AT1 receptor autoantibodies mediate effects of metabolic syndrome on dopaminergic vulnerability.

The metabolic syndrome has been associated to chronic peripheral inflammation and related with neuroinflammation and neurodegeneration, including Parkinson's disease. However, the responsible mechanisms are unclear. Previous studies have involved the brain renin-angiotensin system in progression of Parkinson's disease and the angiotensin receptor type 1 (AT1) has been recently revealed as a major marker of dopaminergic vulnerability in humans. Dysregulation of tissue renin-angiotensin system is a key common mechanism for all major components of metabolic syndrome. Circulating AT1 agonistic autoantibodies have been observed in several inflammation-related peripheral processes, and activation of AT1 receptors of endothelial cells, dopaminergic neurons and glial cells have been observed to disrupt endothelial blood -brain barrier and induce neurodegeneration, respectively. Using a rat model, we observed that metabolic syndrome induces overactivity of nigral pro-inflammatory renin-angiotensin system axis, leading to increase in oxidative stress and neuroinflammation and enhancing dopaminergic neurodegeneration, which was inhibited by treatment with AT1 receptor blockers (ARBs). In rats, metabolic syndrome induced the increase in circulating levels of LIGHT and other major pro-inflammatory cytokines, and 27-hydroxycholesterol. Furthermore, the rats showed a significant increase in serum levels of proinflammatory AT1 and angiotensin converting enzyme 2 (ACE2) autoantibodies, which correlated with levels of several metabolic syndrome parameters. We also found AT1 and ACE2 autoantibodies in the CSF of these rats. Effects of circulating autoantibodies were confirmed by chronic infusion of AT1 autoantibodies, which induced blood-brain barrier disruption, an increase in the pro-inflammatory renin-angiotensin system activity in the substantia nigra and a significant enhancement in dopaminergic neuron death in two different rat models of Parkinson's disease. Observations in the rat models, were analyzed in a cohort of parkinsonian and non-parkinsonian patients with or without metabolic syndrome. Non-parkinsonian patients with metabolic syndrome showed significantly higher levels of AT1 autoantibodies than non-parkinsonian patients without metabolic syndrome. However, there was no significant difference between parkinsonian patients with metabolic syndrome or without metabolic syndrome, which showed higher levels of AT1 autoantibodies than non-parkinsonian controls. This is consistent with our recent studies, showing significant increase of AT1 and ACE2 autoantibodies in parkinsonian patients, which was related to dopaminergic degeneration and neuroinflammation. Altogether may lead to a vicious circle enhancing the progression of the disease that may be inhibited by strategies against production of these autoantibodies or AT1 receptor blockers (ARBs).

Angiotensin type-1 receptor and ACE2 autoantibodies in Parkinson´s disease.

The role of autoimmunity in neurodegeneration has been increasingly suggested. The renin-angiotensin system (RAS) autoantibodies play a major role in several peripheral inflammatory processes. Dysregulation of brain RAS has been involved in neuroinflammation and neurodegeneration. We aimed to know whether angiotensin type-1 receptor (AT1) autoantibodies (AT1 agonists) and angiotensin-converting enzyme 2 (ACE2) autoantibodies (ACE2 antagonists) may be involved in Parkinson's disease (PD) progression and constitute a new therapeutical target. Both AT1 and ACE2 serum autoantibodies were higher in a group of 117 PD patients than in a group of 106 controls. Serum AT1 autoantibodies correlated with several cytokines, particularly Tumor Necrosis Factor Ligand Superfamily Member 14 (TNFSF14, LIGHT), and 27-hydroxycholesterol levels. Serum ACE2 autoantibodies correlated with AT1 autoantibodies. Both autoantibodies were found in cerebrospinal fluid (CSF) of four PD patients with CSF samples. Consistent with the observations in patients, experimental dopaminergic degeneration, induced by 6-hydroxydopamine, increased levels of autoantibodies in serum and CSF in rats, as well as LIGHT levels and transglutaminase activity in rat substantia nigra. In cultures, administration of AT1 autoantibodies enhanced dopaminergic neuron degeneration and increased levels of neuroinflammation markers, which was inhibited by the AT1 antagonist candesartan. The results suggest dysregulation of RAS autoantibodies as a new mechanism that can contribute to PD progression. Therapeutical strategies blocking the production, or the effects of these autoantibodies may be useful for PD treatment, and the results further support repurposing AT1 blockers (ARBs) as treatment against PD progression.

Angiotensin System Autoantibodies Correlate With Routine Prognostic Indicators for COVID-19 Severity.

Objective: We previously showed that angiotensin type-1 receptor and ACE2 autoantibodies (AT1-AA, ACE2-AA) are associated with COVID-19 severity. Our aim is to find correlations of these autoantibodies with routine biochemical parameters that allow an initial classification of patients. Methods: In an initial cohort of 119 COVID-19 patients, serum AT1-AA and ACE2-AA concentrations were obtained within 24 h after diagnosis. In 50 patients with a complete set of routine biochemical parameters, clinical data and disease outcome information, a Random Forest algorithm was used to select prognostic indicators, and the Spearman coefficient was used to analyze correlations with AT1-AA, ACE2-AA. Results: Hemoglobin, lactate dehydrogenase and procalcitonin were selected. A decrease in one unit of hemoglobin, an increase in 0.25 units of procalcitonin, or an increase in 100 units of lactate dehydrogenase increased the severity of the disease by 35.27, 69.25, and 3.2%, respectively. Our binary logistic regression model had a predictive capability to differentiate between mild and moderate/severe disease of 84%, and between mild/moderate and severe disease of 76%. Furthermore, the selected parameters showed strong correlations with AT1-AA or ACE2-AA, particularly in men. Conclusion: Hemoglobin, lactate dehydrogenase and procalcitonin can be used for initial classification of COVID-19 patients in the admission day. Subsequent determination of more complex or late arrival biomarkers may provide further data on severity, mechanisms, and therapeutic options.

Association between xerostomia, oral and general health, and obesity in adults. A cross-sectional pilot study / Asociación entre xerostomía, salud bucal y general, y obesidad en adultos. Un estudio piloto transversal

Background: The objective of this study was to analyse the association between oral and general health variablesand obesity indicators with the sensation of dry mouth or xerostomia as evaluated on the Xerostomia Inventory(XI).Material and Methods: A total of 354 randomly selected subjects participated in this cross-sectional pilot studyand completed an anonymous questionnaire. Anthropometric, clinical, and xerostomic variables were evaluated.Kruskal-Wallis, ANOVA and Bonferroni test were used for multiple comparisons. ROC curves and multinomiallogistic regression were used to determine the (OR) risk of xerostomia.Results: A total of 30.7 % of respondents reported xerostomia based on XI. The dry mouth question, the XItaken as a “gold standard”, showed a diagnostic sensitivity of 70.37 %, and a specificity of 83.27 % (AUC=0.768,p<0.001). Logistical regression showed the highest xerostomia OR was associated to patients with bad self-per-ceived health, 6.31 (CI 95% 2.89-13.80, p<0.001). In the model adjusted for tooth mobility, bone or respiratorydiseases, and the consumption of anxiolytics and antidepressants, the OR was 3.46 (CI 95% 1.47-8.18, p=0.005).Conclusions: a high prevalence of xerostomia was found in this cross-sectional pilot study, which was significantlymore frequent in women, and increased with age. Xerostomia was associated to several systemic diseases, psycho-logical conditions, and oral functional disorders such as tooth mobility.These preliminary results can serve as the basis for developing guidelines for the application of innovative mea-sures designed to improve the quality of life of individuals with xerostomia.(AU)

Autoantibodies against ACE2 and angiotensin type-1 receptors increase severity of COVID-19.

The renin-angiotensin system (RAS) plays a major role in COVID-19. Severity of several inflammation-related diseases has been associated with autoantibodies against RAS, particularly agonistic autoantibodies for angiotensin type-1 receptors (AA-AT1) and autoantibodies against ACE2 (AA-ACE2). Disease severity of COVID-19 patients was defined as mild, moderate or severe following the WHO Clinical Progression Scale and determined at medical discharge. Serum AA-AT1 and AA-ACE2 were measured in COVID-19 patients (n = 119) and non-infected controls (n = 23) using specific solid-phase, sandwich enzyme-linked immunosorbent assays. Serum LIGHT (TNFSF14; tumor necrosis factor ligand superfamily member 14) levels were measured with the corresponding assay kit. At diagnosis, AA-AT1 and AA-ACE2 levels were significantly higher in the COVID-19 group relative to controls, and we observed significant association between disease outcome and serum AA-AT1 and AA-ACE2 levels. Mild disease patients had significantly lower levels of AA-AT1 (p < 0.01) and AA-ACE2 (p < 0.001) than moderate and severe patients. No significant differences were detected between males and females. The increase in autoantibodies was not related to comorbidities potentially affecting COVID-19 severity. There was significant positive correlation between serum levels of AA-AT1 and LIGHT (TNFSF14; rPearson = 0.70, p < 0.001). Both AA-AT1 (by agonistic stimulation of AT1 receptors) and AA-ACE2 (by reducing conversion of Angiotensin II into Angiotensin 1-7) may lead to increase in AT1 receptor activity, enhance proinflammatory responses and severity of COVID-19 outcome. Patients with high levels of autoantibodies require more cautious control after diagnosis. Additionally, the results encourage further studies on the possible protective treatment with AT1 receptor blockers in COVID-19.

Nestin Expression Is Associated with Relapses in Head and Neck Lesions.

BACKGROUND: The aim was to investigate the clinical significance of nestin immunohistochemical expression in head and neck area lesions and to study its role in patient survival and recurrence. METHODS: 39 (44.3%) nasosinus, 37 (42%) major salivary gland (6 submandibular and 31 parotid) and 12 (13.6%) oral cavity lesions of paraffin-embedded samples were retrospectively included. RESULTS: The expression was categorized into grades, negative for 55 (62.5%) cases, grade 1 in 10 cases (11.4%), grade 2 in 12 cases (13.6%), and grade 3 in 11 cases (12.5%); 100% of pleomorphic adenomas were positive for nestin with grade 3 intensity, 100% of polyps and inverted papillomas were negative (p < 0.001). The lowest estimate of disease-free-survival (DFS) was for grade 1 expression, with 50 months, confidence interval (CI): 95% 13.3-23.9 months and the highest for grade 3 expression, 167.9 months (CI: 95% 32.1-105 months; Log-Rank = 14.846, p = 0.002). ROC (receiver operating characteristic) curves revealed that the positivity for nestin (+/-) in relation to malignancy, presented a sensitivity of 50.98%, a specificity of 81.08%, with an area under the curve of 0.667 (p = 0.009). CONCLUSIONS: Nestin could be a useful marker to detect the presence of stem cells in head and neck tumors that have a role in tumor initiation and progression.

Metabolic syndrome and masticatory hypofunction: a cross-sectional study.

The objective of this paper is to clarify the rate of abdominal obesity (AO), waist-to-height ratio (WHtR), metabolic syndrome (MetS) and determine the relationship with the masticatory capacity (MC) in terms of total functional tooth units (t-FTU) in a representative sample of older Spanish adults. This cross-sectional study included 544 adult subjects aged 50 or over, who were prospectively selected and who had participated in a survey conducted in a primary dental care service in a Public Oral Health Service in Spain. Anthropometric, clinical variables and t-FTUs were obtained through a calibrated and well-established protocol. Univariate and multivariate binary and multinomial logistic regression analyses were developed. With regards to the t-FTU or MC, it was poor in 60.3%, good in 17.6%, and complete in 22.1% of the sample. The univariate odss ratio (OR) for MetS and AO increased as the MC decreased and as the age group increased. With regards to gender, women presented with an OR of 5.56 (CI 95% 3.70-8.38). With regards to the WHtR-a3 (WHtR grouped into three categories), the univariate ORs were all significant for morbid obesity compared to the healthy group, with a risk of 6.86 (CI 95% 3.23-14.58) for patients with poor MC compared to those with complete MC. Masticatory hypofunctionality could be associated with the presence of MetS. Clinical relevance: The number of t-FTUs is directly related to AO.

Clinical anatomy of cervical spondylosis

The aim of this study is to describe the anatomical alterations in complementary tests (MRI and EMG) in patients with cervicobrachialgia according to sex and age. Retrospective study of 184 patients with cervicobrachialgia who underwent cervical MRI and EMG. The variables analyzed were gender, age, elements of spondylosis (osteophytes, arthropathy, spondylolisthesis and canal stenosis), the type of disc disease (protrusion and herniated disc) and curvature in the sagittal plane. The EMG was used to evaluate the neurogenic findings in the muscles dependent on the spinal roots of C4 to C8-T1.Average age was 53.65±11.96 years. The patients were evaluated for the presence of osteophytes (n = 111), arthropathy (n = 76), spondylolisthesis (n = 15) and stenosis of the spinal canal (n = 35). The highest incidences were osteophytes in C5-C6 (n = 108), protrusions in C5-C6 (n = 58), herniated disc in C5-C6 (n=18) and neurogenic findings in C7 (n = 130). The rectification of cervical lordosis appeared in 124 patients.S pondylosis increases with age. Disc herniations, disc protrusions and motor radiculopathy are more frequent in the 5th to 6th years of life. In patients with cervicobrachialgia, the sagittal rectification is more common than the normal lordosis

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Volumetric study of the maxillary sinus in patients with sinus pathology.

OBJECTIVES: The aim of this study is 1) to obtain the area and volumes of the maxillary sinuses in patients affected by clinically unilateral sinus pathology by comparing the results to the contralateral sinus and 2) to determine the importance of the volumetric measures when diagnosing the percentage of sinus obliteration. MATERIALS AND METHODS: A single-centre observational retrospective clinical study was conducted in 214 patients with clinically unilateral sinus pathologies. Linear (mm), area (mm2) and volume (mm3) measurements were taken from Cone Beam Computed Tomography (CBCT) images of the affected sinus as well as from the contralateral ones. Histopathological study was performed using haematoxylin/eosin and PAS or Groccot stains. The lesions were classified into non-specific sinusitis, polyps, inverted papilloma, fungal sinusitis, cysts, mucocele and other lesions. Chi-squared test, ANOVA for independent samples and Pearson test were used for the statistical analysis. RESULTS: A total of 100 sinuses were measured in 50 patients (28 men and 22 women, with an age of 43.6 years (SD = 18.3), 50 pathological and 50 healthy contralateral sinuses. The three-dimensional occupation volume of the affected sinuses was 97.1 mm3 (62.5%) vs. 40.6 mm3 (22.8%) in the healthy ones (p<0.0001). The medial-lateral width of the sinus in the frontal plane was significantly higher in the cysts group (32.4 mm, CI: 23-41.8 mm). CONCLUSION: In medical terms, the global percentage of occupation determined using the classic manual determination method does not differ from the three-dimensional percentage calculated using specific complex software.

Ex vivo vs. in vivo antibacterial activity of two antiseptics on oral biofilm.

AIM: To compare the immediate antibacterial effect of two application methods (passive immersion and active mouthwash) of two antiseptic solutions on the in situ oral biofilm. MATERIAL AND METHODS: A randomized observer-masked crossover study was conducted. Fifteen healthy volunteers wore a specific intraoral device for 48 h to form a biofilm in three glass disks. One of these disks was used as a baseline; another one was immersed in a solution of 0.2% Chlorhexidine (0.2% CHX), remaining the third in the device, placed in the oral cavity, during the 0.2% CHX mouthwash application. After a 2-weeks washout period, the protocol was repeated using a solution of Essential Oils (EO). Samples were analyzed for bacterial viability with the confocal laser scanning microscope after previous staining with LIVE/DEAD® BacLight™. RESULTS: The EO showed a better antibacterial effect compared to the 0.2% CHX after the mouthwash application (% of bacterial viability = 1.16 ± 1.00% vs. 5.08 ± 5.79%, respectively), and was more effective in all layers (p < 0.05). In the immersion, both antiseptics were significantly less effective (% of bacterial viability = 26.93 ± 13.11%, EO vs. 15.17 ± 6.14%, 0.2% CHX); in the case of EO immersion, there were no significant changes in the bacterial viability of the deepest layer in comparison with the baseline. CONCLUSIONS: The method of application conditioned the antibacterial activity of the 0.2% CHX and EO solutions on the in situ oral biofilm. The in vivo active mouthwash was more effective than the ex vivo passive immersion in both antiseptic solutions. There was more penetration of the antiseptic inside the biofilm with an active mouthwash, especially with the EO. Trial registered in clinicaltrials.gov with the number NCT02267239. URL: https://clinicaltrials.gov/ct2/show/NCT02267239.