Noncanonical Wnt signaling promotes colon tumor growth, chemoresistance and tumor fibroblast activation.

Colon tumors of the mesenchymal subtype have the lowest overall survival. Snail1 is essential for the acquisition of this phenotype, characterized by increased tumor stemness and invasion, and high resistance to chemotherapy. Here, we find that Snail1 expression in colon tumor cells is dependent on an autocrine noncanonical Wnt pathway. Accordingly, depletion of Ror2, the co-receptor for noncanonical Wnts such as Wnt5a, potently decreases Snail1 expression. Wnt5a, Ror2, and Snail1 participate in a self-stimulatory feedback loop since Wnt5a increases its own synthesis in a Ror2- and Snail1-dependent fashion. This Wnt5a/Ror2/Snail1 axis controls tumor invasion, chemoresistance, and formation of tumor spheres. It also stimulates TGFß synthesis; consequently, tumor cells expressing Snail1 are more efficient in activating cancer-associated fibroblasts than the corresponding controls. Ror2 downmodulation or inhibition of the Wnt5a pathway decreases Snail1 expression in primary colon tumor cells and their ability to form tumors and liver metastases. Finally, the expression of SNAI1, ROR2, and WNT5A correlates in human colon and other tumors. These results identify inhibition of the noncanonical Wnt pathway as a putative colon tumor therapy.

Tatton-Brown-Rahman syndrome: Novel pathogenic variants and new neuroimaging findings.

Tatton-Brown-Rahman syndrome (TBRS) or DNMT3A-overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.

Seven- and thirty-day mortality in digoxin poisoning: Results from the DIGITOX study.

BACKGROUND: Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status and the presence of electrocardiographic and electrolytic disturbances. OBJECTIVE: To identify factors associated with seven-day and thirty-day mortality in digoxin poisoning. DESIGN, SETTINGS AND PARTICIPANTS: A retrospective, observational, multicenter study was conducted across 15 Hospital Emergency Departments (HED) in Spain. All patients over 18 years of age who presented to participating HEDs from 2015 to 2021 were included. The inclusion criteria encompassed individuals meeting the criteria for digoxin poisoning, whether acute or chronic. OUTCOMES MEASURE AND ANALYSIS: To identify independent factors associated with 7-day and 30-day mortality, a multivariate analysis was conducted. This analysis included variables of clinical significance, as well as those exhibiting a trend (p < 0.1) or significance in the bivariate analysis. MAIN FINDINGS: A total of 658 cases of digoxin poisoning were identified. Mortality rates were 4.5% (30 patients) at seven days and 11.1% (73 patients) at thirty days. Regarding 7-day mortality, the mean age of deceased patients was comparable to survivors (84.7 (8.9) vs 83.9 (7.9) years; p = ns). The multivariate analysis revealed that factors independently associated with 7-day mortality encompassed the extent of dependence assessed by the Barthel Index (BI 60-89 OR 0.28; 95% CI 0.10-0.77; p = 0.014 and BI>90 OR 0.22; 95% CI 0.08-0.63; p = 0.005), the identification of ventricular arrhythmias (OR 1.34; 95% CI 1.34-25.21; p = 0.019), and the presence of circulatory (OR 2.84; 95% CI 1.19-6.27; p = 0.019) and neurological manifestations (OR 2.67; 95% CI 1.13-6.27; p = 0.025). Factors independently associated with 30-day mortality encompassed extent of dependence (BI 60-89 OR 0.37; 95% CI 0.20-0.71; p = 0.003 and BI>90 OR 0.18; 95% CI 0.09-0.39; p < 0.001) and the identification of circulatory (OR 2.13; 95% CI 1.10-4.15; p = 0.025) and neurological manifestations (OR 2.39; 95% CI 1.25-3.89; p = 0.006). CONCLUSIONS: The study identifies the degree of dependency assessed by the Barthel Index and the presence of cardiovascular and neurological symptoms as independent predictors of both 7-day and 30-day mortality. Additionally, the detection of ventricular arrhythmia is also an independent factor for 7-day mortality.

Gender and non-communicable diseases in Mexico: a political mapping and stakeholder analysis.

BACKGROUND: Mexico and other low- and middle-income countries (LMICs) present a growing burden of non-communicable diseases (NCDs), with gender-differentiated risk factors and access to prevention, diagnosis and care. However, the political agenda in LMICs as it relates to health and gender is primarily focused on sexual and reproductive health rights and preventing violence against women. This research article analyses public policies related to gender and NCDs, identifying political challenges in the current response to women's health needs, and opportunities to promote interventions that recognize the role of gender in NCDs and NCD care in Mexico. METHODS: We carried out a political mapping and stakeholder analysis during July-October of 2022, based on structured desk research and interviews with eighteen key stakeholders related to healthcare, gender and NCDs in Mexico. We used the PolicyMaker V5 software to identify obstacles and opportunities to promote interventions that recognize the role of gender in NCDs and NCD care, from the perspective of the political stakeholders interviewed. RESULTS: We found as a political obstacle that policies and stakeholders addressing NCDs do not take a gender perspective, while policies and stakeholders addressing gender equality do not adequately consider NCDs. The gendered social and economic aspects of the NCD burden are not widely understood, and the multi-sectoral approach needed to address these aspects is lacking. Economic obstacles show that budget cuts exacerbated by the pandemic are a significant obstacle to social protection mechanisms to support those caring for people living with NCDs. CONCLUSIONS: Moving towards an effective, equity-promoting health and social protection system requires the government to adopt an intersectoral, gender-based approach to the prevention and control of NCDs and the burden of NCD care. Despite significant resource constraints, policy innovation may be possible given the willingness among some stakeholders to collaborate, particularly in the labour and legal sectors. However, care will be needed to ensure the implementation of new policies has a positive impact on both gender equity and health outcomes. Research on successful approaches in other contexts can help to identify relevant learnings for Mexico.

Prognostic value of neutrophil-to-lymphocyte ratio at diagnosis in colorectal cancer: propensity score analysis.

INTRODUCTION: Baseline neutrophil-to-lymphocyte ratio (NLR) at the time of colorectal cancer (CRC) diagnosis has been proposed as a predictor of long-term survival. The aim of the study was to analyse its usefulness in a homogeneous population with control of the main confounding factors. METHODOLOGY: Observational study of 836 patients operated on for CRC who were divided into two groups: NLR ≤ 3.3 vs NLR > 3.3. To control for confounders, they were matched one-to-one by propensity analysis. A final sample of 526 patients remained for study. RESULTS: The two groups were mismatched in terms of age, comorbidity, tumour stage, rectal location, and neoadjuvant therapy. Once matching was performed, baseline NLR was statistically significantly associated with long-term survival (p < 0.001) and behaved as an independent prognostic factor for survival (p = 0.001; HR: 1,996; 95% CI: 1.32-3.00) when adjusted in a Cox regression model using age (p < 0,001; HR: 1,04; IC95%: 1,02-1,06) and the Charlson Comorbidity Index (p < 0,001; HR: 1,40; IC95%: 1,27-1,55). Neoadjuvant therapy lost its statistical significance (p = 0,137; HR: 1,59; IC95%: 0,86-2,93). CONCLUSIONS: A high baseline NLR (> 3.3) in patients with colorectal cancer at diagnosis represents a poor prognostic factor in terms of survival. Its use in routine practice could intensify therapeutic strategies and follow-up in these patients.

Avatar Mice Underscore the Role of the T Cell-Dendritic Cell Crosstalk in Ebola Virus Disease and Reveal Mechanisms of Protection in Survivors.

Ebola virus disease (EVD) is a complex infectious disease characterized by high inflammation, multiorgan failure, the dysregulation of innate and adaptive immune responses, and coagulation abnormalities. Evidence accumulated over the last 2 decades indicates that, during fatal EVD, the infection of antigen-presenting cells (APC) and the dysregulation of T cell immunity preclude a successful transition between innate and adaptive immunity, which constitutes a key disease checkpoint. In order to better understand the contribution of the APC-T cell crosstalk to EVD pathophysiology, we have developed avatar mice transplanted with human, donor-specific APCs and T cells. Here, we show that the transplantation of T cells and APCs from Ebola virus (EBOV)-naive individuals into avatar mice results in severe disease and death and that this phenotype is dependent on T cell receptor (TCR)-major histocompatibility complex (MCH) recognition. Conversely, avatar mice were rescued from death induced by EBOV infection after the transplantation of both T cells and plasma from EVD survivors. These results strongly suggest that protection from EBOV reinfection requires both cellular and humoral immune memory responses. IMPORTANCE The crosstalk between dendritic cells and T cells marks the transition between innate and adaptive immune responses, and it constitutes an important checkpoint in EVD. In this study, we present a mouse avatar model in which T cell and dendritic cell interactions from a specific donor can be studied during EVD. Our findings indicate that T cell receptor-major histocompatibility complex-mediated T cell-dendritic cell interactions are associated with disease severity, which mimics the main features of severe EVD in these mice. Resistance to an EBOV challenge in the model was achieved via the transplantation of both survivor T cells and plasma.

Randomised clinical trial to test the phenolization in sacrococcygeal pilonidal disease.

To test the efficacy and safety of phenolization in uncomplicated Sacrococcygeal pilonidal disease (SPD) the phenolization in uncomplicated SPD is feasible and secure in selected patients in observational studies. The greatest benefits are obtained to reduce the length of sick leave (LSL) and complications. Single-center randomised controlled clinical trial. Patients were recruited at University Hospital of Tarragona Joan XXIII of Spain. Patients were randomised into two treatment groups. All patients with uncomplicated sacrococcygeal disease, localised in the midline and with only 1 fistulous orifice. The patients were randomly assigned to the phenolization group (PhG) or conventional-surgery group (CsG). Both groups were managed without admission. The main endpoint was the recurrence of sacrococcygeal disease. Secondary endpoints included time of sick leave, complications, and readmission. 124 patients were included in the study. No disease recurrence was observed in either group. Clinical follow-up was carried out with a mean of 493.8 days (SD 6.59). The LSL was shorter in the PhG (mean 19.63 days, SD 28.15) than in the CSG (43.95 days, SD 38.60). The LSL reduction was -24.31 days (P .002). The phenolization in selected SPD is a safe and feasible procedure in selected patients. This approach could become the standard of care for patients with selected Sacrococcygeal pilonidal.

Leisure education in youth with developmental disabilities: Effects on individual quality of life, adaptive behavior, and family quality of life.

Leisure participation enhances the learning of adaptive skills and the quality of life in youth with developmental disabilities. The goal of this study was to evaluate the effects of a leisure education program in individuals with developmental disabilities in terms of adaptive behavior and quality of life. Nine participants divided into two small groups and their families were included. A quasi-experimental design was employed to determine whether there was a program effect. The Adaptive Behavior Assessment System, the KIDSCREEN-27, and the Family Quality of Life Scale were administered before and after the intervention. There was a significant increase in social, home, and school skills as well as a better perception of quality of life in relationships with parents, social support, and school. In addition, the program affected the family's perception of practical and emotional support. Findings provide support for the application of this leisure program to enhance quality of life outcomes.

Characteristics of drug poisonings treated in eleven Spanish emergency departments: Differentiated analysis by sex. / Características de las intoxicaciones por drogas atendidas en once servicios de urgencias españoles: Análisis diferenciado por sexo.

In order to identify the sociodemographic, clinical, emergency management and severity differences of drug poisoning treated in Emergency Departments (ED) from a gender perspective, data on patients from 11 Spanish EDs were recorded over 24 months (August 2017-July 2019). The severity of intoxication was compared by sex and was based on the combined adverse event (orotracheal intubation, cardiorespiratory arrest, intensive care hospitalization, and death). We included 4,526 patients (men 75.5%), with a mean age of 33 years. The most frequent drugs were: cocaine (47.8%), cannabis (44.4%) and amphetamines (25.5%). Men consumed more GHB (5.6% vs. 1.9%, p < .001) and less benzodiazepines (8.0% vs. 11.1%, p = .002) and alcohol (57.2% vs. 61.2%, p = .028) than women, with no differences in other types of drugs. Men presented significantly more severe bradycardia (OR = 4.39, 95%CI = 1.03-18.7), chest pain (OR = 1.72, 95%CI = 1.27-2.35) and symptomatic hypertension (OR = 1.56, 95%CI = 1.06-2.30) and less anxiety (OR = 0.74, 95%CI = 0.61-0.89) and vomiting (OR = 0.64, CI95% = 0.51-0.80). Men had more combined adverse events (3.1% vs. 2.0%, p = .047) and a greater intubations (1.9% vs. 1.0%, p = .044), with no significant differences in the adjusted model (OR = 1.349, 95%CI = 0.827-2.202 and OR = 1.371, 95%CI = 0.700-2.685, respectively). Twelve patients died (0.3%), with no differences according to sex. Drug intoxications attended in the ED differ according to sex. GHB, benzodiazepines and alcohol are more frequently involved in men than women. Cardiovascular symptomatology is more prevalent in men, while anxiety and vomiting are more frequent in women, which cannot be explained by differences in sociodemographic characteristics or the drugs used. There were no differences in the severity of the intoxication episodes.

Con el objetivo de identificar, con perspectiva de género, las diferencias sociodemográficas, clínicas, manejo en urgencias y gravedad de las intoxicaciones por drogas atendidas en Servicios de Urgencias Hospitalarias (SUH), se registraron todos los pacientes atendidos en 11 SUH españoles durante 24 meses (agosto 2017-julio 2019). La gravedad de la intoxicación se basó en el evento adverso combinado (intubación orotraqueal, parada cardiorrespiratoria, hospitalización en intensivos, y muerte), comparándose según el sexo. Cuando se encontraron diferencias significativas en sintomatología o gravedad, los resultados se ajustaron por características sociodemográficas y drogas consumidas. Se incluyeron 4.526 pacientes (hombres 75,5%), con edad media de 33 años. Las drogas más frecuentes fueron cocaína (47,8%), cánnabis (44,4%) y anfetaminas (25,5%). Hubo más GHB en hombres (5,6% vs 1,9%, p < ,001) y más benzodiacepinas (8,0% vs 11,1%, p = ,002) y alcohol (57,2% vs 61,2%, p = ,028) en mujeres, sin diferencias en otras de drogas. Los hombres tuvieron significativamente más bradicardia grave (OR = 4,39, IC95% = 1,03-18,7), dolor torácico (OR = 1,72, IC95% = 1,27-2,35) e hipertensión sintomática (OR = 1,56, IC95% = 1,06-2,30) y menos ansiedad (OR = 0,74, IC95% = 0,61-0,89) y vómitos (OR = 0,64, IC95% = 0,51-0,80). Tuvieron también más eventos adversos combinados (3,1% vs 2,0%, p = ,047) y más intubaciones (1,9% vs 1,0%, p = ,044), pero sin diferencias significativas en el modelo ajustado (OR = 1,349, IC95% = 0,827-2,202 y OR = 1,371, IC95% = 0,700-2,685, respectivamente). Fallecieron 12 pacientes (0,3%), sin diferencias según sexo. Concluimos que existen diferencias según el sexo en las drogas que originan intoxicaciones atendidas en los SUH. Las diferencias en sintomatología cardiovascular (más en hombres) y ansiosa o digestiva (más en mujeres) no se explican por diferencias sociodemográficas o de drogas utilizadas. La gravedad de la intoxicación no se ve influida por el sexo.

Percutaneus intermetatarsal ligament release and minimally invasive distal metatarsal osteotomy for treatment second intermetatarsal space syndrome.

BACKGROUND AND OBJECTIVE: Since the description of the syndrome of the second intermetatarsal space, this is a common diagnosis among foot and ankle surgeons. However, no series have been published that consider this syndrome as its own entity. The objective of this study is to evaluate the clinical and radiological results of the release of the intermetatarsal ligament and minimally invasive distal metatarsal osteotomy in patients diagnosed with second space syndrome. MATERIALS AND METHODS: An observational, longitudinal, retrospective study was carried out in patients with a clinical diagnosis of second space syndrome operated on using a minimally invasive technique. For the clinical results, the visual analog scale (VAS) for subjective pain, the Manchester-Oxford Foot Questionnaire (MOXFQ) and the scale for minor metatarsals and interphalangeals of the American Orthopedic Foot and Ankle Society (AOFAS-LMTS) were used for clinical-functional assessment. Consolidation or not of osteotomies was recorded and complications were recorded. RESULTS: Twenty-nine feet in 29 patients were included in the study. After a mean follow-up of 39 months (25-50), clinically and statistically significant improvement was obtained in the scores: pain VAS, scales and subscales of the MOXFQ and the AOFAS-LMTS (p < 0.0001). All osteotomies healed at the end of follow-up and no major complications were recorded. CONCLUSIONS: Percutaneous or minimally invasive surgery, in patients with second intermetatarsal space syndrome, obtains good clinical, functional and subjective results, with few complications. Therefore, we consider it an effective, safe and recommended technique in the hands of experienced surgeons.

Reduced Nucleoprotein Availability Impairs Negative-Sense RNA Virus Replication and Promotes Host Recognition.

Negative-sense RNA viruses (NSVs) rely on prepackaged viral RNA-dependent RNA polymerases (RdRp) to replicate and transcribe their viral genomes. Their replication machinery consists of an RdRp bound to viral RNA which is wound around a nucleoprotein (NP) scaffold, forming a viral ribonucleoprotein complex. NSV NP is known to regulate transcription and replication of genomic RNA; however, its role in maintaining and protecting the viral genetic material is unknown. Here, we exploited host microRNA expression to target NP of influenza A virus and Sendai virus to ascertain how this would impact genomic levels and the host response to infection. We find that in addition to inducing a drastic decrease in genome replication, the antiviral host response in the absence of NP is dramatically enhanced. Additionally, our data show that insufficient levels of NP prevent the replication machinery of these NSVs to process full-length genomes, resulting in aberrant replication products which form pathogen-associated molecular patterns in the process. These dynamics facilitate immune recognition by cellular pattern recognition receptors leading to a strong host antiviral response. Moreover, we observe that the consequences of limiting NP levels are universal among NSVs, including Ebola virus, Lassa virus, and measles virus. Overall, these results provide new insights into viral genome replication of negative-sense RNA viruses and highlight novel avenues for developing effective antiviral strategies, adjuvants, and/or live-attenuated vaccines.IMPORTANCE Negative-sense RNA viruses comprise some of the most important known human pathogens, including influenza A virus, measles virus, and Ebola virus. These viruses possess RNA genomes that are unreadable to the host, as they require specific viral RNA-dependent RNA polymerases in conjunction with other viral proteins, such as nucleoprotein, to be replicated and transcribed. As this process generates a significant amount of pathogen-associated molecular patterns, this phylum of viruses can result in a robust induction of the intrinsic host cellular response. To circumvent these defenses, these viruses form tightly regulated ribonucleoprotein replication complexes in order to protect their genomes from detection and to prevent excessive aberrant replication. Here, we demonstrate the balance that negative-sense RNA viruses must achieve both to replicate efficiently and to avoid induction of the host defenses.

Serodominance Profile in a Dust Mite Complex Region.

BACKGROUND/OBJECTIVE: The objective of this study was to describe the molecular sensitization profile of mite allergy in an area with a high environmental exposure of house dust mites (HDM) and storage mites. METHODS: Skin prick tests were performed with standardized extracts (DIATER, Madrid, Spain). A specific commercial molecular panel (MADx) for Dermatophagoides pteronyssinus (Dpt), Dermatophagoides farinae (Dfar), Lepidoglyphus destructor (Ldt), Tyrophagus putrescentiae (Tput), and Blomia tropicalis (Blot) was correlated with clinical parameters in Galician (northwestern of Spain) HDM allergic patients. RESULTS: Fifty patients (60% female) met the inclusion and exclusion criteria. All of the patient's present rhinitis (50), 28% (14) rhinitis and asthma, and 18% (9) atopic dermatitis (AD). Hundred patients had a positive prick test for Dpt, followed by Dfar (92%), Ldt and Tput (74%), and Blot (68%). More than 50% recognized specific IgE for Der p 1, Der p 2, reaching 86% in the case of Der p 23. No statistically significant differences in IgE levels were found between patients with/without asthma and those with mild or moderate-severe rhinitis. Der p 7 was higher among rhinitis patients (p value 0.05). AD relative risk (RR) was increased in patients sensitized to Der f 2, Der p 2, and Der p 23. Der p 10 decreases the risk to have AD (RR 0.80). CONCLUSION: The evaluation of IgE results in a comprehensive panel of allergens allows differentiation of serological reactivity profiles with their clinical expression, to perform an optimal management. Improvements in component resolved diagnosis and more research on the clinical relevance of mite allergens are needed to achieve a genuine diagnosis leading to specific immunotherapy.

Delayed Pressure Urticaria: Clinical and Diagnostic Features and Response to Omalizumab.

BACKGROUND: Delayed pressure urticaria (DPU) is a rare form of chronic inducible urticaria (CIndU) when it manifests alone. Treatment of DPU is disappointing owing to the lack of response to antihistamines, even when up-dosing. In addition, the absence of randomized clinical trials and the low number of patients included in the studies mean that there is little scientific evidence for the validity of omalizumab in DPU. OBJECTIVE: Objectives of the study were to perform a real-world study of the effectiveness and safety of omalizumab in DPU patients without chronic spontaneous urticaria or other forms of CIndU and to describe their clinical and diagnostic features. METHOD: We performed an ambispective observational study of 14 patients with DPU who did not respond to 2 or more second-generation H1-antihistamines in an up-dosing regimen and/or corticosteroids, montelukast, or cyclosporine. Treatment was initiated with omalizumab 300 mg every 4 weeks. We recorded the following: age, time to diagnosis, previous treatment, diagnostic testing (mean time threshold after removing the stimulus and duration of the lesions), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), D dimer, total IgE, antithyroid peroxidase (anti-TPO) antibodies, and the Urticaria Control Test (UCT) score before and after the first dose. We evaluated the efficacy of omalizumab according to the Urticaria Control Test score. We analyzed the time to complete or satisfactory response after the first dose (superfast) and its adverse effects. RESULTS: Women accounted for 64.28% patients. The mean age at diagnosis was 43.64 (±13.78) years. The time to diagnosis was 4.53 (±5.54) years. The mean time threshold after removing the stimulus was 4.18 h (±2.75). The mean duration of lesions after testing was 32.42 (±13.8) hours. High ERS values (>20.0 mm/h) were detected in 50% of patients. CRP was >0.5 mg/dL in 42.85% and D dimer levels were high (>500.0 ng/mL) in 3/10 patients. Anti-TPO level was normal in 100% of patients. Total IgE was >100 IU/mL in 6/8 patients. Medium UCT levels before treatment with omalizumab were 3.07 (±2.40), reaching 15.28/16 (±1.72) after the first dose of omalizumab. All 14 patients responded superfast, and none experienced an adverse reaction. CONCLUSIONS: Despite the limitation of a low sample size in this real-life study, our findings suggest that omalizumab is a rapid, effective, and safe treatment for patients with DPU refractory to antihistamines in an up-dosing regimen. We recommend omalizumab for patients who do not respond to up-dosing antihistamines and montelukast.

Mutations in the COL18A1 gen associated with knobloch syndrome and structural brain anomalies: a novel case report and literature review of neuroimaging findings.

. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found.  Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism  without the brain malformations typically reported in patients with Knobloch syndrome.

Multivesicular GSK3 sequestration upon Wnt signaling is controlled by p120-catenin/cadherin interaction with LRP5/6.

The Wnt canonical ligands elicit the activation of ß-catenin transcriptional activity, a response dependent on, but not limited to, ß-catenin stabilization through the inhibition of GSK3 activity. Two mechanisms have been proposed for this inhibition, one dependent on the binding and subsequent block of GSK3 to LRP5/6 Wnt coreceptor and another one on its sequestration into multivesicular bodies (MVBs). Here we report that internalization of the GSK3-containing Wnt-signalosome complex into MVBs is dependent on the dissociation of p120-catenin/cadherin from this complex. Disruption of cadherin-LRP5/6 interaction is controlled by cadherin phosphorylation and requires the previous separation of p120-catenin; thus, p120-catenin and cadherin mutants unable to dissociate from the complex block GSK3 sequestration into MVBs. These mutants substantially inhibit, but do not completely prevent, the ß-catenin upregulation caused by Wnt3a. These results, besides elucidating how GSK3 is sequestered into MVBs, support this mechanism as cause of ß-catenin stabilization by Wnt.

Mindfulness-based programs for the prevention of childhood obesity: A systematic review.

INTRODUCTION: The prevalence of overweight and obesity has increased worldwide at an alarming rate in recent decades and has become a serious public health problem. The purpose of this study is to carry out a systematic review of scientific research on mindfulness-based programs for the prevention of childhood obesity carried out in the last 10 years. METHOD: A search of studies that used mindfulness to promote good eating behavior in minors was conducted. After applying the inclusion and exclusion criteria, a total of 16 studies were found. RESULTS: Statistically significant improvements were found in most of the cases where changes in eating habits, food portions, reduction of stress, or reduction of cravings in minors were evaluated. CONCLUSIONS: Mindfulness programs applied to improve eating behaviors appear to be an effective alternative to prevent childhood obesity, but further studies are needed to draw conclusions.

Quality of life against seasonal vs perennial allergens: ESPRINT-15 modified in the pediatric population.

INTRODUCTION: Allergic rhinitis (AR) is a clinical syndrome characterized by IgE-mediated inflammation of the nasal mucosa. The present study investigates the quality of life (QoL) with AR among adults, using widely validated questionnaires, unlike in pediatric patients. MATERIALS AND METHODS: A cross-sectional descriptive observational study was conducted, analyzing the QoL of 102 children with AR aged between 10-15 years, belonging to two health centers (HC) in Zaragoza and two HC in Coruña. The comparison of means between the two groups is carried out using the Student's test or the Mann-Whitney test, considering a value of p˂0.05 to be significant. RESULTS: Around 102 children were studied, with a majority (59.8%) being male and a mean age of 12 years. Around 76.5% have a family history of atopy. It was found that AR is more prevalent in Zaragoza (p ˂0.005), and asthmais highly prevalent in Coruña (p ˂0.001). The most important sensitizations are pollen in Zaragoza (p ˂0.05) and dust mites in A Coruña (p ˂0.001). More treatment needs and associated comorbidities (p˂0.05) were observed in A Coruña. The results of the ESPRINT-15 show that 63% of the patients have a good QoL, 27% fair, and 8.8%, poor. Those sensitized to mites have a worse score (p = 0.02). It was found that 52% of children experienced improvement during home confinement, with no notable differences between the two populations. The use of the mask favored QoL in patients from Zaragoza (p ˂0.001). CONCLUSION: It was concluded that AR influences the QoL in pediatric patients. Greater QoL involvement, need for treatment, and comorbidities are observed in patients sensitized to dust mites compared to those sensitized to pollens. It was also observed that masks improved the symptoms, stopping patients being sensitized to pollens.

Enantiocontrolled Preparation of ϒ-Substituted Cyclohexenones: Synthesis and Kinase Activity Assays of Cyclopropyl-Fused Cyclohexane Nucleosides.

The enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives 1a,b was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.0]heptane scaffold is described. Nucleoside kinase activity assays with this cyclopropyl-fused cyclohexane nucleoside, together with other related nucleosides (2a-e), were performed, showing that thymine- and guanine- containing compounds have affinity for herpes simplex virus Type 1 (HSV-1) thymidine kinase (TK) but not for human cytosolic TK-1, thus pointing to their selectivity for herpetic TKs but not cellular TKs.

Insights into the Structure of the Highly Glycosylated Ffase from Rhodotorula dairenensis Enhance Its Biotechnological Potential.

Rhodotorula dairenensis ß-fructofuranosidase is a highly glycosylated enzyme with broad substrate specificity that catalyzes the synthesis of 6-kestose and a mixture of the three series of fructooligosaccharides (FOS), fructosylating a variety of carbohydrates and other molecules as alditols. We report here its three-dimensional structure, showing the expected bimodular arrangement and also a unique long elongation at its N-terminus containing extensive O-glycosylation sites that form a peculiar arrangement with a protruding loop within the dimer. This region is not required for activity but could provide a molecular tool to target the dimeric protein to its receptor cellular compartment in the yeast. A truncated inactivated form was used to obtain complexes with fructose, sucrose and raffinose, and a Bis-Tris molecule was trapped, mimicking a putative acceptor substrate. The crystal structure of the complexes reveals the major traits of the active site, with Asn387 controlling the substrate binding mode. Relevant residues were selected for mutagenesis, the variants being biochemically characterized through their hydrolytic and transfructosylating activity. All changes decrease the hydrolytic efficiency against sucrose, proving their key role in the activity. Moreover, some of the generated variants exhibit redesigned transfructosylating specificity, which may be used for biotechnological purposes to produce novel fructosyl-derivatives.

Distinctive Toll-like Receptors Gene Expression and Glial Response in Different Brain Regions of Natural Scrapie.

Prion diseases are chronic and fatal neurodegenerative diseases characterized by the accumulation of disease-specific prion protein (PrPSc), spongiform changes, neuronal loss, and gliosis. Growing evidence shows that the neuroinflammatory response is a key component of prion diseases and contributes to neurodegeneration. Toll-like receptors (TLRs) have been proposed as important mediators of innate immune responses triggered in the central nervous system in other human neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, little is known about the role of TLRs in prion diseases, and their involvement in the neuropathology of natural scrapie has not been studied. We assessed the gene expression of ovine TLRs in four anatomically distinct brain regions in natural scrapie-infected sheep and evaluated the possible correlations between gene expression and the pathological hallmarks of prion disease. We observed significant changes in TLR expression in scrapie-infected sheep that correlate with the degree of spongiosis, PrPSc deposition, and gliosis in each of the regions studied. Remarkably, TLR4 was the only gene upregulated in all regions, regardless of the severity of neuropathology. In the hippocampus, we observed milder neuropathology associated with a distinct TLR gene expression profile and the presence of a peculiar microglial morphology, called rod microglia, described here for the first time in the brain of scrapie-infected sheep. The concurrence of these features suggests partial neuroprotection of the hippocampus. Finally, a comparison of the findings in naturallyinfected sheep versus an ovinized mouse model (tg338 mice) revealed distinct patterns of TLRgene expression.