Topological analysis of sharp-wave ripple waveforms reveals input mechanisms behind feature variations.

The reactivation of experience-based neural activity patterns in the hippocampus is crucial for learning and memory. These reactivation patterns and their associated sharp-wave ripples (SWRs) are highly variable. However, this variability is missed by commonly used spectral methods. Here, we use topological and dimensionality reduction techniques to analyze the waveform of ripples recorded at the pyramidal layer of CA1. We show that SWR waveforms distribute along a continuum in a low-dimensional space, which conveys information about the underlying layer-specific synaptic inputs. A decoder trained in this space successfully links individual ripples with their expected sinks and sources, demonstrating how physiological mechanisms shape SWR variability. Furthermore, we found that SWR waveforms segregated differently during wakefulness and sleep before and after a series of cognitive tasks, with striking effects of novelty and learning. Our results thus highlight how the topological analysis of ripple waveforms enables a deeper physiological understanding of SWRs.

Histological and histomorphometric study of human palatal mucosa: Implications for connective tissue graft harvesting.

AIMS: To analyse the histological structure and histomorphometric characteristics of human hard palatal mucosa in order to determine the donor site of choice for connective tissue grafts from a histological point of view. MATERIALS AND METHODS: Palatal mucosa samples from six cadaver heads were harvested at four sites: incisal, premolar, molar and tuberosity. Histological and immunohistochemical techniques were performed, as was histomorphometric analysis. RESULTS: In the current study, we found that the density and size of cells were higher in the superficial papillary layer, whereas the thickness of the collagen bundles increased in the reticular layer. Excluding the epithelium, the mean percentage of lamina propria (LP) and submucosa (SM) was 37% and 63%, respectively (p < .001). LP thickness showed similar values in the incisal, premolar and molar regions, and a significantly greater thickness in tuberosity (p < .001). The thickness of SM increased from incisal to premolar and molar, disappearing in the tuberosity (p < .001). CONCLUSIONS: As dense connective tissue of LP is the tissue of choice for connective tissue grafts, the best donor site from a histological point of view is tuberosity because it is composed only of a thick LP without the presence of a loose submucosal layer.

Immunohistological study of the density and distribution of human penile neural tissue: gradient hypothesis.

Immunohistological patterns of density and distribution of neural tissue in the human penis, including the prepuce, are not fully characterized, and effects of circumcision (partial or total removal of the penile prepuce) on penile sexual sensation are controversial. This study analyzed extra- and intracavernosal innervation patterns on the main penile axes using formalin-fixed, paraffin-embedded human adult and fetal penile tissues, single- and double-staining immunohistochemistry and a variety of neural and non-neural markers, with a special emphasis on the prepuce and potential sexual effects of circumcision. Immunohistochemical profiles of neural structures were determined and the most detailed immunohistological characterizations to date of preputial nerve supply are provided. The penile prepuce has a highly organized, dense, afferent innervation pattern that is manifest early in fetal development. Autonomically, it receives noradrenergic sympathetic and nitrergic parasympathetic innervation. Cholinergic nerves are also present. We observed cutaneous and subcutaneous neural density distribution biases across our specimens towards the ventral prepuce, including a region corresponding in the adult anatomical position (penis erect) to the distal third of the ventral penile aspect. We also describe a concept of innervation gradients across the longitudinal and transverse penile axes. Results are discussed in relation to the specialized literature. An argument is made that neuroanatomic substrates underlying unusual permanent penile sensory disturbances post-circumcision are related to heightened neural levels in the distal third of the ventral penile aspect, which could potentially be compromised by deep incisions during circumcision.

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).

Selective serotonin reuptake inhibitors as a risk factor for dental implant failure: a retrospective clinical study.

The trend in recent decades in Europe and the United States points to an exponential increase in the consumption of antidepressant drugs and, in particular, selective serotonin reuptake inhibitors (SSRIs). This retrospective study aimed to investigate whether there is an association between SSRI intake and dental implant (DI) failure or survival and, secondarily, to investigate the influence of other systemic and local factors. This retrospective cohort study was done in accordance with the the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for observational studies. A total of 170 patients received 573 DIs between 2014 and 2020.The reported DI failure rate was 6.11% (n = 35 DIs). Of these 18.31% failed in patients treated with SSRIs while 4.38% failed in patients who were not prescribed SSRIs (p < 0.001). Specifically, use of these drugs was associated with a hazard ratio rate of DI failure that was 4.53 times higher (95% CI: 1.93 to 10.61), and in the multivariate analysis, a 3.70 times higher adjusted risk was found. A lower DI survival rate at 90 months' follow up was also observed in these patients compared with those not taking them (84.30% vs 96%, respectively; p = 0.00014). With the limitations of the present study it can be affirmed that there is a relation between the intake of SSRIs and DI failure, as well as a lower survival rate in these patients.

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.

Analysis of the Radiological Changes of the Sinus Membrane Using Cone Beam Computed Tomography and Its Relationship with Dental Treatments. A Retrospective Study.

The aim of this study was to identify the most relevant dental factors and iatrogenic causes in the development of pathological changes to the sinus membrane and to analyse their possible influence on the development of odontogenic sinusitis. A descriptive, observational study was designed, with 276 patients who had been evaluated via cone beam computed tomography, analysing possible sinus thickening factors, such as apical infections, endodontic treatments, periodontitis, radicular cysts and impacted teeth, as well as iatrogenic factors caused by implant treatments or the development of oroantral communications produced during tooth extraction manoeuvres. Among the dental factors, periodontitis (47.1%), apical pathology (23.5%) and endodontic treatments (23.1%) were the predominant causes of sinus membrane thickening that most frequently produced an occupancy between 2 and 10 mm. Regarding the implant treatments, the placement of implants through the floor of the maxillary sinus was the main cause (9.8%), followed by sinus elevation techniques (6.2%). Dental extraction was the first cause of oroantral communication (5.0%), being the procedure that caused the greatest thickening of the sinus membrane. This study highlights the importance of dental treatments and iatrogenic factors in sinus pathology, and the need for diagnostic interrelations between the different specialists who address this pathology.

MRI evaluation of the peripheral attachments of the lateral meniscal body: the menisco-tibio-popliteus-fibular complex.

PURPOSE: To determine, identify and measure the structures of the menisco-tibio-popliteus-fibular complex (MTPFC) with magnetic resonance imaging (MRI) in knees without structural abnormalities or a history of knee surgery. METHODS: One-hundred-and-five knees without prior injury or antecedent surgery were analyzed by means of MRI. The average age was 50.1 years ± 14.8. All the measurements were performed by three observers. The peripherical structures of the lateral meniscus body were identified to determine the location, size, and thickness of the entire MTPFC. The distance to other "key areas" in the lateral compartment was also studied and compared by gender and age. RESULTS: The lateral meniscotibial ligament (LMTL) was found in 97.1% of the MRIs, the popliteofibular ligament (PFL) in 93.3%, the popliteomeniscal ligaments (PML) in 90.4% and the meniscofibular ligament (MFL) in 39%. The anteroposterior distance of the LMTL in an axial view was 20.7 mm ± 3.9, the anterior thickness of the LMTL was 1.1 mm ± 0.3, and the posterior thickness of the LMTL 1.2 mm ± 0.1 and the height in a coronal view was 10.8 mm ± 1.9. The length of the PFL in a coronal view was 8.7 mm ± 2.5, the thickness was 1.4 mm ± 0.4 and the width in an axial view was 7.8 mm ± 2.2. CONCLUSIONS: The MTPFC has a constant morphological and anatomical pattern for three of its main ligaments and can be easily identified and measured in an MRI; the MFL has a lower prevalence, considering a structure difficult to identify by 1.5 T MRI.

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.

Asymmetry of dental or joint anatomy or impaired chewing function contribute to chronic temporomandibular joint disorders.

INTRODUCTION: The etiologies of most chronic temporomandibular joint disorders are unknown. However, an association between habitual chewing on a particular side and chronic temporomandibular joint disorders has been reported. The aim of this study was to investigate the differences between sides (affected vs unaffected) of biodynamic factors (including lateral dental guidance determined by dental anatomy) or condylar path angles (determined by temporomandibular joint morphology) and chewing function (physiological alternate chewing vs single habitual chewing side). The study scope was to investigate possible etiological factors to improve the understanding of temporomandibular joint disorders. The null hypothesis was that no difference would be found between sides that are or are not affected by chronic temporomandibular joint disorders in chewing function or in levels of dental or temporomandibular joint remodeling. METHODS: This cross-sectional, double-blind study involved 24 adults with substantial, chronic, unilateral symptoms diagnosed as temporomandibular joint disorders. Chewing function, temporomandibular joint remodeling (using axiography) and dental anatomy (lateral guidance angles using kinesiography) were assessed. RESULTS: Habitual chewing on one particular side was observed in 17 of 24 participants; significantly more (n=15) chewed on the affected side than on the unaffected side (P=0.002 in a two-tailed Fisher's exact test; risk estimate=4.5; 95% CI 1.326-15.277). The condylar path (CP) angle was steeper on the affected side than on the unaffected side (mean (standard deviation)=50.52° (9.98°) versus 45.50° (7.98°); P=0.002 in a two-tailed t-test). The lateral guidance (LG) angles were flatter on the affected side in all 24 participants. CONCLUSION: Our results suggest that habitual chewing on one side may be associated with increasing condylar path, with flattening lateral guidance angles, and also with chronic temporomandibular joint disorder on the habitual chewing side.

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.

Horizontal transmission of Piscirickettsia salmonis from the wild sub-Antarctic notothenioid fish Eleginops maclovinus to rainbow trout (Oncorhynchus mykiss) under experimental conditions.

Piscirickettsia salmonis is the aetiological agent of piscirickettsiosis, a bacterial disease that affects farmed salmonids, causing high mortalities and significant economic losses in the Chilean salmon farm industry. Given the Chilean native fish species Patagonian blenny, Eleginops maclovinus, lives in the vicinity of salmon farms, it is relevant to clarify the epidemiological role that this species could play in the transmission and/or dissemination of this pathogen. This study aimed to evaluate the bidirectional transmission of P. salmonis between the Patagonian blenny and Oncorhynchus mykiss (rainbow trout), via a cohabitation challenge model. The results of this study demonstrated the transmission of the bacteria from Patagonian blennies to rainbow trout, considering the specific mortality in cohabitant rainbow trout, reaching 46%: the necropsy of these specimens, evidencing the characteristic pathological lesions of the disease and the positive results of the qPCR analysis for P. salmonis, in the same individuals. In contrast, no mortalities of Patagonian blenny specimens were recorded in the challenged experimental groups. This study is the first report showing the horizontal transmission of P. salmonis from a native non-salmonid species, such as the Patagonian blenny, to a salmonid species, generating the disease and specific mortality in rainbow trout, using a cohabitation challenge.

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.