaluated for up to 71 mo. The primary outcome was restoration failure (including tooth-level failure: pain, endodontic treatment, and extraction). Cox regression analyses with shared frailty were conducted in the intention-to-treat population, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were derived. We included 727 restorations from 185 participants and reassessed 502 (69.1%) restorations during follow-up. The evaluations occurred between 6 and 71 mo. At baseline, C led to almost 4 times fewer interventions compared with the C+AS strategy. A total of 371 restorations were assessed in the C group, from which 31 (8.4%) were repaired or replaced. In contrast, the C+AS group had 356 restorations assessed, from which 113 (31.7%) were repaired or replaced. During follow-up, 34 (9.2%) failures were detected in the restorations allocated to the C group and 30 (8.4%) allocated to the C+AS group in the intention-to-treat population, with no significant difference between the groups (HR = 0.83; 95% CI = 0.51 to 1.38; P = 0.435, C+AS as reference). In conclusion, a diagnostic strategy focusing on marginal defects results in more initial interventions but does not improve longevity over the caries-focused strategy, suggesting the need for more conservative approaches.

Challenges in conducting clinical research in primary care dentistry.

The integration of dentistry into primary health care is crucial for promoting patient well-being. However, clinical studies in dentistry face challenges, including issues with study design, transparency, and relevance to primary care. Clinical trials in dentistry often focus on specific issues with strict eligibility criteria, limiting the generalizability of findings. Randomized clinical trials (RCTs) face challenges in reflecting real-world conditions and using clinically relevant outcomes. The need for more pragmatic approaches and the inclusion of clinically relevant outcomes (CROs) is discussed, such as tooth loss or implant success. Solutions proposed include well-controlled observational studies, optimized data collection tools, and the integration of artificial intelligence (AI) for predictive modelling, computer-aided diagnostics and automated diagnosis. In this position paper advocates for more efficient trials with a focus on patient-centred outcomes, as well as the adoption of pragmatic study designs reflecting real-world conditions. Collaborative research networks, increased funding, enhanced data retrieval, and open science practices are also recommended. Technology, including intraoral scanners and AI, is highlighted for improving efficiency in dental research. AI is seen as a key tool for participant recruitment, predictive modelling, and outcome evaluation. However, ethical considerations and ongoing validation are emphasized to ensure the reliability and trustworthiness of AI-driven solutions in dental research. In conclusion, the efficient conduct of clinical research in primary care dentistry requires a comprehensive approach, including changes in study design, data collection, and analytical methods. The integration of AI is seen as pivotal in achieving these objectives in a meaningful and efficient way.

Cells, pathways, and models in dyskinesia research.

L-DOPA-induced dyskinesia (LID) is the most common form of hyperkinetic movement disorder resulting from altered information processing in the cortico-basal ganglia network. We here review recent advances clarifying the altered interplay between striatal output pathways in this movement disorder. We also review studies revealing structural and synaptic changes to the striatal microcircuitry and altered cortico-striatal activity dynamics in LID. We furthermore highlight the recent progress made in understanding the involvement of cerebellar and brain stem nuclei. These recent developments illustrate that dyskinesia research continues to provide key insights into cellular and circuit-level plasticity within the cortico-basal ganglia network and its interconnected brain regions.

Structural-functional properties of direct-pathway striatal neurons at early and chronic stages of dopamine denervation.

The dendritic arbour of striatal projection neurons (SPNs) is the primary anatomical site where dopamine and glutamate inputs to the basal ganglia functionally interact to control movement. These dendritic arbourisations undergo atrophic changes in Parkinson's disease. A reduction in the dendritic complexity of SPNs is found also in animal models with severe striatal dopamine denervation. Using 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle as a model, we set out to compare morphological and electrophysiological properties of SPNs at an early versus a chronic stage of dopaminergic degeneration. Ex vivo recordings were performed in transgenic mice where SPNs forming the direct pathway (dSPNs) express a fluorescent reporter protein. At both the time points studied (5 and 28 days following 6-OHDA lesion), there was a complete loss of dopaminergic fibres through the dorsolateral striatum. A reduction in dSPN dendritic complexity and spine density was manifest at 28, but not 5 days post-lesion. At the late time point, dSPN also exhibited a marked increase in intrinsic excitability (reduced rheobase current, increased input resistance, more evoked action potentials in response to depolarising currents), which was not present at 5 days. The increase in neuronal excitability was accompanied by a marked reduction in inward-rectifying potassium (Kir) currents (which dampen the SPN response to depolarising stimuli). Our results show that dSPNs undergo delayed coordinate changes in dendritic morphology, intrinsic excitability and Kir conductance following dopamine denervation. These changes are predicted to interfere with the dSPN capacity to produce a normal movement-related output.

Comparison of dyskinesia profiles after L-DOPA dose challenges with or without dopamine agonist coadministration.

Many patients with Parkinson's disease (PD) experiencing l-DOPA-induced dyskinesia (LID) receive adjunct treatment with dopamine agonists, whose functional impact on LID is unknown. We set out to compare temporal and topographic profiles of abnormal involuntary movements (AIMs) after l-DOPA dose challenges including or not the dopamine agonist ropinirole. Twenty-five patients with PD and a history of dyskinesias were sequentially administered either l-DOPA alone (150% of usual morning dose) or an equipotent combination of l-DOPA and ropinirole in random order. Involuntary movements were assessed by two blinded raters prior and every 30 min after drug dosing using the Clinical Dyskinesia Rating Scale (CDRS). A sensor-recording smartphone was secured to the patients' abdomen during the test sessions. The two raters' CDRS scores were highly reliable and concordant with models of hyperkinesia presence and severity trained on accelerometer data. The dyskinesia time curves differed between treatments as the l-DOPA-ropinirole combination resulted in lower peak severity but longer duration of the AIMs compared with l-DOPA alone. At the peak of the AIMs curve (60-120 min), l-DOPA induced a significantly higher total hyperkinesia score, whereas in the end phase (240-270 min), both hyperkinesia and dystonia tended to be more severe after the l-DOPA-ropinirole combination (though reaching statistical significance only for the item, arm dystonia). Our results pave the way for the introduction of a combined l-DOPA-ropinirole challenge test in the early clinical evaluation of antidyskinetic treatments. Furthermore, we propose a machine-learning method to predict CDRS hyperkinesia severity using accelerometer data.

Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa-Induced Dyskinesia.

BACKGROUND: Current models of levodopa (L-dopa)-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-dopa. However, patients with LID receive combination therapies that often include dopamine agonists. OBJECTIVE: Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether an adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses. METHODS: Different regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-dopa monotreatment or L-dopa combined with ropinirole. RESULTS: We defined chronic regimens of L-dopa monotreatment and L-dopa-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared with the monotreatment group, animals receiving the L-dopa-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced after L-dopa-ropinirole cotreatment compared with L-dopa monotreatment. Moreover, significant group differences were detected upon examining the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-dopa-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-dopa-ropinirole cotreated animals. CONCLUSIONS: Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia.

L-DOPA-induced dyskinesia (LID) in Parkinson's disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70-110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

Non-Apoptotic Caspase-3 Activation Mediates Early Synaptic Dysfunction of Indirect Pathway Neurons in the Parkinsonian Striatum.

Non-apoptotic caspase-3 activation is critically involved in dendritic spine loss and synaptic dysfunction in Alzheimer's disease. It is, however, not known whether caspase-3 plays similar roles in other pathologies. Using a mouse model of clinically manifest Parkinson's disease, we provide the first evidence that caspase-3 is transiently activated in the striatum shortly after the degeneration of nigrostriatal dopaminergic projections. This caspase-3 activation concurs with a rapid loss of dendritic spines and deficits in synaptic long-term depression (LTD) in striatal projection neurons forming the indirect pathway. Interestingly, systemic treatment with a caspase inhibitor prevents both the spine pruning and the deficit of indirect pathway LTD without interfering with the ongoing dopaminergic degeneration. Taken together, our data identify transient and non-apoptotic caspase activation as a critical event in the early plastic changes of indirect pathway neurons following dopamine denervation.

NaOCl Application after Acid Etching and Retention of Cervical Restorations: A 3-Year Randomized Clinical Trial.

This study evaluated the retention of composite resin restorations in noncarious cervical lesions (NCCLs) performed with or without pretreatment with 10% NaOCl solution (deproteinization). A randomized, controlled, split-mouth, double-blinded trial was carried out. Thirty patients with at least two NCCLs were included in the study. The NCCLs were randomly allocated into two treatment groups: control (acid etching with 37% phosphoric acid + placebo solution + Adper Single Bond 2/3M Oral Care + Filtek Z350/3M Oral Care) or experimental group (acid etching with 37% phosphoric acid + 10% NaOCl solution + Adper Single Bond 2 + Filtek Z350). A calibrated examiner evaluated the restorations at baseline (1 week) and recalls (6, 12, 24, and 36 months) using the FDI criteria. The primary outcome evaluated was retention of the restorations. Data were analyzed by the Kaplan-Meier method and the log-rank test (α=0.05). After 3 years, 64 restorations were evaluated in 23 patients. The annual failure rate was 9% for the control group and 17.8% for the experimental group (deproteinization technique). Considering the failures and their distribution among the characteristics of the patients and NCCLs, no statistically significant differences were observed for the control and experimental treatment groups (p=0.077) or the number of teeth in the mouth (p=0.320). Restorations in the mandible (p=0.039) and premolars (p=0.013) showed significantly lower clinical survival rates. The deproteinization pretreatment with a 10% NaOCl solution did not promote additional retention of restorations in NCCLs. (clinicaltrials. gov: NCT03086720).

Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease.

Dopamine replacement therapy with l-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving l-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.

Trajectories of Sugar Consumption and Dental Caries in Early Childhood.

This study verifies the association between the trajectory of sugar consumption and dental caries in the 2015 Pelotas Birth Cohort in Pelotas, Brazil. It was conducted with data from the follow-ups at 3, 12, 24, and 48 mo from the 2015 Birth Cohort, which included 4,275 children born alive in hospitals in Pelotas. Data collection included standardized questionnaires for first caregivers applied by trained interviewers at all follow-ups. Exposure was the trajectory of sugar consumption from 3 to 48 mo (always low, always intermediate, increasing, and always high), obtained by group-based trajectory modeling. The outcome of this study was dental caries, obtained through clinical examination performed by calibrated dentists at 48 mo of age. Socioeconomic conditions and oral health instruction from a health professional during the first 4 y of life were included in the analysis as potential confounders. Prevalence ratios and their 95% confidence intervals were provided from generalized estimating equations with a log-Poisson with robust variance specification. In total, 3,654 (91.1%) children participated in the survey at 48 mo, and 2,806 children had complete data for the analyzes performed. Of these, 1,012 (36.1%; 95% confidence interval [CI], 34.3-37.8) experienced caries, and 723 (25.8%; 95% CI, 24.2-27.4) had cavitated caries. Regarding cavitated caries, the prevalence was 1.48 times higher in the group with increasing sugar consumption than children with always low consumption. There is an association between the trajectory of sugar consumption and dental caries at 48 mo. Children with increasing and always high sugar consumption have the highest prevalence of caries.

Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions.

Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson's disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs. those related to a subject's motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)-a measure based on the physical acceleration of the head of rats-to the local field potential (LFP) oscillatory power in the 1-80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0-26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0-79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25-40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.

Tracking Rats in Operant Conditioning Chambers Using a Versatile Homemade Video Camera and DeepLabCut.

Operant conditioning chambers are used to perform a wide range of behavioral tests in the field of neuroscience. The recorded data is typically based on the triggering of lever and nose-poke sensors present inside the chambers. While this provides a detailed view of when and how animals perform certain responses, it cannot be used to evaluate behaviors that do not trigger any sensors. As such, assessing how animals position themselves and move inside the chamber is rarely possible. To obtain this information, researchers generally have to record and analyze videos. Manufacturers of operant conditioning chambers can typically supply their customers with high-quality camera setups. However, these can be very costly and do not necessarily fit chambers from other manufacturers or other behavioral test setups. The current protocol describes how to build an inexpensive and versatile video camera using hobby electronics components. It further describes how to use the image analysis software package DeepLabCut to track the status of a strong light signal, as well as the position of a rat, in videos gathered from an operant conditioning chamber. The former is a great aid when selecting short segments of interest in videos that cover entire test sessions, and the latter enables analysis of parameters that cannot be obtained from the data logs produced by the operant chambers.

The role of glia in Parkinson's disease: Emerging concepts and therapeutic applications.

Originally believed to primarily affect neurons, Parkinson's disease (PD) has recently been recognized to also affect the functions and integrity of microglia and astroglia, two cell categories of fundamental importance to brain tissue homeostasis, defense, and repair. Both a loss of glial supportive-defensive functions and a toxic gain of glial functions are implicated in the neurodegenerative process. Moreover, the chronic treatment with L-DOPA may cause maladaptive glial plasticity favoring a development of therapy complications. This chapter focuses on the pathophysiology of PD from a glial point of view, presenting this rapidly growing field from the first discoveries made to the most recent developments. We report and compare histopathological and molecular findings from experimental models of PD and human studies. We moreover discuss the important role played by astrocytes in compensatory adaptations taking place during presymptomatic disease stages. We finally describe examples of potential therapeutic applications stemming from an increased understanding of the important roles of glia in PD.

Animal models for preclinical Parkinson's research: An update and critical appraisal.

Animal models of Parkinson's disease (PD) are essential to investigate pathogenic pathways at the whole-organism level. Moreover, they are necessary for a preclinical investigation of potential new therapies. Different pathological features of PD can be induced in a variety of invertebrate and vertebrate species using toxins, drugs, or genetic perturbations. Each model has a particular utility and range of applicability. Invertebrate PD models are particularly useful for high throughput-screening applications, whereas mammalian models are needed to explore complex motor and non-motor features of the human disease. Here, we provide a comprehensive review and critical appraisal of the most commonly used mammalian models of PD, which are produced in rats and mice. A substantial loss of nigrostriatal dopamine neurons is necessary for the animal to exhibit a hypokinetic motor phenotype responsive to dopaminergic agents, thus resembling clinical PD. This level of dopaminergic neurodegeneration can be induced using specific neurotoxins, environmental toxicants, or proteasome inhibitors. Alternatively, nigrostriatal dopamine degeneration can be induced via overexpression of α-synuclein using viral vectors or transgenic techniques. In addition, protein aggregation pathology can be triggered by inoculating preformed fibrils of α-synuclein in the substantia nigra or the striatum. Thanks to the conceptual and technical progress made in the past few years a vast repertoire of well-characterized animal models are currently available to address different aspects of PD in the laboratory.

The Effect of a Charcoal-based Powder for Enamel Dental Bleaching.

CLINICAL RELEVANCE: Charcoal based-powders are not effective for dental bleaching. SUMMARY: Charcoal-based dentifrices for dental whitening are a novelty in the market. Manufacturers claim that such charcoal-based products have whitening, remineralization, antimicrobial, and antifungal properties of charcoal in such products. However, there is no substantial scientific evidence for these claims. This laboratory randomized study was designed to evaluate the whitening properties of a charcoal-based toothpowder. A total of 45 bovine dental enamel discs were randomly distributed into three groups (n=15): group 1, mechanical brushing with a 1450-ppm F toothpaste (control group); group 2, mechanical brushing with an activated charcoal-based powder; group 3, bleaching per the standard protocol using 10% carbamide peroxide. The surface roughness and color of each specimen were analyzed at baseline and after 14 days of experiment. The surface of one randomly selected specimen from each group was examined using a scanning electron microscope (SEM). The Kruskal-Wallis test was used to compare groups at a significance level of 5%. Only group 3 promoted a statistically significant effect on ΔE compared with groups 1 and 2 (p<0.001 and p=0.003, respectively). No statistically significant difference was found between groups for surface roughness (p>0.05). SEM revealed a more irregular surface in group 1 specimens compared with group 2 and 3 specimens. The charcoal-based powder did not seem to have any bleaching effect.

Occlusal and Esthetic Enhancement: A Noninvasive Approach to an Old Dilemma.

This article describes an indirect composite restoration technique for diastema closure and tooth lengthening with a noninvasive approach using regularly available materials such as silicone, composite resin, and an adhesive system. The procedure resulted in occlusal and functional improvement, with diastema closure, protrusive guide adjustment, and an increase in central incisor length. The procedure provided an adequate proportion of the central incisors with an esthetically natural appearance. It also resulted in simple, fast, and accurate manufacturing with a noninvasive esthetic indirect rehabilitation compared with more invasive preparation of ceramic veneers.

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.

Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson's disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5-dependent PLC signaling was causally linked with excessive activation of extracellular signal-regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson's disease.