Endothelin-1 down-regulates nuclear factor erythroid 2-related factor-2 and contributes to perivascular adipose tissue dysfunction in obesity.

Perivascular adipose tissue (PVAT) negatively regulates vascular muscle contraction. However, in the context of obesity, the PVAT releases vasoconstrictor substances that detrimentally affect vascular function. A pivotal player in this scenario is the peptide endothelin-1 (ET-1), which induces oxidative stress and disrupts vascular function. The present study postulates that obesity augments ET-1 production in the PVAT, decreases the function of the nuclear factor erythroid 2-related factor-2 (Nrf2) transcription factor, further increasing reactive oxygen species (ROS) generation, culminating in PVAT dysfunction. Male C57BL/6 mice were fed either a standard or a high-fat diet for 16 weeks. Mice were also treated with saline or a daily dose of 100 mg·kg-1 of the ETA and ETB receptor antagonist Bosentan, for 7 days. Vascular function was evaluated in thoracic aortic rings, with and without PVAT. Mechanistic studies utilized PVAT from all groups and cultured WT-1 mouse brown adipocytes. PVAT from obese mice exhibited increased ET-1 production, increased ECE1 and ETA gene expression, loss of the anticontractile effect, as well as increased ROS production, decreased Nrf2 activity, and downregulated expression of Nrf2-targeted antioxidant genes. PVAT of obese mice also exhibited increased expression of Tyr216-phosphorylated-GSK3ß and KEAP1, but not BACH1 - negative Nrf2 regulators. Bosentan treatment reversed all these effects. Similarly, ET-1 increased ROS generation and decreased Nrf2 activity in brown adipocytes, events mitigated by BQ123 (ETA receptor antagonist). These findings place ET-1 as a major contributor to PVAT dysfunction in obesity and highlight that pharmacological control of ET-1 effects restores PVAT's cardiovascular protective role.

Effect of Telerehabilitation on Pulmonary Function, Functional Capacity, Physical Fitness, Dyspnea, Fatigue, and Quality of Life in COVID-19 Patients: A Systematic Review and Metanalysis.

Background: This study aimed to demonstrate the technological means used to offer telerehabilitation and to evaluate the effect of physical exercise on the population affected by COVID-19. Methods: Clinical trials were searched in the electronic databases Cochrane Library, PubMed/MEDLINE, EBSCO (CINAHL), PEDro, and Web of Science from January 16 to 19, 2023. The effect measure was estimated as mean difference (MD) or standard MD (SMD) with 95% confidence intervals (CI). Subgroup analysis was used to study potential moderating factors. Results: Twenty-four articles, describing trials with a total of 1,344 individuals affected by COVID-19, were included in the qualitative synthesis and 14 articles in the meta-analysis. The pooled results revealed that telerehabilitation improves the functional capacity (MD 79.65 [63.57, 95.73]m, p < 0.00001), agility (MD -0.69 [-1.33, -0.04] s, p = 0.04), lower limb strength and endurance (SMD 0.74 [0.52, 0.96], p < 0.00001), forced expiratory volume in 1 s (MD 0.22 [-0.04, 0.49] L, p = 0.10), and dyspnea (SMD -0.94 [-1.64, -0.24], p = 0.009). The dynamic muscular resistance training associated or not with other exercise modalities led to improvements in muscular strength (MD 4.69 [0.44, 8.94] kg, p = 0.03) and fatigue (SMD -0.97 [-1.74, -0.20], p = 0.01). In addition, telerehabilitation showed improvements in the quality of life in the contagious-phase COVID-19 patients. Although this intervention improved inspiratory muscle strength (MD 13.71 [5.41, 22.0] cmH2O, p = 0.001), it did not favor forced vital capacity. Conclusions: Telerehabilitation contributed to improving functional capacity, inspiratory muscle strength, physical fitness, and quality of life, and reducing dyspnea and fatigue in COVID-19 adult survivors.

A suitable model to investigate acute neurological consequences of coronavirus infection.

OBJECTIVE AND DESIGN: The present study aimed to investigate the neurochemical and behavioral effects of the acute consequences after coronavirus infection through a murine model. MATERIAL: Wild-type C57BL/6 mice were infected intranasally (i.n) with the murine coronavirus 3 (MHV-3). METHODS: Mice underwent behavioral tests. Euthanasia was performed on the fifth day after infection (5 dpi), and the brain tissue was subjected to plaque assays for viral titration, ELISA, histopathological, immunohistochemical and synaptosome analysis. RESULTS: Increased viral titers and mild histological changes, including signs of neuronal degeneration, were observed in the cerebral cortex of infected mice. Importantly, MHV-3 infection induced an increase in cortical levels of glutamate and calcium, which is indicative of excitotoxicity, as well as increased levels of pro-inflammatory cytokines (IL-6, IFN-γ) and reduced levels of neuroprotective mediators (BDNF and CX3CL1) in the mice brain. Finally, behavioral analysis showed impaired motor, anhedonia-like and anxiety-like behaviors in animals infected with MHV-3. CONCLUSIONS: In conclusion, the data presented emulate many aspects of the acute neurological outcomes seen in patients with COVID-19. Therefore, this model may provide a preclinical platform to study acute neurological sequelae induced by coronavirus infection and test possible therapies.

Occurrence of serological reactions for Leptospira spp. in donkeys and mules from Minas Gerais, Brazil.

Research concerning leptospirosis in donkeys and mules has been neglected around the world. Therefore, the aim of this study was to investigate the epidemiological situation of the prevalence of anti-Leptospira spp. antibodies in donkeys and mules from the state of Minas Gerais, Brazil. Blood serum samples were collected from 180 animals (109 donkeys and 71 mules) in two rural properties from the state of Minas Gerais, Brazil, and then submitted to a microscopic agglutination test (MAT). Urea and creatinine values were also quantified. Epidemiological variables such as age, breeding system, contact with other animal species, source of water and food, vaccination against leptospirosis, presence of reproductive alterations, and rodent control were also investigated. From 180 samples collected, 39 (21.67%) showed positive results in the MAT, at a dilution ≥ 1:100. Some animals were reactive for more than one serovar. The serovar Tarassovi was the most frequent (14.07%), followed by Hardjo (11.85%) and Wolffi (11.11%). There was a statistically significant difference between animals from 0 to 3 years of age reactive in the MAT in comparison to the other age groups. Most of the animals had urea and creatinine concentrations within the acceptable reference limit; however, there was a significant increase in creatinine levels in some of the test animals. The studied properties showed differences in some epidemiological aspects such as vaccination of the animals, presence of reproductive problems in the herd, and rodent control. Such aspects pointed as risk factors that may influence the frequency of positive serological results in property 1. The present study demonstrated that the prevalence of leptospirosis in donkeys and mules is high and several serovars are being maintained by these animals, representing a potential public health risk.

Clinical safety and hemodynamic, cardiac autonomic and inflammatory responses to a single session of inspiratory muscle training in obstructive sleep apnea.

PURPOSE: To determine clinical safety and cardiovascular, cardiac autonomic and inflammatory responses to a single session of inspiratory muscle training (IMT) in obstructive sleep apnea (OSA) subjects. METHODS: In a randomized controlled trial individuals of both sexes, aged between 30 and 70 years old with diagnosis of moderate to severe OSA were enrolled. Volunteers with OSA (n = 40) performed an IMT session with three sets of 30 repetitions with a 1-min interval between them. The IMT group (n = 20) used a load of 70% of the maximum inspiratory pressure (MIP), and the placebo group (n = 20) performed the IMT without load. Measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), heart rate variability (HRV), and inflammatory markers were performed pre, post-immediate and 1 h after the IMT session. RESULTS: No differences were shown in SBP, DBP, HRV, or inflammatory markers at any of the intervals analyzed. However, HR in the IMT group was lower ​​1 h after the IMT session compared to the pre-session values ​​(p = 0002). HR was higher in the placebo group when comparing pre × post-immediate (p < 0.001). HR decreased after the first hour in relation to the pre (p < 0.001) and post-immediate (p < 0.001) values. CONCLUSION: IMT sessions promote discreet hemodynamic, cardiac autonomic and inflammatory responses. Therefore, IMT is considered clinically safe and can be performed at home, guided but unsupervised, with lower cost and greater adherence to exercise program for subjects with OSA.

Survey for Leptospira and Brucella in Amazonian manatees, Amazon river dolphins, and a tucuxi in the Brazilian Amazon.

Leptospirosis and brucellosis are zoonotic diseases with global distributions that represent severe hazards to humans and animals. We investigated exposure to Leptospira spp. and Brucella spp. in samples from Amazonian manatees Trichechus inunguis, Amazon river dolphins Inia geoffrensis, and a tucuxi Sotalia fluviatilis. The animals were free-ranging or undergoing in situ rehabilitation in the mid-Solimões River region, Brazilian Amazon. Serum samples from 19 Amazonian manatees were tested by microscopic agglutination test, Rose Bengal test, and 2-mercaptoethanol Brucella agglutination test. Antibodies against Leptospira spp. were detected in 63% of the manatees tested and serovar Patoc was considered the infecting serovar in all positive samples. Titers were generally low, indicating chronic exposure, but higher titers indicative of an active infection were detected in 3 animals. Anti-Brucella spp. antibodies were not detected. Tissue and/or body fluid samples from 12 Amazon river dolphins, a tucuxi, and 2 Amazonian manatees were investigated by multiplex PCR and bacteriology for Leptospira spp. and Brucella spp. All samples were negative. However, Enterococcus faecalis was isolated from uterine fluid, lymph node, and lung of 3 Amazon river dolphins. Bacillus spp. were isolated from milk and synovial fluid from 2 Amazon river dolphins and from a milk sample from 1 Amazonian manatee. Knowledge of the pathogens present in Amazonian manatees, Amazon river dolphins, and tucuxis is of great relevance to species conservation and environmental health. Although no clinical signs were noted, further research is needed to elucidate the clinical relevance of infection by Leptospira sp. serovar Patoc in Amazonian aquatic mammals.

Spatial distribution of Mycobacterium bovis spoligotypes in cattle from the state of Minas Gerais, Brazil.

Genotyping methods have led to a better understanding of the epidemiology of Mycobacterium bovis (M. bovis) infection, and its transmission dynamics, as well as the possible phylogenetic relationships between Mycobacterium strains, thus making bovine tuberculosis control programs more efficient. The goal of this study was to characterize the main spoligotypes of M. bovis isolated from cattle in the State of Minas Gerais, Brazil. It was carried out in 28 municipalities of "Triângulo Mineiro" and "Alto Paranaíba" regions of the state. Viscera samples were obtained from 58 bovines positive for tuberculosis according to comparative cervical tests, and from another 100 bovines with lesions suggestive of tuberculosis, which were donated by the National Agricultural Laboratory of Pedro Leopoldo, Minas Gerais. Microbiological isolation was performed in Stonebrink medium, and molecular identification of mycobacteria was performed by PCR. Genotyping was performed using the spoligotyping method at the Agrobiotechnology and Molecular Biology Institute of National Agricultural Technology Institute-National Scientific and Technical Research Council, Buenos Aires, Argentina. Among the 158 viscera samples, we obtained 40 (25%) isolates of M. bovis, and detected 11 spoligotype patterns, with a predominance of SB1142 (37.5%), SB0121 (25.0%), and SB1145 (10.0%). Other standards, SB0295, SB1050, SB0881, SB1144, SB1802, SB0140, SB0120, and SB0849, varied from 2.5 to 7.5%, heterogeneously distributed among the municipalities. The presence of spoligotypes shared with other Brazilian states and different countries indicates their possible exchange through epidemiological relationships, such as the transit of live animals and/or genetic similarity between strains that share a common ancestor.

Serological and molecular characterization of Leptospira kirschneri serogroup Grippotyphosa isolated from bovine in Brazil.

Leptospirosis is a zoonotic disease caused by a bacterium of the genus Leptospira that affects domestic animals, including cattle. Despite of this importance in livestock, little is known about the epidemiology of leptospirosis in cattle in Brazil and other tropical countries. In this context, the objective of this study was to perform the culture of urine and kidney (n = 372 animals) of slaughtered bovines of Minas Gerais state (Brazil), in order to obtain pure cultures of Leptospira strains and carry out its characterization by serological (microscopic agglutination test) and molecular techniques (rrs, secY sequencing and variable-number tandem-repeat genotyping). One strain, named UFU 02, was obtained from a male bovine without apparent alterations in ante-mortem examination. The strain was characterized belonging to species Leptospira kirschneri and serogroup Grippotyphosa. The serogroup Grippotyphosa is most often described in wild species, suggesting a link between domestic and wild cycles/environments. Considering the importance of the country in livestock breeding, the knowledge about leptospiral strains could help to control the disease in the herds.

"Posterior Tibial Nerve" or "Tibial Nerve"? Improving the reporting in health papers.

AIMS: The primary objective of this study is to identify which term is the most appropriate to use according to anatomical nomenclature: "posterior tibial nerve" or "tibial nerve." Furthermore, this paper intends to show how the use of these terms in papers indexed in important health databases is numerous and to describe the anatomical characteristics of such nerve, to improve future scientific publications. METHODS: This is a descriptive study about the importance of standardizing the use of the terms "posterior tibial nerve" and "tibial nerve" and its anatomy. It comprises three phases: the first is a search in the main databases to identify the use of the terms "posterior tibial nerve" and "tibial nerve." The second phase refers to the consultation of international anatomical terminology to identify the most appropriate term to refer to the nerve, while the third phase is related to the study of the anatomy of this nerve. RESULTS: The term "tibial nerve" is more commonly used, but the use of the term "posterior tibial nerve" is still very substantial. According to international anatomical terminology, the correct term is "tibial nerve," which is a branch of the sciatic nerve. CONCLUSIONS: "Tibial nerve" is the term standardized by international anatomical terminology. The use of terms in accordance with Terminologia Anatomica is important to facilitate the process of teaching and learning, as well as to improve the reporting and interpretation of papers regarding health, and the evidence-based clinical practice.

Correlation between carcass condemnations in slaughterhouses and official notifications of cattle testing positive for tuberculosis.

The objective of this study was to analyze the correlation between condemnations in slaughterhouses situated in Minas Gerais State and notifications to the Brazilian Official Veterinary Service of cattle that were positive for intradermal tuberculin tests. Data were obtained from three slaughterhouses under different surveillance conditions and from the Brazilian Agriculture and Livestock Health Agency for 2011 to 2017. During this period, there was an increase in the number of condemnations of females aged over 36 months, despite the number of females testing with intradermal tests and being reported as positive decreasing. Therefore, there is a discrepancy between the analyzed variables. Since there is a belief that slaughter condemnations can be used as tools for epidemiological surveys in beef and dairy farms, it is advisable for there to be a greater integration of the Brazilian Health Inspection Services in slaughterhouses and Brazilian Agriculture and Livestock defense department. This will ensure safe animal products.

Obstructive sleep apnea does not impair cardiorespiratory responses to progressive exercise performed until exhaustion in hypertensive elderly.

BACKGROUND: Elderly people have a high prevalence to systemic arterial hypertension (SAH) and obstructive sleep apnea (OSA). Both comorbidities are closely associated and inflict damage on cardiorespiratory capacity. METHODS: In order to assess cardiorespiratory responses to the cardiopulmonary exercise test (CPET) among hypertensive elderly with OSA, we enrolled 28 subjects into two different groups: without OSA (No-OSA: apnea/hypopnea index (AHI) < 5 events/h; n = 15) and with OSA (OSA: AHI ≥ 15 events/h; n = 13). All subjects underwent CPET and polysomnographic assessments. After normality and homogeneity evaluations, independent t test and Pearson's correlation were performed. The significance level employed was p ≤ 0.05. RESULTS: Hypertensive elderly with OSA presented lower heart rate recovery (HRR) in the second minute (HRR2) in relation to the No-OSA group. A negative correlation between AHI and ventilation (VE) (r = -0.63, p = 0.02) was found in polysomnography and CPET data comparisons, and oxygen saturation (O2S) levels significantly correlated with VE/VCO2slope (r = 0.66, p = 0.01); in addition, OSA group presented a positive correlation between oxygen consumption and O2S (r = 0.60, p = 0.02), unlike the no-OSA group. CONCLUSIONS: OSA does not affect the CPET variables in hypertensive elderly, but it attenuates the HRR2. The association between O2S during sleep with ventilatory responses probably occurs due to the adaptations in the oxygen transport system unleashed via mechanical respiratory feedback; thus, it has been identified that OSA compromises the oxygen supply in hypertensive elderly.

Effectiveness of inspiratory muscle training on sleep and functional capacity to exercise in obstructive sleep apnea: a randomized controlled trial.

PURPOSE: The aim of this study was to evaluate the effectiveness of inspiratory muscle training (IMT) on sleep and functional capacity to exercise in subjects with obstructive sleep apnea (OSA). METHODS: This is a controlled, randomized, double-blind study conducted in 16 OSA patients divided into two groups: training (IMT: n = 8) and placebo-IMT (P-IMT: n = 8). IMT was conducted during 12 weeks with a moderate load (50-60% of maximal inspiratory pressure-MIP), while P-IMT used a load < 20% of MPI. Total daily IMT time for both groups was 30 min, 7 days per week, twice a day. RESULTS: There was no difference comparing IMT to P-IMT group after training for lung function (p > 0.05) and respiratory muscle strength (p > 0.05). Maximal oxygen uptake (VO2Max) was not significantly different between IMT and P-IMT group (mean difference - 1.76, confidence interval (CI) - 7.93 to 4.41, p = 0.71). The same was observed for the other ventilatory and cardiometabolic variables measured (p > 0.05). A significant improvement in sleep quality was found when Pittsburgh Sleep Quality Index (PSQI) values of IMT and P-IMT group after training were compared (mean difference: 3.7, confidence interval 95% (CI95%) 0.6 to 6.9, p = 0.02) but no significant changes were seen in daytime sleepiness between both groups after the intervention (mean difference: 3.4, CI 95%: - 3.3 to 10.0; p = 0.29). CONCLUSION: According to these results, 12 weeks of moderate load IMT resulted in improved sleep quality, but there were no significant repercussions on functional capacity to exercise or excessive daytime sleepiness.

Correction to: Obstructive sleep apnea does not impair cardiorespiratory responses to progressive exercise performed until exhaustion in hypertensive elderly.

The original version of this article was published online containing two items that require correction, namely the abstract (Results section) and Table 3.

First molecular epidemiological study of Mycobacterium avium subsp. paratuberculosis in cattle and buffalo from different regions of Brazil.

Paratuberculosis is an incurable disease in ruminants with great worldwide economic impact, caused by Mycobacterium avium subsp. paratuberculosis (MAP). The objective of this study was to carry out a study of the molecular epidemiology of the MAP using the restriction enzyme analysis (REA) technique of IS1311 MAP region in biological samples of feces, intestinal tissue, and mesenteric lymph nodes of cattle and buffaloes from six Brazilian states. In total, 109 samples of feces and tissues of cattle and buffaloes were collected from animal paratuberculosis suspected. Twenty-five samples were positive in the detection of the DNA of the IS900 region of MAP and it was possible to type 18 strains in the analysis of the region IS1311, being 100% of them identified as belonging to subtype Bison MAP strain. This is the first epidemiological molecular study of MAP in Brazil. The results indicate that paratuberculosis is widespread in cattle and in buffaloes in several regions of Brazil, and the subtype Bison MAP strain was the only one identified in the samples analyzed in this study, demonstrating the similarity between the strains from different states tested. These results provide the necessary support for the implementation of paratuberculosis control strategies in cattle and buffaloes in Brazil.

Nucleolar persistence during spermatogenesis of the genus Rhodnius (Hemiptera, Triatominae).

The Triatominae subfamily is comprised of 18 genera and six tribes. The tribe Rhodniini is comprised of two genera (Rhodnius and Psammolestes). Nucleolar persistence is defined by the presence of the nucleolus or nucleolar corpuscles during the meiotic metaphase. To date, this phenomenon has been described for 13 species of triatomine that are included in the genera Triatoma, Rhodnius, and Panstrongylus. Thus, because the phenomenon of nucleolar persistence has been described in only two species of the genus Rhodnius, we have analyzed the nucleolar behavior during spermatogenesis of eight species of the genus Rhodnius (R. colombiensis, R. montenegrensis, R. nasutus, R. neglectus, R. neivai, R. pictipes, R. prolixus, and R. robustus), with a focus on nucleolar persistence. By means of cytogenetic analysis with silver ions, nucleolar behavior during spermatogenesis is described in the eight species of Rhodnius analyzed. In all of them nucleolar behavior was similar and the phenomenon of nucleolar persistence was often observed. Therefore, we confirm nucleolar persistence as a peculiarity of the genus Rhodnius. However, it is emphasized that new cytogenetic analysis should be performed in the Triatominae subfamily, more specifically among the 15 genera that do not exhibit the nucleolar behavior described, in order to assess whether this phenomenon is truly a synapomorphy of these hematophagous insects.

Quality of life of leprosy sequelae patients living in a former leprosarium under home care: univariate analysis.

INTRODUCTION: Quality of life (QoL) is a broad concept that has become more important during the last decades. Despite this fact, few studies have been conducted to evaluate leprosy patients, none of which has specifically addressed patients with leprosy sequels submitted to home care. PURPOSE: To evaluate the QoL of leprosy sequel bearers and the factors that may affect their perception of their condition. METHODS: WHOQoL-BREF, a questionnaire developed by the World Health Organization, was administered to 32 people living in the coverage area of a former leprosarium. Patient socio-demographic and care-related caregiver data were collected. Activities of daily living and Instrumental Activities of Daily Living Scales were used to evaluate autonomy. Mini-Mental Status Examination was used to evaluate cognitive status. Simple linear regression analyses were conducted using SPSS Statistical Software and the non-standardized beta values were presented. RESULTS: The patients were mainly female, widowed, elderly, with bone sequels; all had impairment of at least one Instrumental Daily Living Activity. QoL scores were 12.35 in a 4-20 scale (52.18 %) in the physical domain, 12.95 (55.94 %) in the psychological health domain, 13.18 (57.40 %) in the environment domain, and 16.09 (75.56 %) in the social domain. Univariate analysis suggests that instrumental daily activity "capacity of shopping," marital status, and caregiver age were associated with self-perceived QoL. Data were also compared to those from other studies. CONCLUSION: Individuals affected by leprosy had low QoL scores in the physical and psychological health domains and high scores in the social domain. The factors that impact their QoL seem to be related to specific conditions found in the leprosarium and the previous isolation practices.

Estimation of economic losses due to leptospirosis in dairy cattle.

There are few studies that effectively quantify the economic losses resulting from problems caused by leptospirosis in naturally infected dairy cattle. Given this gap, the objective of this study was to propose and apply a method to quantify the economic losses resulting from productive and reproductive problems in a commercial dairy herd naturally infected by Leptospira spp. For this study, the zootechnical and economic indicators at a property with Jersey cattle were analyzed during the period from 2014 to 2017. The leptospirosis outbreak occurred in 2014, and the therapeutic approach was carried out between 2015 and 2017, with the latter considered the year of control of the outbreak. The adopted integrated control strategy consisted of dividing the herd according to the serological results obtained through the microscopic agglutination test, the treatment of reagents with streptomycin, and vaccination against leptospirosis of non-reagent heifers and cows. The method used to evaluate the economic indicators of the property was the calculation of the gross margin by taking into account the implicit and explicit cost parameters associated with the manifestation of leptospirosis. The prevalence rate of leptospirosis decreased from 49.4 % in 2015 to 21.6 % in 2017. There was a reduction in the abortion rate (from 40.00 % in 2014 to 9.00 % in 2017), in the stillborn rate (from 2.63 % in 2014 to 1.69 % in 2017) and an increase in the calving rate (from 65.00 % in 2014 to 86.00 % in 2017). In addition, there were increases in the number of lactating cows (from 38 in 2014-57 in 2017) and the mean times of lactation duration, which increased from 275 days in 2014-295 days in 2017. As a result, the average annual production of milk increased from 164,655 liters in 2014-248,521 liters in 2017. In 2014, when treatment hadn't yet started, the gross margin per liter of milk sold, considering implicit and explicit costs, was US$0.00. In 2015 and 2016, US$0.27 and US$0.30 were obtained, respectively, for this variable. In 2017, with the disease under control on the property, the gross margin per liter of milk reached US$0.36. The gross margin per liter of milk sold was higher in the period when the disease was controlled, showing losses of up to 84 % of the gross margin during the outbreak. Immediate treatment of positive cows and preventive measures had a significant impact on improving the productive and economic efficiency of the property.

Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release.

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 µg/µL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 µg/µL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 µg/µL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.

Eficácia E Custo-Utilidade De Intervenções Para O Tratamento Da Enurese Em Crianças E Adolescentes Sob A Perspectiva Do Sistema Único De Saúde Brasileiro: Effectiveness and Cost-Utility of Interventions for Enuresis Treatment in Children and Adolescents From the Brazilian Single Health System Perspective.

OBJECTIVES: This study aimed to estimate the cost-utility of effective interventions for enuresis treatment in children and adolescents and to calculate the incremental cost-utility ratio from the perspective of the Brazilian Unified Health System in a 1-year time horizon. METHODS: The economic analysis is in 7 stages: (1) survey of evidence of treatments for enuresis, (2) performing the network meta-analysis, (3) estimation of the probability of cure, (4) cost-utility analysis, (5) model sensitivity analysis, (6) analysis of acceptability of interventions by acceptability curve, and (7) monitoring the technological horizon. RESULTS: The association between desmopressin and oxybutynin is the therapeutic strategy with the highest probability of success in the treatment of enuresis in children and adolescents compared with placebo (relative risk [RR] 2.88; 95% confidence interval [CI] 1.65-5.04), followed by the combination therapy between desmopressin and tolterodine (RR 2.13; 95% CI 1.13-4.02), alarm (RR 1.59; 95% CI 1.14-2.23), and neurostimulation (RR 1.43; 95% CI 1.04-1.96). Combination therapy between desmopressin and tolterodine was the only 1 considered not to be cost-effective. Neurostimulation, alarm therapy, and therapy had the respective incremental cost-utility ratio values: R$5931.68, R$7982.92, and R$29 050.56/quality-adjusted life-years. CONCLUSION: Among the therapies that are on the borderline of efficiency, the combined therapy between desmopressin and oxybutynin presents the greatest incremental benefit at an incremental cost that is still feasible, given that it does not exceed the reference value of the cost-effectiveness threshold established in Brazil.