Overexpression of CLDN16 in ovarian cancer is modulated by PI3K and PKC pathways.

Epithelial ovarian cancer (EOC) is the gynecological malignant tumor of poorest prognosis and higher mortality rate. Chemotherapy is the base of high-grade serous ovarian cancer (HGSOC) treatment; however, it favors the emergence of chemoresistance and metastasis. Thus, there is an urge to search for new therapeutic targets, such as proteins related to cellular proliferation and invasion. Herein, we investigated the expression profile of claudin-16 (CLDN16 protein and CLDN16 transcript) and its possible functions in EOC. In silico analysis of CLDN16 expression profile was performed using data extracted from GENT2 and GEPIA2 platforms. A retrospective study was carried out with 55 patients to evaluate the expression of CLDN16. The samples were evaluated by immunohistochemistry, immunofluorescence, qRT-PCR, molecular docking, sequencing, and immunoblotting assays. Statistical analyzes were performed using Kaplan-Meier curves, one-way ANOVA, Turkey posttest. Data were analyzed using GraphPad Prism 8.0. In silico experiments showed that CLDN16 is overexpressed in EOC. 80.0% of all EOC types overexpressed CLDN16, of which in 87% of the cases the protein is restricted to cellular cytoplasm. CLDN16 expression was not related to tumor stage, tumor cells differentiation status, tumor responsiveness to cisplatin, or patients' survival rate. When compared to data obtained from in silico analysis regarding EOC stage and degree of differentiation, differences were found in the former but not in the later, neither in survival curves. CLDN16 expression in HGSOC OVCAR-3 cells increased by 1.95-fold (p < 0.001), 2.32-fold (p < 0.001), and 6.57-fold (p < 0.001) via PKC, PI3K, and estrogen pathways, respectively. Altogether, our results suggest that despite the low number of samples included in our in vitro studies, adding to the expression profile findings, we provided a comprehensive study of CLDN16 expression in EOC. Therefore, we hypothesize that CLDN16 is a potential target in the diagnosis and treatment of the disease.

The impact of lipid metabolism on breast cancer: a review about its role in tumorigenesis and immune escape.

BACKGROUND: Breast cancer (BC) is the second most frequent type of cancer in the world and most common among women, configuring a major challenge to global health. BC is a complex and heterogeneous disease that can be subdivided into distinct tumor types based on the expression of molecular markers predicting patient outcomes and response to therapy. A growing number of studies have tried to expand the known markers by investigating the association of altered lipid metabolism with BC immune escape, progression, and metastasis. In this review, we describe the metabolic peculiarities of each BC subtype, understanding how this influences its aggressiveness and identifying whether these intrinsic vulnerabilities of each subtype can play a role in therapeutic management and may affect immune system cells in the tumor microenvironment. CONCLUSION: The evidence suggests so far that when changes occur in lipid pathways, it can affect the availability of structural lipids for membrane synthesis, lipid synthesis, and degradation that contribute to energy homeostasis and cell signaling functions. These findings will guide the next steps on the path to understanding the mechanisms underlying how lipids alterations are related to disparities in chemotherapeutic response and immune escape in BC. Video Abstract.

Persistent headache attributed to past cervicocephalic artery dissection: clinical characteristics and contributors to headache persistence.

BACKGROUND: Persistent headache/facial/neck pain attributed to past cervicocephalic arterial dissection is under-documented in literature. Our main goal was to evaluate clinical characteristics and contributors to this persistence. METHODS: A retrospective cohort study which included patients with a radiologically confirmed cervicocephalic arterial dissection (2015-2020) in a Portuguese tertiary hospital. Headache persistence was identified through clinical records. A questionnaire aimed to characterize headache in three moments: previous, persistent, and headache at the time of the interview (on average 2.5 years post-event). RESULTS: Ninety-two patients were identified; 24 (26.1%) had headache persistence ≥3 months, and 20 (22.2%) on average after 2.5 years post-event. There were no differences regarding demographics and vascular risk factors among patients with (n = 22) and without (n = 68) headache persistence. The first group had higher previous headache history (68.2% vs 4.4%, p < 0.001), delay in diagnosis (3.6 vs 1.9 days, p < 0.001), and headache/cervicalgia as the first symptom (81.8% vs 41.2%, p < 0.001). At the time of the interview, 20% still reported daily headache. A logistic regression model depicted headache history (OR = 59.8, p < 0.001), acute headache/cervicalgia (odds ratio, OR = 25.4, p = 0.005), posterior circulation dissection (OR = 7.6, p < 0.001), and less than 4 points by National Institutes of Health Stroke Scale score (OR = 5.0, p = 0.025) as contributors to headache persistence. CONCLUSION: Headache persistence post-cervicocephalic arterial dissection is common, and frequently affects patients daily. As it potentially affects functional outcomes and quality of life, the contributors identified in this study may help clinicians manage patients after the acute event.

High molecular weight adiponectin as a biomarker of hypertension in children and adolescents with obesity.

Lower HMW (high molecular weight) adiponectin levels are associated with obesity, insulin resistance, and metabolic syndrome in children and adolescents. However, data on HMW levels in pediatric population with hypertension are lacking. This study aimed to examine the association and predictive capacity of HMW levels, HMW/HOMA-IR, and HMW/APN ratio with hypertension in obese children and adolescents. The 299 pediatric subjects were grouped in obese hypertensive (OH), obese normotensive (ON), and normal weight normotensive (NN). Plasma concentrations of HMW were investigated by ELISA. ANOVA was used to compare study groups, and a binary logistic regression analysis was used to verify if HMW, HMW/HOMA-IR, HMW/APN, APN, APN/HOMA-IR, and HOMA-IR are associated to hypertension regardless obesity in children and adolescents. To compare the strength and performance of each biomarker to classify individuals with and without hypertension, the receiver-operating characteristic (ROC) curve, area under the curve (AUC), and Youden index (J) were evaluated. Both HMW plasma levels and the HMW/HOMA-IR ratio were significantly lower in the OH group when compared to the ON group (HMW: 2.00 ± 1.33 µg/mL vs 2.48 ± 1.48 µg/mL; HMW/HOMA-IR ratio: 0.87 ± 0.95 vs 1.27 ± 1.2; P < 0.05) and NN weight groups (HMW: 2.00 ± 1.33 µg/mL vs 4.02 ± 1.99 µg/mL; HMW/HOMA-IR ratio: 0.87 ± 0.95 vs 2.62 ± 1.86; P < 0.05). Hypertension was associated with lowest HMW (OR = 4.50; 95% CI = 1.41-15.84) and HMW/HOMA-IR (OR = 12.13; 95% CI = 2.51-92.93) regardless of obesity. However, HOMA-IR or the HMW/APN was not significant (P > 0.05). In the ROC curve analyses, the HMW and HMW/HOM-IR were more sensitive to detect hypertension in children and adolescents with obesity.    Conclusion: Low levels of HMW oligomer and HMW/HOM-IR are associated with hypertension in childhood obesity. Thus, these biomarkers could be clinically useful in identifying hypertension in childhood obesity. What is Known: • HMW has previously been reported as the most biologically active isoform of adiponectin, and lower HMW concentrations are associated with obesity, insulin resistance, and metabolic syndrome in children and adolescents. • HMW/HOMA-IR ratio is a sensitive predictor for metabolic syndrome in adults. What is New: • HMW levels are associated with hypertension in children and adolescents, independently of presence of obesity. • HMW was more sensitive to detect hypertension in children and adolescents with obesity when compared to HMW/HOMA-IR, HMW/APN, APN, APN/HOMA-IR, or HOMA-IR.

Headache teleconsultation in the era of COVID-19: Patients' evaluation and future directions.

BACKGROUND AND PURPOSE: Literature regarding headache teleconsultation and patient satisfaction is scarce. The SARS-CoV-2 pandemic led to the restructuring of traditional clinical activity by adopting telemedicine. Our objectives were to evaluate patients' satisfaction with headache teleconsultation by telephone during the SARS-CoV-2 pandemic and assess patients' preferred model of appointment (face-to-face, teleconsultation by telephone, or both). METHODS: Patients with a previous diagnosis of primary headache or neuropathies and facial pain disorders, and at least one telephone headache visit during the first wave of COVID-19, filled out an online questionnaire regarding sociodemographic parameters, satisfaction with teleconsultation, and preferred model of appointment. RESULTS: We included 83 patients (valid response rate of 64.3%); most had migraine (83.1%). Regarding teleconsultation, 81.9% considered this model adequate for follow-up, 88.0% were satisfied with the information provided about the disease/treatment, and 73.5% were satisfied with the medication modification. Ninety percent would agree with a new tele-evaluation if stable after the pandemic. The mixed model was the preferred medical consultation type for the postpandemic period (43.4%), followed by face-to-face visits (33.7%). CONCLUSIONS: Patients were satisfied with the headache teleconsultation during the COVID-19 era. However, an exclusive model of telemedicine does not seem suitable for monitoring all patients. A mixed approach could be integrated into clinical practice after the pandemic to optimize health care.

Neuro-COVID frequency and short-term outcome in the Northern Portuguese population.

BACKGROUND AND PURPOSE: COVID-19-related acute neurological phenotypes are being increasingly recognised, with neurological complications reported in more than 30% of hospitalised patients. However, multicentric studies providing a population-based perspective are lacking. METHODS: We conducted a retrospective multicentric study at five hospitals in Northern Portugal, representing 45.1% of all hospitalised patients in this region, between 1 March and 30 June 2020. RESULTS: Among 1261 hospitalised COVID-19 patients, 457 (36.2%) presented neurological manifestations, corresponding to a rate of 357 per 1000 in the North Region. Patients with neurologic manifestations were younger (68.0 vs. 71.2 years, p = 0.002), and the most frequent neurological symptoms were headache (13.4%), delirium (10.1%), and impairment of consciousness (9.7%). Acute well-defined central nervous system (CNS) involvement was found in 19.1% of patients, corresponding to a rate of 217 per 1000 hospitalised patients in the whole region. Assuming that all patients with severe neurological events were hospitalised, we extrapolated our results to all COVID-19 patients in the region, estimating that 116 will have a severe neurological event, corresponding to a rate of nine per 1000 (95% CI = 7-11). Overall case fatality in patients presenting neurological manifestations was 19.8%, increasing to 32.6% among those with acute well-defined CNS involvement. CONCLUSIONS: We characterised the population of hospitalised COVID-19 patients in Northern Portugal and found that neurological symptoms are common and associated with a high degree of disability at discharge. CNS involvement with criteria for in-hospital admission was observed in a significant proportion of patients. This knowledge provides the tools for adequate health planning and for improving COVID-19 multidisciplinary patient care.

Data Mining for Cardiovascular Disease Prediction.

Cardiovascular diseases (CVDs) aredisorders of the heart and blood vessels and are a major cause of disability and premature death worldwide. Individuals at higher risk of developing CVD must be noticed at an early stage to prevent premature deaths. Advances in the field of computational intelligence, together with the vast amount of data produced daily in clinical settings, have made it possible to create recognition systems capable of identifying hidden patterns and useful information. This paper focuses on the application of Data Mining Techniques (DMTs) to clinical data collected during the medical examination in an attempt to predict whether or not an individual has a CVD. To this end, the CRossIndustry Standard Process for Data Mining (CRISP-DM) methodology was followed, in which five classifiers were applied, namely DT, Optimized DT, RI, RF, and DL. The models were mainly developed using the RapidMiner software with the assist of the WEKA tool and were analyzed based on accuracy, precision, sensitivity, and specificity. The results obtained were considered promising on the basis of the research for effective means of diagnosing CVD, with the best model being Optimized DT, which achieved the highest values for all the evaluation metrics, 73.54%, 75.82%, 68.89%, 78.16% and 0.788 for accuracy, precision, sensitivity, specificity, and AUC, respectively.

The role of marine omega-3 in human neurodevelopment, including Autism Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder - a review.

Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are two increasingly prevalent neurodevelopmental disorders. This rise may be associated with a higher dietary intake of n-6 polyunsaturated fatty acids (PUFAs) and lower of n-3 PUFAs. Docosahexaenoic acid (DHA), a key nutritional n-3 PUFA, is crucial for an optimal offspring's neurodevelopment through the last trimester of pregnancy. Recently, lower DHA levels have been reported in children with ASD and ADHD. The present review summarizes the main research achievements concerning the effect of DHA in children neurodevelopment, in order to elicit its role in the prevention and mitigation of ASD and ADHD. As main finding, a low DHA supply seems to negatively affect childhood neurodevelopment in specific conditions and increase the risk and the severity of ASD or ADHD. Higher DHA status at birth was associated with better childhood neurodevelopmental, but controversial results found in prenatal supplementation raised the hypothesis that the benefits of DHA may be influenced by other factors as socio-economic background and life-style. In conclusion, an optimal DHA provision through maternal diet or breastfeed may promote some neuronal protection in specific offspring's populations, suggesting that DHA may act as a modifiable risk factor for ASD and ADHD.

Capsaicin-like analogue induced selective apoptosis in A2058 melanoma cells: Design, synthesis and molecular modeling.

The use of molecules inspired by natural scaffolds has proven to be a very promising and efficient method of drug discovery. In this work, capsaicin, a natural product from Capsicum peppers with antitumor properties, was used as a prototype to obtain urea and thiourea analogues. Among the most promising compounds, the thiourea compound 6g exhibited significant cytotoxic activity against human melanoma A2058 cells that was twice as high as that of capsaicin. Compound 6g induced significant and dose-dependent G0/G1 cell cycle arrest in A2058 cells triggering cell death by apoptosis. Our results suggest that 6g modulates the RAF/MEK/ERK pathway, inducing important morphological changes, such as formation of apoptotic bodies and increased levels of cleaved caspase-3. Compared to capsaicin, 6g had no significant TRPV1/6 agonist effect or irritant effects on mice. Molecular modeling studies corroborate the biological findings and suggest that 6g, besides being a more reactive molecule towards its target, may also present a better pharmacokinetic profile than capsaicin. Inverse virtual screening strategy found MEK1 as a possible biological target for 6g. Consistent with these findings, our observations suggested that 6g could be developed as a potential anticancer agent.

Quality of life as a prognostic marker in pulmonary arterial hypertension.

BACKGROUND: Improvement in quality of life together with better survival are the ultimate goals in the treatment of pulmonary arterial hypertension (PAH) patients. The objective of this study was to evaluate the health-related quality of life (HRQL) of pulmonary arterial hypertension (PAH) patients with the SF-36 generic questionnaire and to identify the prognostic implication of this assessment. METHODS: Fifty-four consecutive newly diagnosed PAH patients (WHO classification group I) in a single PAH reference center were included. Patients were evaluated at baseline for clinical and hemodynamic parameters, and they subsequently received first-line therapy with either an endothelin receptor antagonist or a phosphodiesterase-5 inhibitor. After 16 weeks of specific PAH therapy, all patients were re-evaluated using a 6MWT and a SF 36 questionnaire, and then they were followed up for at least 36 months. RESULTS: After treatment, the patients demonstrated an improved 6MWT (414 ± 124 m vs. 440 ± 113 m, p = 0.001). Specific PAH therapy also improved the HRQL scores.Patients with a baseline Physical Component Score (PCS) higher than 32 had a better survival rate than those who had a score under 32 (p = 0.04). Similarly, patients with a PCS of at least a 38 after the 16 week therapy period had a better survival rate when compared with those who did not achieve this value (p = 0.016). Unlike the absolute PCS values, the post-treatment PCS variability was unable to predict better survival rates (p = 0.58). CONCLUSIONS: Our findings suggest that HRQL is associated with prognosis in PAH. Furthermore, achieving pre-determined PCS scores might represent a specific goal to be reached in treatment-to-target strategies.

Female sexual dysfunction and distress in premenopausal women with migraine followed in a tertiary headache center: A pilot study.

BACKGROUND: Female sexual dysfunction (FSD) is an underdiagnosed and undertreated problem. Few studies have addressed sexual distress in migraine. We aimed to perform a pilot study to determine if there is an association between migraine and sexual dysfunction/distress in premenopausal women and to identify their respective risk factors. METHODS: Retrospective, cross-sectional pilot study, including 71 premenopausal female patients with migraine, from the headache outpatient clinic of a tertiary hospital, and 34 age-matched-controls. Female Sexual Function Index-6 (FSFI-6), Female Sexual Distress Scale-Revised (FSDS-R), Migraine Disability Assessment (MIDAS) Scale, Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS) and Sleep Health Scale (RU-SATED) were applied. RESULTS: Of the 71 patients [40.0 (IQR = 11.00) years], only 12.7 % (n = 9) were not under migraine prophylactic treatment, and most (n = 33, 62.3 %) reported severe disability (MIDAS-IV). FSD and sexual distress were present in 50.7 % (36) patients with migraine [vs 20.6 % (7) controls]. Migraine patients showed lower FSFI-6 scores [19.0 (9.0) vs 24.0 (6.0), p = 0.005], with significantly lower levels of desire (p = 0.011), lubrication (p = 0.002), and satisfaction (p = 0.013), higher sexual distress [11.2 (25.6) vs 3.2 (9.6), p = 0.001], anxiety (p < 0.001), and depression (p < 0.001) levels, and lower sleep health scores (p = 0.005). Old age of onset, being under preventive medication, anxiety/depression, and dysfunctional sleep, were significantly associated with sexual distress. Certain domains of sexual function were associated with sociodemographic and migraine characteristics, anxiety, depression, and sleep health. CONCLUSIONS: This pilot study highlights the possible association between migraine and elevated sexual dysfunction/distress levels among premenopausal women. It underscores the importance of sexual health assessments in these individuals, particularly those with higher levels of anxiety, depression, or poor sleep quality. It is important to exercise caution when interpreting results, as they may not be applicable to a wider context. This research paves the way for a larger study that will include a broader population of women from the community and encompass patients followed in different levels of health care.

Psychiatric Comorbidities in Neurologic Hospitalizations in Portugal: A Nationwide Retrospective Observational Study.

INTRODUCTION: Psychiatric comorbidities have a significant impact on patients' quality of life and often go undetected in neurologic practice. The aim of this study was to describe and characterize psychiatric comorbidities among patients hospitalized due to a neurologic disorder in mainland Portugal. METHODS: A retrospective observational study was performed by analyzing hospitalization with a primary diagnosis of neurologic disorder defined as categories 76, 77, 79 - 85, 95, 109 of the Clinical Classification Software for International Classification of Diseases, Ninth Revision, Clinical Modification, occurring between 2008 and 2015 in adult patients (≥ 18 years of age). Psychiatric comorbidities were determined as the presence of a secondary diagnosis belonging to the Clinical Classification Software categories 650 to 670. RESULTS: A total of 294 806 hospitalization episodes with a primary diagnosis of a neurologic disorder were recorded in adult patients between 2008 - 2015 in Portuguese public hospitals. Approximately 26.9% (n = 79 442) of the episodes had a recorded psychiatric comorbidity (22.1%; 32.2%, female versus male hospitalizations). Patients with registered psychiatric comorbidities were younger (66.2 ± 16.2 vs 68.6 ± 17.2 with no psychiatric comorbidities, p < 0.001), presented lower all-cause in-hospital mortality rates, and significantly longer mean hospital stays. 'Delirium, dementia, amnestic and other cognitive disorders' were recorded in 7.4% (n = 21 965) of the hospitalizations, followed by alcohol-related disorders in 6.5% (n = 19 302) and mood disorders in 6.1% (n = 18 079). Epilepsy/seizures were the neurologic disorders with the highest proportion of recorded psychiatric comorbidities (39.9%). CONCLUSION: Psychiatric comorbidities were recorded in more than a quarter of the hospitalizations with a primary diagnosis of a Neurologic disorder. Psychiatric comorbidities varied among neurological disorders and were associated with different demographic and clinical features.

Spectrum of cutaneous lesions in a cohort of patients with neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome with a predisposition to the development of central nervous system tumors, ophthalmic manifestations, and dermatological lesions. The latter are present in 70-95% of patients and can precede the evolution of other tumors. However, they are not included in the diagnostic criteria and are frequently undervalued during follow-up. METHODS: An observational cross-sectional study characterizing cutaneous lesions in a cohort of NF2 patients was carried out. Dermatological examinations were performed, and lesions were classified into neural cutaneous tumors (superficial, SNCT, and deep, DNCT), hyperpigmented patches (HyperP), and hypopigmented patches (HypoP). The Dermatology Life Quality Index (DLQI) and EQ-5D questionnaires were applied to evaluate the impact on quality of life. RESULTS: Nineteen patients with a mean age of 36 years were included. Sixteen (84%) patients had cutaneous lesions, mostly developed 10 or more years before the diagnosis. SNCT, DNCT, and HyperP showed similar frequencies (58%). HypoP were observed in only one patient. HyperP developed, on average, earlier than NCT (9.6 vs. 16.5 SNCT, 17.0 DNCT; years). The excised lesions had different histological patterns, including neurofibromas, schwannomas, and a hybrid tumor. Most patients reported a low impact of cutaneous manifestations on the quality of life (DLQI 0 or 1). CONCLUSIONS: Cutaneous lesions are frequent in NF2 and may precede the diagnosis by several years. Their identification is important to establish the diagnosis earlier and potentially reduce morbidity and mortality.

ALDEHYDE DEHYDROGENASE-2 DEFICIENCY AGGRAVATES NEUROINFLAMMATION, NOCICEPTION, AND MOTOR IMPAIRMENT IN A MOUSE MODEL OF MULTIPLE SCLEROSIS.

Aldehyde dehydrogenase-2 deficiency (ALDH2*2) found in 36% of Han Chinese, affects approximately 8% of the world population. ALDH2 is a mitochondrial key enzyme in detoxifying reactive aldehydes to less reactive forms. Studies demonstrate a potential link between ALDH2*2 mutation and neurodegenerative diseases. Multiple sclerosis (MS) is an incurable and disabling neurodegenerative autoimmune disease that induces motor, and cognitive impairment, and hypersensitivity, including chronic pain. Accumulating evidence suggests that reactive aldehydes, such as 4-hydroxynonenal (4-HNE), contribute to MS pathogenesis. Here, using knock-in mice carrying the inactivating point mutation in ALDH2, identical to the mutation found in Han Chinese, we showed that the impairment in ALDH2 activity heightens motor disabilities, and hypernociception induced by experimental autoimmune encephalomyelitis (EAE). The deleterious clinical signs are followed by glial cell activation in the spinal cord and increased 4-HNE levels in the spinal cord and serum. Importantly, the pharmacological ALDH2 activation by Alda-1 ameliorates EAE-induced hypernociception and motor impairment in both wild-type and ALDH2*2KI mice. Reduced hypernociception was associated with less early growth response protein 1 (EGR1), neuronal and glial activation, and reactive aldehyde accumulation in the spinal cord and serum. Taken together, our data suggest that the mitochondrial enzyme ALDH2 plays a role in regulating clinical, cellular, and molecular responses associated with EAE. This indicates that ALDH2 could serve as a molecular target for MS control, with ALDH2 activators, like Alda-1 as potential neuroprotective candidates. Furthermore, ALDH2*2 carriers may be at increased risk of developing more accentuated MS symptoms.

It's in the game: A review of neurological lesions associated with sports.

INTRODUCTION: The practice of sports may lead to neurological injuries. While relatively uncommon (overall incidence of approximately 2.5%), and mostly benign and transient, some conditions may be life-threatening and permanent. Thus, both clinical neurologists and sports physicians should be aware of their existence and relevance. We aimed to review all sports-related neurological injuries and illnesses reported in the literature. METHODS: Following SANRA guidelines, we performed a narrative review and searched PubMed and Scopus databases. Relevant sports were selected based on their recognition as an Olympic sport by the International Olympic Committee. Chronic traumatic encephalopathy (CTE) and other neurodegenerative disorders were not included. RESULTS: A total of 292 studies were included concerning 33 different sports. The most reported neurological injury was damage to the peripheral nervous system. Traumatic injuries have also been extensively reported, including cerebral haemorrhage and arterial dissections. Non-traumatic life-threatening events are infrequent but may also occur, e.g. posterior reversible encephalopathy syndrome, cerebral venous thrombosis, and arterial dissections. Some conditions were predominantly reported in specific sports, e.g. yips in baseball and golf, raising the possibility of a common pathophysiology. Spinal cord infarction due to fibrocartilaginous embolism was reported in several sports associated with minor trauma. CONCLUSION: Sports-related neurological injuries are increasingly receiving more social and medical attention and are an important cause of morbidity and mortality. This review may serve as a guide to physicians managing these challenging situations.

Wnt signaling is involved in crotalphine-induced analgesia in a rat model of neuropathic pain.

The aberrant activation of Wnt/ß-catenin and atypical Wnt/Ryk signaling pathways in the spinal cord is critical for the development and maintenance of neuropathic pain. Crotalphine is a structural analog to a peptide first identified in Crotalus durissus terrificus snake venom, which induces antinociception by activating kappa-opioid and CB2 cannabinoid receptors. Consistent with previous data, we showed that the protein levels of the canonical Wnt/ß-catenin and the atypical Wnt/Ryk signaling pathways are increased in neuropathic rats. Importantly, the administration of crotalphine downregulates these protein levels, including its downstream cascades, such as TCF4 from the canonical pathway and NR2B glutamatergic receptor and Ca2+-dependent signals, via the Ryk receptor. The CB2 receptor antagonist, AM630, abolished the crotalphine-induced atypical Wnt/Ryk signaling pathway activation. However, the selective CB2 agonist affects both canonical and non-canonical Wnt signaling in the spinal cord. Next, we showed that crotalphine blocked hypersensitivity and significantly decreased the concentration of IL-1ɑ, IL-1ß, IL-6, IL-10, IL-18, TNF-ɑ, MIP-1ɑ and MIP-2 induced by intrathecal injection of exogenous Wnt-3a agonist. Taken together, our findings show that crotalphine induces analgesia in a neuropathic pain model by down-regulating the canonical Wnt/ß-catenin and the atypical Wnt/Ryk signaling pathways and, consequently controlling neuroinflammation. This effect is, at least in part, mediated by CB2 receptor activation. These results open a perspective for new approaches that can be used to target Wnt signaling in the context of chronic pain. PERSPECTIVE: Our work identified that crotalphine-induced activation of CB2 receptors plays a critical role in the impairment of Wnt signaling during neuropathic pain. This work suggests that drugs with opioid/cannabinoid activity may be a useful strategy to target Wnt signaling in the context of chronic pain.

Use of Social Networks in the Context of the Dietitian's Practice in Brazil and Changes During the COVID-19 Pandemic: Exploratory Study.

BACKGROUND: Social networks have been pointed out as 1 of the greatest means of spreading information. A large part of the population is already present on these platforms, looking up subjects such as health, nutrition, and food. To reach this audience, it may be important for dietitians to explore social networks. However, there is a gap in scientific studies on exploring the ways in which these platforms are used by dietitians in Brazil, and the roles they play in the profession have not been well defined. OBJECTIVE: This study aims to describe the roles that social networks play in dietitians' practice in Brazil and their mode of use of social networks. This study also aims to identify professionals' perceptions and opinions regarding the use of these tools, as well as changes in behavior on social network usage caused by the COVID-19 pandemic. METHODS: We carried out a quantitative cross-sectional study, collecting data through an online questionnaire, submitted between October 2020 and January 2021 to dietitians registered on the Federal Council of Dietitians. All participants included in the study answered questions about the use of social networks in their professional context. RESULTS: In total, 264 (91.7%) of the 288 participants reported using social networks for professional practice. Instagram was the social network most often used by professionals (224/264, 84.8%). Dietitians (N=288) related to the use of social networks (always to almost always) for sharing information about their services (n=114-72 [39.6%-25%], respectively), following the work of other dietitians (n=172-64 [59.7%-22.2%], respectively), and writing about topics related to food and nutrition (n=166-53 [57.6%-18.4%], respectively). The roles played by social networks in the professional context of dietitians were attracting more clients (210/289, 72.7%) and keeping in touch with them (195/289, 67.5%). Furthermore, 227 (78.5%) of the 289 dietitians strongly agreed that social networks are good tools to promote their services. During the COVID-19 pandemic, 216 (74.7%) of the 289 participants noticed changes in their behavior, feelings, or beliefs on the use of social networks related to professional practice, and 149 (51.6%) have increased the frequency of sharing information about nutrition and health in general on social networks. CONCLUSIONS: The main roles of social networks in the professional context of dietitians are to attract clients and to facilitate the contact between professional and client. The modes of use reported by the professionals included sharing information about their services, following the work of professional colleagues, and writing about topics related to nutrition. Most of them reported believing that social networks are an effective way to disseminate their services. Moreover, most professionals claimed to have noticed changes in their behaviors or beliefs on social media during the COVID-19 pandemic.

Common variable immunodeficiency and its inflammatory neurological manifestations: A case report and literature review.

BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of primary immunodeficiencies characterized by impaired immunoglobulin production and dysregulated immune response. Neurological manifestations have been described in a few patients, and little is known about its clinic and therapeutic approach. Thus, this work aimed to review the literature on it and to help differentiate CVID from its mimics, especially sarcoidosis. METHODS: We described a case report and included a literature review of inflammatory neurological involvement in CVID. RESULTS: A 32-year-old female patient with a medical history of recurrent bacterial infections, temporal focal epilepsy and granulomatous lung disease under study, and cervix squamous cell carcinoma, was initially admitted to the emergency department due to intracranial hypertension. After excluding infectious and neoplastic etiologies, the most likely hypothesis was that granulomatous pulmonary, cerebral, and leptomeningeal inflammatory involvement were associated with sarcoidosis. Two years later, a diagnosis of CVID was made, and the patient was secondarily diagnosed with Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) and related inflammatory brain disease - both complications of CVID. After starting targeted treatment with immunoglobulin replacement and pulse glucocorticoids followed by a chronic taper, the patient became stable. However, three consecutive failures in immunoglobulin intake during the COVID-19 pandemic led to disease recurrence with relapse of neurological manifestations. CONCLUSION: This case illustrates the complex multiple organ manifestations of CVID. When granulomatous conditions arise in these patients, a rare lung disease arising in the context of CVID, the GLILD disease with multisystem involvement, should be taken into consideration. Early treatment with combined steroids and immunotherapy seems to be effective in controlling CVID's neurological manifestations.

Activation of PKCε-ALDH2 Axis Prevents 4-HNE-Induced Pain in Mice.

Protein kinase Cε (PKCε) is highly expressed in nociceptor neurons and its activation has been reported as pro-nociceptive. Intriguingly, we previously demonstrated that activation of the mitochondrial PKCε substrate aldehyde dehydrogenase-2 (ALDH2) results in anti-nociceptive effects. ALDH2 is a major enzyme responsible for the clearance of 4-hydroxy-2-nonenal (4-HNE), an oxidative stress byproduct accumulated in inflammatory conditions and sufficient to induce pain hypersensitivity in rodents. Here we determined the contribution of the PKCε-ALDH2 axis during 4-HNE-induced mechanical hypersensitivity. Using knockout mice, we demonstrated that PKCε is essential for the nociception recovery during 4-HNE-induced hypersensitivity. We also found that ALDH2 deficient knockin mice display increased 4-HNE-induced nociceptive behavior. As proof of concept, the use of a selective peptide activator of PKCε (ΨεHSP90), which favors PKCε translocation to mitochondria and activation of PKCε-ALDH2 axis, was sufficient to block 4-HNE-induced hypersensitivity in WT, but not in ALDH2-deficient mice. Similarly, ΨεHSP90 administration prevented mechanical hypersensitivity induced by endogenous production of 4-HNE after carrageenan injection. These findings provide evidence that selective activation of mitochondrial PKCε-ALDH2 axis is important to mitigate aldehyde-mediated pain in rodents, suggesting that ΨεHSP90 and small molecules that mimic it may be a potential treatment for patients with pain.