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Disturbed sleep is common in asthma. Melatonin has sleep-inducing activity and reportedly affects smooth muscle tone and inflammation. The aim of this study was to evaluate the effect of melatonin on sleep in patients with mild and moderate asthma. This was a randomized, double-blind, placebo-controlled study. Twenty-two consecutive women with asthma were randomized to receive melatonin 3 mg (n = 12) or placebo (n = 10) for 4 weeks. Sleep quality and daytime somnolence were assessed by the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale, respectively. Pulmonary function was assessed by spirometry. Use of relief medication, asthma symptoms, and morning and evening peak expiratory flow rate were recorded daily. Melatonin treatment significantly improved subjective sleep quality, as compared with placebo (p = 0.04). No significant difference in asthma symptoms, use of relief medication and daily peak expiratory flow rate was found between groups. We conclude that melatonin can improve sleep in patients with asthma. Further studies looking into long-term effects of melatonin on airway inflammation and bronchial hyperresponsiveness are needed before melatonin can be recommended in patients with asthma. [ABSTRACT FROM AUTHOR]

Background: Metastatic hormone-sensitive prostate cancer (mHSPC) is treatment-resistant and generally considered incurable. The development of prostate-specific membrane antigen positron emission-computed tomography (PSMA PET/CT) has generated immense expectations due to its diagnostic accuracy in prostate cancer (PCa). PSMA expression of the primary tumor, quantified by SUVmax, is a predictor of oncological outcomes. The role of PSMA-PET/CT SUVmax in metachronous mHSPC treated with ADT plus second-generation antiandrogens (ARSI) is unknown. The main aim of this study was to evaluate 68 Ga-PSMA-11expression (SUVmax) as a potential prognostic biomarker in patients with metachronous mHSPC treated with ADT and first or second-generation antiandrogens. A second aim was to determine the association between PSMA SUVmax and PSA response to hormone therapy., Material and Methods: Patients diagnosed with metachronous mHSPC between July 2017 and February 2023 who developed biochemical recurrence following radical surgery (with or without salvage radiotherapy and/or ADT) or external radiation therapy (with or without ADT) were included. All patients underwent 68  Ga-PSMA-11 PET/CT imaging and the SUVmax value was determined for all measurable locations. The SUVmax value was used for the semiquantitative analysis. The Wilcoxon method was used to compare responders (PSA reduction ≥ 50%) to non-responders (PSA reduction < 50%). The SUVmax value and hormone therapy were evaluated as independent variables relative to the PSA response rate or PSA reduction using the linear regression method. A mixed-effects model (ANOVA) was used for the comparisons., Results: A total of 82 patients were included. Median follow-up was 11.7 months. On the linear regression analysis, patients with a high SUVmax treated with ADT + ARSI showed a greater PSA response (p = 0.034) than those treated with ADT + first-generation antiandrogens. In the mixed-effects model, SUVmax was significant (p = 0.041). On the univariate analysis, PSA at recurrence (HR, 3.2; 95% CI: 1.07-13.6; p = 0.078) and the number of metastases (HR, 4.77; 95% CI 1.1-26.1: p = 0.002) were associated with the type of hormone therapy administered., Conclusions: PSMA-PET/CT SUVmax is a prognostic biomarker that can be used to predict a PSA response to ADT + ARSI in patients with metachronous mHSPC. However, these findings need to be confirmed in larger prospective studies., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

This study mapped definitions of shortened dental configurations and health outcomes employed in association studies. A scoping review was conducted using the PubMed/Medline, Scopus, Web of Science, SciELO and Cochrane databases. Two trained researchers selected studies and extracted data. Studies that investigated the association between shortened dental configurations (exposure) and person-centered outcomes (general and oral health) related to health behavior (dietary patterns). Clinical outcomes were classified according to the International Classification of Functioning, Disability and Health and the International Classification of Diseases of the World Health Organization (WHO). Shortened dental configurations were defined as at least 20/21 teeth or the position of the teeth, including esthetics, dental occlusion and periodontal status (Eichner Index, Shortened Dental Arches, Functional Dentition Classification System, Posterior Occluding Pairs, Functional Tooth Units). The initial search resulted in 12,525 records in English, Portuguese and Spanish, 432 of which addressed the association of interest. General health (n = 203) and oral health (n = 201) were addressed in a similar number of studies. Most outcomes were related to general health (n = 184), the most frequent of which were endocrine, nutritional or metabolic diseases (n = 57) and mental functions (n = 26). Person-centered measures were addressed in 153 studies, most of which were about oral health and oral health-related quality of life (n = 62). Oral health outcomes were predominantly related to intake functions (n = 44) and diseases or disorders of the orofacial complex (n = 24). Dietary patterns (n = 43) and mortality (n = 38) were also studied. The cross-sectional design (n = 257) and non-probabilistic sampling (n = 218) were more frequent. The shortened dental configurations defined by the WHO were the most frequent in the studies (n = 206). The effects of shortened dental configurations have been investigated mainly in relation to endocrine, nutritional or metabolic diseases and measures of oral health-related quality of life. The findings point to a diversity of health outcomes assessed and substantial methodological variability., (© 2024. The Author(s).)

Overactivation of microglial cells seems to play a crucial role in the degeneration of dopaminergic neurons occurring in Parkinson's disease. We have previously demonstrated that glial cell line-derived neurotrophic factor (GDNF) present in astrocytes secretome modulates microglial responses induced by an inflammatory insult. Therefore, astrocyte-derived soluble factors may include relevant molecular players of therapeutic interest in the control of excessive neuroinflammatory responses. However, in vivo, the control of neuroinflammation is more complex as it depends on the interaction between different types of cells other than microglia and astrocytes. Whether neurons may interfere in the astrocyte-microglia crosstalk, affecting the control of microglial reactivity exerted by astrocytes, is unclear. Therefore, the present work aimed to disclose if the control of microglial responses mediated by astrocyte-derived factors, including GDNF, could be affected by the crosstalk with neurons, impacting GDNF's ability to protect dopaminergic neurons exposed to a pro-inflammatory environment. Also, we aimed to disclose if the protection of dopaminergic neurons by GDNF involves the modulation of microglial cells. Our results show that the neuroprotective effect of GDNF was mediated, at least in part, by a direct action on microglial cells through the GDNF family receptor α-1. However, this protective effect seems to be impaired by other mediators released in response to the neuron-astrocyte crosstalk since neuron-astrocyte secretome, in contrast to astrocytes secretome, was unable to protect dopaminergic neurons from the injury triggered by lipopolysaccharide-activated microglia. Supplementation with exogenous GDNF was needed to afford protection of dopaminergic neurons exposed to the inflammatory environment. In conclusion, our results revealed that dopaminergic protective effects promoted by GDNF involve the control of microglial reactivity. However, endogenous GDNF is insufficient to confer dopaminergic neuron protection against an inflammatory insult. This reinforces the importance of further developing new therapeutic strategies aiming at providing GDNF or enhancing its expression in the brain regions affected by Parkinson's disease.

Locally advanced rectal cancer has traditionally been treated with chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, a new strategy, total neoadjuvant therapy, involves the administration of CRT and neoadjuvant chemotherapy with the aim of eradicating micrometastases earlier and achieving greater control of the disease. The use of total neoadjuvant therapy has shown higher rates of pathological complete response and resectability compared with CRT, including improved survival. Nevertheless, distant relapse is the main cause of morbidity and mortality in locally advanced rectal cancer. To address this, new biomarkers are being developed to predict disease response.

The aim of this study was to evaluate the accuracy of pairs of antagonist teeth (epidemiological criterion) for defining pairs of teeth in occlusal contact (clinical criterion) and to estimate the agreement between the prevalence of "shortened dental arch" (SDA) and "functional dentition" (FD) when occlusal units (OUs) or posterior occluding pairs (POPs) are defined by the epidemiological or clinical criterion. Data were collected in an epidemiological oral health survey conducted in a municipality in Minas Gerais, Brazil. OUs and POPs were defined by the epidemiological criterion (dental crown status) or clinical criterion "gold standard" (carbon paper record of occlusal contacts during habitual maximum intercuspation). SDA corresponded to the presence of an intact anterior region and three to five OUs. FD was based on the concomitant presence of ≥ 1 tooth in each arch, 10 teeth in each arch, 12 anterior teeth, ≥ 3 premolar POPs, and ≥ 1 molar POP bilaterally. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the epidemiological criterion were calculated. The study included 197 adults. Sensitivity, specificity, PPV, and NPV were 88.5, 87.9, 92.5, and 81.9%, respectively, and accuracy was 88.3%. The epidemiological criterion proved to be valid and could be used in epidemiological studies to calculate the prevalence of reduced dental configurations that consider POPs. The assessment of oral functionality is an aspect that should be included in the diagnosis of the clinical condition of patients, contributing to a more effective individual and collective oral health care plan.

Colorectal cancer has been considered a worldwide public health problem since current treatments are often ineffective. Irinotecan is a frontline chemotherapeutic agent that has dose-limiting side effects that compromise its therapeutic potential. Therefore, it is necessary to develop a novel, targeted drug delivery system with high therapeutic efficacy and an improved safety profile. Here, micellar formulations composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG 2k ) containing irinotecan were proposed as a strategy for colorectal cancer therapy. Firstly, the irinotecan-loaded micelles were prepared using the solvent evaporation method. Then, micelles were characterized in terms of size, polydispersity, zeta potential, entrapment efficiency, and release kinetics. Cytotoxicity and in vivo antitumor activity were evaluated. The micelles showed size around 13 nm, zeta potential near neutral (-0.5 mV), and encapsulation efficiency around 68.5% (irinotecan 3 mg/mL) with a sustained drug release within the first 8 h. The micelles were evaluated in a CT26 tumor animal model showing inhibition of tumor growth (89%) higher than free drug (68.7%). Body weight variation, hemolytic activity, hematological, and biochemical data showed that, at the dose of 7.5 mg/kg, the irinotecan-loaded micelles have low toxicity. In summary, our findings provide evidence that DSPE-mPEG 2k micelles could be considered potential carriers for future irinotecan delivery and their possible therapeutic application against colorectal cancer.

Background: Socioeconomic inequalities in tooth loss might be minimized or potentialized by the characteristics of the context where people live. We examined whether there is contextual variation in socioeconomic inequalities in tooth loss across Brazilian municipalities., Methods: Data from the 2010 National Oral Health Survey of 9633 adults living in 157 Brazilian municipalities were used. The individual socioeconomic indicators were education and household income. At the municipal level, we used the Municipal Human Development Index (HDI) as our contextual indicator of socioeconomic status (low:< 0.699 versus high: > 0.70). The Relative (RII) and Slope (SII) Indexes of Inequality, Relative (RCI), and Absolute (ACI) Concentration Indexes were calculated to compare the magnitude of education and income-based inequalities among municipalities with low versus high HDI. Multilevel Poisson regression models with random intercepts and slopes were developed., Results: At the individual level, adults with lower education & income reported more tooth loss. The mean number of missing teeth was 9.52 (95% CI: 7.93-11.13) and 6.95 (95% CI: 6.43-7.49) in municipalities with low and high HDI, respectively. Municipalities with high HDI showed higher relative and absolute education-based inequality. For income-based inequalities, higher SII and RCI was observed in municipalities with lower HDI. A significant cross-level interaction indicated that high-education adults reported fewer missing teeth when they lived in municipalities with high HDI compared to adults with the same education level living in low HDI municipalities. For individuals with the lowest education level, there was no difference in the number of teeth between those from municipalities with high and low HDI., Conclusions: There was a social gradient in tooth loss by education and income. Living in disadvantaged municipalities cannot overcome the risk associated with low schooling. The protective effect of higher education can be reduced when people live in disadvantaged areas.

Animal models of human diseases are crucial experimental tools to investigate the mechanisms involved in disease pathogenesis and to develop new therapies. In spite of the numerous animal models currently available that reproduce several neuropathological features of Parkinson disease (PD), it is challenging to have one that consistently recapitulates human PD conditions in both motor behaviors and biochemical pathological outcomes. Given that, we have implemented a new paradigm to expose rats to a chronic low dose of paraquat (PQ), using osmotic minipumps and characterized the developed pathologic features over time. The PQ exposure paradigm used lead to a rodent model of PD depicting progressive nigrostriatal dopaminergic neurodegeneration, characterized by a 41% significant loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc), a significant decrease of 18% and 40% of dopamine levels in striatum at week 5 and 8, respectively, and a significant 1.5-fold decrease in motor performance. We observed a significant increase of microglia activation state, sustained levels of α-synucleinopathy and increased oxidative stress markers in the SNpc. In summary, this is an explorative study that allowed to characterize an improved PQ-based rat model that recapitulates cardinal features of PD and may represent an attractive tool to investigate several mechanisms underlying the various aspects of PD pathogenesis as well as for the validation of the efficacy of new therapeutic approaches that targets different mechanisms involved in PD neurodegeneration., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This study aimed to map evidence-based guidelines for oral care of the dependent elders and perform the cross-cultural adaptation to Brazilian Portuguese. Initially, a systematized review was conducted in Medline, Scielo, Scopus, Web of Science, and Google Scholar databases without restrictions in search period or type of study. Articles in English, Spanish, and Brazilian Portuguese describing evidence-based guidelines for oral care, including oral hygiene recommendations, of institutionalized dependent elders were included as long as they presented an evaluation of evident quality. The guideline that met inclusion criteria was submitted to cross-cultural adaptation after obtaining permission from the original authors. Two hundred and nineteen references were found. Three selected articles described evidence-based guidelines for oral care, but the Oral Health Care Guideline for Older People in Long-term Care Institutions (OGOLI), originally developed and implemented in the Netherlands, was selected. It was based on evidence level A2 and consensus of experts and met the quality requirements of the Appraisal of Guidelines for Research & Evaluation (AGREE). This guideline presents oral care recommendations for elders with different levels of dependence in activities of daily living to be performed by caregivers and nursing staff. The adaptation of the OGOLI was mainly on the attributions of care providers, given the differences in professional regulations between Brazil and the Netherlands. The cross-cultural equivalence between OGOLI and its Brazilian Portuguese version was verified.

Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice. Here, we further addressed the possible early mechanisms that may relate to the observed rise in BP in mice lacking SIK1. SIK1 knockout (sik1 -/- ) and wild-type (sik1 +/+ ) littermate mice were challenged with either a high-salt (8% NaCl) or control (0.3% NaCl) diet for 7 days. Systolic BP was significantly increased in sik1 -/- mice after 7 days of high-salt diet as compared with sik1 +/+ mice and to sik1 -/- counterparts on a control diet. The renin-angiotensin-aldosterone system and the sympathetic nervous system were assayed to investigate possible causes for the increase in BP in sik1 -/- mice fed a 7-day high-salt diet. Although no differences in serum renin and angiotensin II levels were observed, a reduction in aldosterone serum levels was observed in mice fed a high-salt diet. Urinary L-DOPA and noradrenaline levels were significantly increased in sik1 -/- mice fed a high-salt diet as compared with sik1 -/- mice on a control diet. Similarly, the activity of dopamine β-hydroxylase (DβH), the enzyme that converts dopamine to noradrenaline, was significantly increased in the adrenal glands of sik1 -/- mice on a high-salt intake compared with sik1 +/+ and sik1 -/- mice on a control diet. Treatment with etamicastat (50 mg/kg/day), a peripheral reversible DβH inhibitor, administered prior to high-salt diet, completely prevented the systolic BP increase in sik1 -/- mice. In conclusion, SIK1 activity is necessary to prevent the development of salt-induced high blood pressure and associated SNS overactivity.

Background: Oral health-related quality of life (OHRQoL) has important implications for the clinical practice of dentistry and dental research and should contribute to professional judgment about restorative treatments and prosthetic replacement in patients who had reduced dentitions. The aim was to compare the OHRQoL among adults (35-44 years) categorized according to different definitions of reduced dentition and considering the use (or non-use) of dental prosthesis., Methods: This study used data from a probabilistic sample of adults in Sao Paulo, Brazil, 2015. OHRQoL was based on none items of Oral Impacts on Daily Performance (OIDP) index, as prevalence (at least one impact) and extent (the number of items with non-zero score). We used different criteria to assess dentition status: (1) Shortened Dental Arch (SDA): having 3-5 natural occlusal units (OUs) in posterior teeth and intact anterior region; (2) hierarchical functional classification system: a five-level stepwise classification of dentition; and (3) presence of ≥21 teeth. The use or nonuse of dental prosthesis was recorded. Negative binomial regression models involved the adjustment for social determinants of health., Results: Nearly half (53.1%) of the 5753 participating adults had at least one oral health issue impacting OHRQoL. OIDP prevalence in adults with SDA did not differ from those with more OUs (PR = 1.02; 95%CI 0.91-1.13). Individuals with non-functional dentition had worse OHRQoL regardless of their use of a dental prosthesis. Adults with fewer than 21 remaining teeth, ranked significantly higher in OIDP extent, regardless of dental prosthesis use (PR = 1.38; 95%CI 1.16-1.63 with prosthesis; PR = 1.62; 95%CI 1.19-2.20 without dental prosthesis)., Conclusions: Individuals with more missing teeth reported worse OHRQoL regardless of using a dental prosthesis. Preserving a functional dentition, even with missing teeth, is compatible with OHRQoL.

Objective: To analyse the frequency of dependence on others for oral hygiene and its association with hand deformities, frailty and dependence on others for basic activities of daily living (BADL) among elders with a history of leprosy., Background: Dependence on others for oral hygiene has not been considered in multifunctional geriatric assessments., Material and Methods: Edentulous elders with a history of leprosy who used complete dentures and resided in a former leprosy colony were classified as independent or partially/completely dependent on others for brushing their dentures or rinsing and for BADL, and as frail or robust. The presence of hand deformities was assessed by an occupational therapist., Results: 28.4% and 14.9% were completely/partially dependent on others for brushing and rinsing, respectively. The dependence for BADL was observed in 21.6% and hand deformities in 17.6%. A higher odds of dependence for brushing/rinsing was found among elders who were dependent on others for BADL. Brushing dependence (61.5%) was more frequent among participants with hand deformities than those without this condition (21.3%) (OR: 6.8; 95% IC: 1.2-37.9; P = .028). There was no association between frailty and brushing (P = .068) or rinsing (P = .202) dependence., Conclusion: Approximately one-third of elders have a dependence on others for brushing; a smaller proportion is dependent on others for rinsing. Older people who are dependent on others for BADL and who present hand deformities are more likely to be dependent on others for denture brushing and rinsing. Elders may perform oral self-care even when they present frailty., (© 2018 Gerodontology Association and John Wiley & Sons Ltd.)

The use of dopamine replacement therapies (DRT) in the treatment of Parkinson's disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD.

Purpose: A large number of asthmatic patients, particularly females, present inadequate disease control. Depressive symptoms are reportedly common in asthma and have been related to poor disease control, but the mechanism of this association is still unclear. Poor quality sleep, frequently observed in asthmatics, is also a manifestation of depression and has been related to uncontrolled asthma. This study aimed to investigate the relationship between depressive symptoms, sleep quality, and asthma control., Methods: This was a cross-sectional study of 123 women with previous diagnosis of asthma from a reference center in Fortaleza, Brazil. Depressive symptoms were assessed by the Beck Depression Inventory (BDI); quality of sleep was evaluated by the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness by the Epworth Sleepiness Scale (ESS), and asthma control by the Asthma Control Test (ACT)., Results: Inadequate asthma control (ACT <20) was found in 94 (76.4 %) subjects, depressive symptoms in 92 (74.8 %), poor quality sleep (PSQI >5) in 99 (80.49 %), and excessive daytime sleepiness (ESS ≥10) in 34 (27.64 %). Depressive symptoms were associated with both poor quality sleep (R = 0.326) and inadequate asthma control (R = -0.299). Regression analysis showed that depressive symptoms and sleep quality were independent predictors of the level of asthma control., Conclusion: Asthma control in women is independently associated with depressive symptoms and quality of sleep, suggesting that these patients might benefit from simple measures to promote healthy sleep behavior and sleep hygiene and also that routine screening for depression can be relevant, particularly, in poorly controlled cases.

Parkinson's disease is an age-associated progressive neurodegenerative disorder that has gained crescent social and economic impact due to the aging of the western society. All current therapies are symptomatic and fail to reverse or halt the progression of dopaminergic neurons loss. The discovery of the capability of neurotrophic factors to protect these neurons lead numerous research groups to focus their efforts in developing therapies aiming at promoting the control of Parkinson´s disease through the delivery of neurotrophic factors to the brain or by boosting their endogenous levels. Both strategies were successful in inducing protection of dopaminergic neurons and motor recovery in preclinical models of the disease. Contrariwise, very limited success was obtained in clinical studies, where glial cell line-derived neurotrophic factor and neurturin were the neurotrophic factors of choice for Parkinson's disease therapy. These drawbacks motivate the development of novel forms of delivery or the modification of the injected molecules aiming at providing a more stable and effective administration with improved diffusion in the target tissue, and without the immune responses observed in the earliest clinical studies. Although promising results were obtained with some of these new approaches performed in experimental models of the disease, they were not yet tested in human studies. In this review, we present the current knowledge on neurotrophic factors and their role in Parkinson's disease, focusing on the strategies that have been developed to increase their levels in target areas of the brain to achieve protection of dopaminergic neurons and motor behaviour recovery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Parkinson's disease (PD) is characterized by a selective degeneration of nigrostriatal dopaminergic pathway. Epidemiological studies revealed a male predominance of the disease that has been attributed to the female steroid hormones, mainly the estrogen. Estrogen neuroprotective effects have been shown in several studies, however the mechanisms responsible by these effects are still unclear. Previous data from our group revealed that glial cell line-derived neurotrophic factor (GDNF) is crucial to the dopaminergic protection provided by 17β-estradiol, and also suggest that the intracellular estrogen receptors (ERs) are not required for that neuroprotective effects. The present study aimed to investigate the contribution of the G protein-coupled ER (GPER) activation in estrogen-mediated dopaminergic neuroprotection against an insult induced by 1-methyl-4-phenylpyridinium (MPP(+)), and whether GPER neuroprotective effects involve the regulation of GDNF expression. Using primary mesencephalic cultures, we found that GPER activation protects dopaminergic neurons from MPP(+) toxicity in an extent similar to the promoted by a 17β-estradiol. Moreover, GPER activation promotes an increase in GDNF levels. Both, GDNF antibody neutralization or RNA interference-mediated GDNF knockdown prevented the GPER-mediated dopaminergic protection verified in mesencephalic cultures challenged with MPP(+). Overall, these results revealed that G1, a selective agonist of GPER, is able to protect dopaminergic neurons and that GDNF overexpression is a key feature to GPER induced the neuroprotective effects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Dopamine (DA) has been long implicated with the processes of memory. In long-term memory, the hippocampus and ventral tegmental area (VTA) use DA to enhance long-term potentiation, while prefrontal DA D1 receptors are involved in working memory. Deep brain stimulation (DBS) of specific brain areas have been shown to affect memory impairments in animal models. Here, we tested the hypothesis that DBS could reverse memory impairments by increasing the number of dopaminergic cells in the VTA. Rats received DBS at the level of the mammillothalamic tract, the anterior nucleus of the thalamus, and entorhinal cortex before euthanasia. These regions are part of the so-called memory circuit. Brain sections were processed for c-Fos and tyrosine hydroxylase (TH) immunocytochemistry in the VTA and the substantia nigra pars compacta (SNc). c-Fos, TH and c-Fos/TH immunoreactive cells were analyzed by means of stereology and confocal microscopy. Our results showed that DBS of the anterior nucleus of the thalamus induced substantial higher numbers of TH-immunoreactive cells in the VTA, while there were no significant differences between the experimental groups in the number of TH immunoreactive cells in the SNc, c-Fos immunoreactive cells and c-Fos/TH double-labeled cells in both the SNc and VTA. Our findings suggest a phenotypic switch, or neurotransmitter respecification, of DAergic cells specifically in the VTA which may be induced by DBS in the anterior nucleus of the thalamus.

Parkinson's disease (PD) is classically characterized by motor symptoms; however, non-motor symptoms (NMS) are increasingly recognized as relevant in disease-state, given the associated alterations in mood (depression and anxiety) and cognition. Here, particularly in regards to NMS, we aimed to compare the motor, emotional and cognitive behavior of three animal models of PD that trigger dopaminergic (DAergic) degeneration on both brain hemispheres: (i) the 6-hydroxydopamine (6-OHDA, 8 or 6 μg) lesion model; (ii) the paraquat (PQ) induced model, and (iii) a genetic model based on α-synuclein overexpression (α-syn). 6-OHDA and α-syn vector were injected bilaterally in the substantia nigra pars compacta (SNpc) of adult male Wistar rats; as for PQ delivery, micro-osmotic pumps were implanted in the interscapular region. Motor deficits were observed in all models, with histological analysis of tyrosine hydroxylase positive cells in the SNpc revealing a significant loss of DAergic neurons in all animal models. In addition, the α-syn animal model also presented a reduction in exploratory activity, and the 6-OHDA and PQ animals displayed a significant increase in both depressive- and anxiety-like behavior. Interestingly, cognitive impairment (working memory) was only observed in the 6-OHDA model. Overall, these PD models are suitable for mimicking the motor symptoms associated to PD, with each encompassing other relevant NMS components of the disorder that may prove beneficial for further studies in PD.

Neudesin (also known as neuron derived neurotrophic factor, Nenf) is a scarcely studied putative non-canonical neurotrophic factor. In order to understand its function in the brain, we performed an extensive behavioral characterization (motor, emotional, and cognitive dimensions) of neudesin-null mice. The absence of neudesin leads to an anxious-like behavior as assessed in the elevated plus maze (EPM), light/dark box (LDB) and novelty suppressed feeding (NSF) tests, but not in the acoustic startle (AS) test. This anxious phenotype is associated with reduced dopaminergic input and impoverished dendritic arborizations in the dentate gyrus granule neurons of the ventral hippocampus. Interestingly, shorter dendrites are also observed in the bed nucleus of the stria terminalis (BNST) of neudesin-null mice. These findings lead us to suggest that neudesin is a novel relevant player in the maintenance of the anxiety circuitry.

Background: Parkinson's disease (PD) is a chronic neurodegenerative condition that is characterized by motor symptoms as a result of dopaminergic degeneration, particularly in the mesostriatal pathway. However, in recent years, a greater number of clinical studies have focused on the emergence of non-motor symptoms in PD patients, as a consequence of damage on the mesolimbic and mesocortical dopaminergic networks, and on their significant impact on the quality of life of PD patients. Herein, we performed a thorough behavioral analysis including motor, emotional and cognitive dimensions, of the unilateral medial forebrain bundle (MFB) 6-hydroxidopamine (6-OHDA)-lesioned model of PD, and further addressed the impact of pharmacological interventions with levodopa and antidepressants on mood dimensions., Results: Based on apomorphine-induced turning behaviour and degree of dopaminergic degeneration, animals submitted to MFB lesions were subdivided in complete and incomplete lesion groups. Importantly, this division also translated into a different severity of motor and exploratory impairments and depressive-like symptoms; in contrast, no deficits in anxiety-like and cognitive behaviors were found in MFB-lesioned animals. Subsequently, we found that the exploratory and the anhedonic behavioural alterations of MFB-lesioned rats can be partially improved with the administration of both levodopa or the antidepressant bupropion, but not paroxetine., Conclusions: Our results suggest that this model is a relevant tool to study the pathophysiology of motor and non-motor symptoms of PD. In addition, the present data shows that pharmacological interventions modulating dopaminergic transmission are also relevant to revert the non-motor behavioral deficits found in the disease.

The extended amygdala, composed by the amygdaloid nuclei and the bed nucleus of the stria terminalis (BNST), plays a critical role in anxiety behavior. In particular, the link between the central nucleus of the amygdala (CeA) and the BNST seems to be critical to the formation of anxiety-like behavior. Chronic unpredictable stress (CUS) exposure is recognized as a validated animal model of anxiety and is known to trigger significant morphofunctional changes in the extended amygdala. Quite surprisingly, no study has ever analyzed the role of the CeA in the onset of stress-induced anxiety and fear conditioning behaviors; thus, in the present study we induced a bilateral excitotoxic lesion in the CeA of rats that were subsequently exposed to a chronic stress protocol. Data shows that the lesion in the CeA induces different results in anxiety and fear-behaviors. More specifically, lesioned animals display attenuation of the stress response and of stress-induced anxiety-like behavior measured in the elevated-plus maze (EPM) when compared with stressed animals with sham lesions. This attenuation was paralleled by a decrease of stress-induced corticosterone levels. In contrast, we did not observe any significant effect of the lesion in the acoustic startle paradigm. As expected, lesion of the CeA precluded the appearance of fear behavior in a fear-potentiated startle paradigm in both non-stressed and stressed rats. These results confirm the implication of the CeA in fear conditioning behavior and unravel the relevance of this brain region in the regulation of the HPA axis activity and in the onset of anxiety behavior triggered by stress.

Parkinson's disease (PD) is characterised by the preferential loss of dopaminergic neurones from the substantia nigra (SN) that leads to the hallmark motor disturbances. Animal and human studies suggest a beneficial effect of oestrogen to the nigrostriatal system, and the regulation of neurotrophic factor expression by oestrogens has been suggested as a possible mechanism contributing to that neuroprotective effect. The present study was designed to investigate whether the neuroprotection exerted by 17β-oestradiol on nigrostriatal dopaminergic neurones is mediated through the regulation of glial cell line-derived neurotrophic factor (GDNF) expression. Using an in vivo rat model of PD, we were able to confirm the relevance of 17β-oestradiol in defending dopaminergic neurones against 6-hydroxydopamine (6-OHDA) toxicity. 17β-oestradiol, released by micro-osmotic pumps, implanted 10 days before intrastriatal 6-OHDA injection, prevented the loss of dopaminergic neurones induced by 6-OHDA. 17β-oestradiol treatment also promoted an increase in GDNF protein levels both in the SN and striatum. To explore the relevance of GDNF increases to 17β-oestradiol neuroprotection, we analysed, in SN neurone-glia cultures, the effect of GDNF antibody neutralisation and RNA interference-mediated GDNF knockdown. The results showed that both GDNF neutralisation and GDNF silencing abolished the dopaminergic protection provided by 17β-oestradiol against 6-OHDA toxicity. Taken together, these results strongly identify GDNF as an important player in 17β-oestradiol-mediated dopaminergic neuroprotection., (© 2012 The Authors. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology.)

Neuroinflammation is recognized as a major factor in Parkinson's disease (PD) pathogenesis and increasing evidence propose that microglia is the main source of inflammation contributing to the dopaminergic degeneration observed in PD. Several studies suggest that astrocytes could act as physiological regulators preventing excessive microglia responses. However, little is known regarding how astrocytes modulate microglial activation. In the present study, using Zymosan A-stimulated midbrain microglia cultures, we showed that astrocytes secrete factors capable of modulating microglial activation, namely its phagocytic activity and the production of reactive oxygen species since both parameters were highly diminished in cells incubated with astrocytes conditioned media (ACM). Glial cell line-derived neurotrophic factor (GDNF), cerebral dopamine neurotrophic factor (CDNF) and brain-derived neurotrophic factor (BDNF), known to have a neuroprotective role in the nigrostriatal system, are among the candidates to be astrocyte-secreted molecules involved in the modulation of microglial activation. The effect of ACM on Zymosan A-induced microglial activation was abolished when the GDNF present in the ACM was abrogated using a specific antibody, but not when ACM was neutralized with anti-CDNF, anti-BDNF or with a heat-inactivated GDNF antibody. In addition, media conditioned by astrocytes silenced for GDNF were not able to prevent microglial activation, whereas supplementation of non-conditioned media with GDNF prevented the activation of microglia evoked by Zymosan A. Taken together, these results indicate that astrocyte-derived GDNF plays a major contribution to the control of midbrain microglial activation, suggesting that GDNF can protect from neurodegeneration through the inhibition of neuroinflammation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To describe the strategies and results obtained by the early diagnosis and prevention of an oral cancer campaign targeting the population aged 60 years or older developed since 2001 in the state of São Paulo., Methods: The main strategies used to develop the campaign were described based on the review of documents issued by the Health Ministry, National Cancer Institute, São Paulo State Health Department, Oncocentro Foundation of São Paulo, São Paulo City Health Department, School of Public Health at the University of São Paulo (USP), and Santa Marcelina Health Care Center. The impact of the campaign on the incidence of new cases of oral cancer in the target population was evaluated., Results: In 2001, 90,886 elderly were examined vs. 629,613 in 2009. The following strategies were identified: training of professionals, development of printed materials to guide municipal governments in developing the campaign and using standardized codes and criteria, guidelines for data consolidation, establishment of patient referral flows, practical training with a specialist at the basic health care unit after the follow-up examination of individuals presenting changes in soft tissues, and increase in the number of oral diagnosis services. Between 2005 and 2009, there was a significant reduction in the rate of confirmed cases of oral cancer per 100,000 individuals examined, from 20.89 to 11.12 (P = 0.00003)., Conclusions: The campaign was beneficial to the oral health of the elderly and could be extended to include other age groups and regions of the country. It may also provide a basis for the development of oral cancer prevention actions in other countries, as long as local characteristics are taken into account.