Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson's disease models.

BACKGROUND: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. METHODS: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. RESULTS: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. CONCLUSIONS: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.

Impact of the superimposition methods on accuracy analyses in complete-arch digital implant investigation.

OBJECTIVES: To measure the impact of the superimposition methods on accuracy analyses in digital implant research using an ISO-recommended 3-dimensional (3D) metrology-grade inspection software. MATERIALS AND METHODS: A six-implant edentulous maxillary model was scanned using a desktop scanner (7Series; DentalWings; Montreal, Canada) and an intraoral scanner (TRIOS 4; 3Shape; Copenhagen, Denmark) to generate a reference and an experimental mesh, respectively. Thirty experimental standard tesselletion language (STL) files were superimposed onto the reference model's STL using the core features of six superimposition methods, creating the following groups: initial automated pre-alignment (GI), landmark-based alignment (G1), partial area-based alignment (G2), entire area-based alignment (G3), and double alignment combining landmark-based alignment with entire model area-based alignment (G4 ) or the scan bodies' surface (G5). The groups underwent various alignment variations, resulting in sixteen subgroups (n = 30). The alignment accuracy between experimental and reference meshes was quantified by using the root mean square (RMS) error as trueness and its fluctuation as precision. The Kruskal-Wallis test with a subsequent adjusted post-hoc Dunn's pairwise comparison test was used to analyze the data (α = 0.05). The reliability of the measurements was assessed using the intraclass correlation coefficient (ICC). RESULTS: A total of 480 superimpositions were performed. No significant differences were found in trueness and precision among the groups (p > 0.05), except for partial area-based alignment (p < 0.001). Subgroup analysis showed significant differences for partial area-based alignment considering only one scan body (p < 0.001). Initial automated alignment was as accurate as landmark-based, partial, or entire area-based alignments (p > 0.05). Double alignments did not improve alignment accuracy (p > 0.05). The entire area-based alignment of the scan bodies' surface had the least effect on accuracy analyses. CONCLUSIONS: Digital oral implant investigation remains unaffected by the superimposition method when ISO-recommended 3D metrology-grade inspection software is used. At least two scan bodies are needed when considering partial area-based alignments. CLINICAL SIGNIFICANCE: The superimposition method choice within the tested ISO-recommended 3D inspection software did not impact accuracy analyses in digital implant investigation.

Impact of the superimposition methods and the designated comparison area on accuracy analyses in dentate models.

OBJECTIVES: To measure the impact of superimposition methods and the designated comparison area on accuracy analyses of dentate models using an ISO-recommended 3-dimensional (3D) metrology-grade inspection software (Geomagic Control X; 3D Systems; Rock Hill, South Carolina; USA). MATERIALS AND METHODS: A dentate maxillary typodont scanned with a desktop scanner (E4; 3 Shape; Copenhagen; Denmark) and an intraoral scanner (Trios 4; 3 Shape; Copenhagen; Denmark) was used as reference. Eight groups were created based on the core features of each superimposition method: landmark-based alignment (G1); partial area-based alignment (G2); entire tooth area-based alignment (G3); double alignment combining landmark-based alignment with entire tooth area-based alignment (G4); double alignment combining partial area-based alignment with entire tooth area-based alignment (G5); initial automated quick pre-alignment (G6); initial automated precise pre-alignment (G7); and entire model area-based alignment (G8). Diverse variations of each alignment and two regions for accuracy analyses (teeth surface or full model surface) were tested, resulting in a total of thirty-two subgroups (n = 18). The alignment accuracy between experimental and reference meshes was quantified using root mean square (RMS) error as trueness and its repeatability as precision. The descriptive statistics, a factorial repeated measures analysis of variance (ANOVA) and a post hoc Tuckey multiple comparison tests were used to analyze the trueness, and precision (α = 0.05). RESULTS: A total of 576 superimpositions were performed. The unique partial area-based superimposition method demonstrated the least precise alignment and was the sole group to exhibit a significant difference (p<.001). Automated initial pre-alignments demonstrated similar accuracy to other superimposition methods (p>.05). Double alignments did not result in accuracy improvement (p>.05). The designated comparison area displayed differences in both trueness (p<.001) and precision (p<.001), leading to an overall discrepancy of 8 ± 4 µm between selecting the teeth surface or full model surface. CONCLUSIONS: The superimposition method choice within the tested software did not impact accuracy analyses, except when the alignment relies on a unique and reduced area, such as the palatal rugae, a single tooth, or three adjacent teeth on one side. CLINICAL SIGNIFICANCE: The superimposition method choice within the tested ISO-recommended 3D inspection software did not impact accuracy analyses.

Combined cell-based therapy strategies for the treatment of Parkinson's disease: focus on mesenchymal stromal cells.

Parkinson's disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra. Levodopa is an effective and well-tolerated dopamine replacement agent. However, levodopa provides only symptomatic improvements, without affecting the underlying pathology, and is associated with side effects after long-term use. Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson's disease treatment. Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum, release dopamine, integrate into the host neural circuits, and improve motor functions. One of the limiting factors for cell therapy in Parkinson's disease is the low survival rate of grafted dopaminergic cells. Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma, growth factor deprivation, hypoxia, and neuroinflammation. Neurotrophic factors play an essential role in the survival of grafted cells. However, direct, timely, and controllable delivery of neurotrophic factors into the brain faces important limitations. Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival. In this review, we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson's disease, with a focus on neurotrophic factor-secreting cells, with a particular interest in mesenchymal stromal cells; that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.

Outcome measurements and quality of randomized controlled clinical trials of tooth-supported fixed dental prostheses: A systematic review and qualitative analysis.

STATEMENT OF PROBLEM: The lack of consensus regarding a standardized set of outcome measurements and noncompliance with current reporting guidelines in clinical trials of tooth-supported fixed dental prostheses (FDPs) hamper interstudy comparability, compromise scientific evidence, and waste research effort and resources in prosthetic dentistry. PURPOSE: The primary objective of this systematic review was to identify all primary and secondary outcome measurements assessed in randomized controlled trials (RCTs) of tooth-supported FDPs. Secondary objectives were to assess their methodological quality by using the Cochrane Collaboration's risk of bias tool (RoB, v2.0) and their reporting quality by means of a standardized 16-item CONSORT assessment tool through published reports. MATERIAL AND METHODS: An electronic search was conducted in MEDLINE, EMBASE, and Cochrane library to identify all RCT-related articles published in the past 10 years. Differences in RoB were tested with the Pearson chi-square test, and those in CONSORT score with the Student t test. RESULTS: A total of 64 RCTs from 79 publications were deemed eligible. The diversity of outcome measures used in the field is apparent. Twenty percent of the included studies had a low RoB, 79% showed some concerns, and 1% had a high RoB. The mean ±standard deviation CONSORT compliance score was 22.56 ±3.17. Trials adhered to the CONSORT statement reported lower RoB than those that did not adhere (P<.001). RCTs with a low RoB reported more comprehensive adherence to CONSORT guidelines than those with some concerns (MD 4 [95% CI 1.52-6.48]; P=.004). CONCLUSIONS: A standardized core outcome reporting set in clinical research on tooth-supported FDPs remains evident. Adherence to the CONSORT statement continues to be low, with some RoB concerns that can be improved.

Nigral Neurons Degenerating in Parkinson's Disease Express the Angiotensin Receptor Type 1 Gene.

© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

NRF2 Activation and Downstream Effects: Focus on Parkinson's Disease and Brain Angiotensin.

Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson's disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson's disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.

Dose-dependent effect of mesenchymal stromal cells co-grafted with dopaminergic neurons in a Parkinson's disease rat model.

A major limiting factor for cell therapy in Parkinson's disease is the poor survival and reinnervation capacity of grafted dopaminergic neurons, independently of the cell source. Mesenchymal stromal cells (MSCs) have high capability to regulate the local environment through the release of trophic, antiapoptotic and immunomodulatory factors. In this work, we investigated whether co-grafting of MSCs could improve the survival and reinnervation ability of dopaminergic precursors transplanted in animal models of Parkinson's disease. Rats with total unilateral dopaminergic denervation were grafted with a cell suspension of rat dopaminergic precursors (500,000 cells) with or without a high (200,000 cells) or low (25,000 cells) number of MSCs. Eight weeks after grafting, rats were tested for motor behaviour and sacrificed for histological analysis. Our results showed that the survival of dopaminergic neurons and graft-derived striatal dopaminergic innervation was higher in rats that received co-grafts containing a low number of MSCs than in non-co-grafted controls. However, the survival of dopaminergic neurons and graft-derived dopaminergic reinnervation was lower in rats receiving co-grafts with high number of MSCs than in non-co-grafted controls. In conclusion, co-grafting with MSCs or MSCs-derived products may constitute a useful strategy to improve dopaminergic graft survival and function. However, a tight control of MSCs density or levels of MSCs-derived products is necessary.

Dopamine regulates adult neurogenesis in the ventricular-subventricular zone via dopamine D3 angiotensin type 2 receptor interactions.

Adult neurogenesis is a dynamic and highly regulated process, and different studies suggest that dopamine modulates ventricular-subventricular zone (V-SVZ) neurogenesis. However, the specific role of dopamine and the mechanisms/factors underlying its effects on physiological and pathological conditions such as Parkinson's disease (PD) are not fully understood. Recent studies have described counter-regulatory interactions between renin-angiotensin system (RAS) and dopamine in peripheral tissues and in the nigrostriatal system. We have previously demonstrated that angiotensin receptors regulate proliferation and generation of neuroblasts in the rodent V-SVZ. However, possible interactions between dopamine receptors and RAS in the V-SVZ and their role in alterations of neurogenesis in animal models of PD have not been investigated. In V-SVZ cultures, activation of dopamine receptors induced changes in the expression of angiotensin receptors. Moreover, dopamine, via D2-like receptors and particularly D3 receptors, increased generation of neurospheres derived from the V-SVZ and this effect was mediated by angiotensin type-2 (AT2) receptors. In rats, we observed a marked reduction in proliferation and generation of neuroblasts in the V-SVZ of dopamine-depleted animals, and inhibition of AT1 receptors or activation of AT2 receptors restored proliferation and generation of neuroblasts to control levels. Moreover, intrastriatal mesencephalic grafts partially restored proliferation and generation of neuroblasts observed in the V-SVZ of dopamine-depleted rats. Our data revealed that dopamine and angiotensin receptor interactions play a major role in the regulation of V-SVZ and suggest potential beneficial effects of RAS modulators on the regulation of adult V-SVZ neurogenesis.

Interaction between Angiotensin Type 1, Type 2, and Mas Receptors to Regulate Adult Neurogenesis in the Brain Ventricular-Subventricular Zone.

The renin-angiotensin system (RAS), and particularly its angiotensin type-2 receptors (AT2), have been classically involved in processes of cell proliferation and maturation during development. However, the potential role of RAS in adult neurogenesis in the ventricular-subventricular zone (V-SVZ) and its aging-related alterations have not been investigated. In the present study, we analyzed the role of major RAS receptors on neurogenesis in the V-SVZ of adult mice and rats. In mice, we showed that the increase in proliferation of cells in this neurogenic niche was induced by activation of AT2 receptors but depended partially on the AT2-dependent antagonism of AT1 receptor expression, which restricted proliferation. Furthermore, we observed a functional dependence of AT2 receptor actions on Mas receptors. In rats, where the levels of the AT1 relative to those of AT2 receptor are much lower, pharmacological inhibition of the AT1 receptor alone was sufficient in increasing AT2 receptor levels and proliferation in the V-SVZ. Our data revealed that interactions between RAS receptors play a major role in the regulation of V-SVZ neurogenesis, particularly in proliferation, generation of neuroblasts, and migration to the olfactory bulb, both in young and aged brains, and suggest potential beneficial effects of RAS modulators on neurogenesis.

Data on the effect of Angiotensin II and 6-hydroxydopamine on reactive oxygen species production, antioxidant gene expression and viability of different neuronal cell lines.

This article describes the effect of the oxidative stress inducers Angiotensin II and 6-hydroxydopamine (6-OHDA) on different cell lines. The levels of expression Angiotensin type 1 and type 2 receptors in different dopaminergic cell lines are shown. The data indicate that treatment with Angiotensin II and 6-OHDA increases the production of reactive oxygen species (ROS) and decreases cell viability. NRF2 is a transcription factor induced by ROS. We provide data that NRF2 overexpression increases cell viability in response to oxidative stress inducers compared to control cells, and that these inducers can, both separately and in combination, enhance the expression of NRF2-regulated genes heme oxygenase 1 (Hmox1), NAD(P)H quinone dehydrogenase 1 (Nqo1) and Kruppel like factor 9 (Klf9). Interpretation of these data and additional information is presented in the research article "Angiotensin II induces oxidative stress and upregulates neuroprotective signaling from the NRF2 and KLF9 pathway in dopaminergic cells" (Parga et al., 2018) [1].

Angiotensin II induces oxidative stress and upregulates neuroprotective signaling from the NRF2 and KLF9 pathway in dopaminergic cells.

Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor that activates the antioxidant cellular defense in response to oxidative stress, leading to neuroprotective effects in Parkinson's disease (PD) models. We have previously shown that Angiotensin II (AngII) induces an increase in reactive oxygen species (ROS) via AngII receptor type 1 and NADPH oxidase (NOX), which may activate the NRF2 pathway. However, controversial data suggest that AngII induces a decrease in NRF2 signaling leading to an increase in oxidative stress. We analyzed the effect of AngII and the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in culture and in vivo, and examined the effects on the expression of NRF2-related genes. Treatment of neuronal cell lines Mes23.5, N27 and SH-SY5Y with AngII, 6-OHDA or a combination of both increased ROS production and reduced cell viability. Simultaneously, these treatments induced an increase in expression in the NRF2-regulated genes heme oxygenase 1 (Hmox1), NAD(P)H quinone dehydrogenase 1 (Nqo1) and Kruppel like factor 9 (Klf9). Moreover, overexpression of KLF9 transcription factor caused a reduction in the production of ROS induced by treatment with AngII or 6-OHDA and improved the survival of these neuronal cells. Rats treated with AngII, 6-OHDA or a combination of both also showed an increased expression of NRF2 related genes and KLF9. In conclusion, our data indicate that AngII induces a damaging effect in neuronal cells, but also acts as a signaling molecule to activate NRF2 and KLF9 neuroprotective pathways in cellular and animal models of PD.

Prostaglandin EP2 Receptors Mediate Mesenchymal Stromal Cell-Neuroprotective Effects on Dopaminergic Neurons.

Mesenchymal stromal cells (MSCs) have been shown to have useful properties for cell therapy and have been proposed for treatment of neurodegenerative diseases, including Parkinson's disease. However, the mechanisms involved in recovering dopaminergic neurons are not clear. The present study aims to evaluate the pathways and molecules involved in the neuroprotective effect of MSCs. We analyzed the viability of dopaminergic cells from different sources in response to conditioned medium derived from bone marrow MSC (MSC-CM). MSC-CM increased the viability of dopaminergic cells of rat and human origins, having both neuroprotective and neurorescue activities against effects of dopaminergic neurotoxin 6-hydroxydopamine. We found that lipid removal, inhibition of the prostaglandin E2 receptor 2 (EP2), and its signaling pathway were able to block the effects of MSC-CM on a pure population of dopaminergic neurons. Moreover, in primary mesencephalic cultures and hiPSC-derived neurons, inhibition of EP2 signaling caused a reduction in the number of dopaminergic neurons obtained in culture. Taken together, our results demonstrate for the first time the involvement of prostaglandin signaling from MSC in dopaminergic neuron survival through EP2 receptors, and suggest new approaches for treatment of Parkinson's disease.

Paracrine and Intracrine Angiotensin 1-7/Mas Receptor Axis in the Substantia Nigra of Rodents, Monkeys, and Humans.

In addition to the classical hormonal (tissue-to-tissue) renin-angiotensin system (RAS), there are a paracrine (cell-to-cell) and an intracrine (intracellular/nuclear) RAS. A local paracrine brain RAS has been associated with several brain disorders, including Parkinson's disease (PD). Classically, angiotensin II (Ang II) is the main RAS effector peptide and acts through two major receptors: Ang II type 1 and 2 (AT1 and AT2) receptors. It has been shown that enhanced activation of the Ang II/AT1 axis exacerbates dopaminergic cell death. Several new components of the RAS have more recently been discovered. However, the role of new Ang 1-7/Mas receptor RAS component was not investigated in the brain and particularly in the dopaminergic system. In the present study, we observed Mas receptor labeling in dopaminergic neurons and glial cells in rat mesencephalic primary cultures; substantia nigra of rats, monkeys, and humans; and human induced pluripotent stem (iPS) cells derived from healthy controls and sporadic PD patients. The present data support a neuroprotective role of the Ang 1-7/Mas receptor axis in the dopaminergic system. We observed that this axis is downregulated with aging, which may contribute to the aging-related vulnerability to neurodegeneration. We have also identified an intracellular Ang 1-7/Mas axis that modulates mitochondrial and nuclear levels of superoxide. The present data suggest that nuclear RAS receptors regulate the adequate balance between the detrimental and the protective arms of the cell RAS. The results further support that the brain RAS should be taken into account for the design of new therapeutic strategies for PD.

Clinical Study of the 3D-Master Color System among the Spanish Population.

PURPOSE: To study whether the shades of the 3D-Master System were grouped and represented in the chromatic space according to the three-color coordinates of value, chroma, and hue. MATERIALS AND METHODS: Maxillary central incisor color was measured on tooth surfaces through the Easyshade Compact spectrophotometer using 1361 participants aged between 16 and 89. The natural (not bleached teeth) color of the middle thirds was registered in the 3D-Master System nomenclature and in the CIELCh system. Principal component analysis and cluster analysis were applied. RESULTS: 75 colors of the 3D-Master System were found. The statistical analysis revealed the existence of 5 cluster groups. The centroid, the average of the 75 samples, in relation to lightness (L*) was 74.64, 22.87 for chroma (C*), and 88.85 for hue (h*). All of the clusters, except cluster 3, showed significant statistical differences with the centroid for the three-color coordinates (p <0.001). CONCLUSIONS: The results of this study indicated that 75 shades in the 3D-Master System were grouped into 5 clusters following coordinates L*, C*, and h* resulting from the dental spectrophotometer Vita Easyshade compact. The shades that composed each cluster did not belong to the same lightness color dimension groups. There was no special uniform chromatic distribution among the colors of the 3D-Master System.

Natural Tooth Color Estimation Based on Age and Gender.

PURPOSE: Assessment of the predictability of tooth color coordinates according to the CIELab system to estimate the color of the maxillary central incisor based on patient age and gender. MATERIAL AND METHODS: The tooth color of one of the maxillary central incisors of 1361 Caucasian Spanish individuals aged 16 to 89 years, male and female, was measured using the Easyshade compact spectrophotometer. Color coordinates L*, C*, h*, a*, and b* were recorded according to age and gender. RESULTS: The results obtained show that differences in age account for 45% of the total variation of the L (lightness) coordinate; 21% of the variation in coordinate a*, and 17% of the variation in coordinate b* is due to the same reason. At a confidence level of 95% it may be proposed that the mean estimated color difference (ΔEab *) between real natural color and that predicted by the linear regression model is between 6.4 and 6.9 units. CONCLUSIONS: In this sample of Caucasians from Spain, teeth became darker yellow and more reddish with increasing age. The L* coordinate is most strongly related to tooth color in aging.

Effects of Rho Kinase Inhibitors on Grafts of Dopaminergic Cell Precursors in a Rat Model of Parkinson's Disease.

UNLABELLED: In models of Parkinson's disease (PD), Rho kinase (ROCK) inhibitors have antiapoptotic and axon-stabilizing effects on damaged neurons, decrease the neuroinflammatory response, and protect against dopaminergic neuron death and axonal retraction. ROCK inhibitors have also shown protective effects against apoptosis induced by handling and dissociation of several types of stem cells. However, the effect of ROCK inhibitors on dopaminergic cell grafts has not been investigated. In the present study, treatment of dopaminergic cell suspension with ROCK inhibitors yielded significant decreases in the number of surviving dopaminergic neurons, in the density of graft-derived dopaminergic fibers, and in graft vascularization. Dopaminergic neuron death also markedly increased in primary mesencephalic cultures when the cell suspension was treated with ROCK inhibitors before plating, which suggests that decreased angiogenesis is not the only factor leading to cell death in grafts. Interestingly, treatment of the host 6-hydroxydopamine-lesioned rats with ROCK inhibitors induced a slight, nonsignificant increase in the number of surviving neurons, as well as marked increases in the density of graft-derived dopaminergic fibers and the size of the striatal reinnervated area. The study findings discourage treatment of cell suspensions before grafting. However, treatment of the host induces a marked increase in graft-derived striatal reinnervation. Because ROCK inhibitors have also exerted neuroprotective effects in several models of PD, treatment of the host with ROCK inhibitors, currently used against vascular diseases in clinical practice, before and after grafting may be a useful adjuvant to cell therapy in PD. SIGNIFICANCE: Cell-replacement therapy is one promising therapy for Parkinson's disease (PD). However, many questions must be addressed before widespread application. Rho kinase (ROCK) inhibitors have been used in a variety of applications associated with stem cell research and may be an excellent strategy for improving survival of grafted neurons and graft-derived dopaminergic innervation. The present results discourage the treatment of suspensions of dopaminergic precursors with ROCK inhibitors in the pregrafting period. However, treatment of the host (patients with PD) with ROCK inhibitors, currently used against vascular diseases, may be a useful adjuvant to cell therapy in PD.

Correlation of natural tooth colour with aging in the Spanish population.

OBJECTIVES: To analyse natural tooth colour in the Spanish population according to the colour coordinates lightness (L*), chroma (C*), hue (h*), red-green axis (a*) and yellow-blue axis (b*) in order to quantify the correlation and changes of tooth colour with age and sex. METHODS: Natural tooth colour was measured in a sample of 1,361 Spanish participants of both sexes distributed within an age range of 16 to 89 years. The Easyshade Compact spectrophotometer was used and the CIELAB and CIELCh systems were followed. RESULTS: Pearson's bivariate correlations between age and colour coordinates were highly significant for L* (r=-0.674, P≤0.001), h* (r=-0.468, P≤0.001) and C* (r=0.417, P≤0.001). The correlation between age and colour coordinates was stronger for men than for women, for all colour coordinates. The results showed that C*, b* and a* increased by 0.60, 0.56 and 0.26 units/year on average, respectively, whereas L* and h* decreased progressively with age (by 0.60 units/year, on average), and colour differences increased in a systematic way as the gap between the ages being compared grew wider. CONCLUSIONS: The strongest correlation was found between age and L*, then between age and h* (both inverse relationships) and then between age and a*, C* and b* (direct relationships). In addition, a similar degree of change in the colour coordinates L*, C* and h* (of 0.60 units/year on average) was observed for natural tooth colour. Knowledge of the chromatic range of natural teeth may help to choose colour for the replacement of missing elements.

A clinical study relating CIELCH coordinates to the color dimensions of the 3D-Master System in a Spanish population.

STATEMENT OF PROBLEM: The 3D-Master System comprises 26 physical shade tabs and intermediate shades. Determining the relationship among all the groups of lightness, chroma, and hue of the 3D-Master System (Vita Zahnfabrik) and the L*, C*, and h* coordinates is important, because according to the manufacturer, 2 Toothguide 3D-Master shades need to be mixed in a 50:50 ratio to create an intermediate shade. PURPOSE: The purpose of the study was to relate the lightness, chroma, and hue groups of the 3D-Master System with the polar coordinates of the CIELAB chromatic space, L*, C*, and h*, and to quantify the shades tabs and intermediate shades of the 3D-Master System according to color coordinates. MATERIAL AND METHODS: The middle third of the facial surface of a natural maxillary central incisor was measured with an Easyshade Compact spectrophotometer (Vita Zahnfabrik) in 1361 Spanish participants aged between 16 and 89 years. Natural tooth color was recorded in the 3D-Master nomenclature and in the CIE L*, C*, and h* coordinates system. The program used for the present descriptive statistical analysis of the results was SAS 9.1.3. RESULTS: In the L* variable, the minimum was found at 47.0 and the maximum at 91.3. In the C* variable, the minimum was found at 5.9 and the maximum at 49.8, while for h*, the minimum was 67.5 degrees and the maximum 112.0 degrees. CONCLUSIONS: Despite the limitations of this study, the 3D-Master System was found to be arranged according to L*, C*, and h* coordinates in groups of lightness, chroma, and hue. The corresponding groups of lightness, chroma, and hue can be estimated on the basis of L*, C*, and h* coordinates.

Study of the most frequent natural tooth colors in the Spanish population using spectrophotometry.

PURPOSE: To identify the most frequent natural tooth colors using the Easyshade Compact (Vita -Zahnfabrik) spectrophotometer on a sample of the Spanish population according to the 3D Master System. MATERIALS AND METHODS: The middle third of the facial surface of natural maxillary central incisors was measured with an Easyshade Compact spectrophotometer (Vita Zahnfabrik) in 1361 Caucasian Spanish participants aged between 16 and 89 years. Natural tooth color was recorded using the 3D Master System nomenclature. The program used for the present descriptive statistical analysis of the results was SAS 9.1.3. RESULTS: The results show that the most frequent dental color in the total sample studied is 3M1 (7.05%), followed by the intermediate shade 1M1.5 (6.91%) and 2L1.5 (6.02%). CONCLUSION: According to the research methodology used, and taking into account the limitations of this study, it can be proposed that the most frequent color among the Spanish population is 3M1; the most common lightness group is 2; the most frequent hue group according to the 3D Master System is M and the most frequent chroma group is 1.5.