Lysosomes accumulate at the perinuclear region of muscle cells during chick myogenesis.

Lysosomes are involved in a myriad of cellular functions, such as degradation of macromolecules, endocytosis and exocytosis, modulation of several signaling pathways, and regulation of cell metabolism. To fulfill these diverse functions, lysosomes can undergo several dynamic changes in their content, size, pH, and location within cells. Here, we studied some of these parameters during embryonic chick skeletal muscle cells. We used an anti-lysosome-associated membrane protein 2 (LAMP2) antibody to specifically determine the intracellular localization of lysosomes in these cells. Our data shows that lysosomes are highly enriched in the perinuclear region of chick embryonic muscle cells. We also showed that the wingless signaling pathway (Wnt)/ß-catenin signaling pathway can modulate the location of LAMP2 in chick myogenic cells. Our results highlight the role of lysosomes during muscle differentiation and particularly the presence of a subcellular population of lysosomes that are concentrated in the perinuclear region of muscle cells.

Individualized Anesthetic Management of a Patient With Pheochromocytoma and Concurrent Breast Cancer: A Case Report.

Pheochromocytomas are rare tumors that present a challenge for surgical and anesthetic management due to their ability to produce significant amounts of catecholamines. This case report highlights the successful management of a 49-year-old woman simultaneously diagnosed with neurofibromatosis type 1, pheochromocytoma, and breast cancer. A key decision by the multidisciplinary team involving endocrinology, general surgery, senology, intensive care, and anesthesiology was to prioritize breast cancer surgery over pheochromocytoma resection. This decision considered the potential for improved prognosis and the need to minimize chemotherapy dosage. The case emphasizes the importance of thorough perioperative preparation, including assessing end-organ damage and optimizing medical therapy. Intraoperative management effectively navigated periods prone to catecholamine release, and postoperative care was closely monitored. This case demonstrates that with meticulous planning, a multidisciplinary approach, and a precise anesthetic strategy, safe anesthesia is achievable for patients with pheochromocytoma undergoing major elective surgeries other than pheochromocytoma resection, adding valuable knowledge to a scarcely documented clinical area.

Asociación del riesgo a desarrollar diabetes mellitus tipo 2 según la calculadora de la asociación americana de diabetes (ADA) y los hábitos tóxicos no ilícitos en pacientes que residen en una comunidad rural de Peravia, República Dominicana / Association of the risk of developing type 2 diabetes mellitus according to the American Diabetes Association (ADA) calculator and non-illicit toxic habits in patients residing in a rural community in Peravia, Dominican Republic

Introducción: la diabetes mellitus tipo 2 (DM2) se define como un trastorno metabólico caracterizado por niveles de glucosa en sangre crónicamente elevados. La DM2 representa el paradigma de las enfermedades crónicas en las que existe una estrecha asociación entre factores familiares y ambientales. Por este motivo, este estudio tiene como finalidad determinar la asociación del riesgo a desarrollar DM2 y los hábitos tóxicos no ilícitos en pacientes que residen en una comunidad rural de Peravia, República Dominicana. Tales incluyen: alcohol, café y té. Metodología: Estudio observacional, transversal, analítico y prospectivo. Se aplicó cuestionario, recolectaron datos antropométricos y se determinó glucosa capilar a la muestra (n=304). Resultados: la prevalencia a presentar un alto riesgo a desarrollar DM2 en la población es de 35.5%, mientras que la prevalencia a presentar riesgo bajo es de 64.5%. En cuanto a hábitos tóxicos, no existió correlación positiva entre consumo de té y desarrollo de DM2. Sin embargo, sí entre el consumo de café y alcohol. Conclusiones: los habitantes de salinas presentan un bajo riesgo a desarrollar DM2, pero utilizan factores de riesgos modificables que aumentan la prevalencia a DM2.

Introduction: Type 2 diabetes mellitus (DM2) is defined as a metabolic disorder characterized by chronically elevated blood glucose levels. DM2 represents the paradigm of chronic diseases in which there is a close association between family and environmental factors. Therefore, the purpose of this study is to determine the association of the risk of developing DM2 and non-illicit toxic habits in patients residing in a rural community in Peravia, Dominican Republic. Such habits include alcohol, coffee and tea. Methodology: Observational, cross-sectional, analytical and prospective study. A questionnaire was applied, anthropometric data was collected, and capillary glucose was determined in the study sample (n=304). Results: the prevalence of presenting a high risk of developing DM2 in the population is 35.5%, while the prevalence of presenting low risk is 64.5%. Regarding toxic habits, there was no positive correlation between tea consumption and the development of DM2. However, this result differed between consumption of coffee and alcohol. Conclusions: the inhabitants of Salinas have a low risk of developing DM2 but are subject to modifiable risk factors that increase said prevalence.

WNT pathway in focal cortical dysplasia compared to perilesional nonlesional tissue in refractory epilepsies.

BACKGROUND: Focal cortical dysplasia (FCD) is a malformation of cortical development that causes medical refractory seizures, and one of the main treatments may be surgical resection of the affected area of the brain. People affected by FCD may present with seizures of variable severity since childhood. Despite many medical treatments available, only surgery can offer cure. The pathophysiology of the disease is not yet understood; however, it is known that several gene alterations may play a role. The WNT/ß-catenin pathway is closely related to the control and balance of cell proliferation and differentiation in the central nervous system. The aim of this study was to explore genes related to the WNT/ß-catenin pathway in lesional and perilesional brain tissue in patients with FCD type II. METHODS: Dysplastic and perilesional tissue from the primary dysplastic lesion of patients with FCD type IIa were obtained from two patients who underwent surgical treatment. The analysis of the relative expression of genes was performed by a qRT-PCR array (super array) containing 84 genes related to the WNT pathway. RESULTS: Our results suggest the existence of molecular alteration in some genes of the WNT pathway in tissue with dysplastic lesions and of perilesional tissue. We call this tissue of normal-appearing adjacent cortex (NAAC). Of all genes analyzed, a large number of genes show similar behavior between injured, perilesional and control tissues. However, some genes have similar characteristics between the perilesional and lesional tissue and are different from the control brain tissue, presenting the perilesional tissue as a molecularly altered material. CONCLUSION: Our results suggest that the perilesional area after surgical resection of tissue with cortical dysplasia presents molecular changes that may play a role in the recurrence of seizures in these patients. The perilesional tissue should receive expanded attention beyond the somatic mutations described and associated with FCD, such as mTOR, for example, to new signaling pathways that may play a crucial role in seizure recurrence.

A Narrative Review of Speech and EEG Features for Schizophrenia Detection: Progress and Challenges.

Schizophrenia is a mental illness that affects an estimated 21 million people worldwide. The literature establishes that electroencephalography (EEG) is a well-implemented means of studying and diagnosing mental disorders. However, it is known that speech and language provide unique and essential information about human thought. Semantic and emotional content, semantic coherence, syntactic structure, and complexity can thus be combined in a machine learning process to detect schizophrenia. Several studies show that early identification is crucial to prevent the onset of illness or mitigate possible complications. Therefore, it is necessary to identify disease-specific biomarkers for an early diagnosis support system. This work contributes to improving our knowledge about schizophrenia and the features that can identify this mental illness via speech and EEG. The emotional state is a specific characteristic of schizophrenia that can be identified with speech emotion analysis. The most used features of speech found in the literature review are fundamental frequency (F0), intensity/loudness (I), frequency formants (F1, F2, and F3), Mel-frequency cepstral coefficients (MFCC's), the duration of pauses and sentences (SD), and the duration of silence between words. Combining at least two feature categories achieved high accuracy in the schizophrenia classification. Prosodic and spectral or temporal features achieved the highest accuracy. The work with higher accuracy used the prosodic and spectral features QEVA, SDVV, and SSDL, which were derived from the F0 and spectrogram. The emotional state can be identified with most of the features previously mentioned (F0, I, F1, F2, F3, MFCCs, and SD), linear prediction cepstral coefficients (LPCC), linear spectral features (LSF), and the pause rate. Using the event-related potentials (ERP), the most promissory features found in the literature are mismatch negativity (MMN), P2, P3, P50, N1, and N2. The EEG features with higher accuracy in schizophrenia classification subjects are the nonlinear features, such as Cx, HFD, and Lya.

The role of Wnt signaling in Xenopus neural induction.

Development of the central nervous system in amphibians has called attention from scientists for over a century. Interested in the matter of embryonic inductions, Hans Spemann and Hilde Mangold found out that the dorsal blastopore lip of the salamander's embryo has organizer properties. Such an ectopic graft could induce structures in the host embryo, including a neural tube overlying the notochord of a perfect secondary body axis. A couple of decades later, the frog Xenopus laevis emerged as an excellent embryological experimental model and seminal concepts involving embryonic inductions began to be revealed. The so-called primary induction is, in fact, a composition of signaling and inductive events that are triggered as soon as fertilization takes place. In this regard, since early 1990s an intricate network of signaling pathways has been built. The Wnt pathway, which began to be uncovered in cancer biology studies, is crucial during the establishment of two signaling centers in Xenopus embryogenesis: Nieuwkoop center and the blastula chordin noggin expression center (BCNE). Here we will discuss the historical events that led to the discovery of those centers, as well as the molecular mechanisms by which they operate. This chapter highlights the cooperation of both signaling centers with potential to be further explored in the future. We aim to address the essential morphological transformation during gastrulation and neurulation as well as the role of Wnt signaling in patterning the organizer and the neural plate.

Corrigendum: The significance of cephalopod beaks as a research tool: An update.

[This corrects the article DOI: 10.3389/fphys.2022.1038064.].

The significance of cephalopod beaks as a research tool: An update.

The use of cephalopod beaks in ecological and population dynamics studies has allowed major advances of our knowledge on the role of cephalopods in marine ecosystems in the last 60 years. Since the 1960's, with the pioneering research by Malcolm Clarke and colleagues, cephalopod beaks (also named jaws or mandibles) have been described to species level and their measurements have been shown to be related to cephalopod body size and mass, which permitted important information to be obtained on numerous biological and ecological aspects of cephalopods in marine ecosystems. In the last decade, a range of new techniques has been applied to cephalopod beaks, permitting new kinds of insight into cephalopod biology and ecology. The workshop on cephalopod beaks of the Cephalopod International Advisory Council Conference (Sesimbra, Portugal) in 2022 aimed to review the most recent scientific developments in this field and to identify future challenges, particularly in relation to taxonomy, age, growth, chemical composition (i.e., DNA, proteomics, stable isotopes, trace elements) and physical (i.e., structural) analyses. In terms of taxonomy, new techniques (e.g., 3D geometric morphometrics) for identifying cephalopods from their beaks are being developed with promising results, although the need for experts and reference collections of cephalopod beaks will continue. The use of beak microstructure for age and growth studies has been validated. Stable isotope analyses on beaks have proven to be an excellent technique to get valuable information on the ecology of cephalopods (namely habitat and trophic position). Trace element analyses is also possible using beaks, where concentrations are significantly lower than in other tissues (e.g., muscle, digestive gland, gills). Extracting DNA from beaks was only possible in one study so far. Protein analyses can also be made using cephalopod beaks. Future challenges in research using cephalopod beaks are also discussed.

Strain Magnitude Assessed at Rest and During Stress Echocardiography in Patients with Normal Coronary Flow Reserve

Abstract Background Coronary flow and myocardial contractile performance assessed by strain magnitude increase during a dobutamine stress echocardiogram (DSE). Normal coronary flow reserve (CFR) can be attained upon completion of a DSE at age-predicted maximum heart rate (HR) (HRmax = 220 - age)] or submaximal HR [(0.85) HRmax] or before completion (early CFR). Objective To ascertain the association between delta strain and HR in patients with early normal CFR. Methods This prospective study included patients whose normal CFR was obtained before the DSE was completed. Percentage of resting HR (%HRrest) = [(HRrest ÷ HRmax) 100]% and %HR CFR = [(HR at the time of CFR attainment) ÷ (HRmax) 100]% were recorded. Strain was assessed in the left ventricular region of interest, and delta strain was calculated as the difference between the measures obtained at HRrest and after the DSE was completed. Strain agreement analysis for HRrest, %HRrest, and %HR CFR was performed using the kappa coefficient. The Shapiro-Wilk test was used to assess data normality, and the Mann-Whitney test was used to compare the groups. A p-value < 0.05 was considered statistically significant. Results Strain measured -23.3% ± 4.3% at baseline and -31.1% ± 4.9% during the DSE. In delta strain > 8 absolute points, the ROC curves showed an area under the curve of 0.874 ± 0.07 for %HRrest (p = 0.001) and an area under the curve of 0.862 ± 0.07 for %HR CFR (p = 0.001). In delta strain > 8 points, %HRrest ≤ 42.6% of HRmax and %HR CFR ≤ 62.5% of HRmax showed an accuracy of 82.9% and 79.8%, respectively. Conclusion In this study, lower HRrest and HR at the time of CFR attainment had a good association with better myocardial contractile performance, according to the change in strain magnitude.

The Wnt/Beta-Catenin Pathway and Cytoskeletal Filaments Are Involved in the Positioning, Size, and Function of Lysosomes during Chick Myogenesis.

Lysosomes are highly dynamic organelles involved in the breakdown and recycling of macromolecules, cell cycle, cell differentiation, and cell death, among many other functions in eukaryotic cells. Recently, lysosomes have been identified as cellular hubs for the modulation of intracellular signaling pathways, such as the Wnt/beta-catenin pathway. Here we analyzed morphological and functional characteristics of lysosomes in muscle and non-muscle cells during chick myogenesis, as well as their modulation by the Wnt/beta-catenin pathway. Our results show that (i) muscle and non-muscle cells show differences in lysosomal size and its distribution, (ii) lysosomes are found in spherical structures in myoblasts and fibroblasts and tubular structures in myotubes, (iii) lysosomes are found close to the plasma membrane in fibroblasts and close to the nucleus in myoblasts and myotubes, (iv) lysosomal distribution and size are dependent on the integrity of microtubules and microfilaments in myogenic cells, (v) alterations in lysosomal function, in the expression of LAMP2, and in Wnt/beta-catenin pathway affect the distribution and size of lysosomes in myogenic cells, (vi) the effects of the knockdown of LAMP2 on myogenesis can be rescued by the activation of the Wnt/beta-catenin pathway, and (vii) the chloroquine Lys05 is a potent inhibitor of both the Wnt/beta-catenin pathway and lysosomal function. Our data highlight the involvement of the Wnt/beta-catenin pathway in the regulation of the positioning, size, and function of lysosomes during chick myogenesis.

The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/ß-Catenin Signaling Pathway.

The Wnt/ß-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer's disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3ß S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-ß oligomers (AßO) in mice. Finally, quercitrin rescues AßO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/ß-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.

Beyond sex and aggression: testosterone rapidly matches behavioural responses to social context and tries to predict the future.

Although androgens are widely studied in the context of aggression, androgenic influences on prosocial behaviours have been less explored. We examined testosterone's (T) influence on prosocial and aggressive responses in a positively valenced social context (interacting with a pairbond partner) and a negatively valenced context (interacting with an intruder) in socially monogamous Mongolian gerbils. T increased and decreased prosocial responses in the same individuals towards a pairbond partner and an intruder, respectively, both within 30 min, but did not affect aggression. T also had persistent effects on prosocial behaviour; males in which T initially increased prosocial responses towards a partner continued to exhibit elevated prosocial responses towards an intruder male days later until a second T injection rapidly eliminated those responses. Thus, T surges can rapidly match behaviour to current social context, as well as prime animals for positive social interactions in the future. Neuroanatomically, T rapidly increased hypothalamic oxytocin, but not vasopressin, cellular responses during interactions with a partner. Together, our results indicate that T can facilitate and inhibit prosocial behaviours depending on social context, that it can influence prosocial responses across rapid and prolonged time scales, and that it affects oxytocin signalling mechanisms that could mediate its context-dependent behavioural influences.

Species-typical group size differentially influences social reward neural circuitry during nonreproductive social interactions.

We investigated whether nonreproductive social interactions may be rewarding for colonial but not non-colonial species. We found that the colonial spiny mouse (Acomys cahirinus) is significantly more gregarious, more prosocial, and less aggressive than its non-colonial relative, the Mongolian gerbil (Meriones unguiculatus). In an immediate-early gene study, we examined oxytocin (OT) and tyrosine hydroxylase (TH) neural responses to interactions with a novel, same-sex conspecific or a novel object. The paraventricular nucleus of the hypothalamus (PVN) OT cell group was more responsive to interactions with a conspecific compared to a novel object in both species. However, the ventral tegmental area (VTA) TH cell group showed differential responses only in spiny mice. Further, PVN OT and VTA TH neural responses positively correlated in spiny mice, suggesting functional connectivity. These results suggest that colonial species may have evolved neural mechanisms associated with reward in novel, nonreproductive social contexts to promote large group-living.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/ß-Catenin Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/ß-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/ß-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/ß-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

Benefits of combined interventions for cognitive enhancement in older adults / Benefícios de intervenções combinadas para aprimoramento cognitivo em idosos

Objective: To investigate the effects of different combined interventions (Stimullus, MEMO, physical activity, and psychoeducation) on the cognitive performance of older adults. Methods: This is a quasi-experimental study with pre- and post-intervention. Thirty-four older adults underwent different combined interventions for a period of 48 weeks and were evaluated at three different points (pre-intervention; post-cognitive intervention; post-physical activity or psychoeducation intervention). Cognitive domains (verbal episodic memory, executive function, general cognitive performance) and depressive symptoms were evaluated. Results: Postintervention gains in global, attentional, and mnemonic cognition were observed, as well as a reduction in depressive symptoms. The MEMO intervention + physical activity or psychoeducation resulted in greater cognitive gains, while Stimullus + psychoeducation showed benefits only in evocation and the free learning index, while Stimullus + physical activity resulted in improvement in the investigated variables. Conclusion: The results of these combined interventions appear promising for healthy older adults and the impact of these interventions should be discussed with individual older patients and evaluated more broadly in the context of public health.

Objetivo: Investigar os efeitos de diferentes intervenções combinadas (Stimullus, MEMO, física e psicoeducacional) no desempenho cognitivo de idosos. Metodologia: Trata-se de um estudo quase experimental com pré e pós-intervenção. Trinta e quatro idosos foram submetidos a diferentes intervenções combinadas pelo período de 48 semanas e avaliados em três tempos diferentes (pré-intervenção; pós-intervenção cognitiva; pós-intervenção física ou psicoeducacional), nos quais foram analisados domínios cognitivos (memória episódica verbal, funções executivas, desempenho cognitivo geral) e sintomas depressivos. Resultados: Após as intervenções, observaram-se ganhos na cognição global, atencional e mnemônica, bem como redução dos sintomas depressivos. A intervenção MEMO (física ou psicoeducacional) resultou em maiores ganhos cognitivos, enquanto Stimullus + psicoeducacional demonstrou benefícios apenas no índice de evocação e aprendizagem livre, e Stimullus + atividades físicas não apresentou melhora em nenhuma das variáveis investigadas. Conclusão: Os achados positivos dessas intervenções combinadas parecem promissores no contexto de idosos saudáveis, e o impacto dessas intervenções deve ser discutido em relação às especificidades de cada indivíduo idoso e avaliado mais amplamente no contexto de saúde pública.

Parents' mental health and children's emotional regulation during the COVID-19 pandemic / Saúde mental parental e regulação emocional infantil durante a pandemia de COVID-19 / Salud mental parental y regulación emocional infantil durante la pandemia de COVID-19

ABSTRACT The objectives of the study were to investigate parents' mental health before and during the COVID-19 pandemic; to find correlations between parents' mental health and their perceptions of risk, virus exposure, use of preventive measures, COVID-19 knowledge, and social distancing practices; and to analyze correlations between parents' mental health and their perception about children's emotional regulation (ER). Participants were 69 parents of children aged between 5 and 12. The instruments used were ERC, HADS, ABEP, and a questionnaire about COVID-19. Descriptive analyses, the Wilcoxon test, and Spearman's correlation were conducted. The results indicated increased parental anxiety and depression during the pandemic, and a weak negative correlation between parental anxiety and their children's ER. The pandemic acts as a stressor, which impacts the mental health of both parents and children.

RESUMO Os objetivos do estudo foram investigar a saúde mental parental antes e durante a pandemia da COVID-19; verificar as associações entre saúde mental parental e suas percepções de risco, exposição ao vírus, uso de medidas preventivas, conhecimento sobre a COVID-19 e práticas de distanciamento social; e analisar as relações entre saúde mental parental e suas percepções sobre a Regulação Emocional (RE) infantil. Os participantes desta pesquisa foram 69 pais de crianças entre 5 e 12 anos. Os instrumentos utilizados foram: ERC, HADS, ABEP e questionário sobre a COVID-19. Foram realizadas análises descritivas, Teste de Wilcoxon e correlação de Spearman. Foram encontrados aumento dos níveis de ansiedade e depressão parental durante a pandemia, bem como uma correlação negativa fraca entre ansiedade parental e RE infantil. A pandemia, enquanto agente estressor, tende a impactar a saúde mental de pais e crianças.

RESUMEN Los objetivos del estudio fueron investigar la salud mental de los padres antes y durante la COVID-19; comprobar relaciones entre la salud mental de los padres y sus percepciones de riesgo, exposición a virus, uso de medidas preventivas, conocimiento de COVID-19 y prácticas de distanciamiento social y analizar las correlaciones entre la salud mental de los padres y su percepción sobre la Regulación Emocional (RE) de los niños. Los participantes fueron 69 padres de niños de entre 5 y 12 años. Los instrumentos utilizados fueron ERC, HADS, ABEP y un cuestionario sobre COVID-19. Se realizaron análisis descriptivos, la prueba de Wilcoxon y la correlación de Spearman. Los resultados indicaron aumento en la ansiedad y depresión de los padres; correlación negativa débil entre la ansiedad de los padres y la ER de sus hijos. La pandemia actúa como un factor de estrés, que tiene un impacto en la salud mental de padres e hijos.

5-Fluorouracil disrupts ovarian preantral follicles in young C57BL6J mice.

PURPOSE: 5-Fluorouracil (5-FU), an anti-cancer drug, has been used for hepatoblastoma (HB) chemotherapy in children, who may have impaired  ovarian follicle pool reserve with lasting effects to reproduction. Therefore, this study aimed to investigate 5-FU effects on survival, growth, and morphology of ovarian preantral follicles from C57BL6J young mice. METHODS: Experiments were carried-out both in vivo and in vitro. Mice were treated with 5-FU injection (450 mg/kg i.p) or saline and sacrificed 3 days after to obtain ovaries for histology and molecular biology. Ovaries for in vitro studies were obtained from unchallenged mice and cultured under basic culture medium (BCM) or BCM plus 5-FU (9.2, 46.1, 92.2 mM). Preantral follicles were classified according to developmental stages, and as normal or degenerated. To assess cell viability, caspase-3 immunostaining was performed. Transcriptional levels for apoptosis (Bax, Bcl2, p53, Bax/Bcl2) and Wnt pathway genes (Wnt2 and Wnt4) were also analyzed. Ultrastructural analyses were carried-out on non-cultured ovaries. In addition, ß-catenin immunofluorescence was assessed in mouse ovaries. RESULTS: The percentage of all-types normal follicles was significantly lower after 5-FU challenge. A total loss of secondary normal follicles was found in the 5-FU group. The highest 5-FU concentrations reduced the percentage of cultured normal primordial follicles. Large vacuoles were seen in granulosa cells and ooplasm of preantral follicles by electron microscopy. A significantly higher gene expression for Bax and Bax/Bcl2 ratio was seen after 5-FU treatment. A marked reduction in ß-catenin immunolabeling was seen in 5-FU-challenged preantral follicles. In the in vitro experiments, apoptotic and Wnt gene transcriptions were significantly altered. CONCLUSION: Altogether, our findings suggest that 5-FU can deleteriously affect the ovarian follicle reserve by reducing preantral follicles survival.

Pruritus, Allergy and Autoimmunity: Paving the Way for an Integrated Understanding of Psychodermatological Diseases?

Pruritus is a key symptom in allergology and dermatology, contributing to the global and huge impact on quality of life related to skin disorders, both those which are not related to a primary dermatosis (illness) and those which are linked with primary skin lesions (disease). This is particularly evident within psychophysiological dermatoses, a group of psychodermatological diseases where there is a primary dermatosis, where psychological stress plays a role, and where pruritus may represent a major and shared symptom. The etiopathogenesis of pruritus in those disorders sheds light on the link among psychopathological features, psychological stress and the subtle interface between allergic and autoimmune mechanisms, where mast cells play a pivotal role. Allergy has long been recognised as an altered reactivity to exogenous antigens (allergens), defined as an immediate hypersensitivity mediated by immunoglobulin E (IgE). In turn, the immunological understanding of atopy is related to an immediate hypersensitivity reaction to environmental antigens involving T-helper 2 (Th2) responses and the IgE production. Mast cells are major cells in the early phase of allergy, releasing the mediators involved in the symptoms associated with the allergic disease, including pruritus, when the allergen cross-links with IgE, whose mechanisms can be observed in acute urticaria and atopy. Some allergic reactions may persist and allergy may eventually lead to autoimmunity, with the development of a T-helper 1 (Th1) and then IgE-independent inflammation. For instance, in chronic spontaneous urticaria, the mast cell activation may include autoimmune mechanisms, where autoantibodies against the extracellular α subunit of the high-affinity IgE receptor (FcεRIα) and to IgE are observed, with the involvement of Th1 lymphocytes and the production of interferon-γ (INF-γ). The role of autoimmunity is also suggested in the etiopathogenesis of other psychophysiological dermatoses, namely psoriasis, atopic dermatitis and alopecia areata. In the latter, for example, mast cells were reported to be linked with the loss of immune privilege and they are the key cells involved in the experience of pruritus, whose intensity was reported to precede and be correlated with the onset of the hair loss. Furthermore, considering that the role of hair and skin is wide, from psychosocial aspects (communication and social interaction) to vital functions (such as, temperature control), it is straightforward that they are central in our interactions and synchronization with others and the world; thereby, we may admit that the psychophysiological dermatoses could represent a loss of such synchronization. Furthermore, they are often linked with psychopathology which strongly connects with the concept of desynchronization, namely, sleep disorders and depressive symptoms, the clinical expression of a dysfunction in the interplay among mast cells, pineal gland and melatonin, thus the circadian rhythm, as well as their connection with the hypothalamic corticotrophin-releasing hormone (CRH), well-known for its key role in stress response. Moreover, increasing evidence has supported the existence of cutaneous equivalents for these mechanisms, connecting with those central pathways. Thereby, taking all these concepts into consideration, this review intends to look into the updated evidence on the shared biological mechanisms between allergy and autoimmunity, underlining pruritus as a core element, then revisiting the key role of mast cells and discussing the connection with melatonin and immune-inflammatory pathways in the physiopathology of psychophysiological dermatoses, thus paving the way for the understanding of their psychosomatic correlates and a comprehensive psychodermatological approach.