Review of the comparative pathological and immunohistochemical features of human and canine cutaneous melanocytic neoplasms.

Melanocytic neoplasms originate from melanocytes and melanoma, the malignant form, is a common canine neoplasm and the most aggressive human skin cancer. Despite many similarities between these neoplasms in both species, only a limited number of studies have approached these entities in a comparative manner. Therefore, this review compares benign and malignant melanocytic neoplasms in dogs and humans, exclusively those arising in the haired skin, with regard to their clinicopathological, immunohistochemical and molecular aspects. Shared features include spontaneous occurrence, macroscopic features and microscopic findings when comparing human skin melanoma in the advanced/invasive stage and canine cutaneous melanoma, immunohistochemical markers and several histopathological prognostic factors. Differences include the apparent absence of active mutations in the BRAF gene in canine cutaneous melanoma and less aggressive clinical behaviour in dogs than in humans. Further studies are required to elucidate the aetiology and genetic development pathways of canine cutaneous melanocytic neoplasms. Evaluation of the applicability of histopathological prognostic parameters commonly used in humans for dogs are also needed. The similarities between the species and the recent findings regarding genetic mutations in canine cutaneous melanomas suggest the potential utility of dogs as a natural model for human melanomas that are not related to ultraviolet radiation.

Improving droplet microfluidic systems for studying single bacteria growth.

Antimicrobial resistance remains a global threat with ~ 5 million deaths in 2019 alone and 10 million deaths projected every year by 2050. Current tools employed in the analysis of bacteria can be time inefficient, leading to delayed diagnosis and treatment. In this work, we develop a microfluidic setup capable of bacteria incubation and detection of growth in ~ 2 h. We fabricated polydimethylsiloxane (PDMS) microchips via soft lithography, enclosed microchannels by plasma bonding to glass, and utilized PDMS blocks for simplified connection of devices to a flow system. We generated uniform droplets enclosing zero, one or two bacteria within our devices, and incubated droplet-encapsulated bacteria with 100 × lower concentrations of a fluorescence probe of bacterial growth compared to prior work. We assessed bacterial growth via laser induced fluorescence after room temperature incubation for 2 h and obtained a range of signals corresponding to droplets with or without bacteria. Our devices allow for online droplet incubation, monitoring, detection, and tracking. Developing microfluidic chips for single bacteria studies will improve the analysis and treatment of antimicrobial resistance.

Efficacy and safety of tocilizumab in adult-onset Still's disease: Real-life experience from the international AIDA registry.

BACKGROUND/OBJECTIVES: Long-term efficacy and safety of tocilizumab (TCZ) in adult-onset Still's disease (AOSD) mostly derive from small case series. Herein we report a registry-based study investigating TCZ efficacy and safety in a cohort of patients with AOSD evaluated by clinical and serum inflammatory markers as well as drug retention rate analysis. METHODS: This is an international multicentre study analyzing data from patients with AOSD regularly enrolled in the AIDA registry. TCZ efficacy was evaluated between baseline and last follow-up assessment in terms of changes in the Pouchot score and laboratory findings. Drug-retention rate was estimated by the Kaplan-Meier method, while Cox-regression analysis was employed to detect potential predictive factors of treatment withdrawal. RESULTS: Data from 31 patients (15 men, 16 women) refractory to the conventional therapies and treated with TCZ were extracted from the AIDA registry. Mean ± SD time of treatment duration with TCZ was 24.32 ± 20.57 months. Median (IRQ) Pouchot score significantly decreased throughout the study period (p=0.001) with a significant difference between baseline [2.00 (4.00)] and 6 month-follow-up [0.00 (0.00)] (p=0.003) and between baseline and last follow-up assessment [0.00 (0.00)] (p=0.032), while no differences were observed between 6 month-evaluation and last follow-up assessment (p=0.823). Similarly, laboratory parameters significantly decreased from baseline to the last follow-up visit. With regard to drug survival, cumulative TCZ retention rate at 12-, 24-, and 36-month follow-up visit were 83.1%, 71.7% and 63.7%, respectively, without significant differences between biologic naïve patients and those previously treated with other biologics (p=0.329). Likewise, no significant differences were observed between chronic articular course of AOSD and other types of disease course (p=0.938) or between patients co-administered with conventional immunosuppressants and patients receiving TCZ as monotherapy (p=0.778). Cox-regression analysis identified no variable associated with a higher hazard of treatment withdrawal. Treatment was discontinued in 9 patients due to long-term remission (n=4), adverse events (n=2), loss of efficacy (n=1), non-medical reason (n=1) and unspecified cause (n=1). Mean glucocorticosteroids daily dose significantly decreased from baseline (18.36 ± 24.72 mg) to the last follow-up assessment (4.02 ± 4.99 mg, p=0.003). CONCLUSIONS: TCZ allows control of disease activity as well as normalization of serum inflammatory markers in both systemic and chronic articular form of AOSD. Additionally, TCZ displays an excellent drug retention rate while minimizing the risk of long-term exposure to corticosteroids.

Clinical and Eco-Epidemiological Aspects of a Novel Hyperendemic Area of Paracoccidioidomycosis in the Tocantins-Araguaia Basin (Northern Brazil), Caused by Paracoccidioides sp.

Paracoccidioidomycosis (PCM) is the most prevalent systemic mycosis in Brazil. The disease is caused by dimorphic fungi nested within the Paracoccidioides genus. We described 106 PCM cases (47.1 cases/year) at the Tropical Diseases Public Hospital of Tocantins State. PCM was prevalent in males and rural workers over 50 years; the chronic pulmonary form predominated in 67% of cases. The male-to-female ratio was 2.65:1, with more women affected than other endemic regions of Brazil. Urban or indoor activities were reported in women and are ascribed to disease urbanization. qPCR-based assays confirmed the identification of Paracoccidioides DNA in 37 biological specimens. Paracoccidioides sp. DNA was found in 53% of the environmental samples, suggesting autochthonous infections. Therefore, the Tocantins-Araguaia basin must be considered a novel hyperendemic area of PCM in Brazil, reinforcing the importance of including PCM as a notifiable disease, requiring specific diagnosis and health measures.

Involvement of nitric oxide in the neurobiology of fear-like behavior.

Fear is an emotional reaction that arises in dangerous situations, inducing the adaptation to an existing condition. This behavior was conserved in all vertebrates throughout evolution and is observed in mammals, birds, fish, amphibians, and reptiles. The neurocircuitry of fear involves areas of the limbic system, cortical regions, midbrain, and brainstem. These areas communicate with each other so that there is an expression of fear and memory formation to deal with the same situation at another time. The effect of nitric oxide (NO) on fear modulation has been explored. NO is a gaseous compound that easily diffuses through the cell membrane and is produced through the oxidation reaction of l-Arginine to l-citrulline catalyzed by nitric oxide synthase (NOS). Activating the intracellular NO receptor (soluble guanylyl cyclase enzyme - sGC) triggers an enzymatic cascade that can culminate in plastic events in the neuron. NOS inhibitors induce anxiolytic-like responses in fear modulation, whereas NO donors promote fear- and anxiety-like behaviors. This review describes the neurobiology of fear in mammals and non-mammals, how NO is produced in the central nervous system, and how NO acts in fear-like behavior.

Development and Implementation of the AIDA International Registry for Patients With Still's Disease.

Objective: Aim of this paper is to present the design, construction, and modalities of dissemination of the AutoInflammatory Disease Alliance (AIDA) International Registry for patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), which are the pediatric and adult forms of the same autoinflammatory disorder. Methods: This Registry is a clinical, physician-driven, population- and electronic-based instrument implemented for the retrospective and prospective collection of real-world data. The collection of data is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain evidence drawn from routine patients' management. The collection of standardized data is thought to bring knowledge about real-life clinical research and potentially communicate with other existing and future Registries dedicated to Still's disease. Moreover, it has been conceived to be flexible enough to easily change according to future scientific acquisitions. Results: Starting from June 30th to February 7th, 2022, 110 Centers from 23 Countries in 4 continents have been involved. Fifty-four of these have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 175 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry collects baseline and follow-up data using 4449 fields organized into 14 instruments, including patient's demographics, history, clinical manifestations and symptoms, trigger/risk factors, therapies and healthcare access. Conclusions: This international Registry for patients with Still's disease will allow a robust clinical research through collection of standardized data, international consultation, dissemination of knowledge, and implementation of observational studies based on wide cohorts of patients followed-up for very long periods. Solid evidence drawn from "real-life" data represents the ultimate goal of this Registry, which has been implemented to significantly improve the overall management of patients with Still's disease. NCT05200715 available at https://clinicaltrials.gov/.

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Uveitis.

INTRODUCTION: The aim of this paper is to point out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry for paediatric and adult patients with non-infectious uveitis (NIU). METHODS: This is a physician-driven, population- and electronic-based registry implemented for both retrospective and prospective collection of real-world demographics, clinical, laboratory, instrumental and socioeconomic data of patients with uveitis and other non-infectious inflammatory ocular diseases recruited through the AIDA Network. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is thought to collect standardised information for real-life research and has been developed to change over time according to future scientific acquisitions and potentially communicate with other similar instruments. Security, data quality and data governance are cornerstones of this platform. RESULTS: Ninety-five centres have been involved from 19 countries and four continents from 24 March to 16 November 2021. Forty-eight out of 95 have already obtained the approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers). The AIDA Registry collects baseline and follow-up data using 3943 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger/risk factors, therapies and healthcare utilization for patients with NIU. CONCLUSIONS: The development of the AIDA Registry for patients with NIU will facilitate the collection of standardised data leading to real-world evidence and enabling international multicentre collaborative research through inclusion of patients and their families worldwide.

Development and Implementation of the AIDA International Registry for Patients with Non-Infectious Scleritis.

INTRODUCTION: This article points out the design, methods, development and deployment of the international registry promoted by the AutoInflammatory Disease Alliance (AIDA) Network with the aim to define and assess paediatric and adult patients with immune-mediated scleritis. METHODS: This registry collects both retrospective and prospective real-world data from patients with non-infectious scleritis through the Research Electronic Data Capture (REDCap) tool and aims to promote knowledge and real-life evidence from patients enrolled worldwide; the registry also allows the collection of standardised data, ensuring the highest levels of security and anonymity of patients' data and flexibility to change according to scientific acquisitions over time. The communication with other similar registries has been also ensured in order to pursue the sustainability of the project with respect to the adaptation of collected data to the most diverse research projects. RESULTS: Since the launch of the registry, 99 centres have been involved from 20 countries and four continents. Forty-eight of the centres have already obtained a formal approval from their local ethics committees. At present, the platform counts 259 users (95 principal investigators, 160 site investigators, 2 lead investigators, and 2 data managers); the platform collects baseline and follow-up data using 3683 fields organised into 13 instruments, including patient's demographics, history, symptoms, trigger or risk factors, therapies and healthcare utilization. CONCLUSIONS: The development of the AIDA International Registry for patients with non-infectious scleritis will allow solid research on this rare condition. Real-world evidence resulting from standardised real-life data will lead to the optimisation of routine clinical and therapeutic management, which are currently limited by the rarity of this ocular inflammatory condition.

Robust volumetric models for supporting the management of secondary forest stands in the Southern Brazilian Atlantic Forest.

The majority of Atlantic Forest fragments in Southern Brazil are second-growth forests dominated by fast-growing species with considerable market-value timber. Nevertheless, volume prediction models are scarce, especially to estimate tree total volume (i.e., stem plus branches). This study approached the issue through the following aims: to fit and select stem and total volume models (generic and species-specific) using data from 288 harvested trees in a management operation, and to fit generic and species-specific bark factors. The power model embedding diameter at breast height (D) and tree stem or total height (H) presented the greatest prediction strength for both stem and total tree volume. Models including only D to predict total tree volume were similar to double-entry models regarding goodness-of-fit. Therefore, they may be useful in the context of subtropical closed-canopy forests, where the difficulty and uncertainty in H measurements are not trivial. Species-specific models fitted for Miconia cinnamomifolia (DC) Naudin. and Hyeronima alchorneoides Allemão surpassed generic models only for the former species. Nevertheless, the prediction improvement should offset the eventual extra efforts implied in the collection of reliable samples of these species. Finally, bark factors stood as a satisfactory tool for inside bark mean volume estimation.

Participation of extracellular signal-regulated kinases 1/2 in osteoblast and adipocyte differentiation of mesenchymal stem cells grown on titanium surfaces.

Osteoblasts and adipocytes coexist in the implantation site and affect the process of titanium (Ti) osseointegration. As extracellular signal-regulated kinases 1/2 (ERK1/2) are involved in osteogenesis and adipogenesis, the aim of our study was to investigate if the effects of Ti surface topography on osteoblast and adipocyte differentiation are modulated by ERK1/2. The experiments were conducted based on the effect of the ERK1/2 inhibitor, PD98059, on mesenchymal stem cells (MSCs) grown under osteogenic and adipogenic conditions on Ti with nanotopography (Ti-Nano) or on machined Ti (Ti-Machined). The results showed that, in general, ERK1/2 inhibition favored osteoblast and adipocyte differentiation of MSCs grown on Ti-Machined. In MSCs grown on Ti-Nano, ERK1/2 inhibition upregulated the expression of alkaline phosphatase and osteocalcin and reduced extracellular matrix mineralization. In terms of adipocyte differentiation, ERK1/2 inhibition elicited similar MSC responses to Ti-Nano and Ti-Machined, upregulating gene expression of adipocyte markers without affecting lipid accumulation. Our results indicate that, under osteogenic and adipogenic conditions, the responses of MSCs to Ti surface topography in terms of osteogenesis and adipogenesis are dependent on ERK1/2. Thus, a precise modulation of ERK1/2 expression and activity induced by surface topography could be a good strategy to drive the process of implant osseointegration.

Disease Severity Prediction by Spirometry in Adults with Visceral Leishmaniasis from Minas Gerais, Brazil.

Visceral leishmaniasis (VL) is associated with interstitial pneumonitis according to histology and radiology reports. However, studies to address the functional impact on respiratory function in patients are lacking. We assessed pulmonary function using noninvasive spirometry in a cross-sectional study of hospitalized adult VL patients from Minas Gerais, Brazil, without unrelated lung conditions or acute infections. Lung conditions were graded as normal, restrictive, obstructive, or mixed patterns, according to Brazilian consensus standards for spirometry. To control for regional patterns of lung function, we compared spirometry of patients with regional paired controls. Spirometry detected abnormal lung function in most VL patients (70%, 14/20), usually showing a restrictive pattern, in contrast to regional controls and the standards for normal tests. Alterations in spirometry measurements correlated with hypoalbuminemia, the only laboratory value indicative of severity of parasitic disease. Abnormalities did not correlate with unrelated factors such as smoking or occupation. Clinical data including pulmonary symptoms and duration of therapy were also unrelated to abnormal spirometry findings. We conclude that the severity of VL is correlated with a restrictive pattern of lung function according to spirometry, suggesting that there may be interstitial lung involvement in VL. Further studies should address whether spirometry could serve as an index of disease severity in the management of VL.

Thermally Triggered Phase Separation of Organic Electrolyte-Cellulose Solutions.

Organic electrolyte solutions (OES)-binary mixtures of an ionic liquid (IL) with a neutral polar aprotic co-solvent-are being recognized as excellent candidate solvents for the dissolution, derivatization, and sustainable processing of cellulose. These solutions exhibit the beneficially combined properties of rapid-to-instantaneous cellulose dissolution, raised thermal stability, and reduced viscosity, compared to cellulose solutions in the parent ILs. Herein, we report the reversible, thermally triggered phase separation of cellulose solutions in 1-ethyl-3-methylimidazolium acetate with 1,3-dimethyl-2-imidazolidinone. In these solutions, cellulose drives the process of phase separation, resulting in a lower, IL-rich layer in which the biopolymer is segregated. In turn, the upper phase is enriched in the neutral co-solvent. We show that the temperature of phase separation can be fine-tuned by modification of mole fractions of IL, co-solvent, and cellulose. This finding holds promise for the design of strategies for separation and solvent recycling in cellulose chemistry.

Stochastic Loewner evolution relates anomalous diffusion and anisotropic percolation.

We disclose the origin of anisotropic percolation perimeters in terms of the stochastic Loewner evolution (SLE) process. Precisely, our results from extensive numerical simulations indicate that the perimeters of multilayered and directed percolation clusters at criticality are the scaling limits of the Loewner evolution of an anomalous Brownian motion, being superdiffusive and subdiffusive, respectively. The connection between anomalous diffusion and fractal anisotropy is further tested by using long-range power-law correlated time series (fractional Brownian motion) as the driving functions in the evolution process. The fact that the resulting traces are distinctively anisotropic corroborates our hypothesis. Under the conceptual framework of SLE, our study therefore reveals different perspectives for mathematical and physical interpretations of non-Markovian processes in terms of anisotropic paths at criticality and vice versa.

Toxoplasma Gondii Infection of Chicken Embryos Causes Retinal Changes and Modulates HSP90B1 Gene Expression: A Promising Ocular Toxoplasmosis Model.

HSP90B1 is a gene that codifies heat shock protein 108 (HSP108) that belongs to a group of proteins induced under stress situation, and it has close relation with the nervous system, especially in the retina. Toxoplasma gondii causes ocular toxoplasmosis that has been associated with a late manifestation of the congenital toxoplasmosis although experimental models show that morphological alterations are already present during embryological development. Here, we used 18 eyes of Gallus domesticus embryos in 7th and 20th embryonic days to establish a model of congenital ocular toxoplasmosis, experimentally infected in its fifth day correlating with HSP90B1 gene expression. Embryos' eyes were histologically evaluated, and gene expression was performed by real-time polymerase chain reaction (PCR). Our data showed parasite present in the choroid, unusual migration of retinal pigment epithelium, and chorioretinal scars, and a tendency to a lower expression of the HSP90B1 gene upon experimental infection. This is a promising model to better understand T. gondii etiopathogeny.

Coherence of brain electrical activity: a quality of life indicator in Alzheimer's disease?

OBJECTIVE: To investigate the relationships between quality of life (QOL) and clinical and electroencephalogram (EEG) aspects in patients with Alzheimer's disease (AD). METHOD: Twenty-eight patients with mild or moderate AD, 31 with Parkinson's disease (PD), and 27 normal controls (NC) were submitted to: CERAD neuropsychological battery, Hamilton Depression and Anxiety Rating Scales, Functional Activities Questionnaire, QOL scale for patients with AD, and quantitative EEG measures. RESULTS: AD and PD patients had similar QOL (31.0 ± 5.8; 31.7 ± 4.8, respectively), worse than that of NC (37.5 ± 6.3). AD patients had lower global interhemispheric theta coherence (0.49 ± 0.04; 0.52 ± 0.05; 0.52 ± 0.05; respectively) than PD and NC. Multiple linear regression for QOL of AD patients revealed that global interhemispheric theta coherence, and Hamilton depression scores were significant factors (coefficients; 58.2 and -0.27, respectively; R2, 0.377). CONCLUSION: Interhemispheric coherence correlates with QOL regardless of cognitive and functional variables and seems to be a neurophysiological indicator of QOL in AD patients.

Coherence of brain electrical activity: a quality of life indicator in Alzheimer’s disease?Coerência da atividade elétrica cerebral: indicador da qualidade de vida na doença de Alzheimer?

Objective To investigate the relationships between quality of life (QOL) and clinical and electroencephalogram (EEG) aspects in patients with Alzheimer’s disease (AD). Method Twenty-eight patients with mild or moderate AD, 31 with Parkinson’s disease (PD), and 27 normal controls (NC) were submitted to: CERAD neuropsychological battery, Hamilton Depression and Anxiety Rating Scales, Functional Activities Questionnaire, QOL scale for patients with AD, and quantitative EEG measures. Results AD and PD patients had similar QOL (31.0 ± 5.8; 31.7 ± 4.8, respectively), worse than that of NC (37.5 ± 6.3). AD patients had lower global interhemispheric theta coherence (0.49 ± 0.04; 0.52 ± 0.05; 0.52 ± 0.05; respectively) than PD and NC. Multiple linear regression for QOL of AD patients revealed that global interhemispheric theta coherence, and Hamilton depression scores were significant factors (coefficients; 58.2 and -0.27, respectively; R2, 0.377). Conclusion Interhemispheric coherence correlates with QOL regardless of cognitive and functional variables and seems to be a neurophysiological indicator of QOL in AD patients. .

Objetivo Investigar relações entre qualidade de vida (QV) e aspectos clínico-eletrencefalográficos (EEG) em pacientes com doença de Alzheimer (DA). Método Vinte e oito pacientes com DA, 31 com doença de Parkinson (DP) e 27 controles normais (CN) foram submetidos a avaliações neurocognitivas, escala de depressão de Hamilton e de qualidade de vida para pacientes com DA, questionário de atividades funcionais e medidas do EEG. Resultados A QV foi similar nos grupos DA e DP (31,0 ± 5,8; 31,7 ± 4,8, respectivamente), mas inferior ao CN (37,5 ± 6,3). No grupo DA houve menor coerência inter-hemisférica global teta (CIGT) do que em DP e CN (p < 0,05). Regressão múltipla linear para QV no grupo DA revelou a CIGT e a escala de Hamilton como fatores significativos (coeficientes; 58,2; -0,27, respectivamente; R2, 0,377). Conclusão A CIGT correlaciona-se com a QV independentemente de variáveis cognitivas e funcionais e parece ser um indicador neurofisológico da QV em pacientes com DA. .

Cistitis eosinofílica. Causa rara de disuria / Eosinophilic cistitis. A rare cause of dysuria

No disponible

Oral gabapentin treatment accentuates nerve and peripheral inflammatory responses following experimental nerve constriction in Wistar rats.

Gabapentin (GBP) is an anti-convulsive drug often used as analgesic to control neuropathic pain. This study aimed at evaluating whether oral GBP treatment could improve nerve inflammation response after sciatic nerve constriction in association with selected pain and motor spontaneous behavior assessments in Wistar rats. We evaluated nerve myeloperoxidase (MPO) and inflammatory cytokines on the 5th day post-injury, time in which nerve inflammation is ongoing. In addition, the role of GBP on carrageenan-induced paw edema and peritoneal cell migration was analyzed. GBP was given by gavage at doses of 30, 60 and 120mg/kg, 60min prior to chronic constriction of the sciatic nerve (CCSN) and during 5 days post-injury, 12/12h. CCSN animals treated with saline were used as controls and for behavioral and inflammation assessments untreated sham-operated rats were also used. On the 5th day, GBP (60 and 120mg/kg) alleviated heat-induced hyperalgesia and significantly increased delta walking scores in CCSN animals, the latter suggesting excitatory effects rather than sedation. GBP (60mg/kg) significantly increased nerve MPO, TNF-α, and IL-1ß levels, comparing with the saline group. GBP (120mg/kg) reduced the anti-inflammatory cytokine IL-10 nerve levels compared with the CCSN saline group. Furthermore, GBP (60 and 120mg/kg) increased carrageenan-induced paw edema and peritoneal macrophage migration compared with the CCSN saline group. Altogether our findings suggest that GBP accentuates nerve and peripheral inflammatory response, however confirmed its analgesic effect likely due to an independent CNS-mediated mechanism, and raise some concerns about potential GBP inflammatory side effects in widespread clinical use.